Population pharmacokinetics and optimal design of paediatric studies for famciclovir
Kayode Ogungbenro1, Ivan Matthews, Michael Looby
1Centre for Applied Pharmacokinetics Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9, UK. kayode.ogungbenro@manchester.ac.uk
Insights
A population pharmacokinetic model for penciclovir was developed in adults and children. A 10 mg/kg oral dose is recommended for children, with a suggested blood sampling strategy for future studies.
Area of Science:
- Pharmacology
- Clinical Pharmacology
- Drug Development
Background:
- Penciclovir, an antiviral agent, requires pharmacokinetic understanding for optimal dosing.
- Famciclovir serves as a prodrug, necessitating separate pharmacokinetic modeling of penciclovir.
- Pediatric dosing requires specific pharmacokinetic evaluation due to physiological differences.
Purpose of the Study:
- To establish a population pharmacokinetic model for penciclovir in both adult and pediatric populations.
- To determine an appropriate oral penciclovir dose for children based on adult exposure.
- To design a limited sampling strategy for future pediatric pharmacokinetic studies.
Main Methods:
- Population pharmacokinetic modeling was performed using NONMEM V.
- Pharmacokinetic data from six adult and pediatric studies were analyzed.
- MATLAB simulations were used for dose selection and sampling design optimization.
Main Results:
- A two-compartment model with allometric scaling for body weight, age, and creatinine clearance accurately described penciclovir pharmacokinetics.
- An oral dose of 10 mg/kg in children was predicted to achieve similar exposure to 500 mg in adults.
- A sampling window design with five samples per subject across three pediatric age groups was recommended.
Conclusions:
- A robust population pharmacokinetic model for penciclovir in adults and children has been successfully developed.
- The study provides recommendations for prospective study design, including dose adjustments and sampling strategies.
- This research facilitates optimized penciclovir therapy in pediatric populations.
Aims:
To develop a population pharmacokinetic model for penciclovir (famciclovir is a prodrug of penciclovir) in adults and children and suggest an appropriate dose for children. Furthermore, to develop a limited sampling design based on sampling windows for three different paediatric age groups (1-2, 2-5 and 5-12 years) using an adequate number of subjects for future pharmacokinetic studies.
Methods:
Penciclovir plasma data from six different adult and paediatric studies were supplied by Novartis. Population pharmacokinetic modelling was undertaken in NONMEM version VI. Simulations in MATLAB were used to select an oral paediatric dose that gives similar exposure to 500 mg in adults. Optimal sampling times and sampling windows were obtained in MATLAB and simulations in NONMEM were used to select adequate sample sizes for three paediatric age groups.
Results:
A two-compartment, first-order absorption model with an absorption lag time, allometric weight models on V(1), V(2) and Q, and an allometric weight model, age and creatinine clearance as covariates on CL adequately describe the pharmacokinetics of penciclovir in adults and children. Estimated CL (l h(-1) 70 kg(-1)) and V(ss) (l.70 kg(-1)) were 31.2 and 83.1, respectively. An oral dose of 10 mg kg(-1) body weight in children was predicted to give similar exposure as 500 mg in adults. A single sampling windows design (0.25-0.4, 0.5-1, 1.25-1.75, 2.75-3.5 and 7.25-8 h) for five samples per subject and 10 subjects in each of the paediatric age groups is recommended for future studies.
Conclusions:
A population pharmacokinetic model of penciclovir in adults and children has been developed. A prospective study design, including dose adjustment, cohort size and blood sampling design has been recommended.
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