A Population Pharmacokinetic Modeling and Simulation Study of Posaconazole Oral Suspension in Immunocompromised Pediatric Patients

Ther Drug Monit. 2021 Feb 8. doi: 10.1097/FTD.0000000000000877. Online ahead of print.

ABSTRACT

BACKGROUND: Posaconazole oral suspension emerged as a promising candidate for prophylaxis of invasive fungal infections in immunocompromised children. Its pharmacodynamic advantages include a broad-spectrum activity and a favorable safety profile; however, they are overshadowed by its large pharmacokinetic (PK) variability, which might cause subtherapeutic exposure.

AIMS: To develop a population (pop) PK model based on rich sampling data to better understand the PK of posaconazole oral suspension in pediatric patients.

METHODS: Data were obtained from a prospective interventional study involving hospitalized pediatric patients with a hematologic malignancy and prophylactically treated with posaconazole oral suspension. After constructing the popPK model, the probability of target attainment (PTA; 100% T ≥0.7 mg/L) for prophylaxis under fixed, body weight-based, and body surface area-based dosing was evaluated using Monte Carlo simulation.

RESULTS: Fourteen patients contributed 112 posaconazole plasma concentrations. The PK of posaconazole was adequately described by a one-compartment model with lag time 2.71 h [13%]; nonlinear bioavailability ED50 99.1 mg/m2 (fixed); first-order absorption rate constant 0.325 h-1 [27%]; apparent volume of distribution 1,150 L [34%]; and apparent clearance 15.4 L/h [24%] (∼70-kg individual). The bioavailability decreased in the presence of diarrhea and co-treatment with a proton pump inhibitor (PPI). The unexplained interindividual variability in posaconazole PK remained large. The PTA was <85%, irrespective of the simulated dosing strategy. Patients without diarrhea and not administered a PPI had the highest PTA (85% under the fixed 300-mg dosing four times/day).

CONCLUSION: Therapeutic drug monitoring is recommended during prophylactic posaconazole therapy in immunocompromised pediatric patients. Large scale comparative studies are needed to characterize the PK variability between different posaconazole formulations in this cohort.

PMID:33560094 | DOI:10.1097/FTD.0000000000000877