Computer-aided dosage form design. III, Feasibility assessment for an oral prolonged-release phenytoin product

Previous publications described computer-aided methodology for assessing the feasibility of designing prolonged release oral dosage forms containing linear-disposition drugs. Those methods determined all useful release rates and examined those rates to decide whether product development was warrante...

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Bibliographic Details
Published in:Pharmaceutical research 1991-02, Vol.8 (2), p.232-237
Main Authors: IRVIN, J. R, NOTARI, R. E
Format: Article
Language:English
Subjects:
Absorption
Administration, Oral
Biological and medical sciences
Computers
Delayed-Action Preparations
Drug Administration Schedule
Feasibility Studies
General pharmacology
Humans
Medical sciences
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Phenytoin - administration & dosage
Phenytoin - pharmacokinetics
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Summary:Previous publications described computer-aided methodology for assessing the feasibility of designing prolonged release oral dosage forms containing linear-disposition drugs. Those methods determined all useful release rates and examined those rates to decide whether product development was warranted. The present study developed software to obtain similar information for phenytoin, which exhibits Michaelis-Menten disposition. The values for Vmax, Km, and Vd in 27 patients were employed to assess the ability of prolonged absorption to maintain steady-state plasma concentrations between 10 and 20 mg/liter following oral administration at 8-, 12-, and 24-hr intervals. Phenytoin steady-state plasma concentrations in this range were controlled by elimination and were not extended by prolonged absorption. Furthermore, single i.v. bolus doses resulting in an initial plasma level of 20 mg/liter provided concentrations above 10 mg/liter for approximately 1 to 3 days. When an oral multiple-dose regimen was found to maintain steady-state concentrations between 10 and 20 mg/liter, that dose and interval produced concentrations within that range regardless of the absorption rate. While absorption rate was not important, each patient's dose ranges were extremely narrow, emphasizing that dose size was the dominant factor in the control of phenytoin levels.
ISSN:0724-8741
1573-904X
DOI:10.1023/A:1015852306356