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Determining an optimal pharmacokinetic target for dolutegravir

Determining an optimal pharmacokinetic target for dolutegravir

Aida N Kawuma

Pharmacometrics Laboratory, Division of Clinical Pharmacology, The University of Cape Town.

27 July 2021

Dolutegravir has replaced efavirenz as the recommended first-line therapy in low and middle-income countries for the management of HIV. Dolutegravir can effectively and rapidly reduce HIV viral copies in the body. Tuberculosis is the commonest opportunistic infection associated with HIV in resource-limited settings and kills over 25% of HIV-tuberculosis co-infected individuals. Rifampicin which is the mainstay of anti-tuberculosis treatment greatly increases the activity of both UGT1A1 and CYP3A4, the enzymes responsible for breaking down dolutegravir in the liver; meaning that when both drugs are given together, dolutegravir is broken down much faster in the body. Therefore, when co-administered with rifampicin, dolutegravir is given twice daily as opposed to once daily to maintain dolutegravir plasma concentrations above 0.3 mg/L, which has been suggested as the effective concentration. 0.3 mg/L was the median concentration observed in a cohort of virologically suppressed individuals 24 hours after they were given 10 mg of dolutegravir. However, a dolutegravir concentration above 0.064 mg/L is sufficient to inhibit further replication of 90% of the virus in vitro. Therefore maintaining plasma concentrations above this 0.064 mg/L threshold should ideally also be sufficient to achieve desired treatment outcomes. There is now a debate as to which threshold should be targeted when dosing dolutegravir. Should clinicians aim to maintain plasma concentrations above 0.064 or 0.3 mg/L when managing patients? We will use modeling and early phase data to shed light on the question of what threshold should be targeted when dosing dolutegravir.The objectives of the research would be to•   To develop a population pharmacokinetic-pharmacodynamic model describing the dose-concentration-effect relationship for dolutegravir.•   To explore the use and ability of other pharmacokinetic exposure parameters (such as the area under the curve) in guiding dolutegravir dosing.

[{ "PostingID": 1383, "Title": "VIIV-ING111521", "Description": "A Phase 2a, Multicenter, Randomized, Parallel, Double-Blind, Dose Ranging, Placebo-Controlled Study to Compare Antiviral Effect, Safety, Tolerability and Pharmacokinetics of GSK1349572 Monotherapy Versus Placebo Over 10 days in HIV-1 Infected Adults (ING111521)" },{ "PostingID": 1384, "Title": "VIIV-ING112276", "Description": "A Phase IIb study to select a once daily dose of GSK1349572 administered with either abacavir/lamivudine or tenofovir/emtricitabine in HIV-1 infected antiretroviral therapy naive adult subjects" }]

Statistical Analysis Plan