Dolutegravir pharmacokinetics in co-administration with rifampicin.
Kawuma Aida1, Wang Xinzhu2, Boffito Marta2,3, Maartens Gary1, Pillai Colin1, Denti Paolo1
1 University of Cape Town, Division of Clinical Pharmacology 2 Imperial College London, Jefferiss Research Trust Laboratories, Department of Medicine 3 St. Stephen's Centre, Chelsea and Westminster Hospital
Objectives:
Dolutegravir (DTG) is being introduced as first-line antiretroviral therapy across most of Africa. The antitubercular agent rifampicin (RIF) is the mainstay of tuberculosis treatment. Rifampicin is also a potent inducer of both UGT1A1 and CYP3A4, which are involved in dolutegravir metabolism, and of both P-glycoprotein and Breast Cancer Resistance Protein, which are efflux drug transporters of dolutegravir. The interaction between dolutegravir and rifampicin is of particular interest because tuberculosis is the most common opportunistic infection associated with HIV infection in resource-limited settings, killing over 25% of people with HIV-TB coinfection (Tshikuka Mulumba et al. 2012). It has been shown that rifampicin decreases overall dolutegravir exposure and the dolutegravir label now recommends twice-daily dosing of 50 mg for persons co-infected with tuberculosis and on rifampicin-based regimes. However, twice daily dosing presents a number of challenges especially in resource-limited settings including adherence and availability of the single 50mg dolutegravir pill as opposed to the fixed-dose combination pill of dolutegravir-tenofovir-lamivudine. Therefore, assessing the use of alternative dolutegravir dosing regimens when co-administering with rifampicin is important.
The main objective of the analysis was to develop a population pharmacokinetic model in healthy volunteers to characterize dolutegravir pharmacokinetics and its interaction with rifampicin.
Methods:
Pharmacokinetic data were available from a healthy volunteer study in which 16 participants were sequentially given 50 mg of DTG for 7 days, 100 mg of DTG for 7 days, 600 mg of RIF for 14 days, 50 mg of DTG with RIF for 7 days and 100 mg of DTG with RIF for 7days. Intensive pharmacokinetic samples for dolutegravir were obtained on the 7th day of each of the weeks at pre-dose and 2, 4, 8, 12, and 24 hours’ post-dose. Compartmental analysis of the data in NONMEM was employed to develop a pharmacokinetic model to describe dolutegravir drug disposition and to evaluate the extent to which rifampicin co-administration influenced the pharmacokinetics of dolutegravir.
Results:
16 participants were screened and enrolled into the study and 14 (9 males and 5 females) completed all sampling days. The median (range) weight and age was 79.1 (55-105.6) kg and 32 (22-55) years respectively. 11 of the participants were of white ethnicity while one was of Asian ethnicity and two of Afro-Caribbean ethnicity.
The pharmacokinetics of dolutegravir was well described by a linear one-compartment model with first-order absorption. The typical subject was estimated to have a clearance of 1.07 L/h and a volume of distribution of 19.3 L. Rifampicin administration increased dolutegravir clearance significantly by more than 50%, thus lowering overall dolutegravir exposure.
Conclusions:
We propose a pharmacokinetic model of dolutegravir, whose parameter estimates are in keeping with previous reports (Zhang et al. 2015). As previously reported (Dooley et al. 2013), our model captured the induction effect of rifampicin on the efflux drug transporters and enzymes metabolizing dolutegravir, hence significantly increasing its clearance. This model offers a platform to explore different dosing regimens to inform dolutegravir dosing in patients who are co-infected with tuberculosis and on rifampicin-based therapy.
References:
[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.
[2] Zhang J, Hayes S, Sadler BM, Minto I, Brandt J, Piscitelli S, et al. Population pharmacokinetics of dolutegravir in HIV-infected treatment-naive patients. Br J Clin Pharmacol. 2015 Sep;80(3):502–14.
[3]Dooley KE, Sayre P, Borland J, Purdy E, Chen S, Song I, et al. Safety, Tolerability, and Pharmacokinetics of the Hiv Integrase Inhibitor Dolutegravir Given Twice Daily With Rifampin or Once Daily With Rifabutin: Results of a Phase 1 Study Among Healthy Subjects. Jaids Journal of Acquired Immune Deficiency Syndromes. 2013 Jan 1;62(1):21–7