Population pharmacokinetic modelling of dolutegravir, tenofovir and emtricitabine in non-human primates
Aurélie Barrail-Tran (1), Delphine Desjardins (2), Valérie Furlan (3), Jérémie Guedj (4), Olivier Lambotte (5), Roger Le Grand (2), Julie Bertrand (4)
(1) Université Paris-Saclay, AP-HP, Hôpital Bicêtre, Service de Pharmacie, Inserm, CEA, Immunologie des Maladies Virales, Auto-immunes, Hématologiques et Bactériennes, UMR1184, Le Kremlin-Bicêtre, France ; (2) Immunologie des Maladies Virales, Auto-Immunes, Hématologiques et Bactériennes, Université Paris-Saclay, Inserm, CEA, 92265 Fontenay-aux-Roses, France ; (3) Service de Pharmacologie-Toxicologie, Hôpital Bicêtre, AP-HP. Université Paris-Saclay, 94275 Le Kremlin-Bicêtre, France ; (4) Université de Paris, INSERM, IAME, F-75018 Paris, France ; (5) Immunologie des Maladies Virales, Auto-Immunes, Hématologiques et Bactériennes, Service de Médecine Interne Immunologie Clinique, Hôpital Bicêtre, Université Paris-Saclay, AP-HP, Inserm, CEA, 94275 Le Kremlin-Bicêtre, France
Objectives:
Current antiretroviral treatment (ART) is effective in achieving and maintaining undetectable plasma HIV-RNA levels but it does not eradicate the virus from reservoirs [1]. Non-human primate (NHP) models contribute to understand the mechanism of viral persistence under suppressive ART and the outcome after analytical treatment interruption (ATI), in relation to their pharmacological exposure to ART [2]. This analysis aimed to provide the first population approach of a first-line worldwide treatment option [3], dolutegravir (DTG), tenofovir (TNF) and emtricitabine (FTC), administered simultaneously in a NHP model.
Methods:
Non-human primate data
Our study included 53 NHPs: 7 simian immunodeficiency virus (SIV) non-infected NHPs included in a single-dose pharmacokinetic (PK) study and 46 SIV-infected (SIV+) NHPs included in a multi-dose study during 2 years. The antiretroviral therapy was a combination of DTG, TNF and FTC administered by subcutaneous route (SC), except for 6 SIV+ NHPs by oral route during the first 8 weeks. The doses were 2.5/5.1/40 mg/kg by SC route and 20/30/40 mg/kg by oral route, for DTG/TNF/FTC respectively.
For the single-dose PK study, blood samples were collected 1, 2, 4, 6, and 24 h after ART administration. For the multi-dose study, blood samples were collected just before ART administration on days 1, 3, 8, 15, 21, 28, 43, and 58 (n=12) or on days 7, 21, 48 and 72 (n=34) and then every one or two months up to two years after treatment initiation. For 23 NHPs, blood samples were also collected on days 3, 7, 14, 28 and 44 after ATI.
Plasma concentrations of the three drugs were measured by a validated ultra-high-performance liquid chromatography-tandem mass spectrometry method [4].
PK modelling
All data were analysed using a nonlinear mixed-effects approach with the Stochastic Approximation Expectation Maximization algorithm implemented in Monolix 2020R1 [5]. For each drug, model selection on BIC (structural, inter-individual random effect and residual error models) was performed using the single-dose PK study and data after ATI. Interoccasion random effects were added to fit the multi-dose study data. To fit the oral data, we estimated a scale parameter on the bioavailability which was fixed to 1 for SC data.
The final models allowed prediction of DTG, TNF, FTC concentrations over the two-year period for the SIV+ NHPs, using Simulx 2021 [6]. The minimum concentrations (Cmin), as the pre-dose concentrations, were compared to the protein-adjusted (PA) wild-type HIV-1 90% inhibitory concentrations (IC90) (PA-IC90 = 64 ng/mL) for DTG [7], and to IC90 for TNF (2.98 ng/mL) [8] and FTC (51 ng/mL) [9].
Results:
DTG, TNF, FTC concentrations were adequately described by three-compartment models, with first order absorption and elimination. Absorption rate constant was fixed to 1. Oral F were estimated to 0.10, 0.28 and 1.31 for DTG, TNF and FTC respectively.
DTG, TNF and FTC apparent clearances (Cl/F) were 0.10L/h (relative standard error, RSE=3.2%), 0.77 L/h (RSE= 5.1%) and 0.60 L/h (RSE=7.5%) respectively. No correlation was found between the Cl/F of the three drugs.
Interindividual and interoccasion variability estimated on Cl/F were 13.1% and 19.3% for DTG, 17.9% and 10.2% for TNF, 13.0% and 17.6% for FTC, respectively.
Residual variability was less than 32.1 % for the three drugs.
From the first day of treatment, all SIV+ NHPs have predicted DTG and TNF Cmin above their respective PA-IC90 or IC90, but only 21.7% for FTC Cmin. The median (min-max) Cmin predicted over the two-year period of treatment were 560 (356-843) ng/mL, 54 (36-90) ng/mL and 82 (48-144) ng/mL for DTG, TNF and FTC respectively. After ATI, median times (min-max) to have predicted Cmin less than their respective PA-IC90 or IC90 were 7 days (3-11), 59 days (49-89) and 1 day (1-22) for DTG, TNF and FTC respectively.
Conclusions:
The population PK models developed successfully characterize DTG, TNF and FTC PKs in NHPs. DTG, TNF and FTC predicted exposures are expected to suppress viral replication in NHPs and are consistent with pharmacological data observed in humans [10, 11, 12]. As the viral loads were quantified in all the SIV+ NHPs at treatment initiation, during the treatment and for some after the ATI, we will be able to develop PK-viral dynamics models. It will help understand the complex viral/host/drugs interactions in SIV/HIV persistence and the mechanisms leading to post-treatment control.
References:
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[5] https://lixoft.com/products/monolix/
[6] https://lixoft.com/products/simulx/
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