Population pharmacokinetics of rosuvastatin
in pediatric patients with heterozygous familial
hypercholesterolemia
Merran Macpherson, Bengt Hamrén, Marjet J.A.M. Braamskamp, John J.P.
Kastelein,Torbjörn Lundström, 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
1
Supplemental material
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
80 mg rosuvastatin
given over a 7-day
period in children and
adolescents with HeFH
Open-label, nonrandomized,
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)
Systemic exposure of rosuvastatin
increased with dose following single
administration of 10, 40, and 80 mg
Multiple-dose period:
80 mg OD for 7 days
(n=6 who had all
received the 80 mg
single-dose)
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
2
Study no.
(Study period)
PK objectives
Study design
No. of patients
Age, y (range)
Treatments
(all rosuvastatin)
Results
CHARON
(D3561C00002)
(Feb 2010 to Feb
2013)
To characterize the PK
profile of rosuvastatin in
pediatric patients with
HeFH
Long-term
efficacy and
safety study
N=12
Mean age: 8.0
(7–9)
Single dose of 10 mg
No important dose or time-dependent
changes in the PK over a 2-year
period
Open-label, nonrandomized,
parallel-group,
multicenter study
N=196 (including 12
above + 184
additional patients)
Mean age: 11.6
(6 to <18)
Single dose PK for
parent rosuvastatin and
metabolites
Population PK at
steady state.
Doses 5–20 mg: 5 mg
OD during the first 3
months, thereafter
titration to treatment goal
(LDL-C target of <2.85
mmol/L [110 mg/dL])
Maximum dose for pts
<10 years: 10 mg
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
Maximum dose for pts
≥10 years: 20 mg
AUC0-24 area under the plasma concentration-time curve from time zero to 24 h; CL/F, clearance; Cmax maximum plasma concentration; HeFH heterozygous familial
hypercholesterolemia; PK pharmacokinetics; OD once daily; pts patients.
3
Supplemental Table 2. Summary of Predicted Rosuvastatin Exposure (AUCss)
(ng.h/mL)
CHARON
4522IL/00864522IL/0086
Dose
Median (range)
n
Median (range)
n
5 mg
31.5 16.1–53.4)
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.
4
Supplemental Fig. 1. Final base model (described in Table 2) of observed
versus predicted plasma concentrations of rosuvastatin: diagnostic plots
5
Supplemental Fig. 2. Final covariate model (described in Table 2) diagnostic
plots of observed versus predicted plasma concentrations (back transformed
data)
6