PII-084 - POPULATION PHARMACOKINETIC ANALYSIS OF MK-5475 IN HEALTHY PARTICIPANTS AND PATIENTS WITH PULMONARY HYPERTENSION

D. Li¹, Z. Hu¹, S. Mouksassi^2,3, T. Peyret⁴, S. Ayalasomayajula⁵, M. Rizk⁶, M. Johnson⁷, I. Younis⁷; ¹Merck, MRL, Merck & Co., Inc., Rahway, NJ, USA, ²Certara, PA, USA, ³Applied Pharmacometrics Training - Africa Program, c/o Pharmacometrics Africa NPC, Cape Town, South Africa, ⁴Certara, Radnor, PA, USA, ⁵MRL-TMED-QP2, Rahway, NJ, USA, ⁶Merck, Rahway, USA, ⁷Merck, Rahway, NJ, USA.

Background: High systemic exposure with current approved oral sGC pulmonary arterial hypertension (PAH) therapies is associated with unwanted side effects. MK-5475 is an inhaled sGC stimulator developed to minimize side effects for pulmonary hypertension treatment. Our objective was to develop a population pharmacokinetic (popPK) model of MK-5475 and assess how clinical, demographic and disease status covariates influence PK of MK-5475.

Methods: Data from 9 Phase 1 studies in healthy participants and pulmonary hypertension patients were used to develop the popPK model. Across these studies, a total of 230 participants have received either IV injections of MK-5475 of 100 µg or inhaled MK-5475 as single doses up to 480 µg or as multiple once-daily doses up to 380 µg. The sparse PK data from an ongoing Phase 2 study in PAH patients (N=116) is also included in the analysis to develop the population PK model. Fine particle dose was used as the actual dose administered given previously observed differences between formulations. Covariates including age, sex, race, ethnicity, body weight, baseline forced vital capacity (FVC), baseline forced expiratory volume (FEV), baseline peak expiratory flow (PEF), dose, and disease status were assessed for effect on PK.

Results: A two-compartment model with first order absorption kinetics best described the data. Flip-flop kinetics of PK was observed after inhalation of MK-5475. Though dose was found to be a significant covariate on bioavailability (F1) , no clinical meaningful impact on the systemic exposure is observed and the exposure increase approximately proportional to the actual dose. There were no PK differences between healthy participants and pulmonary hypertension patients at the same dose levels.

Conclusion: This is the first popPK model developed for MK-5475 in healthy participants and pulmonary hypertension patients. No PK differences were identified between healthy participants and pulmonary hypertension patients.