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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

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Abstract

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.

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Author notes

  1. Thomas Ludden

    Present address: Department of Pharmaceutical Science, College of Pharmacy, University of Nebraska Medical Center, 600 South 42nd Street, Omaha, Nebraska, 68198

Authors and Affiliations

  1. Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, FDA 5600 Fishers Lane, Rockville, Maryland, 20857

    Mohammad Hossain, Raman Baweja, Thomas Ludden & Raymond Miller

  2. Clinical Pharmacokinetics Unit, The Upjohn Company, Kalamazoo, Michigan

    Eugene Wright

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  1. Mohammad Hossain
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  2. Eugene Wright
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  3. Raman Baweja
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  4. Thomas Ludden
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Hossain, M., Wright, E., Baweja, R. et al. 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. Pharm Res 14, 309–315 (1997). https://doi.org/10.1023/A:1012041920119

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