Aims: To develop a population pharmacokinetic (PK) model of ambrisentan in paediatric patients aged 8 to <18 years with pulmonary arterial hypertension (PAH), compare paediatric ambrisentan systemic exposure to historical adult data, and assess PK–PD relationships. Methods: A previously developed adult population PK model provided an initial step for modelling the 211 PK observations from 39 paediatric patients with PAH in the randomised Phase IIb study AMB112529 (NCT01332331). Subsequently, a population PK model was developed using only paediatric PK data. Steady-state systemic exposure metrics were estimated for the paediatric population and compared with historical adult data (adult patients with PAH and healthy volunteers). Exploratory exposure–response analysis assessed ambrisentan systemic exposure versus change from baseline in 6-minute walking distance in paediatric patients; findings were compared with adult data. An exploratory analysis of ambrisentan exposure versus incidence of ambrisentan-related adverse events in paediatric patients was also performed. Results: The final paediatric population PK model was a two-compartment model which includes the effect of body weight (allometric scaling), first-order absorption and elimination, and absorption lag time. Similar steady-state ambrisentan exposure was confirmed in paediatric patients and historical adult data when differences in body weight were accounted for. There was no apparent correlation in the paediatric or adult population between ambrisentan exposure and change in 6-minute walking distance, or between ambrisentan exposure and incidence of ambrisentan-related adverse events in paediatric patients. Conclusions: Similar ambrisentan exposure and PK–PD profiles were observed in paediatric and adult populations with PAH.

HIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated. A population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure–safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events. A total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50

Intravenous belimumab 10 mg/kg every 4 weeks is indicated in patients with active, autoantibody-positive systemic lupus erythematosus receiving standard systemic lupus erythematosus care. Subcutaneous 200-mg weekly administration, which may prove more convenient for patients and improve adherence, is currently under investigation.

PURPOSE:This study characterized the population pharmacokinetic (pop-PK) and PK/pharmacodynamic (pop-PK/PD) properties of eltrombopag and evaluated platelet count (PLTC) response to different eltrombopag dosages through simulations in Chinese adult patients with chronic primary immune thrombocytopenia (cITP). METHODS:Pop-PK and pop-PK/PD models were developed from Chinese patients with cITP. Model-based simulations were then performed to predict PLTC response. FINDINGS:The pop-PK properties of eltrombopag were described by a 2-compartment model with first-order absorption and elimination and absorption lag time. Steady-state exposure in these Chinese patients was ~55% greater than that in non-East Asian patients. The pop-PK/PD properties of eltrombopag were described by a model with 4 transit compartments where the increase in platelet production rate was linearly related to the plasma eltrombopag concentration. Eleven percent of the patients were identified as nonresponders to eltrombopag. Simulations showed that ~70% to 80% of steady-state PLTC response was achieved at week 2, and the percentages of patients who achieved a PLTC of 50 to 150 × 10(9) cells/L were comparable between weeks 2 and 6 with 12.5-, 25-, 50-, and 75-mg once-daily dosing. The 25-mg once-daily dosage was associated with a more balanced response than were the 12.5-, 50-, and 75-mg once-daily dosages with regard to efficacy (percentages of patients with PLTC 50-150 × 10(9) cells/L, 27% vs 20%, 30%, and 30%, respectively) and the risk for thrombocytosis (percentages of patients with PLTC >250 × 10(9) cells/L, 4% vs 1%, 10%, and 16%). Simulations of PLTCs with the dose-titration regimen showed that ≥42% of patients achieved a PLTC 50 to 150 × 10(9) cells/L at week 6 or later, compared with ≤30% when the 12.5-, 25-, 50-, and 75-mg once-daily fixed doses were given. No more than 5% of patients who underwent dose titration had a PLTC >250 × 10(9) cells/L throughout 24 weeks of treatment, compared with 3%, 7%, 16%, and 24% when the once-daily fixed doses of eltrombopag were given. IMPLICATIONS:The pop-PK and pop-PK/PD properties of eltrombopag in these Chinese adult patients with cITP were adequately characterized in the present analyses. The modeling and simulation results support the eltrombopag dose-titration regimen, with 25 mg once daily as a starting dosage and a 2-week titration interval, in Chinese patients with cITP.

The pharmacokinetics of eltrombopag and its stimulation of platelet production were characterized in patients with chronic hepatitis C virus (HCV) infection to optimize an eltrombopag dosing regimen for treatment of HCV-related thrombocytopenia before and throughout peginterferon (pegIFN)-based antiviral therapy.