Dose selection and population pharmacokinetics of PEG-Intron in patients with chronic myelogenous leukaemia

Abstract

Aims: To assess the dose selection using population pharmacokinetics of Pegylated Intron-alpha2b (PEG-Intron) in patients with chronic myelogenous leukaemia (CML).

Methods: PEG-Intron 3-6 microg kg(-1) was administered subcutaneously once a week and blood samples were collected up to 48 weeks of treatment. A total of 624 samples collected from 137 patients were included in the analysis. Nonlinear mixed-effects modelling was used to analyse the sparsely sampled concentration data from a clinical efficacy trial. Covariates in the analysis included weight, sex, age, race, serum creatinine and estimated creatinine clearance (CLcr).

Results: The apparent clearance of PEG-Intron decreased after repeated dosing. The clearance at treatment week 4 was 42.3 l day(-1) (patients with CLcr 120 ml min(-1)) with interpatient variability 30%. At treatment week 48, the clearance value was reduced to 69% of its week 4 value. CLcr, a composite variable calculated from body weight, sex, age and serum creatinine, had a small but statistically significant influence on the clearance of PEG-Intron. The clearance of PEG-Intron in patients with CML was 40% higher than that of hepatitis C virus-infected patients.

Conclusion: The dose of PEG-Intron 6.0 microg kg(-1) week(-1) appeared appropriate in the treatment of patients with CML.

Figures

Figure 1

Plots of PEG-Intron immunoassay concentration data (pg ml−1) vs. elapsed time from last dose by treatment week. The broken line is the fitted line generated using population mean parameters

Figure 3

Individual T50 estimates vs. covariates and some clinical and demographic variables

Figure 4

Mean PEG-Intron apparent clearance relative to duration of treatment. The solid line is for the current chronic myelogenous leukaemia trial and the three broken lines are for previous chronic hepatitis C trial [9, 10]. The smooth lines (solid and broken) were obtained using local linear regression (‘loess’ function in S-plus). 6.0 mcg/kg (——–), 0.5 mcg/kg (—), 1.0 mcg/kg (—), 1.5 mcg/kg (—)

Figure 2

Individual CL0 estimates vs. covariates and some demographic and clinical variables