M Macpherson (1), B Hamrén (1), Lundström T (2), P Martin (1)
(1) Quantitative Clinical Pharmacology Science, AstraZeneca, (2) Global Medicines Development, AstraZeneca
Objectives: To describe the pharmacokinetic properties of rosuvastatin in children ≥6 to < 18 years of age.
Methods: A two-compartment population model was fitted to a total of 2029 measurable rosuvastatin concentrations from 214 patients using NONMEM 7.2.0. Covariates were evaluated against CL/F by a stepwise forward inclusion (α = 0.01) and backward exclusion (α = 0.001) process to the base model. The final model was evaluated using a VPC, stratified by sampling intensity (intense/sparse), dose and study. The dose equivalent exposure range in healthy adults and patients was graphically compared to children and adolescents with hypercholesterolaemia.
Results: A linear two-compartment disposition model with a 1st order absorption and elimination processes (ADVAN4 TRANS4) adequately described the combined dataset. Dose and time did not significantly affect CL/F within the studied dose and treatment period. Weight and gender were found to be significant covariates for CL/F and remaining between patient variability was moderate (CV 40 %). Age could not significantly explain any additional variability in CL/F. CL/F increased with increasing weight and represented a 2-fold difference (max/min) across the observed weight range and CL/F in female children was approximately 30% lower than in male children. Pharmacokinetics of rosuvastatin in children and adolescents with FH is more similar to healthy adults than adult patients with dyslipidaemia.
Conclusions: The pharmacokinetics of rosuvastatin in children and adolescents with HeFH was adequately described by the population PK model and appears to be predictable with respect to both dose and time. Children with lower body weights had on average lower clearances but it is unlikely that this covariate (as well as gender and age) has a relevant impact on steady state exposure because the youngest children (>6 years to Tanner less than II) are prescribed a maximum dose of 10 mg whereas older children and adolescents can receive up to 20 mg.
References:
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[4] ICH Guidelines E11: Clinical investigation of medicinal products in the paediatric population 2001. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2001.
[5] EMEA: Guideline on the role of pharmacokinetics in the development of medicinal products in the paediatric population European Medicines Agency, Committee for Medicinal Products for Human Use; 1 Jan 2007.
[6] Food and Drug Administration: Guidance for Industry: Population Pharmacokinetics 1999 U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, 1999.
[7] Food and Drug Administration: Guidance for Industry: General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products 1998 U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, 1998.
[8] Tzeng TB, Schneck DW, Birmingham BK, Mitchell PD, Zhang H, Martin PD and Kung LP 2008. Population pharmacokinetics of rosuvastatin: implications of renal impairment, race, and dyslipidaemia. Current Medical Research and Opinion 2008; 24(9): 2575-2585.
Reference: PAGE 23 (2014) Abstr 3255 [www.page-meeting.org/?abstract=3255]
Poster: Drug/Disease modeling - Paediatrics