Aida N Kawuma1, Roeland E Wasmann1, Kelly E. Dooley2, Marta Boffito 3,4, Gary Maartens1, Paolo Denti1
1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. 2 Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 3 St. Stephen's Centre, Chelsea, and Westminster Hospital 4 Imperial College London, Jefferiss Research Trust Laboratories, Department of Medicine
Objectives: Dolutegravir-based regimens are recommended as first-line HIV therapy in low and middle-income countries (LMIC). Rifampicin, the mainstay of tuberculosis (TB) treatment, is a potent inducer of both uridine diphosphate glucuronosyltransferase 1A1 and cytochrome P450 3A4, the enzymes responsible for dolutegravir (DTG) metabolism. To mitigate the risk of suboptimal DTG concentrations during treatment of HIV-TB co-infected individuals with rifampicin (RIF), DTG is dosed at 50 mg twice daily, which is sufficient to maintain trough concentrations (C24) above 0.064 mg/L, the protein-adjusted 90% inhibitory concentration (IC90) for HIV-1(1). An alternative target of C24>0.3 mg/L has been proposed as the DTG effective concentration (EC90). However, twice-daily dosing presents challenges in LMIC where HIV/TB treatment is dispensed as a fixed-dose combination pill. Rifabutin, a less potent inducer of liver enzymes, may offer an alternative to RIF. The objective of this analysis was to characterize the population pharmacokinetics of DTG in co-administration with rifabutin.
Methods: Data were available from two healthy volunteer studies; RADIO and NCT01231542. In RADIO, HIV-negative adults received the following in sequence; 50 mg DTG once-daily (OD) for a week, 100 mg DTG OD for a week, 600 mg RIF OD only for 14 days, 50 mg DTG OD plus 600 mg RIF OD for a week, and 100 mg DTG OD plus 600 mg RIF OD for a week. Steady-state plasma samples were drawn pre-dose and 2, 4, 8, 12, and 24 hours post-dose on the 7th day of each DTG regimen (2).
In NCT01231542, healthy adults were randomized to either of 2 arms (3). Arm-A participants received 50 mg DTG OD for a week, 50 mg DTG twice-daily (BD) for a week, and 50 mg DTG BD with 600 mg RIF OD for 14 days. Arm-B participants received 50 mg DTG OD for a week, then 50 mg DTG OD with 300 mg rifabutin OD for 14 days. Steady-state plasma samples were collected pre-dose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose on the last day of each regimen. In RADIO, DTG concentrations were measured by a reverse-phase ultra-high-performance liquid chromatography method reported previously (2), while in NCT01231542, a liquid chromatographic method with tandem mass spectrometric detection was used (3).
Compartmental analysis of the data in NONMEM (v7.4.3) using the first-order conditional estimation method with interaction was employed to develop a model to describe DTG disposition and to evaluate the extent to which rifabutin co-administration influenced DTG pharmacokinetics (PK). We included between-subject and -occasion random effects on the model parameters assuming a log-normal distribution. Allometric scaling on clearance and volume parameters with weight and fat-free mass were tested (4). We investigated the effect of these covariates on PK parameters; sex, age, RIF, and rifabutin co-administration on clearance, bioavailability, and volume of distribution, plus study as a proxy of food effect (fed: RADIO vs fasted: NCT01231542).
We used the final model to simulate steady-state C24 for 1000 virtual patients while on DTG alone and after co-administration with rifabutin and tested whether these were maintained above the DTG IC90, and EC90 (5).
Results: A total of 41 participants (68% male) were enrolled in both studies; 16 in RADIO and 25 in NCT01231542 (12 in arm-A and 13 in arm-B). The model was developed on a total of 907 samples, none below the lower limit of quantification.
A 2-compartment model with first-order elimination and absorption lag best described the PK of DTG. Typical population estimates for clearance, absorption rate constant, central volume (Vc), and peripheral volume were 1.01 L/h, 1.63 h-1, 13.3 L, and 3.52 L respectively. Rifabutin co-administration decreased DTG Vc by 33.1% (95% CI: 25.1 – 42.3; ΔOFV = -56, p<0.001), leading to lower C24 and higher peak concentrations of DTG by 22.9% (95% CI: 15.0 – 32.0) and 25% (95% CI:19.5 – 33.5), respectively. Simulations showed that when 50 mg DTG is co-administered with rifabutin OD, more than 99% of the individuals attain C24 above the IC90 of 0.064 mg/L. As expected, RIF co-administration increased DTG clearance by 135% (129 – 162; ΔOFV = -200, p<0.001).
Conclusions: Rifabutin changes DTG’s half-life by reducing its Vc. While this leads to lower DTG C24, these still achieve acceptable plasma levels. Therefore, rifabutin without dose adjustment to DTG may offer an alternative to RIF when DTG-based antiretroviral therapy is used.
References:
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[5] Min S, Song I, Borland J, Chen S, Lou Y, Fujiwara T, Piscitelli SC. 2010. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers. Antimicrob Agents Chemother 54:254–8.
Reference: PAGE 29 (2021) Abstr 9677 [www.page-meeting.org/?abstract=9677]
Poster: Drug/Disease Modelling - Infection