Lack of Bioequivalence Between Disulfiram Formulations

Lack of bioequivalence between disulfiram formulations Exemplified by a tablet/effervescent tablet study Andersen, M. P. Lack of bioequivalence between disulfiram formulations. Acta Psychiatr Scand 1992: 86: 31-35. M. P. Andersen Pharmacokinetic Laboratory AIS Dumex (Dumex Ltd. ), DK-2300 Copenhagen Abstract – A comparison of the bioavailability of disulfiram (DSF) after administration of non-effervescent Antabusea tablets (CP Pharmaceuticals, UK) and [email protected] tablets [email protected](A/S Dumex, DK) has been made in two cross-over studies. The first study included 6 volunteers who were given 400 mg DSF after an overnight fast.

The bioavailability of DSF after administration of noneffervescent was found to be only 27 Vo of that achieved with effervescent tablets. The second study included 24 volunteers who were given 800 mg DSF after a light standardized meal. The relative bioavailability of DSF after administration of non-effervescent compared with effervescent tablets was found to be only 34 Yo. In addition to the difference in bioavailability of DSF after administration of the two preparations, a considerable difference was seen between the two studies. A light meal seems both to increase the bioavailability of DSF and to reduce the interindividual variation.

A two to threefold increase in the bioavailability of DSF was found. Thus, the bioavailability of DSF appears to depend o n both the formulation (preparation) and the mode of administration. A lack of bioequivalence between the two investigated DSF preparations was found. Keywords: Disulfiram, methyldiethyldithiocarbamate, bioavailability, pharmacokinetics Introduction Although Disulfiram (DSF) has been used in the treatment of alcoholism for many years [l], its pharmacokinetics, including bioavailability and metabolism, are not very well known.

Recent years have seen the introduction of better analytical equipment and some light has been shed on the metabolism of I X F , but new metabolites are still being discovered. The bioavailability of DSF is, however, difficult to measure, partly because DSF cannot be administered intravenously owing to its insolubility in aqueous media, and partly because, after absorption it almost immediately cleaves to its monomer, diethyldithiocarbamate (DDC) [2,3,4],which is again further metabolised. Thus, DSF is not detectable in plasma after a single administration, only after repeated administrations [5].

The bioavailability of DSF in humans has been studied with radioactive labelled DSF (I4Cor 3sS)[ 1,6, 7, 81. Faeces were collected for at least 72 hours after administration and the radioactivity was measured. Bioavailability was found to be 80-90 Yo, i. e. almost complete. This method has the disadvantage that measurement of the radioactivity is non-selective, and decomposition of DSF before absorption is not taken into account. For comparison of the bioavailability of a particular drug substance in various preparations, measurement of a metabolite in plasma is often a useful indicator of the relative bioavailability.

DSF cleaves to its monomer DDC, which is further metabolised to methyl diethyldithiocarbamate (Me-DDC) [2, 9, 10, 111. Me-DDC is stable in plasma, it is produced in measurable amounts, and it has a “suitable” plasma half-life (tm = 6. 3 hours) [lo]. The serum concentration of MeDDC is thus considered a usable measurement of the relative bioavailability of DSF in the comparison of different preparations. The aim of this study was to compare the bioavailability of DSF after oral administration of [email protected] tablets (produced by CP Pharmaceuticals, UK) and [email protected] effervescent tablets (produced by A/S Dumex, DK).

Materials and methods A pilot study was performed before the main study. Both studies were carried out in a randomised cross- 31 M. P. Andersen j , ii i Figure I: Mean serum concentrations of the DSF metabolite Me-DDC as a function of time after oral administration of [email protected] tablets and [email protected] 2 x 200 mg. (n = 6) Figure 2. Mean serum concentrations of the DSF metabolite Me-DDC as a function of time, after administration of 2 x 400 mg DSF as Antabus” effervescent tablets and 4 x 200 mg DSF as [email protected] (n = 24) Lack of bioequivalence between disulfiram formulations ver design with volunteers. The two trial days were separated by a one-week wash-out period. Blood samples were taken from the volunteers according to the following schedule: Before administration, at 15,30,45,60,90, 120, and 150 minutes, and at 3, 4, 6, 8, 10, 12, and 24 hours. Serum samples were assayed for Me-DDC by a specific liquid chromatographic method [ 121. The limit of quantitation was 5 ng/ml. before and, apart from the light meal, until 4 hours after administration. Twenty-four volunteers were entered in the study (14 men and 10 women; mean age 24 4 years). Results of the main study Mean serum concentrations of Me-DDC as a function of time are shown in Fig. 2. The t,, C,,,, AUC? , and AUC; are given in Table I. C,,, is the maximum Me-DDC serum concentration, and t,,, is the time at which it occurs. The half-life (t,,z) of Me-DDC in serum is calculated on the serum concentrations of Me-DDC in the elimination phase (8-24 hours) by single logarithmic regression. AUC? is the area under the serum concentration time curve calculated by the trapezoidal rule. AUC; is found by adding AUCi4 and

AUC; , where AUC; is calculated on the tl,z and the serum concentration of Me-DDC at 24 hours as estimated by linear regression. The relative bioavailability of Me-DDC AUC; (tabl) F,,, = * 100% AUC; (eff. tabl) after administration of the two preparations is shown in Table I. An analysis of variance on C,,,, t,,, and AUC; was done with the main effects, SUBJECT within SEQUENCE (order of treatments), SEQUENCE, PERIOD and TREATMENT. The results are listed in Table 11. No statistically significant difference was found in the t,,, (p = 0. 96), whereas there was a statistically significant difference in the C,,, (p < 0. 0001) and the AUC; (p