Related Experiment Video
Updated: Aug 10, 2026

A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
Nonlinear mixed effects modeling of single dose and multiple dose data for an immediate release (IR) and a controlled
M Hossain1, E Wright, R Baweja
1Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, FDA, Rockville, Maryland 20857, USA.
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.
Related Concept Videos
One-Compartment Open Model for IV Bolus Administration: General Considerations
The drug's presence in the body is defined by an equation representing the difference between the rates of drug entry and exit. Key parameters—elimination rate constant, half-life,...
Nonlinear Pharmacokinetics: Dependence of Elimination Half-Life and Dose Clearance
A study on guinea pigs examined the...
Bioavailability Study Design: Single Versus Multiple Dose Studies
Drug Accumulation During Multiple Dosing: Repetitive IV Injections
Pharmacodynamic Models: Additive and Proportional Drug Effect Model
Modified-Release Drug Delivery Systems: Drug Release Characteristics

