caa a22 4500 477126871 CHVBK 20180405111652.0 cr unu---uuuuu 170330e19970301xx s 000 0 eng 10.1023/A:1012041920119 doi (NATIONALLICENCE)springer-10.1023/A:1012041920119 Nonlinear Mixed Effects Modeling of Single Dose and Multiple Dose Data for an Immediate Release (IR) and a Controlled Release (CR) Dosage Form of Alprazolam [Elektronische Daten] [Mohammad Hossain, Eugene Wright, Raman Baweja, Thomas Ludden, Raymond Miller] Purpose. NONMEM was applied to single dose and multiple dose bioavailability data for an immediate release (IR) and a controlled release (CR) dosage form of alprazolam to acquire additional information from the data which are not easily obtainable by traditional means. Methods. The objective function value (OBJ) and diagnostic plots were used as measures of goodness of fit of the model to the data. A change in the OBJ value of 7.9 was necessary to show statistical significance (p < 0.005) between two models when the two models differed by 1 parameter. Results. A two-compartment linear model with first-order absorption and elimination best describes the data. Including a lag time, two different rates of absorption (KAIR and KACR), and bioavailability for the CR relative to the IR dosage form significantly improved the fit of the model to the data. Cigarette smoking was associated with a 100% increase in clearance of alprazolam as compared to non-smokers. The higher residual variability observed in this study, where interoccasion variability (IOV) was not initially modeled, could be explained to a large extent by the presence of significant interoccasion variability (IOV). Conclusions. Since alprazolam has been suggested to be mainly metabolized by the CYP3A4 isozyme in humans, it appears that tobacco could be an inducer of CYP3A4 and/or alprazolam may be metabolized by other isozyme(s) (specifically, CYP1A1/1A2) that are induced by cigarette smoke. The population pharmacokinetic model approach combined with exploratory graphical data analysis is capable of identifying important covariates from well-controlled 'data rich' Phase I studies early in drug development. Plenum Publishing Corporation, 1997 alprazolam nationallicence controlled release nationallicence relative bioavailability nationallicence NONMEM nationallicence P450 nationallicence covariate analysis nationallicence interoccasion variability nationallicence Hossain Mohammad Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, FDA 5600 Fishers Lane, 20857, Rockville, Maryland aut Wright Eugene Clinical Pharmacokinetics Unit, The Upjohn Company, Kalamazoo, Michigan aut Baweja Raman Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, FDA 5600 Fishers Lane, 20857, Rockville, Maryland aut Ludden Thomas Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, FDA 5600 Fishers Lane, 20857, Rockville, Maryland aut Miller Raymond Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, FDA 5600 Fishers Lane, 20857, Rockville, Maryland aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/3(1997-03-01), 309-315 0724-8741 14:3<309 1997 14 11095 https://doi.org/10.1023/A:1012041920119 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012041920119 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Hossain Mohammad Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, FDA 5600 Fishers Lane, 20857, Rockville, Maryland aut NATIONALLICENCE 700 1- Wright Eugene Clinical Pharmacokinetics Unit, The Upjohn Company, Kalamazoo, Michigan aut NATIONALLICENCE 700 1- Baweja Raman Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, FDA 5600 Fishers Lane, 20857, Rockville, Maryland aut NATIONALLICENCE 700 1- Ludden Thomas Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, FDA 5600 Fishers Lane, 20857, Rockville, Maryland aut NATIONALLICENCE 700 1- Miller Raymond Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, FDA 5600 Fishers Lane, 20857, Rockville, Maryland aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/3(1997-03-01), 309-315 0724-8741 14:3<309 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer