title: Development of physiologically based pharmacokinetic model to evaluate the relative systemic exposure to quetiapine after administration of IR and XR formulations to adults, children and adolescents.
abstract: Quetiapine is an atypical antipsychotic drug with a high permeability, moderate solubility and defined as a Biopharmaceutics Classification System class ll compound. The pharmacokinetics (PK) of the quetiapine immediate-release (IR) formulation has been studied in both adults and children, but the quetiapine extended-release (XR) formulation has only been conducted in adults. The purpose of the current study was to use physiologically based pharmacokinetic modeling (PBPK) quantitatively to predict the PK of the XR formulation in children and adolescents. Using a 'learn and confirm' approach, PBPK models were developed employing in vitro ADME and physicochemical data, clinical PK data of quetiapine IR/XR in adults and clinical PK data of quetiapine IR in children. These models can predict well the effects of CYP3A4 inhibition and induction on the PK of quetiapine, the PK profile of quetiapine IR in children and adults, and the PK profile of quetiapine XR in adults. The AUC and Cmax ratios (children vs adults) for the different age groups were in reasonable agreement with the observed ratios. In addition, the PBPK model predicted that children and adolescents are likely to achieve a similar exposure following administration of either the XR formulation once daily or the IR formulation twice daily at similar total daily doses. The results from the study can help inform dosing regimens in pediatrics using the quetiapine XR formulation.
authors.affiliation: Simcyp Ltd, Sheffield, UK.
authors.forename: Trevor N
authors.initials: TN
authors.lastname: Johnson
authors.forename: Diansong
authors.initials: D
authors.lastname: Zhou
authors.forename: Khanh H
authors.initials: KH
authors.lastname: Bui
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000494:pharmacology; D002648:Child; D003198:Computer Simulation; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics; D003987:Dibenzothiazepines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007660:Ketoprofen / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000069348:Quetiapine Fumarate; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D002220:Carbamazepine; D007660:Ketoprofen; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: PBPK; extended-release formulation; quetiapine