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Phase I evaluation of pharmacokinetics and tolerability of the HIV‐1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults
Author(s) -
Pene Dumitrescu Teodora,
Joshi Samit R.,
Xu Jianfeng,
Greene Thomas J.,
Johnson Mark,
Butcher Laurie,
Zimmerman Eric,
Webster Lindsey,
Pham Theresa T.,
Lataillade Max,
Min Sherene
Publication year - 2021
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14759
Subject(s) - dolutegravir , tolerability , pharmacokinetics , dosing , medicine , pharmacology , adverse effect , regimen , confidence interval , viral load , human immunodeficiency virus (hiv) , antiretroviral therapy , virology
Aims GSK3640254, a novel, next‐generation maturation inhibitor effective against a range of HIV polymorphisms with no cross‐resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2‐drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed. Methods Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1–5 in period 1, GSK3640254 200 mg QD on Days 1–7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1–7 in period 3. All treatments were administered with a moderate‐fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography and vital signs were monitored. Results Sixteen participants completed the study. GMRs (90% CIs) for dolutegravir area under the plasma concentration–time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118–1.233), 1.09 (1.044–1.138) and 1.24 (1.160–1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04 (0.992–1.094), 0.99 (0.923–1.065) and 0.10 (0.939–1.056), respectively. Dolutegravir plus GSK3640254 coadministration did not meaningfully alter steady‐state exposure to dolutegravir or GSK3640254. No clinically significant trends in tolerability or safety were observed. Conclusion Coadministration of GSK3640254 with dolutegravir did not result in clinically significant drug interaction and was well tolerated.