The impact of standard, medium and high rifampicin doses on induction of drug metabolizing enzymes was evaluated by measuring dolutegravir (UGT1A1 substrate), midazolam (CYP3A4) and digoxin (P-gp) exposures in an open-label, fixed-sequence, 4-phase study in TB-infected HIV-negative adults. Dolutegravir (50 mg twice daily for one week) exposure was compared when dosed with rifampicin at 10 mg/kg (day 14), 20 mg/kg (day 28) and 35 mg/kg (day 42), and 4 weeks after completing TB treatment (at 50 mg once daily). Single dose midazolam (0.025 mg/kg) and digoxin (0.25 mg) were given on PK sampling days. Changes in PK parameters were evaluated by geometric mean ratio (GMR). Dolutegravir and rifampicin PK were available for 33 individuals (median age: 35 years, median weight: 61 kg). Geometric mean for dolutegravir Ctau were 665, 660, 657 ng/mL on day 14, 28, 42 vs 687 ng/mL after completing TB treatment (GMR, 90% CI: 1.01 [0.75-1.36]; 0.97 [0.75-1.27]; 0.87 [0.71-1.07], respectively). Dolutegravir Cmax and AUC0-12h were significantly lower with rifampicin on day 14: 0.59 [0.52-0.67] and 0.72 [0.64-0.81], day 28: 0.60 [0.51-0.69] and 0.71 [0.62-0.81], day 42: 0,59 [0.53-0.65] and 0.72 [0.65-0.80]. The proportion of Ctau above dolutegravir EC90 (342 ng/mL) was 79, 88, 90 and 83% on day 14, 28, 42 and after completion of the TB treatment, respectively. Rifampicin increased supra-proportionally with dose, AUC0-12h GMR, 90% CI: 2.93 [2.35-3.66] (20 mg/kg) and 4.6 [3.65-5.79] (35 mg/kg). Midazolam and digoxin data showed little change with higher rifampicin doses compared to the standard dose. Dolutegravir was reduced to a similar extent with higher rifampicin doses suggesting maximum induction at a rifampicin dose of 10 mg/kg. Furthermore, most individuals remained above the dolutegravir EC90 suggesting that further dolutegravir dose adjustment may not be necessary with high dose rifampicin.

This study aimed to develop the population pharmacokinetic model of dolutegravir (DTG) when co-administered with rifampicin. The developed model was further used to investigate different dosing regimens. Forty HIV/TB- co-infected participants receiving DTG 50 mg once daily with food or DTG 50 mg twice daily without food were enrolled (20 per group) and 332 DTG concentrations were analyzed. The pharmacokinetics of DTG co-administered with rifampicin was best described by a one-compartment model with first-order absorption (incorporating lag time) and elimination. Total bilirubin was the only covariate that significantly affected CL/F. DTG 50 mg twice daily resulted in the highest proportion of individuals achieving in vitro IC90 of 0.064 mg/L and in vivo EC90 of 0.3 mg/L, while more than 90% of individuals receiving DTG 100 mg once daily achieved the in vitro IC90 target. Therefore, DTG 100 mg once daily could serve as an alternative regimen by minimizing the difficulty of drug administration. However, its clinical efficacy requires additional evaluation.

The effect of a higher dose of rifampicin (35 mg/kg) on the pharmacokinetics of dolutegravir or efavirenz was evaluated in coinfected HIV/TB adults. Newly-diagnosed TB patients were randomized to either a standard (10 mg/kg) or a higher (35 mg/kg) dose of rifampicin. Antiretroviral treatment naïve patients were assigned to dolutegravir or efavirenz based regimens. Patients on dolutegravir or efavirenz based regimens at enrolment were maintained on the same regimen, however, dolutegravir was adjusted from once daily to twice daily dosing. Pharmacokinetic sampling was performed 6 weeks post TB treatment initiation with sampling for dolutegravir 12 hours (Ctrough) after the last dose and a mid-dose sampling for efavirenz. Data were available from 128 participants. Geometric mean (95% CI) dolutegravir trough concentration for patients on higher dose rifampicin was lower than for those receiving standard dose rifampicin: 0.46 (0.31-0.67) mg/L versus 0.80 (0.56-1.14) mg/L, with a GMR of 0.57 (0.34-0.97). Using a threshold of 0.3 mg/L, a higher proportion of participants on higher dose rifampicin failed to attain the target dolutegravir through concentration compared to those on standard dose (39% vs 7%, P=0.014). Using a lower target threshold of 0.064 mg/L, the difference in target attainment between higher and standard dose rifampicin was not statistically significant (4.4% vs 3.6%, P=0.999). No patients with dolutegravir concentrations below either target thresholds had a detectable HIV viral load at week 24. The geometric mean for efavirenz mid-dose concentrations for patients on higher dose rifampicin was 37% lower than those receiving the standard dose: 2.94 (95% CI, 1.98-4.36) mg/L vs 4.64 (3.31-6.50) mg/L, with a GMR of 0.63 (0.38-1.07, P=0.083). The proportion of patients who failed to attain the target mid-dose efavirenz concentrations of 1 mg/L was not significantly different between the 2 groups (10.5% on higher-dose vs 3.9% on standard-dose, P=0.565). No patients below the target had a detectable HIV viral load at week 24. Grade 3-4 adverse effects were similar in the high vs standard dose rifampicin arms. Sputum conversion at week 8 was higher in high dose versus standard dose arms. In conclusion, compared to the standard dose, a three-fold dose increase for rifampicin reduced plasma exposure of dolutegravir and efavirenz without loss of virological control of HIV.

Obesity can impact drug pharmacokinetics and consequently the magnitude of drug-drug interactions and the related recommendations for dose adjustment. Virtual clinical drug-drug interaction studies were conducted using physiologically modelling to compare the magnitude of the drug interaction between dolutegravir (50 mg twice daily) and rifampicin (600 mg daily) in non-obese (BMI 18.5-30 kg/m2), obese (BMI 30-40 kg/m2) and morbidly obese (BMI 40-50 kg/m2) individuals. Rifampicin was predicted to decrease dolutegravir AUC by 72% in obese and by 77% in morbidly obese vs 68% in non-obese individuals; however, dolutegravir trough concentrations were reduced to a similar extent (83% and 85% vs 85%). Twice-daily dolutegravir with rifampicin resulted in trough concentrations always above the protein-adjusted 90% inhibitory concentration for all BMI groups and above the 300 ng/mL threshold in a similar proportion for all BMI groups. In conclusion, the combined effect of obesity and induction by rifampicin was predicted to further decrease dolutegravir exposure but not the minimal concentration at the end of the dosing interval. Thus, dolutegravir 50 mg twice daily with rifampicin can be used in individuals with a high BMI up to 50 kg/m2.

This study presented the 48-week outcome of the RADIANT-TB, a phase 2b, non-comparative, randomized, double-blind, placebo-controlled trial of standard vs double dose dolutegravir in individuals with tuberculosis and on rifampicin-based therapy. Participants were randomized to receive dolutegravir/lamivudine/tenofovir and either supplemental dolutegravir or placebo continued for 2 weeks after stopping TB treatment. The outcome was the proportion of individuals with HIV-RNA <50 copies/mL at week 48, treatment emergent dolutegravir resistance and adherence assessed by tenofovir-diphosphate (TFV-DP) on dried blood spots. Overall, 108 participants were included. At week 24, 43 (83%, 95% CI 70-92) of 52 participants in the supplemental dolutegravir arm and 44 (83%, 95% CI 70-92) of 53 participants in the placebo arm had virological suppression. The proportion of individuals with virologic suppression at weeks 24 and 48 were similar between arms but lower at week 48 than at week 24 likely due to declining adherence. None of the 19 participants with study defined virological failure developed treatment emergent resistance to dolutegravir.

Tenofovir/lamivudine/dolutegravir (TLD) is the WHO-preferred first-line regimen but there are limited data on the effectiveness of TLD + 50 mg dolutegravir to overcome the interaction with rifampicin in TB/HIV co-infected individuals. A total of 91 participants with TB/HIV co-infection were included. Of those, 75 were ART-naïve participants starting TLD + 50 mg dolutegravir after 15 days on TB treatment; 10 ART naïve participants starting TLD + 50 mg dolutegravir together with rifampicin, 5 starting TB treatment and changing to TLD + 50 mg dolutegravir after a median of 3.3 y on TLD and 1 starting rifampicin and TLD + 50 mg dolutegravir after changing from EFV/3TC/TDF. Among 89 surviving participants, 6 were lost of follow-up and a further 10 had no HIV-1 RNA result due to missed or remote visits. Thus, the virological outcome was assessed in 73, of whom 69 (95%) had HIV-1 RNA <1000 copies/mL and 68 (94%) had HIV-1 RNA <200 copies/mL. No dolutegravir resistance mutations were detected among 4 participants with HIV-1 RNA >1000 copies/mL. Concomitant rifampicin containing TB treatment and TLD + 50 mg dolutegravir was well tolerated and achieved excellent viral suppression in a cohort of predominantly ART-naïve people with TB/HIV.

Food has been shown to increase dolutegravir concentrations in healthy volunteers by 33-66%. This study aimed to evaluate whether dolutegravir dosed at 50 mg once daily taken with food would be sufficient to compensate the rifampicin inducing effect. The pharmacokinetic study conducted in Bangkok enrolled TB/HIV coinfected adults (stable on rifampicin-containing regimen for drug-susceptible TB), to receive the fixed dose combination dolutegravir/3TC/TDF 50 mg once daily with food or the same drug combination plus an additional dose of dolutegravir 50 mg administered 12 hours later. Geometric mean ratio (GMR) of dolutegravir 50 mg once daily vs 50 mg twice daily were determined and the percent of individuals with dolutegravir Cmin above the protein adjusted IC90 (i.e. 0.064 µg/mL) calculated. Twelve and sixteen participants were enrolled in the study (i.e. dolutegravir 50 mg once daily + food) and control arm (i.e. dolutegravir 50 mg twice daily), respectively. The majority were male (86%) with a median body weight of 57.5 kg. At baseline, median CD4 was 201 cells/µL (IQR 46-304) and median HIV-RNA was 4.9 log10 copies/mL (IQR 3.6-5.6). Dolutegravir Cmax was not statistically different when comparing the study arm versus the control arm. However, dolutegravir AUC was significantly lower (46% decrease) in the study arm with a GMR (90% CI) of 0.54 (0.36-0.81). Similarly, dolutegravir Cmin was significantly lower (70% decrease) in the study arm with a GMR of 0.30 (0.26-0.36) but with 83% and 94% of the study and control arm participants having dolutegravir Cmin above the protein adjusted IC90. At week 12, 83.3% and 75% of the participants in the study and control arm had HIV-RNA <50 copies/mL, respectively. The authors highlighted that even though substantial reductions in dolutegravir Cmin were observed in presence of rifampicin when dosed once daily + food, dolutegravir Cmin levels were mostly above the protein adjusted IC90 and the majority of participants were virologically suppressed at week 12.

This study investigated whether doubling the dolutegravir dose with a once daily dose can mitigate the reduction in dolutegravir exposure seen with rifampicin. Fourteen healthy subjects received dolutegravir (50 mg or 100 mg once daily for 7 days) alone and in combination with rifampicin (600 mg once daily). Rifampicin decreased the Cmax, AUC and C24 of dolutegravir by 35%, 57% and 86% (50 mg once daily) and by 36%, 58% and 88% (100 mg once daily). When compared to 50 mg once daily alone, doubling the dose of dolutegravir to 100 mg once daily in the presence of rifampicin increased dolutegravir Cmax by 9% and decreased AUC and C24 by 26% and 76%, respectively. Although there were substantial reductions in the dolutegravir key pharmacokinetic parameter of C24, dolutegravir concentrations when administered as 100 mg once daily with rifampicin remained above the protein binding-adjusted IC of 64 ng/ml. The authors suggest further study of this dose is required.

Coadministration of twice daily dolutegravir (50 mg twice daily, with lamivudine/tenofovir 300/300 mg, once daily) was studied in 10 HIV-1/TB co-infected subjects receiving rifampicin (600 mg once daily) with isoniazid, ethambutol and pyrazinamide. Dolutegravir trough concentrations were determined after at least 4 weeks of therapy and were 1123 ng/ml (820-1746 mg; median with range). Rifampicin did not significantly impact lamivudine and tenofovir plasma concentrations. After 48 weeks of therapy, two patients had plasma viral loads >50 copies/ml and were found to have dolutegravir trough concentrations below the target of 640 ng/ml, corresponding to an inhibitory quotient of 0.1 and 5. These results suggest that dolutegravir 50 mg twice daily and rifampicin should only be used in subjects without HIV integrase resistance.