196: Predictive Physiologically Based Pharmacokinetic (PBPK) Model Suggests Minimal Drug-Drug Interaction (DDI) Between PPARδ Agonist Mavodelpar (REN001) & Rosuvastatin

Statement of Purpose: Drug interactions that impair the elimination of statins are a significant risk factor for statin-associated myopathy and myotoxicity. The underlying mechanism of elimination, differing by statin, includes both transporters and cytochrome metabolism. Mavodelpar (REN001) is an investigational treatment for patients with primary mitochondrial myopathies (PMM) and long-chain fatty acid oxidation disorders (LC-FAOD). In vitro studies indicate that mavodelpar is not an inhibitor of metabolism by cytochromes P450 but may be a potential inhibitor of certain transporters, including breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3. The statin most likely to be affected by co-administration with mavodelpar is rosuvastatin, a sensitive transporter probe substrate. The purpose of this analysis was to determine the extent of DDIs between mavodelpar and rosuvastatin.

Description of Methods & Materials: A predictive PBPK model (Simcyp V21, Certara, Princeton, NJ) was developed and validated from clinical PK data generated from Phase 1 studies in healthy volunteers. Simulations were then performed to predict the magnitude of the DDI of mavodelpar with rosuvastatin. In the simulations, rosuvastatin (as object drug) was administered as a single dose with and without co-administration of mavodelpar. Simulations of 10 different trials consisting of 10 healthy volunteers (50% female) aged 18 to 55 years consistent with a planned clinical DDI trial were generated. The simulated subjects received a single oral dose of 20 mg rosuvastatin in the absence of mavodelpar and a second dose co-administered with mavodelpar 100 mg daily at steady state. A sensitivity analysis to evaluate the impact of the competitive inhibition constant values for unbound mavodelpar (K_i,u) was performed by reducing the K_i,u values by 10-15–fold in the model. After the simulations were performed, a clinical trial assessing the magnitude of the rosuvastatin-mavodelpar DDI was conducted in healthy volunteers.

Data & Results: Following US Food & Drug Administration DDI guidance criteria, no clinically significant DDIs were predicted between mavodelpar with rosuvastatin based on determined in vitro K_i,u estimates for mavodelpar ( < 1.25-fold change in simulated area under the plasma concentration-time curve from time zero to the end of the dosing interval [AUC_tau] and maximal drug concentration [C_max]). A sensitivity analysis was also performed to evaluate the impact of K_i,u on the estimated DDI magnitude: no clinically significant DDIs were predicted based on OATP1B1 and OATP1B3 transport but a weak DDI interaction was predicted after a 15-fold reduction in BCRP K_i,u ( < 2-fold change in simulated AUC_tau and C_max). In a recently conducted DDI clinical trial with mavodelpar, the C_max ratio was 1.57 and AUC_tau ratio was 1.11 for rosuvastatin. The lack of a significant interaction between single dose rosuvastatin 10 mg and mavodelpar 100 mg QD at steady state in this clinical DDI study was consistent with PBPK model simulations.

Interpretation, Conclusion or Significance: Mavodelpar showed a weak interaction with rosuvastatin based on PBPK modeling; and this was confirmed in a recent DDI clinical study, where no clinically significant PK-based DDIs were observed. These results show that statin co-administration with mavodelpar is not likely to have any clinically meaningful impact on the risk of myopathy.

Disclosures: Maurice Emery is a paid consultant for Reneo Pharmaceuticals, Inc. and Certara UK Ltd. Helen Bridger is an employee of Reneo Pharma Ltd, a subsidiary of Reneo Pharmaceuticals, Inc. and holds stock in Reneo Pharmaceuticals, Inc. Helen Barker is an employee of Reneo Pharma Ltd, a subsidiary of Reneo Pharmaceuticals, Inc. and holds stock in Reneo Pharmaceuticals, Inc. Lynn Purkins is an employee of Reneo Pharma Ltd, a subsidiary of Reneo Pharmaceuticals, Inc. and holds stock in Reneo Pharmaceuticals, Inc. Hannah M. Jones is an employee of Certara UK Ltd and holds stock in the company. Ludwig Vincent is an employee of Certara UK Ltd and holds stock in the company. Annelize Koch is an employee of Simbec-Orion Group Ltd and has no other conflicts of interest regarding the abstract. Danielle Webb is an employee of Simbec-Orion Group Ltd and has no other conflicts of interest regarding the abstract.