Background: Cerebral malaria is a fatal disease. Patients with cerebral malaria are at risk of seizure development, therefore, the co-administration of antimalarial and antiepileptic drugs are needed. Quinine and phenobarbital are standard drugs for the treatment of cerebral malaria with seizures. However, there is no information on the optimal dosage regimens of both drugs when used concomitantly.T he study applied physiologically-based pharmacokinetic (PBPK) modeling for prediction of the optimal dose regimens of quinine and phenobarbital when co-administered in patients with cerebral malaria and concurrent seizures who carry wild type and polymorphic cytochrome P450 (CYP450) 2C9/2C19.
Methods: The whole-body PBPK models for quinine and phenobarbital were constructed based on the previously published information using Simbiology®. One hundred virtual population were simulated. Four published articles were used for model verification. Sensitivity analysis was carried out to determine the effect of the changes in model parameters on AUC0–72h. Simulation of optimal dose regimens was based on standard drug-drug interactions (DDIs), and actual clinical use study approaches.
Results: Dose adjustment of the standard regimen of phenobarbital is not required when co-administered with quinine. The proposed optimal dose regimen for quinine, when co-administered with phenobarbital for patients with a single or continuous seizure in all malaria-endemic areas regardless of CYP2C9/CYP2C19 genotypes, is a loading dose of 1,500 mg IV infusion over 8 hours, followed by 1,200 mg infusion over 8 hours given three times daily, or multiple doses of 1,400 mg IV infusion over 8 hours, given three times daily. In areas with quinine resistance, the dose regimen should be increased as a loading dose of 2,000 mg IV infusion over 8 hours, followed by 1,750 mg infusion over 8 hours given three times daily.
Conclusion: The developed PBPK models are reliable, and successfully predicted the optimal doses regimens of quinine-phenobarbital co-administration with no requirement of CYP2C9/CYP2C19 genotyping.