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Population pharmacokinetic analysis of interaction between dolutegravir and rifampin

Population pharmacokinetic analysis of interaction between dolutegravir and rifampin

Gary Maartens

Department of Medicine University of Cape Town Health Sciences Faculty

06 December 2019

Tuberculosis is the commonest opportunistic infection associated with HIV in resource-limited settings killing over 25% of HIV-TB co-infected persons1. Rifampicin is the mainstay of anti-tuberculosis treatment and forms the backbone of first-line TB treatment options across the world. Because of the overlapping nature of both epidemics especially in Sub-Saharan Africa, HIV persons co-infected with TB will find themselves on dolutegravir containing regimens and on rifampicin based regimes.Dolutegravir belongs to a class of antiretroviral medicines known as integrase inhibitors. It is broken down in the liver mainly by the enzyme UGT1A1 by the CYP3A4 enzyme to a lesser extent. Rifampicin on the other hand greatly increases the activity of both the UGT1A1 and CYP3A4 enzymes. This means that if both drugs are given together, dolutegravir is broken down much faster in the body since the enzymes responsible for this have an increased activity because of the co-administered rifampicin. Secondly, dolutegravir can be actively pumped out of our body cells by efflux drug transporters such as P-glycoprotein and Breast Cancer Resistance Protein whose activity is also increased by rifampicin.Therefore, co-administration of rifampicin based regimes together with dolutegravir containing regimens for HIV may lead to insufficient concentrations of dolutegravir and pause a risk of treatment failure or development of drug resistance insufficient suppression of the HIV virus The current recommendation for HIV TB co-infected persons on a rifampicin based regimen is 50 mg of dolutegravir twice-daily as opposed to the 50mg once-daily dosing for persons who are not co-infected with TB. However, twice daily dosing presents challenges of compliance and availability of the single pill as opposed to a co-formulated, fixed-dose combination pill especially in resource-limited settings which additionally suffer from very high patient-health care provider ratios. Therefore, understanding how rifampicin affects the metabolism of Dolutegravir assessing the use of other dolutegravir dosing regimens such as 100 mg once daily is necessary especially in Sub-Saharan Africa where dolutegravir is only starting to be used.The objectives of the research would be to•   To develop a population pharmacokinetic model for dolutegravir describing the relationship between dose and the resulting drug concentration exposure using clinical trial data.•   To develop a model to characterize rifampicin-induced metabolism of dolutegravir •   To use clinical trial simulation in combination with specific assumptions and model uncertainties for the generation of the potential range of responses to other dosing regimens of dolutegravir in co-administration with rifampicinReferences   1.   Tshikuka Mulumba JG, Atua Matindii B, Kilauzi AL, Mengema B, Mafuta J, Eloko Eya Matangelo G, et al. Severity of Outcomes Associated to Types of HIV Coinfection with TB and Malaria in a Setting Where the Three Pandemics Overlap. J Community Health. 2012 Dec 1;37(6):1234-8.

[{ "PostingID": 19940, "Title": "VIIV-ING117175", "Description": "ING117175: a Phase IIIb, randomized, open-label study of the safety and efficacy of dolutegravir or efavirenz each administered with two NRTIs in HIV-1-infected antiretroviral therapy-naïve adults starting treatment for rifampicin-sensitive tuberculosis" },{ "PostingID": 19941, "Title": "VIIV-ING113099", "Description": "Phase 1, open label, two arm, fixed sequence study to evaluate the effect of rifampin and rifabutin on GSK1349572 pharmacokinetics in healthy male and female volunteers" }]

Statistical Analysis Plan

A.N. Kawuma, R.E. Wasmann, K.E. Dooley, M. Boffito, G. Maartens, P. Denti Population Pharmacokinetic Model and Alternative Dosing Regimens for Dolutegravir Coadministered with Rifampicin Antimicrobial Agents and Chemotherapy (2022) vol 66