CYP450-mediated drug-drug interactions: towards prediction and informed dose recommendation using physiologically-based pharmacokinetic (PBPK) modeling

Une des principales sources de la variabilité de réponse aux médicaments est la variabilité pharmacocinétique pour laquelle les interactions médicamenteuses constituent une des explications les plus fréquentes. Ce travail de thèse consiste en grand partie en la conception et la réalisation de deux études cliniques dans lesquelles les interactions entre les médicaments antiplaquettaires clopidogrel, prasugrel, ticagrelor et le ritonavir, un médicament couramment prescrit chez des patients infectés par le VIH, ont été évaluées. Pour la première fois, le technique de modélisation pharmacocinétique basée sur la physiologie, appelée PBPK, a été utilisé afin de prédire l'ampleur de ces interactions. Il s'agit d'une méthode innovante et prometteuse de prédiction du devenir du médicament dans le corps humain sur la base des données in vitro et in vivo du médicament ainsi que des caractéristiques physiopathologiques du sujet virtuel. Une adaptation de dose permettra de réduire les conséquences cliniques de ces interactions

Usefulness of PBPK Modeling in Incorporation of Clinical Conditions in Personalized Medicine

Personalized medicine aims to determine the most adequate treatment and dose regimen to obtain the maximum efficacy and minimum side effect by taking into account patients' characteristics. For numerous reasons, one being ethical and methodological hurdles in including specific populations in clinical trials, innovative methods for optimization of drugs safety and efficacy in such patients have received increasing interest recently. Physiological-based pharmacokinetic (PBPK) modeling has emerged as a promising approach in designing adequate clinical trials and quantifying anticipated changes in unknown clinical situations. In this review, current state of knowledge on the usefulness of PBPK modeling in estimation of drug exposure in specific medical conditions including pregnancy, pediatrics, elderly, patients with liver or renal impairment, obesity, and following bariatric surgery were outlined. Modulations of key system parameters occurring in these patient populations were illustrated. Furthermore, the application of PBPK approach in dose recommendations and quantification of drug exposure in carriers of genetic polymorphisms was summarized. Despite the uncertainties and knowledge gaps related to parameters influencing drugs bioavailability in each clinical condition, PBPK models provide a valuable support for prospective dose recommendations and efficacy/safety assessment in special populations when consistent clinical data are lacking

Liquid Chromatography-Tandem Mass Spectrometry Method for Ticagrelor and its Active Metabolite Determination in Human Plasma: Application to a Pharmacokinetic Study

Background: Ticagrelor is a highly recommended new antiplatelet agent for the treatment of patients with acute coronary syndrome at moderate or high ischemic risk. There is a real need for rapid and accurate analytical methods for ticagrelor determination in biological fluids for pharmacokinetic studies. In this study, a sensitive and specific LC-MS method was developed and validated for quantification of ticagrelor and its active metabolite (AM) in human plasma over expected clinical concentrations. Methods: Samples were handled by liquid-liquid extraction (LLE). A linear gradient was applied with a mobile phase composed of formic acid 0.1% and acetonitrile with 0.1% of formic acid using a C18 reversed-phase column. MS spectra were obtained by electrospray ionization in negative mode and optimized at 521.4→360.9 m/z, 477.2→361.2 m/z and 528.1→367.9 m/z transitions for ticagrelor, AM and ticagrelor-d7, respectively. Results: This method allowed rapid elution, in less than 4 minutes, and quantification of concentrations as low as 2 ng/mL for ticagrelor and 1 ng/mL for AM using only 100 μL of human plasma. LLE using hexane/ethyl acetate (50/50) was an optimal compromise in terms of extraction recovery and endogenous compounds interference. Trueness values of 87.8% and 89.5% and precisions of 84.1% and 93.8% were obtained for ticagrelor and AM, respectively. Finally, the usefulness of the method was assessed in a clinical trial where a single 180 mg ticagrelor was orally administered to healthy male volunteers. Pharmacokinetic parameters of ticagrelor and its active metabolite were successfully determined. Conclusion: A sensitive and specific quantification LC-MS-MS method was developed and validated for ticagrelor and its active metabolite determination in human plasma. The method was successfully applied to a clinical trial where a single ticagrelor 180 mg dose was orally administered to healthy male volunteers. The described method allows quantification of concentrations as low as 2 ng/mL of ticagrelor and 1 ng/mL of the metabolite using only 100 μL of plasma

Prediction of drug-drug interactions using physiologically-based pharmacokinetic models of CYP450 modulators included in Simcyp software

In recent years, Physiologically-Based PharmacoKinetic (PBPK) modeling has received growing interest as a useful tool for assessment of drug PK. It has demonstrated to be informative and helpful to quantify the modification in drug exposure due to specific physio-pathological conditions, age, genetic polymorphisms, ethnicity and particularly drug-drug interactions (DDIs). In this paper, the prediction success of DDIs involving various cytochrome P450 isoenzyme (CYP) modulators namely ketoconazole (a competitive inhibitor of CYP3A), itraconazole (a competitive inhibitor of CYP3A), clarithromycin (a mechanism-based inhibitor of CYP3A), quinidine (a competitive inhibitor of CYP2D6), paroxetine (a mechanism-based inhibitor of CYP2D6), ciprofloxacin (a competitive inhibitor of CYP1A2), fluconazole (a competitive inhibitor of CYP2C9/2C19) and rifampicin (an inducer of CYP3A) were assessed using Simcyp® software. The aim of this report was to establish confidence in each CYP-specific modulator file so they can be used in the future for prediction of DDIs involving new victim compounds. Our evaluation of these PBPK models suggested that they can be successfully used to evaluate DDIs in untested scenarios. The only noticeable exception concerned quinidine inhibitor model which requires further improvement. Additionally, other important aspects such as model validation criteria were discussed

Intestinal permeability and P-glycoprotein-mediated efflux transport of ticagrelor in Caco-2 monolayer cells

Ticagrelor is the unique reversible oral antiplatelet drug commercialized today. During this study, the intestinal permeability of ticagrelor and its potential P-glycoprotein (P-gp)-mediated active transport were assessed. To this end, bidirectional transport of ticagrelor was performed across Caco-2 (human epithelial colorectal adenocarcinoma) monolayer model in the presence and absence of potent P-gp inhibitor valspodar. Ticagrelor presented an apical-basolateral apparent permeability coefficient (Papp ) of 6.0 × 10(-6) cm/s. On the other hand, mean efflux ratio (ER) of 2.71 was observed for ticagrelor describing a higher efflux permeability compared to the influx component. Valspodar showed a significant inhibitory effect on the efflux of ticagrelor suggesting involvement of P-gp in its oral disposition. Co-incubation of the P-gp inhibitor decreased the efflux Papp of ticagrelor from 1.60 × 10(-5) to 1.13 × 10(-5) cm/s and decreased its ER by 70%. Results suggest a modest active transport of ticagrelor by P-gp across the Caco-2 cell monolayer. The co-administration of ticagrelor with a P-gp inhibitor seems altogether unlikely to have an extended impact on pharmacokinetics of ticagrelor and cause bleeding events in patients

Prediction of Metabolic Interactions With Oxycodone via CYP2D6 and CYP3A Inhibition Using a Physiologically Based Pharmacokinetic Model

Evaluation of a potential risk of metabolic drug-drug interactions (DDI) is of high importance in the clinical setting. In this study, a physiologically based pharmacokinetic (PBPK) model was developed for oxycodone and its two primary metabolites, oxymorphone and noroxycodone, in order to assess different DDI scenarios using published in vitro and in vivo data. Once developed and refined, the model was able to simulate pharmacokinetics of the three compounds and the DDI extent in case of coadministration with an inhibitor, as well as the oxymorphone concentration variation between CYP2D6 extensive metabolizers (EM) and poor metabolizers (PM). The reliability of the model was tested against published clinical studies monitoring different inhibitors and dose regimens, and all predicted area under the concentration-time curve (AUC) ratios were within the twofold acceptance range. This approach represents a strategy to evaluate the impact of coadministration of different CYP inhibitors using mechanistic incorporation of drug-dependent and system-dependent available in vitro and in vivo data

Characterization of oxycodone in vitro metabolism by human cytochromes P450 and UDP-glucuronosyltransferases

The hepatic metabolism of oxycodone by cytochromes P450 (CYP) and the UDP-glucuronosyltransferases (UGT), the main metabolic enzymes of phase I and phase II, respectively, was assessed in vitro. The N-demethylation by CYP3A4/5 and the O-demethylation by CYP2D6 in human liver microsomes (HLM) followed Michaelis-Menten kinetics, with intrinsic clearances of 1.46μL/min/mg and 0.35μL/min/mg, respectively. Although noroxycodone and oxymorphone mainly contribute to the elimination of oxycodone, the simulated total in vivo clearance using in vitro phase I metabolism was underestimated. For the first time, metabolism of oxycodone by UGT was deeply investigated using HLM, recombinant enzymes and selective inhibitors. Oxycodone-glucuronide was mainly produced by UGT2B7 (Km=762±153μM, Vmax=344±20 peak area/min/mg) and to a lesser extent by UGT2B4 (Km=2454±497μM, Vmax=201±19 peak area/min/mg). Finally, the kinetics of the drug-drug interactions were assessed using two CYP and UGT cocktail approaches. Incubations of HLM with phase I and phase II drug probes showed that oxycodone mainly decreased the in vitro activities of CYP2D6, CYP3A4/5, UGT1A3, UGT1A6 and UGT2B subfamily with an important impact on UGT2B7

Impact of Boosted Antiretroviral Therapy on the Pharmacokinetics and Efficacy of Clopidogrel and Prasugrel Active Metabolites

Prasugrel and clopidogrel are inhibitors of the ADP-P2Y12 platelet receptor used in acute coronary syndrome patients. They require bioactivation via isoenzymes such as cytochrome P450 (CYP) 3A4, CYP2C19 and CYP2B6. Ritonavir and cobicistat are potent CYP3A inhibitors, prescribed as pharmacokinetic (PK) enhancers in the treatment of human immunodeficiency virus (HIV) infection