Clinical pharmacokinetics and dose recommendations for posaconazole gastro-resistant tablets in children with Cystic Fibrosis

Objectives To investigate the population pharmacokinetics of posaconazole gastro-resistant tablets in children with Cystic Fibrosis (CF), and perform simulations to recommend optimal doses. Patients and methods Children from a paediatric CF centre who had received posaconazole tablets and underwent therapeutic drug monitoring were identified from Pharmacy records. Relevant clinical data was collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A step-wise covariate model building exercise evaluated the influence of interacting medicines and liver function. Results One hundred posaconazole serum concentrations were collected from 37 children with a median age of 14 years (range 7-17). Posaconazole pharmacokinetics were adequately described by a one-compartment model with inter-individual variability on clearance. Dose simulations demonstrated a 77-83% probability of attaining a trough target of 1 mg/L with a dose of 300 mg every 12 hours for 2 doses then 300 mg once daily (OD) in children aged 6-11 years; and 86-88% with a dose of 400 mg every 12 hours for 2 doses then 400 mg OD in adolescents aged 12-17 years. This dose scheme also yields a 90% probability of achieving an AUC of 30 mg.h/L. AUC and trough concentration were highly correlated (r2=0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30mg.h/L in 90% of patients. Conclusions A starting dose of 300mg OD in 6-11 years and 400mg OD in 12-17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg.h/L