The pharmacokinetics of mianserin suppositories for rectal administration in dogs and healthy volunteers: a pilot study

Abstract

Background: We formulated mianserin suppositories for the treatment of delirium and evaluated their pharmacokinetics by measuring plasma drug concentrations in dogs and healthy human volunteers.

Methods: Mianserin suppositories were prepared by a melting technique using Tetramide® tablets and Witepsol H-15 as the suppository base. Pharmacokinetics of this 30-mg mianserin preparation were evaluated in three beagle dogs and three healthy adult males, in line with ethics committee approval. Plasma mianserin levels were determined using gas chromatography-mass spectrometry.

Results: In dogs, the maximum plasma mianserin concentration (Cmax) was 1.3 ± 0.4 ng/mL, the time to Cmax (tmax) was 5.5 ± 4.3 h, and the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) was 18.9 ± 1.9 h・ng/mL. In humans, the Cmax was 14.6 ± 6.3 ng/mL, the tmax was 8 h, and the AUC0-24 was 266 ± 103 h・ng/mL.

Conclusions: The current study characterized the pharmacokinetics of mianserin suppositories in dogs and humans. As compared to oral administration, the suppositories produced a lower Cmax and a delayed tmax, although AUC0-24 values were comparable. It will be necessary to identify an appropriate dose that produces an adequate plasma mianserin concentration for effective and safe clinical use.

Trial registration: UMIN000013853.

Keywords: Delirium; Mianserin; Pharmacokinetics; Suppository.

Fig. 1

Pharmacokinetics of 30 mg mianserin after rectal and oral administration to beagle dogs. Data show the mean ± SD, n = 3

Fig. 2

Pharmacokinetics of 30 mg mianserin after rectal administration in healthy adult males. Closed squares represent the data from healthy adult males receiving 30 mg mianserin by rectal administration. Data show the mean ± SD, n = 3. The solid line represents the curve fitted according to the 1-compartment model with first-order absorption equation (1). In order to estimate ka and Vd, mianserin pharmacokinetic data after rectal administration were fitted to equation (1) by nonlinear least-squares regression analysis with a fixed ke value. The estimated values of ka and Vd/F were 0.146 ± 0.052 1/h (mean ± SD, n = 3) and 1395 ± 497 L, respectively

Fig. 3

Predicted pharmacokinetics after rectal administration of mianserin by suppository. a 30 mg × 1, b 30 mg × 2, c 60 mg × 2