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Multiple-Dose Pharmacokinetics and Pharmacodynamics of Adinazolam in Elderly Subjects

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Abstract

The pharmacokinetics and pharmacodynamics of adinazolam (AD) were evaluated in 21 elderly subjects (mean age, 69 ± 4 years) at four dose levels during a placebo-controlled, double-blind, dose escalation regimen in which the oral dose was varied from 10 to 60 mg daily, in divided doses. Fifteen subjects received adinazolam mesylate; six received placebo. Plasma samples collected during a single dosing interval in each dosing period (3 days) were assayed for adinazolam and monodesmethyl adinazolam (NDMAD) by high-performance liquid chromatography (HPLC). Urine samples were collected during a single interval during the 20- and 40-mg daily dose periods and assayed for NDMAD by HPLC. Pharmacologic effects of adinazolam were assessed using psychomotor performance tests and sedation ratings. Adinazolam pharmacokinetics were linear over the dosage range studied. Daily dose had no significant effect on dose-normalized AUC and C max for AD. Dose-normalized NDMAD AUC values as well as β values were not significantly affected by the daily dose of adinazolam. The ratio NDMAD/AD was not substantially affected by the dose. Renal clearance of NDMAD for the 20-and 40-mg daily doses were 5.6 ± 2.1 and 5.5 ± 2.2 liters/hr, respectively, and did not correlate with creatinine clearance. Adinazolam and NDMAD did not substantially accumulate in elderly subjects, even upon multiple dosing at 8-hr intervals. The dosing regimens in this experiment appeared to be well tolerated in the elderly, as performance tests and sedation scores indicated no substantial dose-related effects of adinazolam on psychomotor performance.

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Authors and Affiliations

  1. Clinical Pharmacokinetics Unit, The Upjohn Company, Kalamazoo, Michigan, 49001

    Joseph C. Fleishaker, J. Paul Phillips & Randall B. Smith

  2. Kalamazoo Clinical Investigational Complex, The Upjohn Company, Kalamazoo, Michigan, 49001

    Thomas C. Smith

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  1. Joseph C. Fleishaker
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  2. J. Paul Phillips
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  3. Thomas C. Smith
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  4. Randall B. Smith
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Fleishaker, J.C., Phillips, J.P., Smith, T.C. et al. Multiple-Dose Pharmacokinetics and Pharmacodynamics of Adinazolam in Elderly Subjects. Pharm Res 6, 379–386 (1989). https://doi.org/10.1023/A:1015975214070

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