Once daily dosing of dolutegravir in combination with rifampicin in infants and children living with HIV: A population pharmacokinetic approach

follows: GP-FDC group (75 mg G + 75 mg P, 150 L/thigh), G group (150 mg G, 150 L/thigh), P group (150 mg P, 150 L/thigh) and GP group (75 mg G, 150 L/left thigh + 75 mg P, 150 L/right thigh).A second set of experiments evaluated the effects of different GP-FDC active doses (18.75, 37.5 and 75 mg) on the pharmacokinetics (PK) by changing the dosing volume (0.075, 0.15 and 0.3 mL of GP-FDC at 500 mg/mL) or GP-FDC suspension strength (0.3 mL of GP-FDC at 125, 250 and 500 mg/mL).For all studies, blood samples were collected from the lateral tail vein up to 90 days' post-dose.G and P concentrations were quantified in plasma using a validated method by LC-MS/MS.Results: GP-FDC showed plasma concentration-time profiles above the reported median human C trough for both G and P over the 90 days.However, for single drug-LAI suspensions, plasma concentrations of P were above the human Ctrough over 70 days for both P alone and GP groups, whereas a more rapid drop in plasma concentrations were observed for G in both G and GP groups, after 35 and 28 days, respectively.In the second set of experiments, a linear dose-dependent PK was observed with increasing volume, with a proportional increase in the AUC 0-tlast for both G and P (G: 106, 220 and 390 gh/mL and P: 157, 346 and 513 gh/ml for 0.075, 0.15 and 0.3 mL, respectively).Conversely, when dose was titred by GP-FDC suspension strength, a non-dose linear increase in the AUC0-tlast for both G and P was observed (G: 156, 325 and 390 gh/mL and P: 200, 400 and 513 gh/mL for 125, 250 and 500 mg/mL).Notwithstanding, both experimental conditions provided appropriate plasma exposures; while the 18.75 mg dose maintained G and P exposure above the human C trough for 5 and 11 weeks, respectively, the 37.5 and 75 mg doses maintained plasma exposures above the human C trough for both G and P throughout the 90 days.Conclusions: Plasma exposure of both G and P between GP-FDC and single drug-LAI suspensions suggested that P helps to maintain a longer terminal half-life for G.Moreover, PK data demonstrate a sustained exposure over a period of 90 days for both G and P in rats when novel GP-FDC is administered.Optimization of drug ratios, as well as GLP toxicology assessments, is required to progress to human clinical trials.