Clinical pharmacokinetics and dose recommendations for posaconazole gastroresistant tablets in children with cystic fibrosis. (30th August 2021)

• Record Type: Journal Article
• Authors: Bentley, Siân; Davies, Jane C; Gastine, Silke; Donovan, Jackie; Standing, Joseph F
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 76:Number 12(2021)
• Page Start: 3247
• Page End: 3254
• Publication Date: 2021-08-30
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkab312
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: Objectives: To investigate the population pharmacokinetics of posaconazole gastroresistant 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 were collated from case notes and electronic patient records and used to develop an allometrically scaled population pharmacokinetic model. A stepwise 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 h for two doses then 300 mg once daily (OD) in children aged 6–11 years; and 86%–88% with a dose of 400 mg every 12 h for two doses then 400 mg OD in adolescents aged 12–17 years. This dose scheme also yielded a 90% probability of achieving an AUC of 30 mg·h/L. AUC and trough concentration were highly correlated (r 2 = 0.98). Simulations showed that trough concentrations of >0.75 mg/L would exceed an AUC of 30 mg·h/L in 90% of patients. Conclusions: A starting dose of 300 mg OD in those aged 6–11 years and 400 mg OD in those aged 12–17 years (following loading doses) yields a 90% probability of attaining an AUC of 30 mg·h/L.