Pharmacometrics of clobazam in pediatrics: Prediction of effective clobazam doses for Dravet syndrome
| Autor: | Hui-May Chu, Dwain Tolbert, Ene I. Ette |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Adult Male Pediatrics medicine.medical_specialty Clobazam Adolescent Population Epilepsies Myoclonic 03 medical and health sciences Young Adult 0302 clinical medicine Pharmacokinetics Dravet syndrome medicine Humans Dosing education Child education.field_of_study Dose-Response Relationship Drug business.industry Lennox Gastaut Syndrome Infant Middle Aged medicine.disease Pharmacometrics NONMEM 030104 developmental biology Treatment Outcome Neurology Tolerability Child Preschool Anticonvulsants Female Neurology (clinical) business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Epilepsy research. 157 |
| ISSN: | 1872-6844 |
| Popis: | To describe the use of a population pharmacokinetic (PopPK) model incorporating weight and ontogeny to identify effective clobazam (CLB) dosing for use in a clinical trial in pediatric patients with Dravet syndrome.Pharmacokinetic data were combined from 3 CLB trials (OV-1012, OV-1017, and study 301) and a simulated study (study 401) for a total of 1306 CLB and 1305 N-desmethyl clobazam (N-CLB) samples from 193 Lennox-Gastaut syndrome patients and healthy subjects aged 6 months to 45 years. A structured approach based on US Food and Drug Administration guidance and pharmacometric knowledge discovery was developed using a nonlinear mixed-effects approach. Graphing and fitting using logistical weight regression were used to identify covariates for inclusion in the final model, which was evaluated using goodness-of-fit criteria and validated using prediction-corrected visual predictive check (pcVPC). Using the final PopPK model, a simulation study determined CLB and N-CLB distributions after 4 weeks of 1.5 and 2.0 mg/kg CLB.The parameters of the final PopPK model were similar to previous reports. Fixed-effect parameters were precisely estimated, with no significant increase in NONMEM objective function value. Intersubject variability estimates were similar to previous reports, with35% shrinkage associated with parameter variability, except for intercompartmental clearance and apparent volumes of distribution of peripheral compartments. Goodness-of-fit plots and pcVPC show that the model adequately described CLB and N-CLB data. The CLB/N-CLB ratio in virtual study subjects aged3 years was 0.23 for 1.5 and 2.0 mg/kg and was 0.14 for subjects aged ≥3 years, which is 2 to 3 times those reported in a previous stiripentol/CLB/valproate study in which seizure improvement was reported.The PopPK model dosing parameters of 1.5 and 2.0 mg/kg are likely to result in efficacious concentrations of CLB and N-CLB in pediatric patients as young as 16 months. Dosages exceeding 1.5 mg/kg should be monitored for tolerability, particularly in patients aged2 years, as there may be a higher incidence of sedation. |
| Databáze: | OpenAIRE |
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