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Pharmacokinetically determined cyclosporine dosage in young children
K Hoppu1, O Koskimies, C Holmberg
1Children's Hospital, Helsinki, Finland.
Insights
Individualizing cyclosporine dosing in young children is crucial due to pharmacokinetic variability. This study determined appropriate doses for children aged 1.1-2.5 years to achieve target blood levels post-renal transplantation.
Area of Science:
- Pharmacology
- Pediatric Nephrology
- Transplantation Medicine
Background:
- Cyclosporine pharmacokinetics exhibit significant inter-individual variability.
- Dosing recommendations for cyclosporine in young children are lacking.
- Accurate dosing is essential for therapeutic efficacy and minimizing toxicity in pediatric renal transplant recipients.
Purpose of the Study:
- To investigate cyclosporine pharmacokinetics in children aged 1.1-2.5 years before renal transplantation.
- To determine appropriate individual cyclosporine doses to achieve target steady-state blood levels (200-300 µg/L) post-transplantation.
- To evaluate the bioavailability of oral versus intravenous cyclosporine administration.
Main Methods:
- Ten pediatric patients (1.1-2.5 years) undergoing renal transplantation were studied.
- Cyclosporine was administered as a single oral dose (10 mg/kg) or a 4-h IV infusion (3 mg/kg).
- Blood concentrations were measured for 24 hours using radioimmunoassay to determine pharmacokinetic parameters (t1/2, clearance, volume of distribution, bioavailability).
Main Results:
- Mean terminal half-life (t1/2) was 9.3 hours, with a wide range (2.8-20.4 h).
- Mean oral bioavailability was low (21.8%), necessitating higher oral doses.
- Calculated daily doses for target trough levels were 5 mg/kg (IV) and 21 mg/kg (oral), often requiring three divided doses daily.
- Predicted doses closely matched actual doses used in the first 10 days post-transplant, with observed mean concentration of 196 µg/L.
Conclusions:
- Individualized pharmacokinetic profiling is essential for optimizing cyclosporine therapy in young pediatric renal transplant recipients.
- Oral cyclosporine demonstrates low bioavailability in this age group, requiring careful dose adjustments.
- The study provides a basis for establishing safe and effective cyclosporine dosing strategies in very young children undergoing renal transplantation.
Abstract:
To account for the individual variability in cyclosporine pharmacokinetics and the non-existence of dosing recommendations in young children, we studied the pharmacokinetics of cyclosporine before renal transplantation in ten children aged 1.1-2.5 years, to determine the appropriate individual dose. Our aim was to reach a steady-state cyclosporine blood level of 200-300 micrograms/l, 8 h after a dose in the first days after renal transplantation. Cyclosporine was given as a single oral dose (10 mg/kg) or as a 4-h i.v. infusion (3 mg/kg), and the blood concentration was determined for 24 h by a specific monoclonal radioimmunoassay. The mean terminal cyclosporine half-life (t1/2) was 9.3 h (range 2.8-20.4), blood clearance 10.8 ml/min per kilogram (range 6.8-22.7) and volume of distribution 2.8 l/kg (range 1.4-4.7). The bioavailability of oral cyclosporine was low; the mean amount absorbed was 21.8% of the administered dose (range 11-35). The mean calculated dose needed to attain the intended predose blood cyclosporine level of 200-300 micrograms/l at steady-state was 5 mg/kg per day for i.v. and 21 mg/kg per day for oral administration. In view of the short t1/2, we used three doses/day. The validity of the predicted doses is shown by the mean cyclosporine doses used during the first 10 days after transplantation, which were 93.5% of the calculated oral and 96.6% of the calculated i.v. doses. The observed mean cyclosporine concentration during the same period was 196 micrograms/l.