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) due to its poor solubility in the gastrointestinal (GI) tract and 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 that could explain the observed data from Phase I clinical 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. Efflux transporters on the gut wall (P-gp and BCRP) were implemented to better characterize ATS absorption process. Metabolism was assessed enzymatically and implied different cytochrome P450 isoforms (CYPs) and UDP-glucuronosyltransferases (UGTs). Volume of distribution at steady-state (Vss) was optimized through a tissue-to-plasma partition coefficients scalar to best predict previously reported value. The permeability limited liver model was used to parameterize the active hepatic uptake of ATS through different organic anion transporting polypeptide (OATPs) and the sodium taurocholate co-transporting polypeptide (NTCP). Gut wall first pass effect was optimized through a scaling factor for intestinal UGTs to best predict observed oral bioavailability. Finally, biliary, and renal excretion were implemented in the model. Two different single dose clinical trials at 40 (n = 100) and 80 (n = 96) mg dose levels were simulated with a female proportion of 50% in order to externally validate the model. Exposition PK endpoints (e.g. AUC0-t, Cmax and Tmax) were predicted with Simcyp Simulator v19 [7].
Results: Graphical comparison of predicted and observed plasmatic concentration (Cp) values of ATS showed a good agreement between the model and the experimental dataset, with most of the observed data being within the 95% CI of the predicted profiles. Median predicted (observed) values of Cmax, Tmax and AUC0-60 for ATS 40 mg were 0.018 mg/L (0.033 mg/L), 1.4 h (1.4 h) and 0.152 mg/L·h (0.172 mg/L·h), respectively, while median predicted (observed) values of Cmax, Tmax and AUC0-48 for the highest commercially available dose level (e.g., 80 mg) were 0.036 mg/L (0.045 mg/L), 1.5 h (1.4 h) and 0.299 mg/L·h (0.155 mg/L·h), respectively. The model also adequately predicted the low oral bioavailability (14%) of ATS, a systemic clearance of 36 L/h and a volume of distribution at steady-state (Vss) of 5.5 L/kg. The model also predicted a high contribution of enzymatic glucuronidation through UGTs to overall elimination of ATS, as it accounted for more than 50% of total systemic clearance of this drug.
Conclusions: The PBPK model here presented is able to properly describe the time-course of ATS plasma concentrations after oral administration of both 40 and 80 mg of ATS-Ca in healthy volunteers. Predicted exposure metrics were within the 2-fold range of the observed values and primary pharmacokinetic parameters (e.g., Vd and CL) agreed with previously published values. The high fraction of ATS metabolized by UGTs is in good agreement with the main metabolic pathway for ATS elimination (lactonization, hydroxylation and hydrolysis) and confirms the relevance of glucuronidation in ATS disposition. However, 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 29 (2021) Abstr 9836 [www.page-meeting.org/?abstract=9836]
Poster: Drug/Disease Modelling - Absorption & PBPK