PI-084 - POPULATION PHARMACOKINETIC ANALYSIS OF SOTATERCEPT IN JAPANESE HEALTHY PARTICIPANTS AND JAPANESE PARTICIPANTS WITH PULMONARY ARTERIAL HYPERTENSION.

Z. Hu¹, M. KAKARA², A. Chawla¹, O. Egbelowo³, S. Ayalasomayajula⁴, F. Gheyas⁵, C. HASEGAWA⁶, I. Younis⁷; ¹Merck & Co., Rahway, NJ, USA, ²MSD K. K., Tokyo, Tokyo, Japan, ³Merck & Co., West Point, PA, USA, ⁴MRL-TMED-QP2, Rahway, NJ, USA, ⁵MRL-TMED-QP2, Rahway, NJ, United States, ⁶MSD K.K., Tokyo, Tokyo, Japan, ⁷Merck, Rahway, NJ, USA.

Background: Sotatercept, a recombinant activin receptor type IIA fusion protein, is approved for the treatment of pulmonary arterial hypertension (PAH) in adults in USA and Europe. The population pharmacokinetics (PK) of sotatercept in healthy participants and participants with PAH have been described earlier. The objective of this study is to further characterize the PK of sotatercept in Japanese healthy and PAH populations and evaluate the influence of Japanese ethnicity on sotatercept PK.

Methods: PK data obtained from a Phase 1 study (healthy) and open label Phase 3 study (PAH patients) conducted in Japan were added to the existing population PK analysis dataset containing data from non-Japanese healthy and PAH participants. An external qualification was performed using the parameter estimates from the existing model to predict sotatercept concentrations collected in Japanese Phase 1 and Phase 3 Studies. The model was re-estimated and refined using pooled data including Japanese and non-Japanese participants. Stepwise covariate modeling was performed to explore the potential effect of Japanese ethnicity on PK parameters, including clearance, central volume, peripheral volume, first-order absorption rate constant, and bioavailability.

Results: Sotatercept plasma PK in Japanese participants was best described by a 2-compartment model with first-order absorption for the subcutaneous (SC) route of administration, data defined rates for intravenous (IV) infusions, and linear elimination. External qualification of the existing population PK model showed good concordance between simulated and observed PK profiles in Japanese participants. The final model parameter estimates from the re-estimated population PK model including Japanese data showed minimal change compared to previous parameter estimates. Japanese ethnicity was not found to be a significant predictor of sotatercept PK. PK simulation based on the re-estimated model showed overlapping Cavg,ss between Japanese vs non-Japanese PAH populations (GM [GCV%]: 7.38 [30.59%]) vs. 7.79 [36.56%]) following the 0.7mg/kg Q3W dosing regimen.

Conclusion: The PK properties of sotatercept are similar between Japanese and non-Japanese participants, supporting the same recommended dose of sotatercept for Japanese PAH population.