Pharmacokinetics of Intravaginal, Self-Administered Artesunate Vaginal Inserts Among Healthy Women in Kenya

Background Cervical precancer (CIN2/3) remains undertreated in low- and middle-income countries due to limited access to screening and healthcare providers, contributing towards high cervical cancer mortality rates. Self administered intravaginal therapies, such as artesunate, may help to expand access to cervical precancer treatment. However, data on the systemic absorption and pharmacokinetics of intravaginal artesunate are lacking. Objective This study aimed to characterize the pharmacokinetics and safety parameters of intravaginally administered artesunate. Methods This is a Phase I, single arm, open label pharmacokinetic study of 12 healthy women in Kisumu, Kenya who self-administered 200 mg artesunate vaginal pessaries once daily for 5 consecutive days under direct observation with daily safety assessments. Participants returned each day for supervised dosing and adverse-effect assessments on days 1 to 4 without pharmacokinetic blood sampling. On day 5, participants administered the final dose and underwent serial blood sampling at 0.25, 0.5, 1, 2, 4, 6, and 8 hours. Plasma concentrations of artesunate and dihydroartemisinin (DHA), its active metabolite, were quantified and pharmacokinetic parameters estimated using non-compartmental analysis. Results Artesunate and its active metabolite dihydroartemisinin (DHA) were detectable in all participants, with mean (SD) Cmax values of 83.7 (42.7) ng/mL and 97.0 (53.1) ng/mL, respectively, and a mean DHA AUC(0.T)h of 504.2 (281.1) ng.h/mL. Additionally, the mean Tmax values for Artesunate and DHA are 4.17(1.59) hours and 6.33 (1.67) hours respectively. Due to delayed absorption (Tmax), area under the serum concentration versus time curve (AUC), apparent clearance, and elimination half-life could not be calculated. The treatment was well tolerated with no serious adverse events. Conclusion Peak DHA concentrations (range 19.7 to 180.6 ng/mL) were substantially lower than those reported for intravenous and oral administration with interpatient variability (CV 54.8% for Cmax and 55.8% for AUC0 T) hours) consistent with those reported for other non-intravenous routes of administration. Intravaginally-administered artesunate yielded low, yet measurable, systemic exposure with delayed Tmax. These findings support further investigation of intravaginal artesunate as a safe self-administered treatment for cervical precancer.