Population pharmacokinetics of rosuvastatin
in pediatric patients with heterozygous familial hypercholesterolemia

Merran Macpherson, Bengt Hamrén, Marjet J.A.M. Braamskamp, John J.P. Kastelein,TorbjörnLundström, Paul D. Martin

M. Macpherson

Wright Dose Ltd, Charter House, 2 Woodlands Road, Altrincham, Cheshire, UK

P. D. Martin
AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK

B. Hamrén, T. Lundström
AstraZeneca, Mölndal, Sweden

M.J.A.M. Braamskamp, J.J.J.P. Kastelein
Department of Vascular Medicine, and Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands

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Supplementalmaterial

Supplemental Table 1. Clinical studies Involved in model building and validation and summary of individual study PK results

Study no.
(Study period) / PK objectives / Study design / No. of patients
Age, y (range) / Treatments
(all rosuvastatin) / Results
4522IL/0086
(Jul 2001 to Nov 2002) / To determine the PK of single oral doses of 10, 40, and 80 mg rosuvastatin and the PK of multiple doses of 80mg rosuvastatin given over a 7-day period in children and adolescents with HeFH / Open-label, non-randomized, sequential-group, single-center study / N=18
Mean age: 14
(10–17) / Single-dose period:
10 mg (n=6)
40 mg (n=6)
80 mg (n=6)
Multiple-dose period:
80 mg OD for 7days (n=6 who had all received the 80 mg single-dose) / Systemic exposure of rosuvastatin increased with dose following single administration of 10, 40, and 80 mg
Following multiple doses, Cmax and AUC0-24 were ~19% and 49% greater than corresponding values following single doses
No important time-dependent changes between Days 1 and 7
CL/F appeared to be dose independent
CHARON (D3561C00002)
(Feb 2010 to Feb 2013) / To characterize the PK profile of rosuvastatin in pediatric patients with HeFH
Single dose PK for parent rosuvastatinand metabolites
Population PK at steady state. / Long-term efficacy and safety study
Open-label, non-randomized, parallel-group, multicenter study / N=12
Mean age: 8.0
(7–9)
N=196 (including 12 above +184 additional patients)
Mean age:11.6
(6 to <18) / Single dose of 10mg
Doses 5–20mg: 5mg OD during the first 3 months, thereafter titration to treatment goal (LDL-C target of <2.85 mmol/L [110mg/dL])
Maximum dose for pts <10 years: 10mg
Maximum dose for pts ≥10 years: 20mg / No important dose or time-dependent changes in the PK over a 2-year period
Children with lower body weights had on average lower clearances but any impact is negated by dose titration regimen
CL/F in these children and adolescents is similar to healthy adults

AUC0-24area under the plasma concentration-time curve from time zero to 24 h;CL/F, clearance;Cmaxmaximum plasma concentration;HeFHheterozygous familial hypercholesterolemia;PKpharmacokinetics;ODonce daily; ptspatients.

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SupplementalTable 2.Summary of Predicted Rosuvastatin Exposure (AUCss) (ng.h/mL)

CHARON / 4522IL/00864522IL/0086
Dose / Median (range) / n / Median (range) / n
5 mg / 31.516.1–53.4) / 19 / N/A / N/A
10 mg / 67.9 (35.1–329) / 56 / 73.3 (27.6–118) / 6
20 mg / 116 (44.4–373) / 121 / N/A / N/A
40 mg / N/A / N/A / 408 (121–577) / 6
80 mg / N/A / N/A / 433 (254–661) / 6

AUCss area under the plasma concentration time curve at steady-state; N/A not applicable.

Supplemental Fig. 1.Final base model (described in Table 2) of observed versus predicted plasma concentrations of rosuvastatin: diagnostic plots


Supplemental Fig. 2.Final covariate model (described in Table 2) diagnostic plots of observed versus predicted plasma concentrations (back transformed data)

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