Vaginal Suppositories Containing SHetA2 to Treat Cervical Dysplasia: Pharmacokinetics of Daily Doses and Preliminary Safety Profile.

SHetA2 is a new drug with potential to treat cervical dysplasia, but only 0.02% of the dose is absorbed into the cervix after oral administration. By contrast, 23.9% of the dose is absorbed into the cervix after vaginal administration. This study determines the pharmacokinetic and pharmacodynamic parameters after daily vaginal doses of SHetA2 in suppositories and assesses its safety. Daily dosed mice maintained therapeutic concentrations of SHetA2 in the cervix for 65 h. The steady-state area under the curve concentration versus time (AUCcervix) after the last dose was similar to that after a single dose indicating that there was no drug accumulation in the cervix. By contrast, the maximum drug concentration (Cmax-cervix) was smaller in the daily dosed group (52.19 µg/g) than after a single dose (121.84 µg/g), whereas the half-life (t1/2-cervix) was also shorter in the daily dosed group (9.94 h) than after a single dose (23.32 h). Notably, daily vaginal doses of SHetA2 reduced the levels of cyclin D1 (the pharmacodynamic endpoint) to a larger extent (∼45%) than after the administration of a single dose (∼26%). No adverse effects were observed in the mice for the duration of the study; thus, daily vaginal doses of SHetA2 appear to be safe.

Influence of the estrus cycle of the mouse on the disposition of SHetA2 after vaginal administration.

SHetA2 is a novel compound with the potential to treat cervical dysplasia, but has poor water solubility. A vaginal suppository formulation was able to achieve therapeutic concentrations in the cervix of mice, but these concentrations were variable. Histological analysis indicated that mice in the same group were in different stages of their estrous cycle, which is known to induce anatomical changes in their gynecological tissues. We investigated the effects of these changes on the pharmacokinetics and pharmacodynamics of SHetA2 when administered vaginally. Mice were synchronized to be either in estrous or diestrus stage for administration of the SHetA2 suppository. Pharmacokinetic parameters were calculated from the SHetA2 concentrations vs. time data. The reduction in the expression of cyclin D1 protein in the cervix was used as pharmacodynamic endpoint. Mice dosed during diestrus had a larger AUCcervix (335 µg mL h-1), higher Cmax (121.8 ±â€¯38.7 µg/g) and longer t1/2-cervix (30.3 h) compared to mice dosed during estrus (120 µg mL h-1, 44.6 ±â€¯29.5 µg/g and 3.6 h respectively). Therapeutic concentrations of SHetA2 were maintained for 48 h in the cervix of mice dosed during diestrus and for only 12 h in the estrus group. The treatment reduced the expression of cyclin D1 protein in the cervix of mice in the estrus to a larger extent. These results indicate that the estrous cycle of mice influences significantly the disposition of SHetA2 after vaginal administration and may also influence its efficacy.