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

ABSTRACT

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.