Background Common comorbidities associated with gout, including obesity, hypertension, diabetes, and chronic kidney disease, may confer a greater risk of drug-drug interaction (DDI) through both polypharmacy and disease-associated alterations in drug absorption, distribution, metabolism, or excretion. Currently available anti-inflammatory and urate-lowering therapies used for management of gout are associated with significant DDIs. BCX4208 is an oral, once-daily, purine nucleoside phosphorylase inhibitor in clinical development for the chronic management of gout. In a Phase 2 pharmacokinetic (PK) study of BCX4208, a dose-dependent reduction in serum uric acid was observed .
Objectives To assess the potential for BCX4208 to (1) interact with cytochrome P450 enzymes, (2) interact with drug transporters, and (3) induce or act as a substrate of metabolizing enzymes.
Methods BCX4208 was incubated in human liver microsomes with marker substrates for CYP1A2, CYP2A6, CYP2C8 CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5, and the catalytic activity of these isoforms was determined. BCX4208 was incubated with human primary hepatocytes and induction of CYP1A2, CYP2B6, CYP2C9, CYP3A4/5, MDR1 (P-glycoprotein [P-gp]), and MRP2 was assessed. BCX4208 was assessed as an inhibitor of human P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3 and BSEP.
Results CYP isoforms: No significant inhibition of catalytic activity by BCX4208 was observed for CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 (IC50 >50 μM). In addition, BCX4208 was not shown to be a time-dependent inhibitor of CYP3A4/5. BCX4208 did not induce protein synthesis or enzyme activity for CYP1A2, CYP2B6, CYP2C9, and CYP3A4 in primary hepatocyte cultures (IC50 >10 μM). Drug transporters: BCX4208 did not induce protein synthesis of MDR1 or MRP2 in primary human hepatocytes (EC50 >10μM). BCX4208 did not inhibit P-gp- (IC50 >300 μM) and at 10 μM did not significantly inhibit BCRP-, OAT1, OATP1B1-, OATP1B3 and BSEP-mediated transport of probe substrate. Compared to vehicle control, BCX4208 at 10 μM inhibited the transport of probe substrates of OAT3, OCT1 and OCT2 with inhibition of 18.1%, 22.6% and 20.6%, respectively. In addition, BCX4208 was not a substrate for the OAT1 transporter. At the maximum dose (40 mg) used in phase 2B studies, the plasma Cmax of BCX4208 was 0.159 μM, a concentration that is at least 50-fold lower than IC50 values determined in CYP or renal transporter inhibition studies.
Conclusions BCX4208 does not induce or inhibit cytochrome P450 isoforms, has low potential as a P-gp substrate or inducer, and is not an inhibitor of common transporters. BCX4208 undergoes renal elimination and is not metabolized by liver cells. Therefore, there is a low risk of DDIs between BCX4208 and drugs commonly taken by patients with gout.
Fitz-Patrick D et al. Arthritis Rheum. 2010;62(suppl 10):150
Disclosure of Interest S. Bantia Employee of: BioCryst Pharmaceuticals, L. Harman Employee of: BioCryst Pharmaceuticals, A. Hollister Employee of: BioCryst Pharmaceuticals, P. Pearson Consultant for: BioCryst Pharmaceuticals