The Pharmacogenetics of OATP1B1 Variants and their impact on the Pharmacokinetics and Efficacy of Elbasvir/Grazoprevir

Abstract

Aim: To evaluate the effect of SLCO1B1 genetic variants on grazoprevir pharmacokinetics and efficacy. Methods: A retrospective analysis of 1578 hepatitis C virus-infected participants from ten Phase II/III clinical trials. Results: Relative to noncarriers of the risk allele, geometric mean ratios (95% CI) of grazoprevir area under curve (AUC)_0–24 were: rs4149056 (risk allele C), one copy, 1.13 (1.06–1.21), two copies, 1.43 (1.16–1.77); and rs11045819 (risk allele A), one copy, 0.93 (0.87–1.00); two copies, 0.78 (0.61–1.00). The rs2306283 variant was not associated with grazoprevir exposure. None of the SLCO1B1 variants were associated with sustained virologic response. Conclusion: Genetic variants in SLCO1B1 were associated with modest changes in grazoprevir pharmacokinetics, but not with meaningful differences in efficacy.

Keywords::

• elbasvir
• grazoprevir
• hepatitis C virus
• organic anion transporting polypeptide (OATP) 1B1
• pharmacogenetics
• SLCO1B1

Author contributions

Conception, design, or planning of the study: Z Guo, L Caro, MN Robertson, R Blanchard, PM Shaw. Acquisition of the data: Z Guo, P Hoover, C Wudarski, K Maiuri, R Blanchard, PM Shaw. Analysis of the data: Z Guo, P Hwang, PM Shaw. Interpretation of the results: Z Guo, L Caro, MNR, Y-H Wang, R Mogg, DV Mehrotra, R Blanchard, PM Shaw. Drafting of the manuscript: Z Guo, PM Shaw. Critically reviewing or revising the manuscript for important intellectual content: Z Guo, L Caro, MN Robertson, P Hwang, P Hoover, C Wudarski, K Maiuri, Y-H Wang, R Mogg, DV Mehrotra, R Blanchard, PM Shaw. All authors approved the manuscript for submission.

Acknowledgments

We thank the participants and clinical research unit staff who participated in this study.

Financial & competing interests disclosure

This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). MSD’s involvement in the trial and manuscript development is represented by employee authors and their contributions. All authors were employees of MSD at the time of the analyses. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Professional medical writing and editorial assistance was provided by JM Kulak of ApotheCom (Yardley, PA, USA) and was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Ethical conduct of research

All studies in this analysis were carried out in accordance with the Declaration of Helsinki, current guidelines on Good Clinical Practices and local ethical and legal requirements. All participants provided written informed consent before trial entry.

Data sharing statement

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA’s data sharing policy, including restrictions, is available at www.engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to [email protected].

Additional information

Funding

This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). MSD’s involvement in the trial and manuscript development is represented by employee authors and their contributions. All authors were employees of MSD at the time of the analyses. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Professional medical writing and editorial assistance was provided by JM Kulak of ApotheCom (Yardley, PA, USA) and was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.