119: Quantitative Assessment of Drug-Drug Interaction (DDI) Potential of BIIB122 on Oral Contraceptives Using a Physiologically-based Ppharmacokinetic Model

Statement of Purpose, Innovation or Hypothesis: BIIB122 (DNL151) is an investigational drug in development for treatment of Parkinson’s disease. In a clinical DDI study of BIIB122 with a sensitive CYP3A4 index substrate, midazolam (MDZ), BIIB122 was found to be a weak CYP3A4 inducer (reduces mean AUC_inf of MDZ by 27%, while mean C_max of MDZ remains unchanged). Most oral contraceptives (OC) contain two synthetic steroid hormones, a progestin and an estrogen. Commonly used progestins are metabolized by CYP3A, although the simulated relative contribution of CYP3A to the systemic clearance (f_m,CYP3A4) of different progestins varies: drosperinone (DRSP, f_m,CYP3A4 = 73%) and levonorgestrel (LNG, f_m,CYP3A4 = 37%). The metabolism of ethinyl estradiol (EE) involves multiple enzymes including CYP3A (EE, f_m,CYP3A4 = 20%). Therefore, an investigational drug’s induction effect on CYP3A could decrease progestin and estrogen concentrations, potentially leading to unintended pregnancy and breakthrough bleeding, respectively.

Description of Methods & Materials: The potential for pharmacokinetic (PK) DDI with BIIB122 as a perpetrator and OCs: DRSP, LNG, or EE as victims was investigated using SimCYP® physiologically-based pharmacokinetic (PBPK) modeling (Version 21). The BIIB122 PBPK model was developed using in vitro, in vivo and clinical Phase 1 PK data from a single ascending dose (SAD) study and verified using clinical PK data from a multiple ascending dose (MAD) study. BIIB122 PBPK model was further refined to simulate CYP3A4 induction of MDZ after multiple dose administration and verified with results from the clinical DDI study with MDZ. The refined and verified PBPK model was applied for prediction of CYP3A4 induction by BIIB122 effect on OCs. Specifically, DDI simulation explored the impact on PK of OC following concomitant multiple oral dosing of BIIB122 at 225 mg QD over 20 days with multiple oral dosing of DRSP (3.0 mg QD), LNG (0.25 mg QD), and EE (0.03 mg QD). BIIB122 steady state is achieved after 10 days of daily dosing. Simcyp V21 library files for EE and DRSP were used for DDI simulation along with a Simcyp research file for LNG.

Data & Results: DDI simulations indicated that following concomitant multiple dosing with BIIB122 over 20 days, the predicted ratios of the geometric means (90% CIs) for DRSP AUC_0-tau and C_max were 0.82 (90% CI 0.81–0.84) and 0.90 (90% CI 0.89–0.91), respectively; for LNG AUC_0-tau and C_max were 0.90(90% CI 0.89–0.91) and 0.96 (90% CI 0.95–0.96), respectively; and for EE, AUC_0-tau and C_max were 0.93(90% CI 0.92–0.94) and 0.95 (90% CI 0.94–0.95), respectively.

Interpretation, Conclusion or Significance: The results of PBPK modeling and DDI simulations of BIIB122 with OCs showed no significant change in systemic exposure or PK of EE, DRSP, and LNG, predicting no clinically significant DDI during concomitant administration of OCs with BIIB122, as per ICH M12 (2022).

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