A Methodological Comparison of Two Formulations of Temazepam in Pharmacokinetic and Pharmacodynamic Aspects

Abstract

In a double-blind and cross-over study 12 healthy subjects took temazepam 20 mg in two different formulations (soft gelatine capsule or uncoated tablet) and matched placebo at one-week intervals. Plasma temazepam concentrations at 0.5, 1, 2, 3, 8, 12 and 24 hours after treatment were analyzed by gas chromatography. Psychomotor performance was measured objectively (digit symbol substitution, letter cancellation, Maddox wing test) and subjectively (visual analogue scales) before the drug intake and 1, 2 and 3 hours later and the plasma benzodiazepine concentrations were analyzed also by radioreceptor bioassay. The two different formulations were compared in pharmacokinetic and pharmacodynamic terms, and the gas chromatographic and radioreceptor assays were compared. The soft gelatine capsule produced higher peak plasma concentrations than the uncoated tablet. The computed AUCs and elimination half-lives proved to be similar after either formulation. A satisfactory correlation between the bioassayed benzodiazepine concentrations and chemically assayed temazepam was shown. In pharmacodynamic terms the results suggest a shorter and somewhat smaller subjective response for the capsule than for the tablet form.

The use of microcomputer‐based psychomotor tests for the evaluation of benzodiazepine effects on human performance: a review with emphasis on temazepam.

“…The availability of different formulations of temazepam seems to have no significant effect on the performance effects associated with the drug's use. The peak plasma level is slightly, but not significantly, higher and the time to peak plasma level is shorter for the soft gelatin capsule than for either the hard gelatin capsule or for tablets (Fuccella, 1979;Tuomainen, 1989). However, elimination half-life and area under the curve calculations were the same for all formulations.…”

“…Subjective analogue scales showed a significant increase in 'sleepiness' after all active treatments which was greatest between 0.5 and 3 h. A significant increase in the 'clumsiness' rating occurred after temazepam, diazepam, nitrazepam and desmethyldiazepam which was most pronounced between 0.5 and 3 h. Saccadic duration was increased and peak saccadic velocity was lowered after all five treatments indicating altered function of the neurones in the pontine reticular formation and suggestive of impaired motor function. (Fuccella, 1979;Tuomainen, 1989). However, elimination half-life and area under the curve calculations were the same for all formulations.…”

“…To date, a strong correlation between the impairment or trend towards impairment indicated in these studies and the level of drug or metabolites in body fluids has not been established for temazepam or other benzodiazepines Greenblatt et al, 1989;Griffiths et al, 1986;Jansen et al, 1986;Johnson et al, 1990;Kuitunen et al, 1990;Linnoila et al, 1990;Mattila et al, 1986;Seppala et al, 1976;Tuomainen, 1989). Many of the studies that analyzed drug and metabolite levels in plasma did not attempt to correlate those levels to performance effects.…”

The effects of temazepam and ethanol on human psychomotor performance

“…Howevei, other studies have shown no impairment the morning after doses of up to 60 mg with various schedules of administration and test of reaction time, critical flicker fusion, and digit symbol substitution [Carrington and Hindmarch 1980;Griffiths et al 1986;Nicholson 1979;Roth et al 1979;Stanley et al 1987]. Studies in which the effects of temazepam have been evaluated on the day of administration have also been conducted and have shown no impairment on digit symbol substitution after a 15 mg dose in ahard gelatincapsule [Greenblatt 1989] and impairment for up to 3 h after a single 20 mg dose in a soft gelatin capsule on digit symbol substitution and the Maddox wing test for heterophoria [Tuomainen 1989]. The results from many of the studies are difficult to compare based on varied dosing schedules, the doses of temazepam, and the different formulations used (e. g. hard versus soft gelatin capsules).…”