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

A Blank; A Eidam; M Haag; N Hohmann; J Burhenne; M Schwab; Sfj van de Graaf; M R Meyer; H H Maurer; K Meier; J Weiss; T Bruckner; A Alexandrov; S Urban; G Mikus; W E Haefeli

doi:10.1002/cpt.744

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

Clin Pharmacol Ther. 2018 Feb;103(2):341-348. doi: 10.1002/cpt.744. Epub 2017 Jun 21.

Authors

A Blank^{1

2}, A Eidam^{1

2}, M Haag^{3

4}, N Hohmann^{1

2}, J Burhenne^{1

2}, M Schwab^{3

4

5

6}, Sfj van de Graaf⁷, M R Meyer^{1

8}, H H Maurer⁸, K Meier^{1

2}, J Weiss^{1

2}, T Bruckner⁹, A Alexandrov¹⁰, S Urban^{2

11}, G Mikus^{1

2}, W E Haefeli^{1

2}

Affiliations

¹ Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
² German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany.
³ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tübingen, Stuttgart, Germany.
⁴ German Center for Infection Research (DZIF), Tübingen Partner Site, Tübingen, Germany.
⁵ Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen, Germany.
⁶ Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany.
⁷ Tytgat Institute for Liver and Intestinal Research & Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
⁸ Experimental and Clinical Toxicology, Saarland University, Homburg, Germany.
⁹ Institute of Medical Biostatistics and Medical Informatics, Heidelberg University Hospital, Heidelberg, Germany.
¹⁰ Myr GmbH, Bad Homburg, Germany.
¹¹ Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany.

PMID: 28543042
DOI: 10.1002/cpt.744

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.

Publication types

Clinical Trial
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Adult
Antiviral Agents / administration & dosage*
Antiviral Agents / adverse effects
Antiviral Agents / pharmacokinetics
Bile Acids and Salts / blood*
Biomarkers / blood
Cytochrome P-450 CYP3A / metabolism
Drug Interactions
Female
Humans
Injections, Subcutaneous
Lipopeptides / administration & dosage*
Lipopeptides / adverse effects
Lipopeptides / pharmacokinetics
Male
Middle Aged
Organic Anion Transporters, Sodium-Dependent / antagonists & inhibitors
Organic Anion Transporters, Sodium-Dependent / metabolism
Prospective Studies
Reverse Transcriptase Inhibitors / administration & dosage
Reverse Transcriptase Inhibitors / adverse effects
Reverse Transcriptase Inhibitors / pharmacokinetics*
Risk Assessment
Symporters / antagonists & inhibitors
Symporters / metabolism
Tenofovir / administration & dosage
Tenofovir / adverse effects
Tenofovir / pharmacokinetics*
Up-Regulation
Young Adult

Substances

Antiviral Agents
Bile Acids and Salts
Biomarkers
Lipopeptides
Organic Anion Transporters, Sodium-Dependent
Reverse Transcriptase Inhibitors
Symporters
myrcludex-B
sodium-bile acid cotransporter
Tenofovir
CYP3A protein, human
Cytochrome P-450 CYP3A