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Comparative Bioavailability of Oral Granule Formulations of the HIV Antiretroviral Drugs Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate

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Abstract

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus-1 infection, available as a single tablet in combination with other antiretroviral agents or as a fixed-dose regimen with lamivudine and tenofovir disoproxil fumarate (TDF). Alternative formulations of these drugs are being developed for individuals who have difficulty swallowing tablets. Two phase 1 trials were conducted, both in 24 healthy adults, to assess the pharmacokinetics of uncoated and coated oral granule formulations of doravirine, lamivudine, and TDF administered alone and with vanilla pudding or apple sauce. The pharmacokinetics for all uncoated granules, and of coated lamivudine and TDF granules, were similar to those of currently marketed tablets (geometric mean ratios [GMRs] 0.92–1.04). Coated doravirine granules had decreased AUC0–∞ (11%) and Cmax (23%) values versus the tablet. The pharmacokinetics were similar for uncoated and coated doravirine granules administered with or without pudding (GMRs 0.96–1.10); administration with apple sauce increased doravirine AUC0–∞ (26–29%), Cmax (56–59%), and C24 (20–21%) versus administration of granules alone. Lamivudine granules administered with pudding or apple sauce decreased AUC0–∞ and Cmax (14–25%) versus granules alone. Tenofovir AUC0–∞, Cmax, and C24 increased for TDF granules administered with pudding or apple sauce versus alone (11–23%). Pharmacokinetic differences when administering doravirine, lamivudine, or TDF as uncoated or coated granules versus tablets, or when granules were administered with (versus without) pudding or apple sauce, are not considered clinically meaningful, supporting further development of these granule formulations.

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Fig. 1

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Acknowledgments

The authors would like to thank the trial participants and staff. In addition, the authors would like to thank Marty Behm for his help with the study, Robert Valesky for bioanalytical support, and Karen Thompson for input regarding formulation development.

Medical writing assistance, under the direction of the authors, was provided by Kirsty Muirhead, PhD, of CMC AFFINITY, McCann Health Medical Communications, and Claire Lavin, PhD, on behalf of CMC AFFINITY, in accordance with Good Publication Practice (GPP3) guidelines. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Author information

Correspondence to Marian Iwamoto.

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Conflict of interest

KLY, ADB, LF, SK, IT, M-HV, PF, SAS, and MI are current or former employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may own stock and/or stock options in Merck & Co., Inc., Kenilworth, NJ, USA.

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Yee, K.L., DiBenedetto, A., Fan, L. et al. Comparative Bioavailability of Oral Granule Formulations of the HIV Antiretroviral Drugs Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate. AAPS PharmSciTech 21, 91 (2020). https://doi.org/10.1208/s12249-020-1630-6

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KEY WORDS

  • doravirine
  • lamivudine
  • TDF
  • granules
  • bioavailability