In JoVE (1)

Other Publications (79)

Articles by Alexander A. Vinks in JoVE

 JoVE Medicine

Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS

1iC42 Clinical Research and Development, University of Colorado, Anschutz Medical Campus, 2Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, 3Food and Drug Administration (FDA), Center of Drug Evaluation Research - Office of Generic Drugs, 4Transplant Clinical Research, University of Cincinnati

JoVE 52424

Other articles by Alexander A. Vinks on PubMed

The Application of Population Pharmacokinetic Modeling to Individualized Antibiotic Therapy

International Journal of Antimicrobial Agents. Apr, 2002  |  Pubmed ID: 11978502

This paper describes applications of population pharmacokinetic modeling to the optimization of antibiotic dosing. Parametric and nonparametric pharmacokinetic modeling approaches are discussed. Population models can be important extensions of therapeutic drug monitoring (TDM) in infectious disease. The concept of population model-based individualized antimicrobial therapy is described. With the availability of population modeling for obtaining PK parameter estimates, the focus has shifted to quantifying the antimicrobial effect and linking kinetics to drug effects. Examples of integrated pharmacokinetic-pharmacodynamic (PK-PD) models to describe bacterial killing as a function of drug concentration are discussed. Application of PK-PD mathematical models that correlate with microbiological and clinical outcomes will provide us with a better rationale for the proper dose selection of anti-infective therapy in different patient populations.

NONMEM and NPEM2 Population Modeling: a Comparison Using Tobramycin Data in Neonates

Therapeutic Drug Monitoring. Jun, 2002  |  Pubmed ID: 12021626

Nonlinear mixed effects modeling (NONMEM) and nonparametric expectation maximization (NPEM2) have both been used in population modeling of tobramycin. We compared both methods for differences in population pharmacokinetic parameters in relation to error models used. Predictive performance was compared between models. A group of 470 neonates who had received tobramycin according to a gestational age (GA)-dependent dosing interval was analyzed according to a one-compartment model with NONMEM and NPEM2. Additional models were constructed where the assay error pattern in NPEM2 mimicked NONMEM residual error and vice versa. Individual pharmacokinetic parameter estimates were compared. Predictive performance was evaluated in a separate group of 61 patients. Population estimates and variation coefficients (CV) for optimal models were NONMEM K(el) 0.071 h(-1) (27%), V(d) 0.59 L/kg (9%); NPEM2 K(el) 0.079 h(-1) (42%), V(d) 0.65 L/kg (48%). Forcing NONMEM to use the NPEM2 error pattern as residual error or vice versa resulted in smaller differences in CVs of the estimates. NONMEM gave less bias (P < 0.05) than NPEM2 and comparable precision with this approach. In conclusion NONMEM and NPEM2 are dissimilar in population estimates. Differences in ranges of pharmacokinetic parameter estimates between NONMEM and NPEM2 are largely determined by the method of incorporating error patterns in both programs.

Population Pharmacokinetic Analysis of Nonlinear Behavior of Piperacillin During Intermittent or Continuous Infusion in Patients with Cystic Fibrosis

Antimicrobial Agents and Chemotherapy. Feb, 2003  |  Pubmed ID: 12543656

The purpose of this study was to describe the nonlinear pharmacokinetics of piperacillin observed during intermittent infusion and continuous infusion by using a nonparametric population modeling approach. Data were 120 serum piperacillin concentration measurements from eight adult cystic fibrosis (CF) patients. Individual pharmacokinetic parameter estimates during intermittent infusion or continuous infusion were calculated by noncompartmental analysis and with a maximum iterative two-stage Bayesian estimator. To simultaneously describe concentration-time data during intermittent infusion and continuous infusion, nonlinear models were parameterized as two-compartment Michaelis-Menten models. Models were fit to the data with the nonparametric expectation maximization algorithm. The calculations were executed on a remote supercomputer. Nonlinear models were evaluated by log-likelihood estimates, residual plots, and R(2) values, and predictive performance was based on bias (mean weighted error [MWE]) and precision (mean weighted square error [MWSE]). A linear pharmacokinetic model could not describe combined intermittent infusion and continuous infusion data well. A good population model fit to the intermittent infusion and continuous infusion data was obtained with the constructed nonlinear models. Maximum a posteriori probability (MAP) Bayesian R(2) values for the nonlinear models were 0.96 to 0.97. Median parameter estimates for the best nonlinear model were as follows: K(m), 58 +/- 75 mg/liter (mean and standard deviation); V(max), 1,904 +/- 1,009 mg/h; volume of distribution of the central compartment, 14.1 +/- 3.0 liters; k(12), 0.63 +/- 0.41 h(-1); and k(21), 0.37 +/- 0.19 h(-1). The median bias (MWE) and precision (MWSE) values for MAP Bayesian estimation with the Michaelis-Menten model were 0.05 and 4.6 mg/liters, respectively. The developed nonlinear pharmacokinetic models can be used to optimize piperacillin therapy administered via continuous infusion in patients with CF and have distinct advantages over conventional linear models.

Pharmacodynamics of Ziprasidone in Children and Adolescents: Impact on Dopamine Transmission

Journal of the American Academy of Child and Adolescent Psychiatry. Aug, 2003  |  Pubmed ID: 12874491

Ziprasidone is an atypical antipsychotic with a high ratio of 5-HT(2A) to D(2) receptor antagonism. It is also an agonist at 5-HT(1A), which has been shown in rats to increase dopamine in prefrontal cortex. The objective of this study was to probe the dopamine agonist and antagonist pharmacodynamic properties of ziprasidone in youth.

Absorption and Clearance of +/-3,4-methylenedioxymethamphetamine from the Plasma of Neonatal Rats

Neurotoxicology and Teratology. Nov-Dec, 2004  |  Pubmed ID: 15451048

A limited number of studies exist describing the effects of +/-3,4-methylenedioxymethamphetamine (MDMA) during perinatal development, although the number of MDMA users has increased dramatically, and this increase is greatest in people of child-bearing age. Previous experimental studies show that exposure to MDMA during part of the third trimester-equivalent (postnatal days P1-20 in rats) cause two distinct types of learning and memory deficits (sequential and spatial) if exposed on P11-20, but not if exposure occurs on P1-10. In the present study, we examined differences in the ability of neonatal rats to eliminate MDMA. Rat offspring were given a single dose of 20 mg/kg MDMA on either P1 or 11, and plasma was collected at 1 of 10 time points during a 10-h period. MDMA concentrations were assessed by liquid chromatography/mass spectrometry (LC/MS). Indices of absorption did not differ as a function of exposure age. Exposure age differences in the clearance rate and half-life of MDMA were observed, such that the P1-treated animals had a significantly more rapid clearance and a shorter half-life than P11-treated animals did. These changes are in the same direction as the behavioral differences reported previously between P1-10 and P11-20 MDMA exposure groups. However, the pharmacokinetic differences were not commensurate with the behavioral changes in that the clearance differences at the two ages are quantitative whereas the behavioral differences were qualitative (no effects from P1-10 exposure and large effects from P11-20). Although the data do not suggest a mechanism for the learning deficits, they indicate that pharmacokinetic differences may contribute to the effects seen when exposure is begun on P11.

Pharmacokinetic/pharmacodynamic Modelling of Antibacterials in Vitro and in Vivo Using Bacterial Growth and Kill Kinetics: the Minimum Inhibitory Concentration Versus Stationary Concentration

Clinical Pharmacokinetics. 2005  |  Pubmed ID: 15656698

The minimum inhibitory concentration (MIC) is the in vitro reference value to describe the activity of an antibacterial against micro-organisms. It does not represent the dynamic effect of the antimicrobial at any point in time, but rather the total antimicrobial effect over the incubation period at a fixed concentration.

Pharmacodynamics of Midazolam in Pediatric Intensive Care Patients

Therapeutic Drug Monitoring. Feb, 2005  |  Pubmed ID: 15665754

The aim of the study was to study a possible pharmacokinetic-pharmacodynamic (PK-PD) relationship for midazolam in pediatric intensive care patients and to determine how adequate sedation could be reached using the COMFORT scale as sedation scale. Twenty-one pediatric intensive care patients (2 days to 17 years) received a midazolam infusion (0.05-0.4 mg/kg/h, 3.8 hours to 25 days). Sedation levels were determined using the COMFORT scale as well as plasma concentrations of midazolam and metabolites. An evident PK-PD relationship was not found. In 20 of the 21 patients midazolam dosing could be effectively titrated to the desired level of sedation, assessed by the COMFORT scale. Based on our findings that there is no relationship between pharmacokinetic parameters and pharmacodynamic outcome, we recommend that midazolam dosing should be titrated according to the desired clinical effect in combination with a validated assessment instrument, eg, the COMFORT scale.

Relationship Between Minimum Inhibitory Concentration and Stationary Concentration Revisited: Growth Rates and Minimum Bactericidal Concentrations

Clinical Pharmacokinetics. 2005  |  Pubmed ID: 15966758

Development of a Population Pharmacokinetic Model for Carbamazepine Based on Sparse Therapeutic Monitoring Data from Pediatric Patients with Epilepsy

Clinical Therapeutics. May, 2005  |  Pubmed ID: 15978311

Population models can be important extensions of therapeutic drug monitoring (TDM), as they allow estimation of individual pharmacokinetic parameters based on a small number of measured drug concentrations.

A Retrospective Analysis Using Monte Carlo Simulation to Evaluate Recommended Ceftazidime Dosing Regimens in Healthy Volunteers, Patients with Cystic Fibrosis, and Patients in the Intensive Care Unit

Clinical Therapeutics. Jun, 2005  |  Pubmed ID: 16117983

Over the past decades, the relationship between the pharmacokinetic (PK) properties of antibiotics, MICs, and clinical effects has been increasingly well understood. Interpatient variability in the PK profile, however, has only recently been recognized as a major factor in predicting the outcome in individual patients and establishing breakpoints for clinical susceptibility. Most predictions to date have used data from healthy volunteers.

Search for an Association Between the Human CYP1A2 Genotype and CYP1A2 Metabolic Phenotype

Pharmacogenetics and Genomics. May, 2006  |  Pubmed ID: 16609368

The genotype responsible for more than 60-fold interindividual differences in human hepatic CYP1A2 constitutive expression is not understood. Resequencing the human CYP1A1_CYP1A2 locus (39.6 kb) in five major geographically isolated subgroups recently led to the identification of 85 single nucleotide polymorphisms (SNPs), 57 of which were double-hit SNPs. Here, we attempted to correlate the CYP1A2 genotype with a metabolic phenotype. We chose 16 SNPs (all having a minor allele frequency > or =0.05 in Caucasians) to genotype 32 DNA samples (26 Caucasians, six Ethiopians) in which CYP1A2 metabolism had previously been determined. From 280 subjects (five locations worldwide) that had been CYP1A2-phenotyped, we genotyped the 10 highest, 14 lowest and eight intermediate DNA samples. Although no SNP was significant (P<0.05), possibly due to the small sample size, we found a trend for several of the six SNPs across the CYP1A2 linkage disequilibrium block associated with the trait. Five CYP1A2 haplotypes were inferred, two of which had not previously been reported; haplotype 1A2H10 showed the greatest association with CYP1A2 activity. Regulatory sequences responsible for the large interindividual differences in hepatic CYP1A2 gene basal expression might reside, in part, with some of these CYP1A2 SNPS but, in large part, might be located either cis (in nearby sequences not yet haplotyped) or trans in that they are not linked to the gene. We conclude that no SNP or haplotype in the CYP1A2 gene has yet been identified that can unequivocally be used to predict the metabolic phenotype in any individual patient.

Monitoring of Inosine Monophosphate Dehydrogenase Activity As a Biomarker for Mycophenolic Acid Effect: Potential Clinical Implications

Therapeutic Drug Monitoring. Apr, 2007  |  Pubmed ID: 17417067

Mycophenolic acid (MPA) is a reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) and, in combination with other immunosuppressive drugs, effectively inhibits rejection in solid organ transplant recipients. MPA has a relatively narrow therapeutic window and exhibits wide inter- and intrapatient pharmacokinetic (PK) variability. This has stimulated the use of therapeutic drug monitoring as a strategy to tailor the MPA exposure to each patient's individual needs. Despite increasing therapeutic drug monitoring use, PK-assisted dosing is not universally adopted in part because of MPA's complex PK behavior. Targeting inosine monophosphate IMPDH activity as a surrogate pharmacodynamic (PD) marker of MPA-induced immunosuppression may allow for increased precision when used in an integrated PK-PD fashion, providing a more accurate assessment of efficacy and aid in limiting toxicity. IMPDH activity displays wide interpatient variability but relatively small intrapatient variability even after long-term administration of MPA. The advent of calcineurin and corticosteroid-sparing regimens necessitates more patient-specific PK-PD parameters, which can be used throughout the posttransplant period to optimize MPA exposure and immediate and long-term graft and patient outcomes. Quantification of IMPDH posttransplant may serve as a stable, surrogate PD marker of MPA-induced immunosuppression when combined with current PK and monitoring strategies.

Pharmacokinetics of Aztreonam in Healthy Subjects and Patients with Cystic Fibrosis and Evaluation of Dose-exposure Relationships Using Monte Carlo Simulation

Antimicrobial Agents and Chemotherapy. Sep, 2007  |  Pubmed ID: 17576827

Aztreonam (AZM) is a monobactam antibiotic with a high level of activity against gram-negative micro-organisms, including Pseudomonas aeruginosa. We evaluated AZM pharmacokinetics and pharmacokinetic-pharmacodynamic relationships in patients with cystic fibrosis (CF) and healthy subjects. Pharmacokinetic data in eight CF patients and healthy subjects that were matched for age, gender, weight, and height were obtained and analyzed by using the nonparametric adaptive grid algorithm. Probabilities of target attainment using percentages of time of unbound concentration above the MIC (fT>MIC) were obtained by using a Monte Carlo simulation. AZM total body clearance was significantly higher in CF patients (100.1 +/- 17.1 versus 76.2 +/- 7.4 ml/min in healthy subjects; P < 0.01). The pharmacokinetic parameter estimates for terminal half-life (1.54 +/- 0.17 h [mean +/- the standard deviation]) and volume of distribution (0.20 +/- 0.02 liters/kg in patients with CF patients were not different from those in healthy subjects. Monte Carlo simulations with a target of a fT>MIC of 50 to 60% at a dose of 1,000 mg every 8 h indicated a clinical breakpoint of 4 mg/liter and 1 to 2 mg/liter for healthy subjects and CF patients, respectively. This study using matched controls showed that AZM total body clearance and not the volume of distribution is higher in CF patients as a result of increased renal clearance. Pharmacokinetic parameter estimates in healthy subjects resulted in a clinical susceptibility breakpoint of < or =4 mg/liter for a dose of 1,000 mg every 8 h. Patients suspected of having high clearance rates, such as CF patients, should be monitored closely, with dosing regimens adjusted accordingly.

Concentration-effect Relationship of Ceftazidime Explains Why the Time Above the MIC is 40 Percent for a Static Effect in Vivo

Antimicrobial Agents and Chemotherapy. Sep, 2007  |  Pubmed ID: 17576831

Growth-kill dynamics were characterized in vitro, and the parameter estimates were used to simulate bacterial growth and kill in vivo using both mouse and human pharmacokinetics. The parameter estimates obtained in vitro predicted a time above the MIC of between 35 and 38% for a static effect in mice after 24 h of treatment.

Trend in Therapeutic Monitoring of Immunosuppressive Drugs

MLO: Medical Laboratory Observer. Jul, 2007  |  Pubmed ID: 17695969

Continuous Infusion of Beta-lactams

Current Opinion in Critical Care. Oct, 2007  |  Pubmed ID: 17762242

Continuous infusion of beta-lactam antibiotics is becoming increasingly popular. The background and current clinical evidence are discussed. Tools to apply continuous infusion are analyzed.

Plasma Pharmacokinetic Characteristics of Risperidone and Their Relationship to Saliva Concentrations in Children with Psychiatric or Neurodevelopmental Disorders

Clinical Therapeutics. Jul, 2007  |  Pubmed ID: 17825699

Risperidone is a second-generation antipsychotic agent widely used in the treatment of schizophrenia and other psychotic disorders in adults. Risperidone is probably the most frequently used atypical antipsychotic in the pediatric population.

Pharmacokinetics of Mycophenolic Acid, Tacrolimus and Sirolimus After Gastric Bypass Surgery in End-stage Renal Disease and Transplant Patients: a Pilot Study

Clinical Transplantation. May-Jun, 2008  |  Pubmed ID: 18482049

Promising data regarding the safety and efficacy of gastric bypass surgery (GBS) as an option to address obesity in the transplant population are emerging. The data lack on how GBS may alter the pharmacokinetics (PK) of modern immunosuppression. The objective of this study was to describe the alterations in the PK of modern immunosuppressants and the GBS population.

Severe Neurologic Side Effects in Patients Being Treated for Hemophagocytic Lymphohistiocytosis

Pediatric Blood & Cancer. May, 2009  |  Pubmed ID: 19137570

Hemophagocytic Lymphohistiocytosis (HLH) is characterized by uncontrolled inflammation that is generally fatal without immune modulating chemotherapy. At Texas Children's Hospital, we have observed significant central nervous system (CNS) toxicity in several patients treated for HLH according to the Histiocyte Society protocol HLH-2004 in which cyclosporine is given early in the treatment regimen.

Drug-metabolizing Enzyme Genotypes and Aggressive Behavior Treatment Response in Hospitalized Pediatric Psychiatric Patients

Journal of Child and Adolescent Psychopharmacology. Aug, 2009  |  Pubmed ID: 19702490

The aim of this study was to examine the association between the CYP2D6 and CYP2C19 genotype-predicted combined phenotypes and short-term measures of psychotropic efficacy and toxicity.

Personalizing Drug Selection Using Advanced Clinical Decision Support

Biomedical Informatics Insights. Jun, 2009  |  Pubmed ID: 19898682

This article describes the process of developing an advanced pharmacogenetics clinical decision support at one of the United States' leading pediatric academic medical centers. This system, called CHRISTINE, combines clinical and genetic data to identify the optimal drug therapy when treating patients with epilepsy or Attention Deficit Hyperactivity Disorder. In the discussion a description of clinical decision support systems is provided, along with an overview of neurocognitive computing and how it is applied in this setting.

Pharmacokinetics of Amantadine in Children with Impaired Consciousness Due to Acquired Brain Injury: Preliminary Findings Using a Sparse-sampling Technique

PM & R : the Journal of Injury, Function, and Rehabilitation. Jan, 2010  |  Pubmed ID: 20129511

To evaluate the pharmacokinetics of amantadine in children with impaired consciousness from acquired brain injury.

Alternate-day Micafungin Antifungal Prophylaxis in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation: a Pharmacokinetic Study

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Oct, 2010  |  Pubmed ID: 20546908

Disseminated fungal infection is a major cause of morbidity and mortality in children undergoing hematopoietic stem cell transplantation (HSCT). Prophylaxis with amphotericin B can be limited by renal toxicity. Oral triazoles can be limited by poor absorption, large interindividual pharmacokinetic (PK) variability, and hepatic toxicity, leading to interruptions in therapy and breakthrough infections. Intravenous (i.v.) micafungin has potential advantages, because of its better safety profile, specifically in terms of hepatic and renal toxicity, and lack of drug-drug interactions with common medications used in the HSCT setting. We hypothesized that higher dose micafungin (3 mg/kg) every other day will provide drug exposure similar to standard dosing (1 mg/kg) given daily, and improve patient compliance in very young children in whom oral medications can be challenging, at reduced administration costs. Both animal and adult patient data support the use of this approach. Fifteen children (M/F = 11/4, aged < or =10 years; mean: 3.9 years, range: 0.6-10 years) with various hematologic, metabolic, and immune deficiency disorders undergoing HSCT received a single dose of micafungin (3 mg/kg) i.v. over 1 hour. Dose selection was based on published PK data in pediatric patients, and exploration of different dosing regimens using Monte Carlo PK/PD simulation. Blood samples were drawn around this dose and PK analysis was conducted using standard noncompartmental methods. Micafungin at 3 mg/kg dose was well tolerated in all patients. Measurable plasma concentrations were present in all cases at 48 hours. Half-life and clearance observed were comparable to previous pediatric PK data, with clearance being higher than adults as expected. Volume of distribution was higher in our patients compared to published pediatric data, likely because of a larger proportion of very young children in our study cohort. After correction for protein binding, concentrations at the end of the dosing interval during maintenance treatment remain above the minimum inhibitory concentration (MIC) of highly susceptible fungal pathogens. These data suggest that alternate day micafungin dosing, as described here, may provide an attractive alternative for antifungal prophylaxis in HSCT patients and merits further evaluation.

Longitudinal Comparison of Thyroxine Pharmacokinetics Between Pregnant and Nonpregnant Women: a Stable Isotope Study

Therapeutic Drug Monitoring. Dec, 2010  |  Pubmed ID: 20962709

The treatment of maternal hypothyroidism presents clinicians with a unique challenge, because dosing regimens previously developed and validated for nonpregnant women cannot be easily extrapolated to dosing in pregnancy. Thyroid hormone requirement increases by 20% to 40% early during pregnancy, persisting throughout gestation. Accordingly, women with treated hypothyroidism need to increase their levothyroxine dose to prevent maternal hypothyroidism and the associated impaired cognitive development and increased fetal mortality. We investigated the pharmacokinetic properties of levothyroxine during pregnancy through the use of a novel, traceable form of levothyroxine. The objective was to conduct a longitudinal study to determine whether levothyroxine pharmacokinetics differ in the pregnant versus nonpregnant state. We used a unique C-levothyroxine-tracer method to distinguish between endogenous and exogenous levothyroxine and studied the pharmacokinetics of a single oral dose of levothyroxine using tandem mass spectrometry. Moreover, we were able to detect single dose amounts of the drug, in picogram/mL concentrations. The area under the curve was 23.0 ng*h/mL in pregnancy and 14.8 ng*h/mL in nonpregnant women (P < 0.03) with median serum half-lives of 32.1 hours and 24.1 hours, respectively (P < 0.04). Further research involves the measurement of free thyroxine on these samples using tandem mass spectrometry. Future work should focus on the mechanisms responsible for the gestational differences in pharmacokinetics and whether these should necessitate dose schedule changes in pregnancy.

Inosine Monophosphate Dehydrogenase (IMPDH) Activity As a Pharmacodynamic Biomarker of Mycophenolic Acid Effects in Pediatric Kidney Transplant Recipients

Journal of Clinical Pharmacology. Mar, 2011  |  Pubmed ID: 20418509

Monitoring inosine monophosphate dehydrogenase (IMPDH) activity as a biomarker of mycophenolic acid (MPA)-induced immunosuppression may serve as a novel approach in pharmacokinetics (PK)/pharmacodynamics (PD)-guided therapy. The authors prospectively studied MPA pharmacokinetics and IMPDH inhibition in 28 pediatric de novo kidney transplant recipients. Pretransplant IMPDH activity and full PK/PD profiles were obtained at 3 different occasions: 1 to 3 days, 4 to 9 days, and approximately 6 months after transplant. Large intra- and interpatient variability was noted in MPA pharmacokinetics and exposure and IMPDH inhibition. MPA exposure (AUC(0-12 h)) was low early posttransplant and increased over time and stabilized at months 3 to 6. Mean pretransplant IMPDH activity (6.4 ± 4.6 nmol/h/mg protein) was lower than previously reported in adults. In most of the patients, IMPDH enzyme activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory E(max) model (EC(50) = 0.97 mg/L). This study suggests the importance of early PK/PD monitoring to improve drug exposure. Because IMPDH inhibition is well correlated to MPA concentration, pretransplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population.

Pharmacokinetics and Pharmacodynamics of Mycophenolic Acid and Their Relation to Response to Therapy of Childhood-onset Systemic Lupus Erythematosus

Seminars in Arthritis and Rheumatism. Feb, 2011  |  Pubmed ID: 20655577

Mycophenolic acid (MPA) is the active form of mycophenolate mofetil (MMF), which is currently used off-label as immunosuppressive therapy in childhood-onset SLE (cSLE). The objectives of this study were to (1) characterize the pharmacokinetics (MPA-PK) and pharmacodynamics (MPA-PD) of MPA and (2) explore the relationship between MPA-PK and cSLE disease activity.

The Evolution of Population Pharmacokinetic Models to Describe the Enterohepatic Recycling of Mycophenolic Acid in Solid Organ Transplantation and Autoimmune Disease

Clinical Pharmacokinetics. Jan, 2011  |  Pubmed ID: 21142265

With the increasing use of mycophenolic acid (MPA) as an immunosuppressant in solid organ transplantation and in treating autoimmune diseases such as systemic lupus erythematosus, the need for strategies to optimize therapy with this agent has become increasingly apparent. This need is largely based on MPA's significant between-subject and between-occasion (within-subject) pharmacokinetic variability. While there is a strong relationship between MPA exposure and effect, the relationship between drug dose, plasma concentration and exposure (area under the concentration-time curve [AUC]) is very complex and remains to be completely defined. Population pharmacokinetic models using various approaches have been proposed over the past 10 years to further evaluate the pharmacokinetic and pharmacodynamic behaviour of MPA. These models have evolved from simple one-compartment linear iterations to complex multi-compartment versions that try to include various factors, which may influence MPA's pharmacokinetic variability, such as enterohepatic recycling and pharmacogenetic polymorphisms. There have been major advances in the understanding of the roles transport mechanisms, metabolizing and other enzymes, drug-drug interactions and pharmacogenetic polymorphisms play in MPA's pharmacokinetic variability. Given these advances, the usefulness of empirical-based models and the limitations of nonlinear mixed-effects modelling in developing mechanism-based models need to be considered and discussed. If the goal is to individualize MPA dosing, it needs to be determined whether factors which may contribute significantly to variability can be utilized in the population pharmacokinetic models. Some pharmacokinetic models developed to date show promise in being able to describe the impact of physiological processes such as enterohepatic recycling. Most studies have historically been based on retrospective data or poorly designed studies which do not take these factors into consideration. Modelling typically has been undertaken using non-controlled therapeutic drug monitoring data, which do not have the information content to support the development of complex mechanistic models. Only a few recent modelling approaches have moved away from empiricism and have included mechanisms considered important, such as enterohepatic recycling. It is recognized that well thought-out sampling schedules allow for better evaluation of the pharmacokinetic data. It is not possible to undertake complex absorption modelling with very few samples being obtained during the absorption phase (which has often been the case). It is important to utilize robust AUC monitoring which is now being propagated in the latest consensus guideline on MPA therapeutic drug monitoring. This review aims to explore the biological factors that contribute to the clinical pharmacokinetics of MPA and how these have been introduced in the development of population pharmacokinetic models. An overview of the processes involved in the enterohepatic recycling of MPA will be provided. This will summarize the components that complicate absorption and recycling to influence MPA exposure such as biotransformation, transport, bile physiology and gut flora. Already published population pharmacokinetic models will be examined, and the evolution of these models away from empirical approaches to more mechanism-based models will be discussed.

Mycophenolate, Clinical Pharmacokinetics, Formulations, and Methods for Assessing Drug Exposure

Transplantation Reviews (Orlando, Fla.). Apr, 2011  |  Pubmed ID: 21190834

This article summarizes part of a consensus meeting about mycophenolate (MPA) therapeutic drug monitoring held in Rome under the auspices of The Transplantation Society in November 2008 (Clin J Am Soc Nephrol. 2010;5:341-358). This part of the meeting focused on the clinical pharmacokinetics of MPA and included discussion on how to measure MPA (active drug) exposure and the differences between the currently available formulations.

Pediatric Aspects of Therapeutic Drug Monitoring of Mycophenolic Acid in Renal Transplantation

Transplantation Reviews (Orlando, Fla.). Apr, 2011  |  Pubmed ID: 21454065

Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppressive therapy in pediatric renal and heart transplant recipients. Children undergo developmental changes (ontogeny) of drug disposition, which may affect drug metabolism of the active compound mycophenolic acid (MPA). Therefore, a detailed characterization of MPA pharmacokinetics and pharmacodynamics in this patient population is required. In general, the overall efficacy and tolerability of MMF in pediatric patients appear to be comparable with those in adults, except for a higher prevalence of gastrointestinal adverse effects in children younger than 6 years. The currently recommended dose in pediatric patients with concomitant cyclosporine is 1200 mg/m(2) per day in 2 divided doses; the recommended MMF dose with concomitant tacrolimus or without a concurrent calcineurin inhibitor is 900 mg/m(2) per day in 2 divided doses. Recent data suggest that fixed MMF dosing results in MPA underexposure (MPA-area under the concentration-time curve (AUC(0-12)), <30 mg × h/L) early posttransplant in approximately 60% of patients. To achieve adequate MPA exposure in most patients, an initial MMF dose of 1800 mg/m(2) per day with concomitant cyclosporine and 1200 mg/m(2) per day with concomitant tacrolimus for the first 2 to 4 weeks posttransplant has been suggested. As in adults, there is an approximately 10-fold variability in dose-normalized MPA-AUC(0-12) values between pediatric patients after renal transplantation, strengthening the argument for concentration-controlled dosing of the drug. Although the clinical utility of therapeutic drug monitoring of MPA for graft outcome and patient survival is still controversial, potential indications are the avoidance of underimmunosuppression, particularly in patients with high immunologic risk in the initial period posttransplant, in patients who are treated with protocols that explore the possibilities of calcineurin inhibitor minimization, withdrawal or even complete avoidance, and steroid withdrawal or avoidance regimens that might also benefit from intensified therapeutic drug monitoring of MPA. An additional indication especially in adolescent patients is the monitoring of drug adherence. Therapeutic drug monitoring of MPA in pediatric solid organ transplantation using limited sampling strategies is preferable over drug dosing based on trough level monitoring only. Several validated pediatric limited sampling strategies are available. Clearly, more research is required to determine whether pediatric patients will benefit from therapeutic drug monitoring of MPA for long-term maintenance immunosuppression with MMF.

Better Medicines for 300 Million Children in China: Report on Recent Progress

Paediatric Drugs. Jun, 2011  |  Pubmed ID: 21500867

Pharmacokinetics of Levetiracetam in Neonates with Seizures

The Journal of Pediatrics. Jul, 2011  |  Pubmed ID: 21592494

The pharmacokinetics of levetiracetam were determined prospectively in 18 neonates with seizures. Neonates were found to have lower clearance, higher volume of distribution, and a longer half-life as compared with older children and adults. Mild somnolence was the only adverse effect.

Optimal Study Design for Pioglitazone in Septic Pediatric Patients

Journal of Pharmacokinetics and Pharmacodynamics. Aug, 2011  |  Pubmed ID: 21667139

The objective was to demonstrate the methodology and process of optimal sparse sampling pharmacokinetics (PK). This utilized a single daily dose of pioglitazone for pediatric patients with severe sepsis and septic shock based upon adult and minimal adolescent data. Pioglitazone pharmacokinetics were modeled using non-compartment analysis WinNonlin Pro (version 5.1) and population kinetics using NONMEM (version 7.1) with first order conditional estimation method (FOCE) with interaction. The initial model was generated from single- and multiple-dose pioglitazone PK data (15 mg, 30 mg, and 45 mg) in 36 adolescents with diabetes. PK models were simulated and overlaid upon original data to provide a comparison best described by a single compartment, first order model. The optimal design was based on the simulated oral administration of pioglitazone to three groups of pediatric patients, age 3.8 (2-6 years), weight 14.4 (7-28 kg); age 9.6 (6.1-11.9 years), weight 36.5 (28.1-48 kg) and age 15.5 (12-17 years,) weight 61.6 (48.1-80 kg). PFIM (version 3.2) was used to evaluate sample study size. Datasets were compiled using simulation for each dose (15, 30 and 45 mg) for the potential age/weight groups. A target dose of 15 mg daily in the youngest and middle groups was considered appropriate with area under the curve exposure levels (AUC) comparable to studies in adolescents. The final optimal design suggested time points of 0.5, 2, 6 and 21 h for 24 h dosing. This methodology provides a robust method of utilizing adult and limited adolescent data to simulate allometrically scaled, pediatric data sets that allow the optimal design of a pediatric trial. The pharmacokinetics of pioglitazone were described adequately and simulated data estimates were comparable to literature values. The optimal design provided clinically attainable sample times and windows.

Important Role of Population Pharmacokinetic/pharmacodynamic Modeling in Pediatric Therapeutics

The Journal of Pediatrics. Sep, 2011  |  Pubmed ID: 21764403

Nonsteroidal Anti-inflammatory Drugs May Reduce Enterohepatic Recirculation of Mycophenolic Acid in Patients with Childhood-onset Systemic Lupus Erythematosus

Therapeutic Drug Monitoring. Oct, 2011  |  Pubmed ID: 21860343

The large interindividual differences observed in mycophenolic acid (MPA) pharmacokinetics (MPA-PK) are in part attributed to the large variability in enterohepatic recirculation (EHC) of the drug. The main metabolite of MPA, MPA glucuronide is actively secreted into the bile via the multidrug resistance-associated protein 2 (MRP2) transporter. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the MRP2 transporter, which can alter EHC and drug exposure. Here, we evaluated the effects of this potential drug-transporter interaction on MPA-PK in a cohort of patients with childhood-onset systemic lupus erythematosus on mycophenolate mofetil therapy.

Pharmacokinetics of Prednisolone at Steady State in Young Patients with Systemic Lupus Erythematosus on Prednisone Therapy: an Open-label, Single-dose Study

Clinical Therapeutics. Oct, 2011  |  Pubmed ID: 21982386

Current prednisone dosing in the treatment of young patients with childhood-onset systemic lupus erythematosus (cSLE) is largely based on achieving balance between therapeutic efficacy and toxicity, with weight-based dosing a common clinical practice. Despite the widespread use of prednisone, few attempts have been made to improve its clinical dosing regimen, and response to prednisone therapy remains variable.

Characteristics of Successful Recruitment in Prospective Pediatric Pharmacogenetic Studies

Clinical Therapeutics. Dec, 2011  |  Pubmed ID: 22136977

There is a need to explore feasible means of accruing an appropriate study cohort to help fill the knowledge gap between pharmacogenetic contributions to drug response and clinical application in the pediatric population.

Optimizing Immunosuppressive Drug Dosing in Pediatric Renal Transplantation. Part of a Special Series on Paediatric Pharmacology, Guest Edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni

Pharmacological Research. Feb, 2012  |  Pubmed ID: 22015636

Kidney transplantation in pediatric patients has become a successful and routine procedure, with overall 1-year patient and graft survival rates exceeding 95%. These success rates, however, are not maintained in the long-term, as reported 10-year graft survival rates are in the 50-60% range. Further improvement of long-term allograft survival in pediatric transplantation requires specific focus on long term complications such as increased cardiovascular risk and over-immunosuppression, two linked conditions. One approach to avoid inadequate immunosuppression is to more aggressively tailor immunosuppressive treatment based on individual patient needs. This strategy is currently pursued in the pediatric transplant setting by implementation of individualized therapeutic management of drug concentrations and total exposure. In addition, there is increasing evidence that pharmacogenetic testing may equally benefit individualized immunosuppressive therapy through the identification of SNPs and haplotypes predictive of encoding of proteins involved in drug transport, metabolism and response (efficacy/toxicity). The next challenge will be to provide real time web-based access to all patient information including pharmacokinetic, pharmacodynamic and genotyping data as part of a dosing algorithm or decision support tool with the ultimate goal to adaptively predict and control immunosuppressant exposure and response in individual patients to improve long-term outcomes after kidney transplantation.

Development of Population PK Model with Enterohepatic Circulation for Mycophenolic Acid in Patients with Childhood-onset Systemic Lupus Erythematosus

British Journal of Clinical Pharmacology. May, 2012  |  Pubmed ID: 22053944

This study aimed to develop a population pharmacokinetic (PK) enterohepatic recycling model for MPA in patients with childhood-onset systemic lupus erythematosus (cSLE).

Pharmacogenetics and Anesthetic Drugs

Current Clinical Pharmacology. May, 2012  |  Pubmed ID: 22432844

The incidence and potential for serious adverse drug reactions (SADRs) in anesthesia are high due to the narrow therapeutic indices of anesthetic and analgesic drugs and high interindividual variability in drug responses. Genetic factors contribute to a majority of these SADRs. Pharmacogenetics (PG), the study of genetic effects on drug action, is strongly related to the field of anesthesia; historically, succinylcholine apnea and malignant hyperthermia were among the first PG disorders reported. Recent years have strengthened this affiliation with an emerging wide base of knowledge of the effects of genetic variations on the pharmacodynamics and pharmacokinetics of anesthetic drugs. Here, we review the history of anesthetic PG, the important genes influencing enzymes involved in anesthetic drug metabolism, the influence of genotypic expression and the potential ramifications of recent discoveries on the practice of clinical anesthesia. Epigenetics and functional genomics are also discussed. The article also addresses various critical deficits in our current knowledge of PG related to anesthesia that account for the minimal clinical translation of the findings in this area in the present time. The review concludes that in addition to enhanced data generation facilitated by rapidly evolving genetic techniques, robust clinical study designs in a large sample and sound statistical analyses are essential prerequisites for the successful clinical implementation of research findings to individual perioperative care for every patient.

Risk of Tacrolimus Toxicity in CYP3A5 Nonexpressors Treated with Intravenous Nicardipine After Kidney Transplantation

Transplantation. Apr, 2012  |  Pubmed ID: 22491658

Tacrolimus is commonly prescribed for immunosuppression, yet it can cause acute and chronic kidney injury. Continuous intravenous nicardipine (CIVN), prescribed for posttransplant hypertension, inhibits tacrolimus metabolism by cytochrome P450 (CYP) 3A4 and could lead to tacrolimus overexposure in patients genetically lacking the alternative pathway for tacrolimus metabolism, CYP3A5.

Pharmacogenetics in Perioperative Medicine

Current Opinion in Anaesthesiology. Aug, 2012  |  Pubmed ID: 22673786

This review will discuss the most recent developments in pharmacogenetics of commonly used perioperative medications, new collaboration networks in the field of personalized medicine, and future clinical implications of pharmacogenetics.

Propofol Clearance in Morbidly Obese Children and Adolescents: Influence of Age and Body Size

Clinical Pharmacokinetics. Aug, 2012  |  Pubmed ID: 22690673

Given the alarming increase in obesity among children undergoing surgery, the main aim of this study was to characterize propofol clearance in a cohort of morbidly obese children and adolescents in relation to their age and body weight characteristics.

Population Pharmacokinetic Modeling of Risperidone and 9-hydroxyrisperidone to Estimate CYP2D6 Subpopulations in Children and Adolescents

Therapeutic Drug Monitoring. Oct, 2012  |  Pubmed ID: 22929407

The study aims were to characterize risperidone and (±)-9-hydroxyrisperidone pharmacokinetic (PK) variability in children and adolescents and to evaluate covariate effects on PK parameters.

Morphine Clearance in Children: Does Race or Genetics Matter?

Journal of Opioid Management. Jul-Aug, 2012  |  Pubmed ID: 22941849

Interindividual variability in analgesic response and adverse effects of opioids because of narrow therapeutic indices are major clinical problems. Morphine is an opioid commonly used in children to manage perioperative pain. Al-though size and age often are considered primary covariates for morphine pharmacokinetic models, the impact of other factors important in personalizing care such as race and genetic variations on morphine disposition is not well documented.

Update in Fetal Anesthesia for the Ex Utero Intrapartum Treatment (EXIT) Procedure

International Anesthesiology Clinics. 2012  |  Pubmed ID: 23047444

UGT1A9, UGT2B7, and MRP2 Genotypes Can Predict Mycophenolic Acid Pharmacokinetic Variability in Pediatric Kidney Transplant Recipients

Therapeutic Drug Monitoring. Dec, 2012  |  Pubmed ID: 23131697

Mycophenolic acid (MPA) exposure in pediatric patients with kidney transplant receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic variants in glucuronosyltransferases (UGTs) and of multidrug resistance-associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in pediatric renal transplant recipients who were on mycophenolic mofetil maintenance therapy.

Summary of the National Institute of Child Health and Human Development-best Pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop-Pediatric Biopharmaceutics Classification System Working Group

Clinical Therapeutics. Nov, 2012  |  Pubmed ID: 23149009

The Biopharmaceutics Classification System (BCS) allows compounds to be classified based on their in vitro solubility and intestinal permeability. The BCS has found widespread use in the pharmaceutical community to be an enabling guide for the rational selection of compounds, formulation for clinical advancement, and generic biowaivers. The Pediatric Biopharmaceutics Classification System (PBCS) Working Group was convened to consider the possibility of developing an analogous pediatric-based classification system. Because there are distinct developmental differences that can alter intestinal contents, volumes, permeability, and potentially biorelevant solubilities at different ages, the PBCS Working Group focused on identifying age-specific issues that need to be considered in establishing a flexible, yet rigorous PBCS.

Federal Legislation and the Advancement of Neonatal Drug Studies

The Journal of Pediatrics. Jan, 2013  |  Pubmed ID: 23110945

Evaluation of Propofol Anesthesia in Morbidly Obese Children and Adolescents

BMC Anesthesiology. 2013  |  Pubmed ID: 23602008

Poor characterization of propofol pharmacokinetics and pharmacodynamics in the morbidly obese (MO) pediatric population poses dosing challenges. This study was conducted to evaluate propofol total intravenous anesthesia (TIVA) in this population.

Population Pharmacokinetics of Sirolimus in Pediatric Patients with Neurofibromatosis Type 1

Therapeutic Drug Monitoring. Jun, 2013  |  Pubmed ID: 23666574

The narrow therapeutic index and large interpatient variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with neurofibromatosis type 1 (NF1). The objectives of this study were to estimate sirolimus clearance in a cohort of children with NF1 using data collected in a concentration-guided trial, to evaluate the effect of treatment duration on clearance and dose requirements, and to evaluate the association of sirolimus clearance with patient-specific factors, including age, weight, body surface area (BSA), race, and sex.

Developmental Changes in Morphine Clearance Across the Entire Paediatric Age Range Are Best Described by a Bodyweight-dependent Exponent Model

Clinical Drug Investigation. Jul, 2013  |  Pubmed ID: 23754691

Morphine clearance has been successfully scaled from preterm neonates to 3-year-old children on the basis of a bodyweight-based exponential (BDE) function and age younger or older than 10 days. The aim of the current study was to characterize the developmental changes in morphine clearance across the entire paediatric age range.

OCT1 Genetic Variants Influence the Pharmacokinetics of Morphine in Children

Pharmacogenomics. Jul, 2013  |  Pubmed ID: 23859569

Large interindividual variability in morphine disposition could contribute to unpredictable variability in morphine analgesia and adverse events. Caucasian children have more adverse effects and slower morphine clearance than African-American children. To study variations in intravenous morphine pharmacokinetics in children, we examined the influence of genetic polymorphisms in OCT1.

Quantification of the 5-lipoxygenase Inhibitor Zileuton in Human Plasma Using High Performance Liquid Chromatography-tandem Mass Spectrometry

Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. Oct, 2013  |  Pubmed ID: 24029553

Zileuton is an orally active, selective inhibitor of 5-lipoxygenase, which catalyzes the first step in the conversion of arachadonic acid into leukotrienes. Given the important role of leukotrienes in inflammation and cell signaling, multiple studies have investigated the efficacy of zileuton in the treatment of human disease. Examples of disease targets include asthma, ulcerative colitis, rheumatoid arthritis, and more recently, acne, ischemic/reperfusion injury, inflammatory pain, and sickle cell anemia. Zileuton is currently approved for the prophylaxis and chronic treatment of asthma. We report the development and validation of a sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of zileuton in human EDTA plasma. The range of reliable response was 3.05-20,000ng/mL in human plasma. The calibration curves had a correlation coefficient of r(2)>0.99. The intra-day precision was 3.4-5.3%. The inter-day precision ranged from 4.5% to 7.3% and inter-day accuracy from 100% to 107%. No matrix interferences, ion suppression/enhancement, or carry-over was observed. The assay met all predefined acceptance criteria and was subsequently employed to measure plasma zileuton concentrations in a clinical trial.

Lower Vancomycin Serum Trough Concentrations Might Not Be the Answer

The Pediatric Infectious Disease Journal. Dec, 2013  |  Pubmed ID: 24569315

Developmental Trajectory of Intestinal MDR1/ABCB1 MRNA Expression in Children

British Journal of Clinical Pharmacology. May, 2014  |  Pubmed ID: 23879365

Utilization of Optimal Study Design for Maternal and Fetal Sheep Propofol Pharmacokinetics Study: a Preliminary Study

Current Clinical Pharmacology. Feb, 2014  |  Pubmed ID: 24219004

Multiple blood samples are generally required for measurement of pharmacokinetic (PK) parameters. D-optimal design is a popular and frequently used approach for determination of sampling time points in order to minimize the number of samples, while optimizing the estimation of PK parameters. Optimal design utilizing ADAPT (v5, BSR, University of Southern California, Los Angeles) developed a sparse sampling strategy to determine measurement of propofol in pregnant sheep. Propofal was administered as supplemental anesthetic agent to inhalation anesthesia to mimic anesthesia for open fetal surgery. In our preliminary study, propofol 3 mg/kg was given as a bolus to the ewe, followed by propofol infusion at rate 450 mcg/kg/min for 60 minutes, then decreased to 75 mcg/kg/min for 90 more minutes and then ceased. A three compartment model described the PK parameters with the fetus assumed as the third compartment. Initially, sampling times were chosen from thirteen time points as previously stated in the literature. Using priori propofol PK estimates, the final 9 sample time points were proposed in an optimal design with a change in infusion rate occurring between 65 and 75 minutes and sampling proposed at 5, 15, 25, 65, 75, 100, 110, 150, and 180 minutes. D-optimal design optimized the number and timing of samplings, which led to a reduction of cost and man power in the study protocol while preserving the ability to estimate propofol PK parameters in the maternal and fetal sheep model. Initial evaluation of samples collected from three sheep using the optimal design strategy confirmed the performance of the design in obtaining effective PK parameter estimates.

Optimization of Mycophenolic Acid Therapy Using Clinical Pharmacometrics

Drug Metabolism and Pharmacokinetics. 2014  |  Pubmed ID: 24351871

  Novel approaches applying quantitative clinical pharmacology or pharmacometrics have been increasingly embraced by the drug development community in the last decade. State-of-the-art population modeling and simulation enable better characterization and prediction of drug exposure. For narrow therapeutic index drugs such as mycophenolic acid (MPA) which exhibit large inter-individual variation in drug exposure, pharmacometric analysis can be of great clinical benefit. This review aims to summarize the recent progress of using pharmacometric tools toward individualized MPA therapeutics. The population pharmacokinetic models including those developed for special populations and Bayesian estimators for therapeutic drug management will be reviewed. Special attention will be given to new methodologies such as nonparametric population modeling and the physiological-based pharmacokinetics modeling (PBPK) that emerged recently as alternatives to the parametric population approach to predict MPA exposure. D-Optimal design strategies applied in clinical study design will also be reviewed. Lastly, the potential of using a pharmacodynamic based optimal treatment strategy by focusing on MPA's target enzyme inosine monophosphate dehydrogenase (IMPDH) will be discussed.

Similar MPA Exposure on Modified Release and Regular Tacrolimus

Therapeutic Drug Monitoring. Jun, 2014  |  Pubmed ID: 24365986

Concomitant immunosuppression may affect the mycophenolate mofetil exposure. Astellas developed a once-daily modified release formulation of tacrolimus (TacMR) with the potential to reduce the likelihood of nonadherence. It is unknown whether mycophenolic acid (MPA) area under the concentration-time curve (AUC) differs between the 2 tacrolimus (Tac) formulations. In a 2-by-2 crossover design, 20 stable renal transplant recipients on twice-daily Tac either continued their usual Tac therapy (n = 10, group 1) or switched to TacMR for a 12-week period (n = 10, group 2), after which the patients crossed over to the other formulation for another 12-week period. Pharmacokinetic profiles using limited sampling strategies were obtained before randomization (visit 1), and at 12 (visit 2) and 24 weeks (visit 3) at steady state. MPA AUC was calculated using the Pawinski formula. When analyzing visits on Tac, TacMR, and back on Tac combined, the MPA AUC for all 20 patients at baseline was 42.24 (16.98), 37.18 (13.75), and 40.09 (16.69) mg·h·L(-1), respectively, which was not statistically significant using repeated measures (P = 0.1327, R(2) = 0.1109). We conclude that MPA pharmacokinetic profiles are not altered when converting patients from Tac to TacMR.

Dose Optimisation of Antibiotics in Children: Application of Pharmacokinetics/pharmacodynamics in Paediatrics

International Journal of Antimicrobial Agents. Mar, 2014  |  Pubmed ID: 24389079

The judicious use of antibiotics to combat infections in children relies upon appropriate selection of an agent, dose and duration to maximise efficacy and to minimise toxicity. Critical to dose optimisation is an understanding of the pharmacokinetics and pharmacodynamics of available drugs. Optimal dosing strategies may take advantage of pharmacokinetic/pharmacodynamic (PK/PD) principles so that antibiotic dosing can be individualised to assure effective bacterial killing in patients who have altered pharmacokinetics or who have infections with less susceptible or resistant organisms. This review will outline the fundamentals of antimicrobial pharmacokinetics/pharmacodynamics through discussion of antibacterial agents most often used in children. We aim to highlight the importance of dose optimisation in paediatrics and describe non-conventional dosing strategies that can take advantage of PK/PD principles at the bedside.

Effects of Unbound Mycophenolic Acid on Inosine Monophosphate Dehydrogenase Inhibition in Pediatric Kidney Transplant Patients

Therapeutic Drug Monitoring. Dec, 2014  |  Pubmed ID: 24739663

Mycophenolic acid (MPA) is a key immunosuppressive drug that acts through inhibition of inosine monophosphate dehydrogenase (IMPDH). MPA is commonly measured, as part of therapeutic drug monitoring, as the total concentration in plasma. However, it has been postulated that the free (unbound) fraction of MPA (fMPA) is responsible for the immunosuppressive effects. In this study, a sensitive low volume high-performance liquid chromatography (HPLC) assay was developed to measure fMPA concentrations to explore the relationship between fMPA and IMPDH activity.

Individualised Antibiotic Dosing for Patients Who Are Critically Ill: Challenges and Potential Solutions

The Lancet. Infectious Diseases. Jun, 2014  |  Pubmed ID: 24768475

Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.

The Effect of ABCG2 Genotype on the Population Pharmacokinetics of Sunitinib in Patients with Renal Cell Carcinoma

Therapeutic Drug Monitoring. Jun, 2014  |  Pubmed ID: 24825438

Sunitinib, a multitargeted tyrosine kinase inhibitor, offers favorable therapeutic outcomes to patients with advanced renal cell carcinoma. However, to maximize the clinical benefits, an effective therapeutic management strategy with dose optimization is essential. The objectives of this analysis were to describe the pharmacokinetics (PK) of sunitinib by a population PK approach and to quantitatively evaluate the effect of potential predictive factors including ABCG2 genotype on the PK of sunitinib.

Population Pharmacokinetic-pharmacodynamic Modelling of Mycophenolic Acid in Paediatric Renal Transplant Recipients in the Early Post-transplant Period

British Journal of Clinical Pharmacology. Nov, 2014  |  Pubmed ID: 24837828

The purpose of this study was to develop a population pharmacokinetic and pharmacodynamic (PK-PD) model for mycophenolic acid (MPA) in paediatric renal transplant recipients in the early post-transplant period.

Sirolimus for Non-progressive NF1-associated Plexiform Neurofibromas: an NF Clinical Trials Consortium Phase II Study

Pediatric Blood & Cancer. Jun, 2014  |  Pubmed ID: 24851266

Patients with Neurofibromatosis Type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. There are no standard treatment options for PN other than surgery, which is often difficult due to the extensive growth and invasion of surrounding tissues. Mammalian Target of Rapamycin (mTOR) acts as a master switch of cellular catabolism and anabolism and controls protein translation, angiogenesis, cell motility, and proliferation. The NF1 tumor suppressor, neurofibromin, regulates the mTOR pathway activity. Sirolimus is a macrolide antibiotic that inhibits mTOR activity.

Current Management of Neonatal Abstinence Syndrome Secondary to Intrauterine Opioid Exposure

The Journal of Pediatrics. Sep, 2014  |  Pubmed ID: 24948346

Meropenem in Children Receiving Continuous Renal Replacement Therapy: Clinical Trial Simulations Using Realistic Covariates

Journal of Clinical Pharmacology. Dec, 2014  |  Pubmed ID: 25042683

Meropenem is frequently prescribed in children receiving continuous renal replacement therapy (CRRT). Fluid overload is often present in critically ill children and affects drug disposition. The purpose of this study was to develop a pharmacokinetic model to (1) evaluate target attainment of meropenem dosing regimens against P. aeruginosa in children receiving CRRT and (2) estimate the effect of fluid overload on target attainment. Clinical trial simulations were employed to evaluate target attainment of meropenem in various age groups and degrees of fluid overload in children receiving CRRT. Pharmacokinetic parameters were extracted from published literature, and 287 patients from the prospective pediatric CRRT registry database provided realistic clinical covariates including patient weight, fluid overload, and CRRT prescription characteristics. Target attainment at 40% and 75% time above the minimum inhibitory concentration was evaluated. Clinical trial simulations demonstrated that children greater than 5 years of age achieved acceptable target attainment with a dosing regimen of 20 mg/kg every 12 hours. In children less than 5, however, increased dosing of 20 mg/kg every 8 hours was needed to optimize target attainment. Fluid overload did not affect target attainment. These in silico model predictions will need to be verified in vivo in children receiving meropenem and CRRT.

ABCC3 and OCT1 Genotypes Influence Pharmacokinetics of Morphine in Children

Pharmacogenomics. Jul, 2014  |  Pubmed ID: 25155932

Large interindividual variability in morphine pharmacokinetics could contribute to variability in morphine analgesia and adverse events.

Age-dependent Changes in Sirolimus Metabolite Formation in Patients with Neurofibromatosis Type 1

Therapeutic Drug Monitoring. Jun, 2015  |  Pubmed ID: 25162215

Sirolimus is an inhibitor of mammalian target of rapamycin, which exhibits large interindividual pharmacokinetic variability. We report sirolimus pharmacokinetic data collected as part of a concentration-controlled multicenter phase II clinical trial in pediatric patients with neurofibromatosis type 1. The purpose of this study was to explore the effect of growth on age-dependent changes in sirolimus clearance with a focus on cytochrome P450 3A (CYP3A) subfamily mediated metabolism.

Validation of a Pediatric Population Pharmacokinetic Model for Vancomycin

Therapeutic Drug Monitoring. Jun, 2015  |  Pubmed ID: 25423413

Vancomycin is often required to treat serious infections in children, including methicillin-resistant Staphylococcus aureus infections. The pharmacodynamic index that best predicts efficacy with vancomycin use for methicillin-resistant S. aureus infection in adults is the 24-hour area under the curve (AUC) over the minimum inhibitory concentration. Although multiple pediatric population pharmacokinetic (PK) vancomycin models have been published, few use Bayesian optimization. The current standard of care remains measuring vancomycin serum trough concentrations as a surrogate marker of AUC.

A Phase I Study of Cixutumumab (IMC-A12) in Combination with Temsirolimus (CCI-779) in Children with Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Report

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Apr, 2015  |  Pubmed ID: 25467181

To determine the MTD, dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors.

A Safety and Dose Escalation Study of Intravenous Zinc Supplementation in Pediatric Critical Illness

JPEN. Journal of Parenteral and Enteral Nutrition. Feb, 2015  |  Pubmed ID: 25700179

Background: Critically ill children have low plasma zinc (pZn), correlating with organ failure. Since Zn influences inflammation, immune function, and glucose control, Zn supplementation is a plausible therapeutic modality. We sought to determine a safe dose of intravenous (IV) Zn to restore pZn in critically ill children. Methods: Stepwise dose escalation study of IV Zn supplementation at a tertiary children's hospital. All children (<10 years) admitted to the pediatric intensive care unit with a Pediatric Risk of Mortality III score >5, or ≥1 new organ failure were eligible. After consent, patients were sequentially enrolled into 4 dosing groups: (1) no zinc, (2) Zn250: 250 mcg/kg/d ZnSO4, (3) Zn500: 500 mcg/kg/d ZnSO4, or (4) Zn750: 750 mcg/kg/d ZnSO4. ZnSO4 was administered 3 times daily for 7 days. pZn was measured at baseline, end of first ZnSO4 infusion, 1 hour postinfusion, and 7 hours postinfusion on day 1, then daily through days 2-7. Interleukin-6 (IL-6), C-reactive protein (CRP), and lymphocyte subsets were measured on days 1 and 3. Glucose was measured 3 times daily for 7 days. Results: Twenty-four patients were enrolled. Baseline demographics were similar among groups. Baseline pZn was low in all patients (mean [SD], 41.8 [16.0] mcg/dL). pZn increased over the study period in supplemented groups; however, mean pZn in the Zn750 group exceeded the 50th percentile. pZn was not associated with IL-6, CRP, or lymphocyte subsets among groups. Degree of hyperglycemia did not differ among groups. No patient had a study-related adverse event. Conclusions: IV zinc supplementation at 500 mcg/kg/d restores pZn to near the 50th percentile and is well tolerated.

Population Pharmacokinetic-pharmacodynamic Modeling and Dosing Simulation of Propofol Maintenance Anesthesia in Severely Obese Adolescents

Paediatric Anaesthesia. Sep, 2015  |  Pubmed ID: 25975390

Optimal dosing of propofol to maintain appropriate anesthetic depth is challenging in severely obese (SO) adolescents. We previously reported that total body weight (TBW) is predictive of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD) of propofol in SO adolescents, using bispectral index (BIS), and toward developing PK/PD model-based dosing guidelines.

Pharmacokinetic Modeling of Therapies for Systemic Lupus Erythematosus

Expert Review of Clinical Pharmacology. 2015  |  Pubmed ID: 26143647

With the increasing use of different types of therapies in treating autoimmune diseases such as systemic lupus erythematosus (SLE), there is a need to utilize pharmacokinetic (PK) strategies to optimize the clinical outcome of these treatments. Various PK analysis approaches, including population PK modeling and physiologically based PK modeling, have been used to evaluate drug PK characteristics and population variability or to predict drug PK profiles in a mechanistic manner. This review outlines the PK modeling of major SLE therapies including immunosuppressants (methotrexate, azathioprine, mycophenolate and cyclophosphamide, among others) and immunomodulators (intravenous immunoglobulin). It summarizes the population PK modeling, physiologically based PK modeling and model-based individualized dosing strategies to improve the therapeutic outcomes in SLE patients.

Pharmacokinetics of Meropenem in Children Receiving Continuous Renal Replacement Therapy: Validation of Clinical Trial Simulations

Journal of Clinical Pharmacology. Jul, 2015  |  Pubmed ID: 26222329

Meropenem is frequently prescribed in critically ill children receiving continuous renal replacement therapy (CRRT). We previously used clinical trial simulations to evaluate dosing regimens of meropenem in this population and reported that a dose of 20 mg/kg every 12 hours optimizes target attainment. Meropenem pharmacokinetics were investigated in this prospective, open-label study to validate our previous in silico predictions. Seven patients received meropenem (13.8-22 mg/kg) administered intravenously every 12 hours as part of standard care. A mean dose of 18.6 mg/kg of meropenem was administered, resulting in a mean peak concentration of 80.1 μg/mL. Meropenem volume of distribution was 0.35 ± 0.085 L/kg. CRRT clearance was 40.2 ± 6.6 mL/(min · 1.73 m(2) ) and accounted for 63.4% of the total clearance of 74.8 ± 36.9 mL/(min · 1.73 m(2) ). Simulations demonstrated that a dose of 20 mg/kg every 12 hours resulted in a time above the minimum inhibitory concentration (%fT > MIC) of 100% in 5 out of 7 subjects, with a %fT > MIC of 93% and 43% in the remaining 2 subjects. We conclude that CRRT contributed significantly to the total clearance of meropenem. A dosing regimen of 20 mg/kg achieved good target attainment in critically ill children receiving CRRT, which is consistent with our previously published in silico predictions.

The Impact of CYP3A5*3 Polymorphism on Sirolimus Pharmacokinetics: Insights from Predictions with a Physiologically-based Pharmacokinetic Model

British Journal of Clinical Pharmacology. Aug, 2015  |  Pubmed ID: 26256674

Sirolimus is an mTOR inhibitor metabolized by CYP3A4 and CYP3A5. Reported effects of CYP3A5 polymorphisms on sirolimus pharmacokinetics (PK) have shown unexplained discrepancies across studies. We quantitatively assessed the effect of CYP3A5*3 status on sirolimus PK by in vitro assessment and simulation using a physiologically-based PK (PBPK) model. In addition, we explored designs for an adequately powered pharmacogenetic association study.

Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome: A Pilot Study

The Journal of Pediatrics. Sep, 2015  |  Pubmed ID: 26364984

To characterize the population pharmacokinetics of oral methadone in neonates requiring pharmacologic treatment of neonatal abstinence syndrome and to develop a pharmacokinetic (PK) model toward an evidence-based treatment protocol.

Evaluation of Target Attainment of Vancomycin Area Under the Curve in Children With Methicillin-Resistant Staphylococcus Aureus Bacteremia

Therapeutic Drug Monitoring. Oct, 2015  |  Pubmed ID: 26378371

Vancomycin is often required to treat methicillin-resistant Staphylococcus aureus bacteremia in children. Treatment failure occurs in up to 50% of adults and is associated with a 24-hour area under the curve/minimum inhibitory concentration (AUC24h/MIC) <400. We sought to identify patient factors associated with vancomycin AUC and whether AUC24h/MIC <400 was predictive of treatment failure in children.

Milrinone Dosing Issues in Critically Ill Children with Kidney Injury: A Review

Journal of Cardiovascular Pharmacology. Oct, 2015  |  Pubmed ID: 26448275

Milrinone is an inotropic drug used in a variety of clinical settings in adults and children. The efficacy of milrinone in pediatric low cardiac output syndrome following cardiac surgery is reported. Its primary route of removal from the body is through the kidney as unchanged drug in the urine. Milrinone is not known to be efficiently removed by extracorporeal dialytic therapies, and thus has the potential to cause serious adverse effects and potentially worsen renal function in patients experiencing acute kidney injury.AKI is an important public health issue that is associated with increased morbidity, mortality and cost. It is a known risk factor for the development of chronic kidney disease. There are no specific therapies to mitigate AKI once it has developed, and interventions are focused on supportive care and dose adjustment of medications. Estimating glomerular filtration rate (GFR) based on height and serum creatinine is the most commonly used clinical method for assessing kidney function and modification of medication doses.The purpose of this review is to discuss our current understanding of milrinone pharmacokinetics and pharmacodynamics in children with AKI and to describe the potential use of urinary biomarkers to guide therapeutic decision making for milrinone dosing.

Variable Eculizumab Clearance Requires Pharmacodynamic Monitoring to Optimize Therapy for Thrombotic Microangiopathy After Hematopoietic Stem Cell Transplantation

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Oct, 2015  |  Pubmed ID: 26456258

Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with eculizumab. We measured eculizumab serum concentrations, total hemolytic complement activity, and plasma sC5b-9 concentrations. Population PK/PD analyses correlated eculizumab concentrations with complement blockade and clinical response and determined interindividual differences in PK parameters. We also compared transplant survival in patients treated with eculizumab (n = 18) with patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n = 11). In the PK analysis, we found significant interpatient variability in eculizumab clearance, ranging from 16 to 237 mL/hr/70 kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, was a significant determinant of eculizumab clearance and disease response. Sixty-one percent of treated patients had complete resolution of TMA and were able to safely discontinue eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared with untreated patients (56% versus 9%, P = .003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. Our eculizumab dosing algorithm, including pr-treatment plasma sC5b-9 concentrations, patient's actual body weight, and the first eculizumab dose (mg), accurately determined eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.

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