Objectives: The study describes the pharmacokinetics (PK) of the protease inhibitor nelfinavir and its active metabolite M8 in children and evaluates the influence of patient-related factors on nelfinavir plasma levels.
Methods: HIV-1-infected children treated with nelfinavir every 8 h (q8h) were eligible for inclusion in this retrospective study. 0-8 h intensive plasma pharmacokinetics (PK) sampling was performed at steady state. Nelfinavir maximum concentration (Cmax), area under the plasma concentration-time curve in 0-8 h (AUC0-8), trough level at the 8 h time point (C8) and relative apparent oral clearance (CI*F/kg) were calculated.
Results: Twenty-four children (median age: 4.5 years, median nelfinavir dose: 28 mg/kg q8h) were included. Nelfinavir PK were highly variable: 10/24 children had an AUC0-8 below the value of 12.5 mg/l x h, which has previously been associated with an increased virological failure rate in children. With children aged < 2 years and a dose of 20 mg/kg q8h, a non-significant trend was observed to more AUC0-8 < 12.5 mg/l x h [odds ratio (OR) (95% CI): 2.44 (0.41-14.7) and 8.7 (0.79-95), respectively]. Nelfinavir C8 correlated strongly with AUC0-8 (r = 0.89, P < 0.001). C8 > 0.69 mg/l predicted an AUC0-8 > 12.5 mg/l x h with 71% sensitivity and 80% specificity. Dose of nelfinavir per body surface area was a better predictor of AUC0-8 than dose per body weight.
Conclusion: Nelfinavir PK show high interindividual variability in children. Children < 2 years old tend to be at increased risk for low nelfinavir levels. These data show that the nelfinavir dose of 20 mg/kg q8h is inadequate in most children. Also, these data suggest that paediatric dosing of nelfinavir based on body surface area should be considered. Therapeutic drug monitoring (TDM) can detect abnormal plasma levels and is therefore useful in optimizing nelfinavir therapy in HIV-infected children. However, further research is needed to more firmly establish a therapeutic range for nelfinavir in children.