The NTCP‐inhibitor Myrcludex B: Effects on Bile Acid Disposition and Tenofovir Pharmacokinetics

Abstract

Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 124-fold (taurocholic acid). Coadministration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long-term effects of elevated bile acids will require critical evaluation.

Review article: clinical pharmacology of current and investigational hepatitis B virus therapies

“…Accumulation of 10 mg SC bulevirtide in healthy volunteers occurs as the steady‐state AUC and the C max were 1.79 and 2.40‐fold higher compared with first dose, respectively. No renal excretion of bulevirtide was observed . The DDI potential between bulevirtide and 300 mg TDF given orally and midazolam (micro dose IV) were investigated.…”

“…Blank et al concluded there was no clinically relevant drug interaction between bulevirtide and TDF. TFV C max was 246 ng/mL alone vs 210 ng/mL with bulevirtide, but the AUC was bioequivalent (2200 vs 2080 h*ng/mL) .…”

“…Blank et al concluded there was no clinically relevant drug interaction between bulevirtide and TDF. TFV C max was 246 ng/mL alone vs 210 ng/mL with bulevirtide, but the AUC was bioequivalent (2200 vs 2080 h*ng/mL) . The mechanism for the small reduction in C max is unclear, but bile acids (which are increased with bulevirtide) may induce organic anion transporter (OAT) 3 .…”

“…Midazolam clearance was 1020 mL/min when given alone vs 869 mL/min with TDF and 724 mL/min with TDF + bulevirtide ( P = .02 vs baseline). These results were unexpected and conflict with in vitro findings that mild cytochrome P450 (CYP) 3A4 (CYP3A4) inhibition was established at bulevirtide concentrations of 2 μmol/L, which is higher than the typical plasma concentrations of bulevirtide in healthy volunteer studies . Increased conjugated taurine bile acids are associated with inducing CYP(3A4) and drug‐transporters through stimulation of nuclear receptors .…”

Na+‐taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice

“…The Na + ‐taurocholate cotransporting polypeptide (NTCP) is the major hepatic uptake transporter of conjugated bile salts, and deficiency of NTCP results in reduced clearance of bile salts from the circulation and increased systemic bile salt levels . Administration of myrcludex B, a selective NTCP‐binding peptide currently used as hepatitis B and D virus entry inhibitor, also causes high systemic bile salt levels, which are tolerated very well in humans and rodents . We investigated whether myrcludex B reduces cholestatic liver injury in mice.…”