Steady-state pharmacokinetics of pravastatin in children with familial hypercholesterolaemia

Objective: To determine pharmacokinetic data for pravastatin in children, since current data are insufficient in this age group. Subjects and methods: A 2-week, multiple-dose, steady-state pharmacokinetic study was carried out with pravastatin 20mg daily in 24 children with familial hypercholesterolaemia (aged 8-16 years; 12 prepubertal, 12 pubertal). A plasma concentration-time curve was performed on day 14. Pharmacokinetic curves for each individual were constructed using nonparametric methods, yielding area under the plasma concentration-time curve (AUC), maximum plasma concentration (C-max) and half-life (t(1)/(2)). Clearance values and volumes of distribution were calculated from these parameters. Cholesterol lowering was observed on day 14 and 6 weeks after the start of pravastatin. Results: The Cmax in prepubertal (group A) children (52.1 +/- 27.0 mug/L [mean +/- SD]) differed, although not significantly (p = 0.09, unpaired two-tailed t-test), from the C-max in adolescents (group B) [31.7 +/- 29.2 mug/L]. There was a moderate negative correlation between Cmax and age (Spearman correlation r = -0.42; p = 0.04). The AUC in prepubertal children (91.3 +/- 39.7 mug (.) h/L) did not differ significantly from the AUC in adolescents (69.3 +/- 57.0 mug (.) h/L). The t(1)/(2) was the same for the two groups: 2.5 +/- 1.1h. Clearance values (CL/f) varied widely between the two groups (group A: 4.3 +/- 1.8 L/min; group B: 11.0 +/- 11.9 L/min; p = 0.08). A moderate positive correlation was found between clearance and age (Spearman correlation r = 0.36; p = 0.09). A large variation was found in the volumes of distribution within the two groups (group A: 31.2 mL/kg [SD 26.7], group B:37.0 mL/kg [SD 29.6]; p = 0.12). A very weak positive correlation was found between age and volume of distribution (Spearman correlation r = 0.11; p = 0.61). A 27% low-density lipoprotein-cholesterol reduction from baseline was achieved at day 14. Conclusions: Body surface area and gender did not influence the pharmacokinetics of pravastatin in children aged 8-16 years. On the basis of our findings there are no reasons to use pravastatin at a dosage according to bodyweight or to use different dosage regimens from those in adults. However, for prepubertal children half the advised starting dose for adults may be sufficient