Population pharmacokinetics of deferiprone in healthy subjects

Abstract

AIMS: To characterize the pharmacokinetics of deferiprone in healthy subjects using a model-based approach and to assess the effect of demographic and physiological factors on drug exposure. METHODS: Data from 55 adult healthy subjects receiving deferiprone (solution 100 mg ml-1) were used for model building purposes. A population pharmacokinetic analysis was performed using NONMEM v.7.2. The contribution of gender, age, weight and creatinine clearance (CLcr) on drug disposition was evaluated according to standard forward inclusion, backward deletion procedures. Model selection criteria were based on graphical and statistical summaries. RESULTS: A one compartment model with first order oral absorption was found to describe best the pharmacokinetics of deferiprone. Simulated exposure values were comparable with previously published data. Mean AUC estimates were 45.8 and 137.4 mg l-1 h, whereas Cmax increased from 17.6 to 26.5 mg l-1 after administration of 25 and 75 mg kg-1 doses, respectively. Gender differences in the apparent volume of distribution (20%) have been identified, which are unlikely to be of clinical relevance. Furthermore, simulation scenarios reveal that dose adjustment is required for patients with reduced CLcr. Doses of 60, 40 and 25 mg kg-1 for patients showing mild, moderate and severe renal impairment are proposed based on CLcr values of 60-89, 30-59 and 15-29 ml min-1, respectively. CONCLUSIONS: Our analysis has enabled the assessment of the impact of gender and CLcr on the pharmacokinetics of deferiprone. Moreover, it provides the basis for dosing recommendations in renal impairment. The implication of these covariates on systemic exposure is currently not available in the prescribing information of deferiprone.