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Comparative Bioavailability of Oral Granule Formulations of the HIV Antiretroviral Drugs Doravirine, Lamivudine, and Tenofovir Disoproxil Fumarate.
- Source :
-
AAPS PharmSciTech [AAPS PharmSciTech] 2020 Feb 13; Vol. 21 (3), pp. 91. Date of Electronic Publication: 2020 Feb 13. - Publication Year :
- 2020
-
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 AUC <subscript>0-∞</subscript> (11%) and C <subscript>max</subscript> (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 AUC <subscript>0-∞</subscript> (26-29%), C <subscript>max</subscript> (56-59%), and C <subscript>24</subscript> (20-21%) versus administration of granules alone. Lamivudine granules administered with pudding or apple sauce decreased AUC <subscript>0-∞</subscript> and C <subscript>max</subscript> (14-25%) versus granules alone. Tenofovir AUC <subscript>0-∞</subscript> , C <subscript>max</subscript> , and C <subscript>24</subscript> 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.
- Subjects :
- Adult
Anti-HIV Agents administration & dosage
Anti-Retroviral Agents administration & dosage
Biological Availability
Cross-Over Studies
Female
HIV Infections drug therapy
HIV Infections metabolism
Humans
Lamivudine administration & dosage
Male
Middle Aged
Pyridones administration & dosage
Reverse Transcriptase Inhibitors administration & dosage
Tablets
Tenofovir administration & dosage
Triazoles administration & dosage
Young Adult
Anti-HIV Agents pharmacokinetics
Anti-Retroviral Agents pharmacokinetics
Lamivudine pharmacokinetics
Pyridones pharmacokinetics
Reverse Transcriptase Inhibitors pharmacokinetics
Tenofovir pharmacokinetics
Triazoles pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1530-9932
- Volume :
- 21
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- AAPS PharmSciTech
- Publication Type :
- Academic Journal
- Accession number :
- 32060665
- Full Text :
- https://doi.org/10.1208/s12249-020-1630-6