ABSTRACT
PURPOSE: Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis. METHODS: PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects modeling approach. RESULTS: Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs. CONCLUSION: The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.
Subject(s)
Bosentan/pharmacokinetics , Dioxanes/pharmacokinetics , Endothelin Receptor Antagonists/pharmacokinetics , Models, Biological , Pyridines/pharmacokinetics , Pyrimidines/pharmacokinetics , Receptors, Endothelin/metabolism , Sulfonamides/pharmacokinetics , Tetrazoles/pharmacokinetics , Bosentan/administration & dosage , Dioxanes/administration & dosage , Dose-Response Relationship, Drug , Endothelin Receptor Antagonists/administration & dosage , Humans , Infusions, Intravenous , Male , Nonlinear Dynamics , Pyridines/administration & dosage , Pyrimidines/administration & dosage , Sulfonamides/administration & dosage , Tandem Mass Spectrometry , Tetrazoles/administration & dosageABSTRACT
This study provides whole-body physiologically-based pharmacokinetic models of the strong index cytochrome P450 (CYP)1A2 inhibitor and moderate CYP3A4 inhibitor fluvoxamine and of the sensitive CYP1A2 substrate theophylline. Both models were built and thoroughly evaluated for their application in drug-drug interaction (DDI) prediction in a network of perpetrator and victim drugs, combining them with previously developed models of caffeine (sensitive index CYP1A2 substrate), rifampicin (moderate CYP1A2 inducer), and midazolam (sensitive index CYP3A4 substrate). Simulation of all reported clinical DDI studies for combinations of these five drugs shows that the presented models reliably predict the observed drug concentrations, resulting in seven of eight of the predicted DDI area under the plasma curve (AUC) ratios (AUC during DDI/AUC control) and seven of seven of the predicted DDI peak plasma concentration (Cmax ) ratios (Cmax during DDI/Cmax control) within twofold of the observed values. Therefore, the models are considered qualified for DDI prediction. All models are comprehensively documented and publicly available, as tools to support the drug development and clinical research community.
Subject(s)
Caffeine/pharmacokinetics , Cytochrome P-450 CYP1A2/metabolism , Fluvoxamine/pharmacokinetics , Midazolam/pharmacokinetics , Rifampin/pharmacokinetics , Theophylline/pharmacokinetics , Administration, Oral , Algorithms , Area Under Curve , Caffeine/administration & dosage , Caffeine/chemistry , Cytochrome P-450 CYP1A2/chemistry , Cytochrome P-450 CYP3A/chemistry , Cytochrome P-450 CYP3A/metabolism , Drug Interactions , Fluvoxamine/administration & dosage , Fluvoxamine/chemistry , Humans , Midazolam/administration & dosage , Midazolam/chemistry , Models, Biological , Models, Molecular , Rifampin/administration & dosage , Rifampin/chemistry , Theophylline/administration & dosage , Theophylline/chemistryABSTRACT
BACKGROUND AND OBJECTIVES: Bosentan is a competitive antagonist on endothelin receptor A and B (ETA and ETB), displacing the endogenous binding partner endothelin-1 (ET-1) from its binding sites. After administration of escalating single doses of 10-750 mg as an intravenous (i.v.) infusion, bosentan showed dose-dependent pharmacokinetics (PK). The aim of this analysis was to develop a PK model of bosentan after i.v. administration including competitive antagonism with ET-1 and to analyze its influence on blood pressure and heart rate with a combined pharmacokinetic/pharmacodynamic (PK/PD) model. METHODS: PK/PD data from 70 young male Caucasian subjects were analyzed after single i.v. administration of 10, 50, 250, 500, and 750 mg of bosentan. Population analyses, simulations, and evaluation were performed using a non-linear mixed-effects modeling approach. RESULTS: The PK of bosentan was best described by a two-compartment, target-mediated drug disposition (TMDD) model. ET-1 plasma and urine profiles were successfully integrated into the bosentan two-compartment, TMDD model encompassing competition for the same receptor. A multiple-peak phenomenon of bosentan plasma concentrations after i.v. administration was best described by a diurnal expression or reappearance of ET receptors on the cell surface. Blood pressure was best described by an E max model; heart rate was modeled as a compensatory effect of changes in blood pressure. CONCLUSION: The developed competitive PK/PD model of bosentan and ET-1 after i.v. administration provides a first step towards understanding the complex PK properties of bosentan and offers a valuable tool for future PK/PD research.
