Evaluation of the potential impact of seladelpar on the pharmacokinetics of midazolam, tolbutamide, simvastatin, rosuvastatin, and atorvastatin

Introduction: Seladelpar (SEL) is an oral first-in-class selective PPAR-delta agonist (-delpar) indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to UDCA, or as monotherapy in patients (pts) unable to tolerate UDCA. SEL is mainly metabolised by cytochrome P450 (CYP) CYP2C9, and to a lesser extent by CYP2C8 and CYP3A4.

Objectives: Here, we tested the effects of SEL on CYP3A4, CYP2C9, organic anion-transporting polypeptide (OATP), and breast cancer resistance protein (BCRP), using midazolam, tolbutamide, simvastatin, rosuvastatin, and atorvastatin in clinical drug-drug interaction studies.

Methodology: Healthy pts received a single dose of midazolam (15 mg), tolbutamide (500 mg), simvastatin (80 mg), or rosuvastatin (20 mg) with or without SEL coadministration (single or multiple doses) in crossover studies. The effect of SEL on CYP3A4 and OATP was also tested in moderately obese hyperlipidemia pts in a parallel group design comparing atorvastatin (20 mg) with or without SEL. Pharmacokinetic (PK) parameters included maximum plasma concentration (C_max) and area under the plasma concentration curve (AUC).

Results: Midazolam levels were not affected by SEL; geometric mean ratio (GMR) (90% CI) of midazolam C_max, and AUC_0–inf with vs without SEL (200 mg once daily [QD]) were 0.94 (0.84, 1.06) and 0.98 (0.91, 1.06), respectively. Tolbutamide levels were not affected by SEL; GMR (90% CI) of tolbutamide C_max and AUC_0-inf with or without SEL (200 mg, 2 doses, at least 7 days apart with washout) were 1.03 (0.97, 1.09) and 1.00 (0.98, 1.03), respectively. Simvastatin levels were not altered with SEL (200 mg single dose); GMR (90% CI) for simvastatin C_max and AUC_0-inf were 0.95 (0.78, 1.14) and 1.17 (0.97, 1.41), respectively. SEL did not significantly decrease rosuvastatin levels; GMR (90% CI) for rosuvastatin C_max and AUC_0-inf with or without SEL (10 mg single dose) were 0.86 (0.69, 1.07) and 0.87 (0.70, 1.07), respectively. Atorvastatin levels were similar with or without SEL (50 mg QD); GMR (90% CI) for atorvastatin C_max, and AUC_all with or without SEL were 0.88 (0.54, 1.43), and 0.85 (0.57, 1.27), respectively.

Conclusion: SEL did not significantly impact the PK of midazolam, tolbutamide, simvastatin, rosuvastatin, and atorvastatin. Thus, it is unlikely that SEL would have a clinically significant impact on drugs that are substrates of CYP3A4, CYP2C9, OATP, or BCRP.

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Artikel online veröffentlicht:
04. September 2025