Manel Aouri(1), Monia Guidi (1,2), Catalina Barcelo (1), Matthias Cavassini(3), Thierry Buclin(1), Laurent A. Decosterd(4), Chantal Csajka (2,3), and the Swiss HIV Cohort Study.
1 Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland, 2 School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland , 3Division of Infectious Diseases, University Hospital Center, University of Lausanne, 4Innovation & Development, Laboratory of Clinical Pharmacology, Service of Biomedicine, University Hospital and University of Lausanne, Lausanne, Switzerland
Objectives: Dolutegravir (DTG), the latest integrase inhibitor (INIs) approved for HIV treatment is coformulated in a single tablet regimen with abacavir and lamivudine. DTG has demonstrated potent antiviral activity and a very good tolerability and is widely prescribed in HIV-infected patients (1). DTG is primarily metabolized via UDP-glucuronosyltransferase (UGT 1A1) with a minor component of CYP3A4 (2). The aim of this observational study was to characterize DTG pharmacokinetic profile, to quantify interpatient variability and to identify potential factors that could influence drug exposure.
Methods: All dolutegravir plasma concentrations data were collected as part of routine therapeutic drug monitoring performed in our centre, between June 2014 and December 2015 from HIV treatment-naive and experimented patients. A population PK analysis was performed by comparing various structural models using NONMEM®. The effect of relevant demographic factors and co-medications on dolutegravir disposition was explored.
Results: A total of 594 plasma levels were measured in 514 HIV-positive patients under steady state regimen conditions. Plasma concentrations ranged between 31 and 7971 ng/mL. A one-compartment model with first order absorption and elimination best characterized dolutegravir pharmacokinetics. Average DTG clearance was 0.93 (L/h), volume of distribution 18.9 (L), and absorption rate constant 1.27 (h-1).The inter-subject variability on CL was estimated at 27%. Among the demographic covariates tested, body weight and age influenced positively and moderately DTG CL (29% and 24% respectively) as well as smoking status (17%). Coadminisation of atazanavir decreased DTG clearance by 38% and the association of darunavir increased the clearance of DTG (14%).
Conclusions: The variability in DTG pharmacokinetics appears lower than for other antiretroviral drugs. Several covariates were identified impacting DTG exposure however their effect appears to be relatively modest and seems not to be clinically significant except for atazanavir coadministration.
References:
[1] FDA. 2013. TIVICAY (dolutegravir) FULL PRESCRIBING INFORMATION. administration FaD, http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204790lbl.pdf.
[2] Castellino S, Moss L, Wagner D, Borland J, Song I, Chen S, Lou Y, Min SS, Goljer I, Culp A, Piscitelli SC, Savina PM. 2013. Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans. Antimicrob Agents Chemother 57:3536-3546.
Reference: PAGE 25 (2016) Abstr 5998 [www.page-meeting.org/?abstract=5998]
Poster: Drug/Disease modeling - Infection