LB-033 - ROLE OF P-GLYCOPROTEIN IN THE INTESTINAL ABSORPTION OF MAVODELPAR IN HUMANS: SUPPORT FROM A PBPK MODEL.

M. Emery¹, H. Bridger², H. Barker², L. Purkins³, H. Jones⁴, L. Vincent⁴; ¹Akamai Clin Pharm Consulting, Inc., Kula, Hawaii, United States, ²Reneo Pharma Ltd, , , ³Vice President of Clinical Operations, , , ⁴Certara UK Limited, Simcyp Division, , .

Background: Mavodelpar (100 mg QD) is an investigational oral medication for patients with primary mitochondrial myopathy. Pharmacokinetics were linear from 25 mg to 250 mg in clinical studies, consistent with no significant dose-dependent effect on absorption; however, an in vitro screening assay identified mavodelpar as a potential P-glycoprotein (P-gp) substrate with high and inconsistent efflux ratios (>15.7-142), suggesting possible nonspecific binding (NSB) in the test system. Therefore, additional investigations were conducted to quantitatively assess mavodelpar as a substrate for P-gp intestinal transport, including an in-silico assessment using a predictive physiologically based pharmacokinetic (PBPK) model.

Methods: A polarized monolayer of Maudin-Darby canine kidney cells stably expressing human P-gp was used to investigate NSB and to estimate Km and Vmax for input into the PBPK model. The predictive model using Advanced, Dissolution, Absorption, and Metabolism (Simcyp, Certara, Princeton, NJ, USA) was developed, and simulations were performed to determine the impact of P-gp on mavodelpar absorption.

Results: In vitro studies demonstrate significant, concentration-dependent NSB with a recovery range of 17.4 (±0.781)% at 1 μM to 59.7 (±1.87)% at 100 μM. Addition of 0.1% bovine serum albumin improved recovery and was used to determine mavodelpar kinetic parameters (Km, 43.2 [±19.5] μM; Jmax 4.36 [±1.36] pmol/min.cm2). Efflux ratios were >2 above the nominal concentration range of 1 μM to 30 μM but were < 1 at concentrations >100 μM, suggesting saturation of P-gp. Intestinal concentrations from 25 mg and 100 mg doses of mavodelpar are predicted to be 194 and 776 µM, respectively, 4.5- and 18-fold above the in vitro–determined Km. A mavodelpar dose of 100 mg is likely to result in saturation of P-gp and unlikely to be impacted by a P-gp inhibitor. In silico predictions from the PBPK model support the in vitro findings and do not predict P-gp inhibition from a significant interaction with mavodelpar.

Conclusion: Mavodelpar is a likely P-gp substrate that is readily saturated at clinically relevant concentrations and is unlikely to be the object of drug-drug interactions (DDI) from a P-gp inhibitor.