There are growing concerns about dolutegravir (DTG)-related neuropsychiatric adverse events and about differences in the characteristics of people living with HIV infection (PLWH) potentially associated with higher risks of said side effects. Several studies have shown that DTG was stopped more frequently among women, older PLWH, and PLWH who initiated abacavir (ABC) at the same time. This study aimed to clarify the factors affecting the pharmacokinetics (PKs) of DTG in a real-life cohort of PLWH using a population PK approach.
The model-building strategy was based on a previously published model developed from premarketing trials (1-compartment model with first-order absorption and a lag time). Sparse therapeutic drug monitoring data were obtained from a real-life cohort of 279 PLWH, and population PK analysis was performed using Monolix software. A stepwise covariate model-building strategy was used to evaluate any relevant effects of age, body weight, gender, total bilirubin, smoking status, formulations of DTG, morning versus evening dosing, backbone therapy, and other comedications including CYP/UGT inducers/inhibitors.
For a typical 70-kg PLWH, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.748 L/h and 14.6 L, respectively. Of the demographic factors evaluated, body weight was a significant covariate for CL/F and for V/F. Smokers had a 17% higher CL/F relative to nonsmokers. Both strong enzyme inhibitors (eg, atazanavir) and inducers (eg, rifampicin) had marked effects on DTG exposure, with potential clinical implications. Ritonavir-boosted darunavir was found to moderately increase clearance of DTG by 23%. No significant effect of ABC-based backbone therapy was observed on the PK parameters of DTG.
Our results did not support the hypothesis that ABC, by competing with the DTG metabolic pathway, may significantly increase DTG exposure leading to potential drug toxicity.
*Hospices Civils de Lyon, GHS-Centre de Biologie Sud, Pierre Bénite;
†Hospices Civils de Lyon, Maladies Infectieuses et Tropicales, Hôpital Croix-Rousse; and
‡Hospices Civils de Lyon, Maladies Infectieuses et Tropicales, GH Édouard Herriot, Lyon, France.
Correspondence: François Parant, PharmD, GHS—Centre de Biologie Sud, UM Pharmacologie—Toxicologie, Chemin du Grand-Revoyet, Pierre Bénite Cedex 69495, France (e-mail: firstname.lastname@example.org).
All authors contributed to the interpretation of data, the drafts, and the final version of the manuscript.
The authors declare no conflict of interest.
Part of this study was presented at the “18èmes Journées Nationales d'Infectiologie” (poster VIH-23), June 21–23, 2017, Saint-Malo, France.
Received July 26, 2018
Accepted January 01, 2019