Pharmaceutical Research

, Volume 14, Issue 3, pp 309–315 | Cite as

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

  • 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.

alprazolam controlled release relative bioavailability NONMEM P450 covariate analysis interoccasion variability 


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Copyright information

© Plenum Publishing Corporation 1997

Authors and Affiliations

  • Mohammad Hossain
    • 1
  • Eugene Wright
    • 2
  • Raman Baweja
    • 1
  • Thomas Ludden
    • 1
  • Raymond Miller
    • 1
  1. 1.Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and ResearchRockville
  2. 2.Clinical Pharmacokinetics UnitThe Upjohn CompanyKalamazoo

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