Assessment of the Drug-Drug Interaction Potential of Lotiglipron (PF-07081532) with Midazolam, Omeprazole, Dabigatran, Rosuvastatin, and the Oral Contraceptives Levonorgestrel and Ethinyl Estradiol.

Two Phase 1 open-label studies were conducted in otherwise healthy participants, with BMI classified as overweight/obesity, to assess the potential of lotiglipron (a glucagon-like peptide-1 receptor agonist) as precipitant for pharmacokinetic (PK) drug-drug interactions (DDIs) when co-administered with substrates of cytochrome P450 (CYP) 3A (midazolam and oral contraceptive containing levonorgestrel/ethinyl estradiol [LE/EE]) and CYP2C19 (omeprazole) enzymes, and substrates of p-glycoprotein (dabigatran), breast cancer resistance protein and organic anion transporting polypeptide transporters (rosuvastatin). Potential PK DDI between semaglutide and midazolam was also assessed. Co-administration with lotiglipron led to modest dose-dependent decreases in midazolam area under the concentration-time curve (AUC) (up to 30%), no clinically relevant changes in exposures of oral contraceptive (LE/EE), substantial reductions in omeprazole AUC (up to 70%) and clinically relevant increases in rosuvastatin AUC (up to 2.3-fold). Upon co-administration with lotiglipron, maximum observed plasma concentration (C) of dabigatran decreased (up to 55%) with no significant changes in AUC. No significant changes were observed in midazolam exposure (AUCand C) following co-administration with semaglutide. Across both studies a subset of lotiglipron-treated participants (31% and 19% in Studies 1 and 2, respectively) had elevations in liver transaminases (alanine/aspartate aminotransferase >3 × ULN), which (based on PK data) were associated with reduced ability of the liver to transport/metabolize drugs cleared by multiple pathways. Based on the results of the two Phase 1 studies reported here along with the results of a Phase 2 study where transaminases elevations were also noted, both Phase 1 studies were prematurely terminated along with the clinical development of lotiglipron. ClinicalTrials.gov identifiers: NCT05671653; NCT05788328.