Population Pharmacokinetics Analysis of Quetiapine Extended-release Formulation in Japanese Patients with Bipolar Depression |
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| Affiliation: | 1. Astellas Pharma Inc, Tokyo, Japan;2. Astellas Pharma Inc, Ibaraki, Japan;3. Astellas Pharma Global Development Inc, Northbrook, IL, USA;1. Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Immunology, Tufts University School of Medicine, Boston, MA, USA;2. Sackler School of Graduate Biomedical Sciences, Program in Pharmacology and Experimental Therapeutics, Tufts University, Boston, MA, USA;3. Department of Internal Medicine, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA;4. Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA;1. Department of Radiology and Neuroradiology, Ernst Moritz Arndt University Greifswald, Ferdinand-Sauerbruch-Straße NK, Greifswald, D-17475, Germany;2. Department of Clinical Pharmacology, Ernst Moritz Arndt University Greifswald, Felix Hausdorff-Strasse 3, Greifswald, D-17475, Germany;3. Department of Biopharmacy and Pharmaceutical Technology, Ernst Moritz Arndt University Greifswald, Felix Hausdorff-Strasse 3, Greifswald, D-17475, Germany;1. Medical Education, American College of Physicians, Philadelphia, PA, USA;2. Consulting Services, Xcenda, Palm Harbor, FL, USA;3. Janssen Scientific Affairs LLC, Titusville, NJ, USA;4. University of Connecticut School of Pharmacy, Storrs, Connecticut, USA;5. Evidence-Based Practice Center, Hartford Hospital, Hartford, CT, USA;1. Movement Disorders Center, Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil;2. Functional Neurosurgery Division, Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil;3. Service of Interdisciplinary Neuromodulation (SIN), Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry, University of São Paulo, São Paulo, Brazil |
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| Abstract: | PurposeThe objectives of this study were to explore covariates of plasma quetiapine concentrations after oral administration of quetiapine extended-release formulation (XR), and to examine the exposure–response relationship in Japanese patients with bipolar depression, using population pharmacokinetics (PopPK) modeling.MethodsIn a multicenter, randomized, double-blind, placebo-controlled study of quetiapine XR in patients with bipolar depression, plasma for the measurement of quetiapine concentration was collected at weeks 2, 4, 8, 12, 20, 28, and 52 during oral administration of 150 or 300 mg once daily of quetiapine XR before bedtime. A PopPK model of quetiapine XR was developed using nonlinear mixed-effects modeling with first-order conditional estimation with interactions. The exposure–response relationship was examined using post-hoc exposures. The post-hoc AUC estimate was plotted against the change in the Montgomery-Åsberg Depression Rating Scale (ΔMADRS) total score from baseline to 8 weeks following once-daily doses at 300 mg.FindingsThe final PopPK analysis dataset contained 322 patients and 1162 observations (cutoff data at week 28; cutoff date, February 2016). The plasma quetiapine concentration–time profile in patients with bipolar depression after oral administration of quetiapine XR was represented well using a 1-compartment with first-order absorption model. Covariate analysis led to the selection of γ-glutamyl transpeptidase on apparent oral clearance and body weight on apparent volume of distribution as covariates. The final population mean values of apparent oral clearance and apparent volume of distribution were 87.7 L/h and 277 L, respectively, and the interindividual %CVs were 32.6% and 75.0%, respectively.ImplicationsThe effects of covariates on PK parameters were not large compared with the interindividual variability. In addition, there was no clear relationship between the AUC and ΔMADRS. ClinicalTrials.gov identifier: NCT01725308. |
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| Keywords: | bipolar disorder exposure–response Japanese population pharmacokinetics quetiapine extended-release formulation |
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