Authors: Singh R, Baker M, Thapar M, Gibb D, Turkova A, Ford D, Ruel T, Wiznia A, Farhad M, Alvero C, Green J, Bollen P, Colbers A, Burger D, Acosta E
Published in: 12th International Workshop on HIV Pediatrics
Background: HIV treatment options remain limited in children. The recent Tivicay (dolutegravir, DTG) pediatric regulatory submissions propose WHO weight-band based recommendations for once-daily dosing in children ≥4 weeks of age using combined datasets from two pediatric studies: IMPAACT P1093 and ODYSSEY (PENTA20). These doses were informed by the Population PK (PopPK) analysis described below.
Methods: P1093 is a Phase I/II, non-comparative pharmacokinetic (PK) and safety study in HIV-1 infected children (≥4 weeks to <18 years of age). ODYSSEY is a non-inferiority, phase II/III study comparing the efficacy and toxicity of DTG plus 2 NRTIs vs. standard of care in infants and children. Intensive and sparse PK samples following dosing with film coated tablets (FCT), granules and dispersible tablet (DT) formulations in the fasted state and without regard to food were collected in P1093; intensive PK samples using FCTs and DTs in fasted state were collected in ODYSSEY. A PopPK model was developed with data from P1093 (1711 concentrations from n=151 participants) and ODYSSEY (939 concentrations from n=88 participants) to characterize PK, covariates, and associated variability. The final PopPK model simulated exposures across weight bands, doses, and formulations which were compared with established adult reference data.
Results: Of N=239 participants included, baseline age ranged from 0.17-17.5 years and weight from 3.9-91 kg, 50% were male and 80% were black. The model described study data and associated variability well with estimated mean (interindividual variability) CL/F=1.03L/h (29%) and V/F=13.6 L (107%). Based on observed and simulated data, dose stratification by age (<6 months and ≥6 months) in the 6 to <10 kg weight band (10 and 15 mg DTG DT, respectively) was proposed to account for metabolic enzyme maturation. The proposed doses are 5mg DT in 3 to <6kg; 10 mg DT in 6 to<10kg and <6 months, 15mg DT in 6 to <10kg and ≥6months, 20mg DT in 10 to <14kg, 25mg DT in 14 to <20kg and 30mg DT or 50 mg FCT in >20kg. At these doses, the simulated 24- hour concentration (C24h) was consistent across weight bands, similar to observed data, and met the minimum target concentrations of 0.697μg/mL. Similarly, simulated 24-hour area-under-the-curve (AUC24h) met the minimum target (46 h*μg/mL) across weight bands. Simulated maximum concentration (Cmax) results were 0.96 to 1.79- fold those observed historically in adults at the approved dose of DTG 50 mg BID (4.15 μg/mL). The safety exposure-response analysis demonstrated no relationships between PK parameters and adverse events.
Conclusions: Using FCT and DT formulations, DTG dosing in children ≥4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed PK variability was higher in this pediatric population and no additional safety concerns were observed.