Francesco Bellanti (1), Meindert Danhof (1), Oscar Della Pasqua (1, 2)
(1) Division of Pharmacology, Leiden Academic Centre for Drug Research, the Netherlands; (2) Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, UK
Objectives: To characterise the pharmacokinetics of deferiprone [1, 2] using a model-based approach and assess the effect of demographic and physiological factors on drug exposure; and to evaluate the adequacy of the current dosing regimen in patients with renal impairment.
Methods: Data from 55 adult healthy subjects receiving deferiprone (solution 100 mg/ml) were used for model building purposes. A population pharmacokinetic analysis was performed using NONMEM VII. The contribution of gender, age, weight, and creatinine clearance 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 best describe the pharmacokinetics of deferiprone. Goodness-of-fit plots, visual predictive check (VPC) and NPDE summaries indicated that the model provides an unbiased description of the data. Simulated AUC and Cmax were comparable with literature references [3, 4, 5]. Gender differences in the apparent volume of distribution (20% difference) have been identified, which may contribute to an increase in peak concentrations in females. Furthermore, simulation scenarios reveal that dose adjustment is required for patients with reduced creatinine clearance. Doses of 60, 40 and 25 mg/kg for patients showing mild, moderate and severe renal impairment are proposed based on creatinine clearance values of 60-89, 30-59 and 15-29 ml/min, respectively.
Conclusions: Our analysis has enabled the assessment of the impact of gender and creatinine clearance 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.
References:
[1] Galanello R, Campus S. Deferiprone chelation therapy for thalassemia major. Acta Haematol. 2009; 122(2-3):155–64.
[2] Barman Balfour JA, Foster RH. Deferiprone: a review of its clinical potential in iron overload in beta-thalassaemia major and other transfusion-dependent diseases. Drugs. 1999; 58(3):553–78.
[3] Fassos FF, Klein J, Fernandes D, et al. The pharmacokinetics and pharmacodynamics of the oral iron chelator deferiprone (L1) in relation to hemoglobin levels. Int J Clin Pharmacol Ther. 1996; 34(7):288-92.
[4] Limenta LMG, Jirasomprasert T, Jittangprasert P, et al. Pharmacokinetics of Deferiprone in Patients with Beta-thalassemia. Clin Pharmacokinet. 2011; 50(1):41–50.
[5] Stobie S, Tyberg J, Matsui D, et al. Comparison of the pharmacokinetics of 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in healthy volunteers, with and without co-administration of ferrous sulfate, to thalassemia patients. Int J Clin Pharmacol Ther Toxicol. 1993; 31(12):602-5.
Reference: PAGE 23 () Abstr 3131 [www.page-meeting.org/?abstract=3131]
Poster: Methodology - Covariate/Variability Models