NDLI: Use of a Local Sensitivity Analysis to Inform Study Design Based on a Mechanistic Toxicokinetic Model for γ-Hydroxybutyric Acid

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Use of a Local Sensitivity Analysis to Inform Study Design Based on a Mechanistic Toxicokinetic Model for γ-Hydroxybutyric Acid

Content Provider	Springer Nature Link
Author	Felmlee, Melanie A. Krzyzanski, Wojciech Morse, Bridget L. Morris, Marilyn E.
Copyright Year	2011
Abstract	γ-Hydroxybutyric acid (GHB), a drug of abuse, demonstrates complex toxicokinetics with capacity-limited metabolism and active renal reabsorption. The objectives of the present study were to conduct a local sensitivity analysis of a mechanistic model for the active renal reabsorption of GHB and to use the results to inform the design of future studies aimed at developing therapeutic strategies for treating GHB overdoses. A local sensitivity analysis was used to assess the influence of parameter perturbations on model outputs (plasma concentrations and urinary excretion of GHB). Further, a sensitivity index was calculated for each perturbed parameter to assess the specific segments of the time course that are critical to parameter estimation. Model outputs were simulated for rats dosed with 200, 400, 600, and 1,000 mg/kg GHB intravenously and individual parameters were perturbed by two-, five-, and tenfold higher and lower than the nominal value. Model outputs were sensitive to perturbations in clearance and volume parameters. In contrast, model outputs were found to be insensitive to changes in distributional parameters suggesting that additional tissue distribution data is required. Based on the sensitivity analysis the 1,000-mg/kg GHB dose can be eliminated from future studies as the parameters can be adequately estimated from the lower doses. To further validate the use of this model, dose-specific sampling schedules were designed based on model predictions for doses of 600 and 1,500 mg/kg. These sampling schedules were able to adequately capture the inflection point and terminal elimination phase of the plasma concentration–time profiles obtained.
Starting Page	240
Ending Page	254
Page Count	15
File Format	PDF
ISSN	12341234
Journal	The AAPS Journal
Volume Number	13
Issue Number	2
e-ISSN	15507416
Language	English
Publisher	Springer US
Publisher Date	2011-03-09
Publisher Institution	American Association of Pharmaceutical Scientists
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	active renal reabsorption gamma-hydroxybutyric acid monocarboxylate transporters sensitivity analysis Pharmacy Biotechnology Biochemistry Pharmacology/Toxicology
Content Type	Text
Resource Type	Article

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Mechanistic Toxicokinetic Model for γ-Hydroxybutyric Acid: Inhibition of Active Renal Reabsorption as a Potential Therapeutic Strategy

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