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Pediatric Development of Bosentan Facilitated by Modeling and Simulation
Jochen Zisowsky1, Martine Géhin1, Andjela Kusic-Pajic2
1Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
Paediatric Drugs
|January 13, 2017
Summary
Pharmacokinetic models for bosentan in children were developed to guide dosing for pulmonary arterial hypertension. These models revealed age-related changes affecting drug clearance, aiding in pediatric study design and dose selection.
Area of Science:
- Pharmacology
- Pediatric Pharmacokinetics
Background:
- Bosentan is approved for treating adult pulmonary arterial hypertension.
- Understanding pediatric pharmacokinetics is crucial for safe and effective treatment.
Purpose of the Study:
- To develop pharmacokinetic models for bosentan in pediatric patients.
- To provide guidance for pediatric study design and dose selection.
Main Methods:
- A physiologically based pharmacokinetic model was adapted from adult data.
- Pediatric-specific factors like body weight, age, and enzyme maturation were incorporated.
- Population pharmacokinetic modeling identified relevant covariates.
Main Results:
- Model predictions showed distinct exposures for 0.5 mg/kg and 2 mg/kg doses.
- A 2-hour sampling time point improved exposure estimation accuracy.
- Lower exposure in children was attributed to maturation-related clearance changes, confirmed by clinical data.
Conclusions:
- Maturational changes in drug clearance and body weight are key to pediatric bosentan pharmacokinetics.
- Physiologically based and population pharmacokinetic modeling supported pediatric dose selection.
- Model-based estimates optimized pediatric study design, reducing the number of participants needed.
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