Dose Optimisation of Posaconazole and Therapeutic Drug Monitoring in Pediatric Patients

Abstract

Experience in the clinical use of posaconazole (PCZ) in pediatric patients is limited, and no specific dose recommendations exist. This study aimed to investigate an appropriate dosing regimen, and assess the exposure-response relationships of PCZ in children. We reviewed the medical records of inpatients aged <18 years who subjected to PCZ concentrations monitoring. Clinical data, PCZ dosing and monitoring data were collected. A total of 375 PCZ trough concentrations (Cmin) from 105 pediatric patients were included. For children receiving PCZ for prophylaxis, the median doses required to achieve the therapeutic range at the ages of <6, 6–12 and >12 years were 14.80, 14.52 and 12.90 mg/kg/day, respectively (p = 0.001); and for those receiving PCZ for treatment, the median doses were 23.50, 20.96 and 15.38 mg/kg/day, respectively (p = 0.001). Among children taking PCZ for prophylaxis, 12% developed a proven or probable breakthrough IFIs; the median PCZ concentrations were significantly lower than those children with successful treatment response (0.43 versus 1.20 μg mL−1; p < 0.001). 79.2% patients taking PCZ for treatment had a positive clinical response, and the median PCZ concentrations were significantly higher than those children with disease progression (1.06 versus 0.53 μg mL−1; p = 0.024). No association between Cmin values and hepatotoxicity was observed. Factors such as age, CRP, ALT and co-administration with proton pump inhibitors exhibited significant effects on PCZ Cmin. It is necessary to adjust the dosing regimens based on PCZ Cmin to individualize antifungal therapy and provide guidelines for dose adjustment in children.

Population Pharmacokinetics of Posaconazole in Immune-Compromised Children and Assessment of Target Attainment in Invasive Fungal Disease

“…In healthy adults, PPIs have been shown to reduce maximal serum concentration of PSZ after OS dosing by around 46% [ 20 ]. In children, one population PK analysis estimated a 42% reduction in OS bioavailability during concomitant PPI administration (and no or limited effect of H2RAs), while another study reported a significant decline in target attainment percentage while receiving both OS and PPIs [ 13 , 34 ], which are similar if not somewhat reduced effects compared with our study results. These findings of heavily reduced suspension bioavailability of PSZ are underpinned by its poor solubility, solubility rate-limited absorption (i.e., Biopharmaceutical Classification System [BCS] class II), and, most importantly, its pH-dependent solubility (i.e., reduced solubility at elevated gastric pH) that have been extensively characterized in the literature [ 35 ].…”

“…Bioavailability has been observed to be dose-limited in both adults (up to 800 mg/dose) [ 41 ] and children (up to 700 mg/dose) [ 13 , 14 ], although a full exploration of nonlinearity, as well as additional dose-limiting factors such as palatability, has not been conducted. The target serum concentrations for TDM have been suggested by the British Society of Medical Mycology and supported by a previous retrospective analysis study in Chinese children [ 34 ]. These are general guidelines for maximizing prophylaxis and treatment efficacy, and thus the target attainment analysis does not guarantee favorable outcomes (prevention of breakthrough infections or complete cure of IFD) in all cases, especially in instances of drug-resistant pathogens.…”