Dolutegravir dispersible tablets for infants and young children: early PK, safety and efficacy
Polly Clayden, HIV i-Base
Once daily dolutegravir dispersible tablets achieved exposure within target range for most children aged four weeks to less than six years, participating in IMPAACT P1093. But due to moderate inter-patient variability, higher dosing is likely to be needed for children two to less than six years of age.
These results were presented at the 10th International Workshop on HIV Paediatrics.
IMPAACT P1093 is an ongoing phase 1/2 open label pharmacokinetic (PK), safety, and dose-finding study of dolutegravir (DTG).
Film coated tablets are approved for older children (aged 6 and above) in the US and EU. A 5 mg DTG dispersible tablet (DTG-DT) paediatric formulation is being evaluated for younger children.
Theodore Ruel presented intensive PK and 4-week safety (primary outcomes) as well as tolerability and efficacy data for DTG-DT tested infants and children ages 4 weeks to <6 years.
Dosing in P1093 is by age cohort. Thirty-two children were enrolled to achieve 30 with evaluable data, 10 in each cohort: 4 weeks to <6 months; 6 months to <2 years and 2 years to <6 years.
Of these children, 43% were female; at baseline 90% had CD4 percent >14 and 53% had viral load >50, 000 cells/mL.Over 80% were from Africa (Botswana, South Africa, Tanzania and Zimbabwe) and the remainder were enrolled from Brazil, Thailand and the US.
Participants received DTG-DT as monotherapy at enrollment, or added to stable-failing or empiric initial background regimens and were dosed using weight-band tables. See table 1.
Table 1: Initial DTG-DT once daily dosing table
|Weight band (kg)||Dose (mg)||Dose (mg/kg) for weight range|
|Lower weight||Upper weight|
|3 to <6||5||1.67||0.83|
|6 to <10||10||1.67||1.00|
|10 to <14||15||1.50||1.07|
|14 to <20||15||1.79||1.25|
|20 to <25||20||1.50||1.20|
Intensive 24-hour PK sampling was completed between days 5–10, after which background regimens were optimised based on genotypes. Fifteen of the participants received AZT/3TC, four ABC/3TC, and five received LPV/r with either one or two NRTIs, as background regimens.
From adult data, targets (range) for geometric mean (GM) exposures were AUC24h 46 (37–86) mgxh/L and C24h 750 (500–2260) ng/mL.
Median (range) age (in years) and doses (in mg/kg), followed by the GM (arithmetic CV%) AUC24h (mgxh/L) and C24h (ng/mL) were as follows: 2 to <6 years 4.0 (2.1–5.9), 1.1 (0.8–1.6), 40 (36%) and 461 (59%); 6 months to <2 years 1.2 (0.9–1.9), 1.2 (1.0–1.4), 51 (38%) and 711 (60%); and 4 weeks to 6 months 0.34 (0.28–0.39), 1.2 (0.9–1.7), 61 (44%) and 1207 (55%).
DTG exposures showed moderate inter-patient PK variability: 8/10 in each of the two younger cohorts achieved C24h above the lower acceptable limit (>500 ng/mL), but only 4/10 achieved the lower limit in the 2 to <6 years cohort.
DTG-DT was well-tolerated, with no grade 3 or 4 adverse events or discontinuations attributed to study drug. At 4 weeks, 24/30 (80%) subjects had viral load <400 copies/mL or a >2 log decrease.
Higher doses of DTG are now being evaluated for the 2 to <6 years age group. And the next protocol version of P1093 allows for additional enrollments to ensure data to support WHO weight band and age-based dosing.
Ruel T. Pharmacokinetic and 4-week safety/efficacy of dolutegravir (S/GSK1349572) dispersible tablets in HIV-infected children aged 4 weeks to <6 years: results from IMPAACT P1093. 10th International Workshop on HIV Paediatrics. 20 –21 July 2018. Oral abstract 2.
http://regist2.virology-education.com/presentations/2018/10PED/16_ruel.pdf (PDF Slides)