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

Abstract

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 formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir.

Interpretation: Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg.

Funding: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.

Figure 1

Substudy profile for cohorts weighing 20 kg to less than 25 kg Non-adherence was predefined as a trough concentration-predose concentration ratio of more than 15. FCT=film-coated tablet. DT=dispersible tablets. PK=pharmacokinetic. *Two participants in the 20 kg to less than 25 kg weight band contributed safety data on 25 mg FCT in part one and subsequently on 50 mg FCT (n=1) or 30 mg dispersible tablets (n=1) in part two.

Figure 2

Substudy profile for cohort weighing 25 kg to less than 40 kg FCT=film coated tablet. *The child with haemolysed samples on the 25mg FCT had a valid pharmacokinetic curve on the increased dose of 50 mg FCT. †One participant (30·6 kg at pharmacokinetic assessment day) was dosed at 25 mg, although slightly out of weight band and included in the weight band 25 kg to less than 30 kg for pharmacokinetics and safety analyses. One participant (30·7 kg at the pharmacokinetic assessment day) was on 35 mg FCT but was given 25 mg FCT at the pharmacokinetic assessment day only and included in the weight band 25 kg to less than 30 kg for pharmacokinetic analyses and in weight band 30 kg to less than 40 kg for safety analyses. ‡Pharmacokinetic non-adherence predefined as a trough concentration-predose concentration ratio of more than 15. §For one child the pharmacokinetic profile while on 35 mg was excluded from pharmacokinetic analysis. The pharmacokinetic profile while on 50 mg from the same child showed no signs of non-adherence and was included in the pharmacokinetic analysis.

Figure 3

Dolutegravir mean plasma concentration versus time profiles by weight band and dose 30 mg dispersible tablet was given as six 5 mg DTs. 50 mg was a single film-coated tablet. 35 mg FCT was given as one 25 mg FCT plus one 10 mg FCT. 25 mg was given as a single film-coated tablet. Adult reference lines (grey) indicate published geometric mean trough concentrations for 50 mg once daily or twice daily. Orange horizontal line expresses the in vivo EC90 (0·32 mg/L). FCT=film-coated tablets. DT=disperisble tablets. EC90=effective concentration at which 90% of maximal viral inhibition is achieved.

Figure 4

Individual dolutegravir C_trough, AUC_0–24h, and C_max in children weighing 20 kg to less than 25 kg Horizontal black lines indicate geometric means per dose. Orange line indicates dolutegravir in-vivo EC₉₀. Grey dashed lines indicate published geometric mean adult reference values for 50 mg once-daily (lower line) and twice-daily doses (upper line). C_trough=trough concentration. AUC_0–24h=area under the concentration-time curve from 0 to 24 h. C_max=maximum concentration. EC₉₀=the effective concentration at which 90% of maximal viral inhibition is achieved in a 10-day monotherapy study. *Dispersible tablets.

Figure 5

Individual dolutegravir C_trough, AUC_0–24h, and C_max on the initial dolutegravir dose and after switch to adult formulation Children weighing 25 kg to less than 30 kg (A). Children weighing 30 kg to less than 40 kg (B). Grey dashed lines indicate published geometric mean adult reference values for 50 mg once-daily (lower line) and twice-daily doses (upper line). Red dashed line indicates the effective concentration at which 90% of maximal viral inhibition is achieved in a 10-day monotherapy study (EC₉₀). C_trough=trough concentration. AUC_0–=24h=area under the concentration-time curve from 0 to 24 h. C_max=maximum concentration.