You are here
ADEQUATE DOLUTEGRAVIR EXPOSURE DOSED BID WITH RIFAMPICIN IN CHILDREN 6 TO
Hylke Waalewijn1, Hilda Mujuru2, Pauline Amuge3, Mark Cotton4, Pauline Bollen1, Man Chan5, Shabinah Ali5, Ebrahim Variava6, Shafic Makumbi7, Angela Colbers<
1Radboud University Medical Center, Nijmegen, Netherlands,2University of Zimbabwe, Harare, Zimbabwe,3Baylor College of Medicine Children's Foundation, Kampala, Uganda,4Stellenbosch University, Cape Town, South Africa,5MRC Clinical Trials Unit at UCL, London, UK,6University of the Witwatersrand, Johannesburg, South Africa,7Joint Clinical Research Centre, Mbarara, Uganda
Adults with HIV/TB co-infection on dolutegravir (DTG)-based antiretroviral therapy (ART) can overcome the induction effect of rifampicin (RIF) by doubling the DTG dose (50mg twice(BID) instead of once(QD) daily. We undertook a pharmacokinetic (PK) substudy nested within the ongoing ODYSSEY randomised controlled trial (#NCT02259127) to evaluate DTG PK in HIV/TB co-infected children while receiving DTG BID+RIF and DTG QD.
Children aged 6-<18 years receiving DTG BID+RIF were eligible; we aimed to include 6 children aged 6-<12 years and 6 children 12-<18 years. A 12h PK curve was constructed for children on DTG BID in the last month of RIF treatment and subsequently, a 24h PK curve on DTG QD ≥4 weeks after stopping RIF. Geometric mean ratios (GMRs) were estimated comparing DTG PK parameters between the 2 periods and individual Ctrough levels below EC90 (0.32 mg/L) were summarised. All children who received DTG BID+RIF aged ≥6 years were followed for serious adverse events(SAEs), grade 3/4 clinical/laboratory adverse events(AEs) and any AEs resulting in ART modification from start of DTG BID to 30 days after return to DTG QD.
Of 30 eligible children, 17 were enrolled in the PK substudy; 13/17 participants undertaking PK had 1 evaluable PK curve. 12/13 were black African, median (range) age 12.3 (6.8-16.1) years and 31.3 (19.8-48.5) kg. 12 PK curves were evaluable for DTG BID+RIF (5 on 25mg BID and 7 on 50mg BID) and 11 for DTG QD (5 on 25mg QD and 6 on 50mg QD). GMRs (90% CI) for DTG BID+RIF versus DTG QD (reference) for Ctrough, AUC0-24h and Cmax were 1.59 (1.09-2.33), 1.20 (0.90-1.59), and 0.98 (0.79-1.21), respectively. Oral clearance of DTG with RIF was increased 1.7-fold, with 41% reduction in elimination half-life. Findings were similar in children above and below 12 years old. AUC0-24h GMRs in children 20kg receiving WHO 2019-recommended DTG 50mg dose was 1.00 (0.61-1.62) and 1.47 (0.99-2.19) for children on 25mg dose. One child on DTG 25mg QD without RIF had Ctrough
Twice daily dolutegravir dosing was safe and sufficient to overcome rifampicin enzyme-inducing effect in HIV/TB co-infected children aged 6-<18 years, including in children 20kg receiving new WHO doses (DTG 50mg).