Clinical Assessment of Breast Cancer Resistance Protein (BCRP)-Mediated Drug-Drug Interactions of Sepiapterin with Curcumin and Rosuvastatin in Healthy Volunteers.

Background and objective: Sepiapterin, also known as PTC923 and CNSA-001, is a synthetic form of endogenous sepiapterin being developed as a novel oral treatment for phenylketonuria. Sepiapterin is a natural precursor of tetrahydrobiopterin (BH₄) and, when orally administered, is converted to BH₄ via the pterin salvage pathway. In vitro studies have demonstrated that both sepiapterin and BH₄ are both substrates and inhibitors of the breast cancer resistance protein (BCRP) transporter. This phase I study investigated BCRP-mediated drug-drug interactions of sepiapterin as a victim and as a perpetrator.

Methods: An open-label, fixed-sequence, four-period, crossover, single-dose study was conducted in adult male and female healthy volunteers (18-55 years of age). In a given treatment period, subjects received a single oral dose of sepiapterin (20 mg/kg), sepiapterin (20 mg/kg) plus curcumin (2 g), rosuvastatin (10 mg), or rosuvastatin (10 mg) plus sepiapterin (60 mg/kg). The pharmacokinetics of sepiapterin, its metabolite BH₄, and rosuvastatin were studied, and geometric mean ratios of exposures in the presence and absence of the BCRP inhibitor curcumin or sepiapterin were estimated. The presence of the BCRP c.421C>A polymorphism was evaluated in all subjects.

Results: A total of 29 subjects were enrolled and included in the safety analysis. Among them, 26 subjects were included in the pharmacokinetic and drug-drug interaction analyses. Following oral administration 20 mg/kg sepiapterin, sepiapterin was rapidly and extensively converted to BH₄, and BH₄ maximum observed concentration (415.0 ng/mL) was observed 4.95 h (time to maximum observed concentration) post-dose. Sepiapterin maximum observed concentration and area under the concentration-time curve from time 0 to time of the last quantifiable measurement or the last sample collection time (AUC_last) were <1% of BH₄ values. Coadministration of the BCRP inhibitor curcumin (2 g) increased BH₄ maximum observed concentration, AUC_last, and area under the concentration-time curve from time 0 extrapolated to infinity by 24%, 21%, and 20%, respectively. When sepiapterin was coadministered with the BCRP substrate rosuvastatin, there was no effect on the pharmacokinetics of rosuvastatin. BCRP c.421C/A carriers (n = 4) had higher plasma exposures of BH₄ (1.39 × for AUC_last) and rosuvastatin (1.61 × for AUC_last) than c.421C/C carriers (n = 22). Greater increases in BH₄ exposures (1.33 vs 1.18 for AUC_last) were observed in c.421C/A carriers compared with c.421C/C carriers when sepiapterin was coadministered with curcumin. All treatments were well tolerated during the study.

Conclusions: Oral coadministration of the BCRP inhibitor curcumin slightly increased the plasma exposure of sepiapterin and its metabolite BH₄ in healthy volunteers. This modest increase was deemed not clinically meaningful. Sepiapterin did not alter the pharmacokinetics of the BCRP substrate rosuvastatin.