Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1‐OH‐midazolam in morbidly obese and weight loss surgery patients

Abstract

This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1‐OH‐midazolam in morbidly obese patients receiving oral and i.v. midazolam before (n = 20) and one year after weight loss surgery (n = 18), thereby providing insight into the influence of weight loss surgery on CYP3A activity in the gut wall and liver. In a semiphysiologically based pharmacokinetic (semi‐PBPK) model in which different blood flow scenarios were evaluated, intrinsic hepatic clearance of midazolam (CLint,H) was 2 (95% CI 1.40–1.64) times higher compared to morbidly obese patients before surgery (P < 0.01). Midazolam gut wall clearance (CLint,G) was slightly lower in patients after surgery (P > 0.05), with low values for both groups. The results of the semi‐PBPK model suggest that, in patients after weight loss surgery, CYP3A hepatic metabolizing capacity seems to recover compared to morbidly obese patients, whereas CYP3A mediated CLint,G was low for both populations and showed large interindividual variability.

Semimechanistic Population Pharmacokinetic Model to Predict the Drug–Drug Interaction Between S‐ketamine and Ticlopidine in Healthy Human Volunteers

“…dosing. Physiological compartments for gut wall, portal vein, and liver were added in a sequential manner to account for the disposition kinetics of S ‐ketamine ( Figure 1) according to the simplified quasi‐steady‐state approximation approach25, 32 ( Supplementary Information S2 ). …”

“…The simplified quasi‐steady‐state approximation approach was used in the specification of differential equations for model specifications 25. Based on the pcVPCs, the implementation of the well‐stirred model to describe the clearances in the gut wall and liver sites adequately captured S ‐ketamine elimination.…”

“…For all three substances, we commenced with a simple empirical one‐compartment model, and nested models were developed in a stepwise manner. The optimum number of compartments to account for drug disposition kinetics was optimized at first, after which the physiological compartments for gut wall, portal vein, and liver were added to the structural model 24, 25. Physiological parameters incorporated into the model were obtained from the previously published studies ( Table 1).…”

Children in clinical trials: towards evidence-based pediatric pharmacotherapy using pharmacokinetic-pharmacodynamic modeling

“…hepatic blood flow) and drug-specific parameters (e.g. extraction ratio) were combined, leading to the conclusion that in morbidly obese patients, hepatic CYP3A activity is reduced in comparison to healthy volunteers but normalizes one year after weight loss surgery (100). This approach does not require as much information as a full PBPK or systems pharmacology model, which is not always experimentally deducible.…”

“…As some system-specific information is lacking, e.g. liver blood flow in special populations (100), different scenarios for this physiological parameter were tested for their influence on the conclusion. Ultimately, methods combining the population approach, based on outcome data, and the systems approach are being developed.…”