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Published on: April 9, 2014
Pharmacokinetics of nelfinavir in children: influencing factors and dose implications
Alina S Bergshoeff1, Pieter L A Fraaij, Annemarie M C van Rossum
1University Medical Centre, Department of Clinical Pharmacy, Nijmegen, The Netherlands. A.Bergshoeff@akf.umcn.nl
Insights
Nelfinavir pharmacokinetics (PK) are highly variable in children, with younger children at greater risk for inadequate drug levels. Dosing by body surface area and therapeutic drug monitoring are suggested for optimizing nelfinavir therapy in HIV-infected children.
Area of Science:
- Pharmacology
- Pediatric HIV Treatment
- Drug Metabolism
Background:
- Nelfinavir is a protease inhibitor used in treating HIV-1 infection.
- Understanding nelfinavir pharmacokinetics (PK) in children is crucial for effective treatment.
- Patient-related factors can significantly influence drug plasma levels.
Purpose of the Study:
- To describe the pharmacokinetics (PK) of nelfinavir and its active metabolite M8 in HIV-infected children.
- To evaluate how patient-specific factors impact nelfinavir plasma concentrations.
- To assess the adequacy of current nelfinavir dosing regimens in pediatric populations.
Main Methods:
- Retrospective study of HIV-1 infected children receiving nelfinavir every 8 hours (q8h).
- Intensive 0-8 hour plasma PK sampling at steady state.
- Calculation of nelfinavir maximum concentration (Cmax), area under the curve (AUC0-8), trough level (C8), and oral clearance (CI*F/kg).
Main Results:
- High interindividual variability in nelfinavir PK observed among 24 children.
- 10 out of 24 children had AUC0-8 below 12.5 mg/l x h, linked to virological failure.
- Children under 2 years with a 20 mg/kg q8h dose showed a trend towards lower AUC0-8.
- Nelfinavir trough levels (C8) strongly correlated with AUC0-8 (r=0.89, P<0.001).
- Dosing by body surface area predicted AUC0-8 better than weight-based dosing.
Conclusions:
- Nelfinavir PK exhibits significant variability in children, necessitating careful dosing.
- Children under 2 years are at higher risk for suboptimal nelfinavir exposure.
- The 20 mg/kg q8h nelfinavir dose appears inadequate for many pediatric patients.
- Consideration of body surface area for pediatric nelfinavir dosing is recommended.
- Therapeutic drug monitoring (TDM) is valuable for optimizing nelfinavir therapy in children.
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.
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