Manoranjenni Chetty (1), Sibylle Neuhoff (1), Zoe Barter (1), Karen Yeo (1), Kefeng Sun (2), Haojing Rong (3), Ivy H Song (4)
(1) Certara UK Ltd, Simcyp Division, UK;(2) Quantitative Solutions, Shire, a Takeda company, USA; (3) Preclinical Development, Kymera Therapeutics, USA; (4) Quantitative Clinical Pharmacology, Shire, a Takeda company, USA
Objectives: Maribavir is an orally bioavailable antiviral drug being evaluated in Phase 3 trials for the treatment of cytomegalovirus infections in transplant recipients. In humans, maribavir is primarily metabolized by the 3A4 isozyme of cytochrome P450 (CYP3A4) [1] and has demonstrated linear pharmacokinetics (PK) at doses up to 1200 mg twice daily (BID) [2]. A physiologically based PK (PBPK) model was constructed to predict plasma concentration–time profiles of maribavir and to evaluate the likely impact of co-administration of CYP3A4 inhibitors and inducers on the PK of maribavir. The aim of this modeling and simulation study was to provide guidance on dose adjustments for maribavir when co-administration with CYP3A4 inducers and inhibitors is needed.
Methods: A combination of in vitro and clinical PK data obtained following administration of a single oral dose of maribavir 400 mg was used to develop the PBPK model, using the Simcyp® Simulator (Certara UK Ltd, Simcyp Division, Sheffield, UK; Version 17 Release 1). Observed PK data following administration of single oral doses of maribavir 800 mg and 1600 mg were used to verify model performance. Further verification with clinical data included PK profiles of maribavir from healthy subjects following a single oral dose of maribavir 400 mg administered in the absence and presence of ketoconazole (400 mg single dose), and multiple oral 400-mg doses of maribavir administered in the absence and presence of rifampicin (600 mg once daily [QD]). The model was then applied prospectively to predict interactions with other CYP3A4 inducers and inhibitors. Simulations were then used to predict doses of maribavir that were required to maintain mean area under the curve (AUC), maximum concentration (Cmax), and concentration 12 hours after dosing (C12h) in the desired range when maribavir was co-administered with CYP3A4 modulators.
Results: Predictions of the likely outcomes of interaction with rifampicin 600 mg QD, phenobarbital 100 mg QD, phenytoin 300 mg QD, carbamazepine 200–400 mg QD, and efavirenz 600 mg QD in a healthy population indicated geometric mean maribavir Cmax ratios, with and without an inducer, of 0.54, 0.72, 0.68, 0.77, and 0.74, respectively. Corresponding predicted maribavir AUC0–12h ratios, with and without an inducer, were 0.35, 0.60, 0.57, 0.70, and 0.56, respectively. The predicted maribavir C12h ratios, with and without an inducer, were 0.04, 0.31, 0.30, 0.53, and 0.21, respectively. CYP3A4 inhibitors such as ketoconazole, ritonavir, erythromycin, and diltiazem can increase maribavir exposure; however, the magnitude of change in maribavir exposure is less than two-fold.
Conclusions: Maribavir has demonstrated acceptable safety/tolerability at doses up to 1200 mg BID, which is three times the 400 mg BID dose used in Phase 3 trials [3]. Therefore, the exposure increase with the presence of CYP3A4 inhibitors is of minimal safety concern and maribavir can be dosed with CYP3A4 inhibitors without dose adjustment. CYP3A4 inducers significantly reduce maribavir exposure; therefore, to ensure antiviral efficacy (correlated to C12h), a maribavir dose increase is necessary when co-administering with CYP3A4 inducers. A maribavir dose increase is recommended to 800 mg BID with carbamazepine, to 1200 mg BID with phenobarbital or phenytoin, and to 1600 mg BID with efavirenz. Rifampicin caused significant reductions in maribavir exposure, which cannot be overcome by a maribavir dose increase up to 1600 mg BID. Therefore, co-administration of maribavir with rifampicin should be avoided and alternative antibacterial therapy should be considered.
Funding: This study was funded by Shire, a Takeda company.
References:
[1] Song I, et al. Transplantation & Cellular Therapy (TCT) Annual Meeting; Houston, TX. 2019. Poster 510.
[2] Lalezari JP, et al. Antimicrob Agents Chemother. 2002;46:2969–76.
[3] Maertens J, et al. N Engl J Med. 2019;381:1136–47.
Reference: PAGE () Abstr 9407 [www.page-meeting.org/?abstract=9407]
Poster: Drug/Disease Modelling - Absorption & PBPK