Drug-drug interaction potential of the HBV and HDV entry inhibitor myrcludex B assessed in vitro.

BACKGROUND

Myrcludex B is a first-in-class virus entry inhibitor for patients with chronic hepatitis B or B/D infections. In patients it will be coadministered with drugs needed for the disease or comorbidities. We aimed to define the risk of drug-drug interactions by characterizing the influence of myrcludex B on relevant drug transporting and metabolizing enzymes in vitro.

METHODS

Inhibition of P-glycoprotein (P-gp; ABCB1), breast cancer resistance protein (BCRP/ABCG2), and the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1/SLCO1B1 and OATP1B3/SLCO1B3) was measured in cells over-expressing the respective transporter using fluorogenic substrates. Inhibition of cytochrome P450 enzymes (CYPs) was assessed with commercially available kits. mRNA induction of drug transporting and metabolizing enzymes was measured in LS180 cells after 4 days of treatment by quantitative real-time PCR. Pregnane X receptor (PXR) activation was assessed using a reporter-gene assay.

RESULTS

Whereas activities of P-gp and BCRP were not influenced by myrcludex B, OATP1B1 and OATP1B3 were specifically inhibited with a 50% inhibitory concentration (IC50) of 0.5 and 8.7 µM, respectively. Myrcludex B weakly inhibited all CYPs tested at concentrations ≥10 µM except CYP2D6, which was not inhibited at concentrations up to 2 µM. Myrcludex B had no influence on mRNA expression of CYP1A1, CYP3A4, UGT1A3, ABCB1, ABCC2 and ABCG2, and on PXR activity.

CONCLUSIONS

Our in vitro study suggests that myrcludex B is not at major risk of acting as a perpetrator drug. A potential inhibition of the uptake transporters OATP1B1 and OATP1B3 and a previous clinical finding of potential CYP3A inhibition, requires further evaluation and should be carefully addressed in future trials.