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FRI0401 BCX4208, a novel enzyme inhibitor for chronic management of GOUT, shows a low risk of potential drug-drug interactions
  1. S. Bantia1,
  2. L. Harman2,
  3. A. Hollister3,
  4. P. Pearson4
  1. 1Research Biology Dept
  2. 2Bioanalytical Chemistry
  3. 3Clincial Pharmacology, Biocryst Pharmaceutical, Durham, NC
  4. 4Pearson Pharma Partners, Westlake Village, CA, United States


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 [1].

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.

  1. 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

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