Evaluation of coproporphyrins as clinical endogenous markers for OATP1B

BACKGROUND: Transporters involved drug-drug interactions (DDI) are attracting increasing attention in drug development. When developing new drugs, appropriate endogenous markers for detecting transporter inhibition will be helpful. Coproporphyrins (CP-I and CP-III) may be used to assess OATP1B activity and monitor OATP1B-mediated DDIs in the clinical setting. Therefore, the purpose of this study was to evaluate CP-I and CP-III as clinical endogenous markers for OATP1B activity. METHODS: Eighteen healthy subjects were screened to receive RO7049389 (an inhibitor of OATP1B) 800 mg b.i.d. for 6 days and a single dose of pitavastatin (a probe drug of OATP1B) orally before and after RO7049389. Plasma concentrations of pitavastatin, CP-I, and CP-III, and amount of CP-I and CP-III excreted in urine were measured. The area under the curve (AUC) change of pitavastatin, before and after RO7049389, was compared with AUC and urine pharmacokinetic (PK) parameter changes of CP-I and CP-III. RESULTS: Seventeen healthy subjects completed the study with one subject discontinued due to an AE of vomiting. After multiple dosing of RO7049389, the AUC0-12 hours of pitavastatin increased 1.95-fold (90% CI:1.58-2.41], while AUC0-12 hours of CP-I and CP-III increased 3.00-(90% CI: 2.35-3.82) and 2.84-fold (90% CI: 2.22-3.65), respectively. Renal clearance (CLrenal) of CP-I and CP-III decreased by 31% (90% CI: 23-39%) and 70% (90% CI: 61-77%), respectively. CONCLUSION: CP-I and CP-III have the potential to be used as endogenous markers to evaluate OATP1B inhibition in clinical trials. Renal clearance played an important role in the elimination of CP-I and CP-III. The plasma PK parameters should be used together with urine PK parameters to monitor OATP1B activity.