Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial.

Laura Dickinson, Rohan Gurjar, Wolfgang Stöhr, Stefano Bonora, Andrew Owen, Antonio D'Avolio, Adam Cursley, Jean-Michel Molina, Gerd Fäetkenheuer, Linos Vandekerckhove, Giovanni Di Perri, Anton Pozniak, Laura Richert, François Raffi, Marta Boffito

Journal: The Journal of antimicrobial chemotherapy 2021;75(3):628-639

PMID: 31754703

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Abstract

OBJECTIVES

NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure.

METHODS

Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0-24 and C24 with time to virological failure was evaluated by Cox regression.

RESULTS

Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P<0.001). No significant relationship was demonstrated between darunavir AUC0-24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53-9.80), P=0.269; and 1.82 (0.61-5.41), P=0.279, respectively].

CONCLUSIONS

Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.

Address: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK.; Medical Research Council Clinical Trials Unit at University College London, London, UK.; University of Turin, Unit of Infectious Diseases, Turin, Italy.; University of Paris, Diderot Infectious Diseases, Paris, France.; University Köln, Unit of Internal Medicine, Köln, Germany.; Ghent University and Ghent University Hospital, HIV Translational Research Unit, Ghent, Belgium.; Chelsea and Westminster NHS Trust, London, UK.; University of Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR 1219, Bordeaux, France.; Nantes University Hospital, Infectious and Tropical Diseases, Nantes, France.; Chelsea and Westminster NHS Trust, London, UK.; Imperial College London, London, UK.

DOI: 10.1093/jac/dkz479

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MeSH Terms: Adult, Anti-HIV Agents, Constitutive Androstane Receptor, Darunavir, Emtricitabine, Female, HIV Infections, Humans, Liver-Specific Organic Anion Transporter 1, Male, Multidrug Resistance-Associated Protein 2, Pharmacogenetics, Raltegravir Potassium, Ritonavir, Tenofovir, Viral Load