Javier Reig-López (1,2), Alfredo GarcÃa-Arieta (3), Matilde Merino-Sanjuan (1,2) and VÃctor Mangas-Sanjuan (1,2)
(1) Department of Pharmacy Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Valencia, Spain. (2) Interuniversity Institute of Recognition Research Molecular and Technological Development, Valencia, Spain. (3) Service of Pharmacokinetics and Generic Medicines, Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Spanish Agency for Medicines and Health Care Products
Introduction: Atorvastatin (ATS) is one of the most frequently prescribed 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase reversible inhibitors, also known as statins[1]. ATS shows low oral bioavailability and non-linear pharmacokinetics (PK) attributed to the contribution of saturable processes in absorption, metabolism and excretion [2]. Several physiologically based pharmacokinetic models (PBPK) have been recently published able to describe ATS disposition and evaluate drug-drug interactions (DDIs)[3-6]. However, those PBPK models lack to consider enzymatic and transport processes in gut and liver and the use of solid oral dosage forms.
Objectives: The aim of this work was to develop a PBPK model for ATS and its primary active metabolite 2-hydroxy-atorvastatin (2-OH-ATS) that could explain the observed data from bioequivalence trials.
Methods: The PBPK model developed included the Advanced Dissolution, Absorption and Metabolism (ADAM) model with a solubility-limited process for the solid oral dosage form. The absorption process incorporated passive and active drug absorption and an active efflux transporter for ATS. Metabolism was assessed enzymatically and implied different cytochrome P450 isoforms (CYPs) and UDP-glucuronosyltransferases (UGTs), and an additional unspecific hepatic clearance for 2-OH-ATS. A permeability limited liver model was used to parameterize the active hepatic uptake of both ATS and 2-OH-ATS through different organic anion transporting polypeptide (OATPs) and the sodium taurocholate co-transporting polypeptide (NTCP). Biliary and renal excretion were implemented in the model. Finally, a total of 128 patients were simulated in two single dose clinical trials of 64 patients each, with a female proportion of 50%. Exposition PK parameters (e.g. AUC, Cmax and Tmax) were predicted with Simcyp Simulator v19[7] and compared to those observed. Results were analyzed using RStudio v1.2.5019.
Results: Graphical comparison of predicted and observed plasmatic concentration (Cp) values of ATS showed a good agreement between the model and the experimental data, with most of the observed data being in the 95% CI of the predicted values. Volume of distribution at steady state (VSS) was predicted by Simcyp applying a scalar to all tissue-to-plasma partition coefficients. Intrinsic clearances (CLint) for a H+-Monocarboxylic acid Co-Transporter (MCT) and the Breast Cancer Resistant Protein (BCRP) in the apical membrane of the enterocyte were optimized in order to best fit the observed data. Final values were: 0.03 mL/min for the MCT mediated uptake and 6 mL/min for the BCRP mediated efflux. Mean predicted (observed) values of Cmax, Tmax and AUC0-48 for ATS were 0.049 mg/L (0.048 mg/L), 1.8 h (1.4 h) and 0.214 mg/L·h (0.156 mg/L·h), respectively. The model also predicted low bioavailability (6%) and a systemic clearance of 48 L/h. The exposure endpoints (Cmax and AUC0-48) of 2-OH-ATS were slightly underpredicted: 0.008 mg/L (0.046 mg/L) and 0.085 mg/L·h (0.223 mg/L·h), respectively.
Conclusions: The PBPK model here presented is able to properly describe the time-course of ATS plasma concentrations after oral administration of 80mg of ATS in healthy volunteers. Predicted exposure metrics agreed with published values for ATS. However, the PBPK model underpredicted the exposure of 2-OH-ATS, probably due to the fact that 2-OH-ATS is mostly generated through the CYP-mediated hydroxylation of the lactone form of ATS, instead of direct hydroxylation of the open acid form. Further studies are needed in order to obtain a complete PBPK model able to properly account for the metabolism processes from the lactone form of ATS.
References:
[1] Riedmaier S. et al. UDP-Glucuronosyltransferase (UGT) Polymorphisms Affect Atorvastatin Lactonization In Vitro and In Vivo. Clinical Pharmacology & Therapeutics. 2010:87(1).
[2] Lennernäs H. Clinical Pharmacokinetics of Atorvastatin. Clin. Pharmacokinet. 2003:42(13).
[3] Zhang T. Physiologically based pharmacokinetic modelling of disposition and drug-drug interactions for atorvastatin and its metabolites. Eur J Phar Sci. 2015:77.
[4] Duan P, Zhao P and Zhang L. Physiologically Based Pharmacokinetic (PBPK) Modeling of Pitavastatin and Atorvastatin to Predict Drug-Drug Interactions (DDIs). Eur. J. Drug Metab. Pharmacokinet. 2017:42.
[5] Morse et al. Physiologically-Based Pharmacokinetic Modeling of Atorvastatin Incorporating Delayed Gastric Emptying and Acid-to-Lactone Conversion. CPT Pharmacometrics Syst. Pharmacol. 2019:8.
[6] Li et al. Prediction of pharmacokinetic drug-drug interactions causing atorvastatin induced rhabdomyolysis using physiologically based pharmacokinetic modelling. Biomedicine & Pharmacotherapy. 2019:119.
[7] Simcyp Version 19. 2019. Certara UK Limited (Simcyp Division).
Reference: PAGE () Abstr 9316 [www.page-meeting.org/?abstract=9316]
Poster: Drug/Disease Modelling - Absorption & PBPK