(M0930-11-65) A Mechanistic PBPK Model for Maraviroc to Elucidate the Dose Related Non-Linearity in Oral Absorption using a Middle-Out Approach

Purpose: Maraviroc (MVC) is indicated for the treatment of individuals infected with CCR5-tropic HIV-1. The recommended dose of MVC is 150 mg BID with a potent CYP3A inhibitor (with or without CYP3A inducers), 300 mg BID (without CYP3A inhibitors or inducers), 600 mg BID with CYP3A weak/moderate inducers. MVC is metabolised by CYP3A4 (fm 0.75) and CYP3A5 (fm 0.25) and is also a substrate for P-glycoprotein (P-gp) efflux in the intestine and the liver [1] and a substrate for hepatic OATP1B1 sinusoidal uptake [1]. After single oral administration to humans (3 – 1300 mg) the dose-exposure relationship shows a marked nonproportionality in Cmax and AUC, with super-proportional increases up to doses of 300 mg [2]. A mechanistic PBPK model that can capture the non-linearity due to gut P-gp efflux is not yet available.

Methods: The physicochemical & blood binding parameters for the MVC PBPK model were incorporated from the literature (LogPo:w 2.35; diprotic base pKa 3.3; 7.7; blood to plasma ratio 0.59; fraction unbound in plasma 0.241). Since MVC is freely soluble at all human gut pHs, the model considered the drug in solution form. The sinusoidal uptake (OATP1B1) and P-gp canalicular efflux in the liver was modelled using in vitro experimental data from Kimoto et al. [2]. The intestinal passive permeability was predicted using a mechanistic permeability model [3] calibrated using published in vitro MDCK permeability data. The in vitro intrinsic clearance (CLint) for CYP3A4 and CYP3A5 were adopted from Tseng et al. [4]. The non-linearity due to gut P-gp efflux was modelled using Michaelis-Menten (MM) kinetic parameters obtained from a combination of sensitivity analysis of clinical data [5] and monitoring the saturation of simulated gut apical efflux transport clearance as a function of dose and Km. Simulations were conducted using Simcyp Simulator (Version 20) and the model was applied to predict plasma concentration – time profiles for MVC in healthy subjects after single and multiple oral dose administration. Due to the low passive permeability of MVC (0.2 x 10^-4 cm/s), a gut uptake transporter (CLint 0.018 µL/min) was included in the model for the efflux to be effective in the different regions of the intestine. The PBPK model was also used to evaluate drug-drug interactions (DDI) in the presence of CYP3A4 and P-gp inhibitors (Ketoconazole, Atazanavir) and inducers (Rifampicin, Efavirenz).

Results: The developed MVC model was reasonably successful in predicting the dose related nonlinearity observed in vivo due to P-gp gut efflux over the dose range 50 mg to 1200 mg [Figure 1]. The model was also successful in predicting satisfactorily the extent of DDI (expressed as ratio of predicted and observed AUC Interaction Ratio (AUC-IR)) between MVC and Ketoconazole (AUC-IR < 1.2 fold); Rifampicin (AUC-IR < 1.35 fold); Atazanavir (AUC-IR < 1.2 fold); Efavirenz (AUC-IR < 2 fold) [Figure 2].

Conclusion: The MVC PBPK model based on the middle out approach was successful in highlighting the interplay between MVC and gut 3A4 and P-gp and its net effect on the Fg with increasing dose. The inclusion of a gut uptake component and its interplay with the P-gp efflux as well as metabolism with gut CYP3A4 and CYP3A5 highlighted the effect of increasing dose on the resultant Cmax and AUC to recover the observed non-linearity.

References: [1] Kimoto et al. DMD 47:493–503, 2019;
[2] Walker et al. DMD 33:587–595, 2005
[3] Pade et al. Biopharm Drug Dispos. 38 (2): 94-114, 2017
[4] Tseng et al. DMD 46:493–502, 2018
[5] PMDA Biopharmaceutic Report- Maraviroc (https://www.pmda.go.jp/drugs/2008/P200800055/40007900_22000AMX02448000_K100_1.pdf)


Figure 1: MVC Dose normalised Cmax vs. Dose; Observed data from Walker et al. 2005


Figure 2: AUC interaction ratios of MVC predicted vs. observed in the presence of various interactants: Keto: Ketoconazole 400 mg QD; RIF: Rifampicin 600 mg QD; EFV: Efavirenz 600 mg QD; ATZ: Atazanavir 400 mg QD