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A Physiologically Based Pharmacokinetic Model Incorporating Extrahepatic Metabolism Explains Voriconazole Pediatric Bioavailability Differences
Author(s) -
Zane Nicole Rachele,
Thakker Dhiren R.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb544
Subject(s) - bioavailability , pharmacokinetics , confidence interval , clearance , pharmacology , medicine , toxicokinetics , metabolism , chemistry , urology
Voriconazole, a potent antifungal, is cleared predominantly via oxidative metabolism. Clearance is 3‐fold higher and bioavailability is nearly one‐half in children compared to adults. To explain these differences, a physiologically based pharmacokinetic model was developed employing Simcyp. Physiochemical and hepatic in vitro data, derived from adult and pediatric tissues, were utilized in the model. Simulated populations contained 100 patients (10 trials with 10 patients each). Adult and pediatric clearance values were within 20 and 25% of observed values, respectively. Adult PK parameters were within reasonable estimates of published values and the bioavailability 95% confidence interval was 69–93%, well within the clinically observed range. Pediatric IV parameters were well predicted, demonstrating that the model could predict hepatic clearance. However, the oral model over predicted PK values and the bioavailability 95% confidence interval was nearly 2‐fold higher than observed. Incorporating intestinal metabolism improved PK predictions and the 95% confidence for bioavailability was 27–76%, better encompassing the clinically observed range of 44–66%. Overall, pediatric bioavailability improved when intestinal metabolism was included in the model providing an explanation for PK differences between adults and children which, until now, has not been reported.