15.6
Relation pharmacocinétique-pharmacodynamique : Problématiques
L’approche empirique de l’optimisation du traitement médicamenteux repose sur l’établissement d’une corrélation entre la réponse pharmacologique et la…
La relation pharmacocinétique–pharmacodynamique, ou PK–, relie la réponse pharmacologique à la concentration du médicament au site cible, telle que reflétée dans les niveaux plasmatiques de médicaments.
La modélisation peut devenir complexe en raison de la présence de mélanges racémiques, de l’influence de la liaison aux protéines, de l’impact de la distribution différée, de la formation de métabolites actifs et du développement de tolérance acquise.
De nombreux médicaments sont administrés sous forme de mélanges racémiques, dans lesquels un seul isomère actif stimule la réponse, rendant le ratio isomères crucial pour l’efficacité.
De plus, la réponse au médicament est plus précisément corrélée à la concentration plasmatique non liée, car la liaison aux protéines modifie les niveaux de médicaments libres et complique la modélisation PK–.
Outre la liaison aux protéines, de nombreux médicaments agissent sur les tissus extravasculaires, nécessitant des temps d’équilibre plus longs et retardant la réponse.
Certains médicaments produisent des métabolites pharmacologiquement actifs dans l’organisme. Les niveaux plasmatiques de ces métabolites peuvent mieux être corrélés à la réponse thérapeutique que ceux du médicament parent.
De plus, l’usage chronique de certains médicaments peut entraîner une tolérance acquise, soit par un métabolisme accéléré, soit par une réponse diminuée, modifiant la relation PK–au fil du temps.
View the full transcript and gain access to JoVE Core videos
Q1: Why is unbound drug concentration more important than total plasma concentration in PK-PD modeling?
Drug response correlates more accurately with unbound plasma concentration because protein binding alters free drug levels available to act at the target site. Total plasma concentration includes both bound and unbound drug, but only unbound drug can produce a pharmacological effect. Variations in protein binding between patients complicate PK-PD modeling when based solely on total concentration measurements.
Q2: How do active metabolites complicate the relationship between drug concentration and therapeutic response?
Some drugs produce pharmacologically active metabolites in the body whose plasma levels may correlate better with therapeutic response than the parent drug itself. Basing the PK-PD relationship solely on parent drug concentration can obscure the true concentration-response relationship. Examples include imipramine, amitriptyline, and propranolol, where metabolite activity significantly contributes to the overall therapeutic effect.
Q3: What causes delayed response in drugs acting on extravascular tissues?
Many drugs act on extravascular tissue rather than plasma, requiring longer equilibration times between the plasma and the site of action. This distribution delay means the pharmacological response lags behind plasma drug concentration changes. For example, the anticoagulant effect of dicoumarol shows long delays because it is an indirect measure of drug effect at the tissue level.
Q4: Why does the isomer ratio matter in racemic drug mixtures?
Many drugs are administered as racemic mixtures containing two optically active enantiomers, but typically only one active isomer drives the pharmacological response. A change in the ratio of active to inactive isomers can lead to significant differences in pharmacological response and efficacy. The isomer ratio is therefore crucial to predicting and maintaining consistent therapeutic outcomes.
Q5: How does acquired tolerance alter the PK-PD relationship over time?
Chronic use of some drugs may lead to acquired tolerance through either enhanced metabolism or diminished pharmacodynamic response. Pharmacokinetic tolerance involves increased drug elimination, while pharmacodynamic tolerance reflects reduced tissue responsiveness. Both mechanisms alter the PK-PD relationship, meaning the same plasma concentration may produce a weaker effect with repeated dosing.
Q6: What advantage does PK-PD modeling offer over empirical dose-response approaches?
PK-PD modeling correlates pharmacological response with plasma drug concentration or body drug amount rather than administered dosage, providing more precise predictions. Empirical approaches are costly, time-consuming, and often yield poor correlation due to formulation factors and drug elimination variability. Modeling assumes response is proportional to drug concentration at the site of action, reflected in plasma levels.
Q7: How does the duration of therapeutic action sometimes exceed plasma drug concentration persistence?
In some drugs like reserpine, the therapeutic action outlasts the measurable plasma drug concentration, creating a disconnect between plasma levels and observed effect duration. This occurs when drugs bind tightly to tissue receptors or produce sustained biochemical changes that persist after the drug is eliminated. Understanding this relationship is essential for predicting dosing intervals and the influence of elimination half-life on effect duration.