Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial

Abstract

Summary Background Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV. Methods We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial ( NCT02259127 ) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (C trough ) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses. Findings Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) C trough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM C trough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM C trough was 0·39 mg/L (48%), which was 54% lower than the GM C trough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM C trough was 0·46 mg/L (63%), which was 45% lower than the GM C trough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, C trough was close to the adult reference (with similar estimates on the two formulation...

Dolutegravir in the long term in children and adolescents: frequent virological failure but rare acquired genotypic resistance

“…Pharmacokinetics sub‐studies of the randomized ODYSSEY trial recently suggested that adult dolutegravir 50 mg film‐coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing ≥ 20 kg [15]. In our retrospective study, where subjects initiated dolutegravir before the revision of dolutegravir paediatric dosing guidelines, low dolutegravir plasma levels may have contributed to VF in some patients weighing 20–30 kg (and receiving 25 mg dolutegravir once daily).…”

Dolutegravir dosing for children with HIV weighing less than 20 kg: pharmacokinetic and safety substudies nested in the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

“…Results of other nested pharmacokinetic substudies are reported elsewhere. 5,6 In the first substudy, we enrolled children weighing 14 kg to less than 20 kg. Following a review of results, we did a second substudy in this weight band, using a different dolutegravir formulation and dose.…”

“…3 The more recently introduced integrase inhibitor, dolutegravir, has the potential to change the use of ART for children; in adults and older children, dolutegravir has high virological efficacy, good tolerability, minimal drug-drug interactions, and a high barrier to resistance. 4 , 5 These characteristics combined with a low effective dose and, consequently, low manufacturing costs and small formulation size have made dolutegravir a preferred treatment option for most countries regardless of income status.…”

Optimised paediatric antiretroviral treatment to achieve the 95-95-95 goals

“…Further pharmacokinetic evaluation conducted as a substudy of the Odyssey trial evaluated the use of the 50 mg tablet in children between 20 kg and 30 kg. 11 Acceptable pharmacokinetics and side-effect profile supported the USFDA registration of DTG 50 mg daily in children from 20 kg. In addition, the new dosage recommendation was added to the WHO and several national guidelines, including the South African national ART guidelines.…”