Cervical cancer, a disease of the cervix – the entrance of the womb is the second common cause of cancer in women around the world. Women in low- and middle-income countries like Kenya face the highest burden of cervical cancer. Cervical cancer is caused by human papillomavirus (HPV) infection. It can be prevented through vaccination against the HPV virus, and screening to find early changes in the cervix, called precancerous changes – scientifically called cervical intraepithelial neoplasia, which can be treated by a medical provider to prevent it from progressing to cancer. The HPV vaccines are new in Kenya and other low-income countries, and most women over 20 years of age have never been vaccinated. Screening for cervical cancer and treating precancerous lesions will prevent millions of unvaccinated women from getting diagnosed with cervical cancer. Current treatments for cervical precancer rely on a healthcare provider to perform them. In countries like Kenya and other LMICs where there are few nurses and doctors, many women found with precancer are often referred to far facilities to access treatment. Due to costs and other challenges, many women are unable to access referral centers with providers who can treat cervical precancer. Scientists are studying whether women with cervical precancer can use self-administered treatments with medications like a cream or pessary, to treat precancer, instead of relying on a health care provider to perform the treatment. One self-administered treatment being studied is a pessary formulation of the medication Artesunate, which is used to treat malaria in Africa and other places. A study in the United States has shown that Artesunate pessaries (vaginal inserts) are safe to use for precancer treatment, and ~ 70% women who used them were cured. Before Artesunate can be considered as a precancer treatment in Kenya and places like it, scientists need to understand whether using Artesunate as an intravaginal pessary can affect how it works to treat malaria – whether using it intravaginally can reduce its effect as a malaria treatment (developing resistance). This study is being done to investigate the blood levels of Artesunate when women use artesunate pessaries in the dosing being studied for cervical precancer. In other words, scientists are asking whether if a woman uses 200mg of artesunate pessary daily for five days, the medication can be found in the blood which could result in the medication being resistant to treating malaria. This is unlikely as the dosage used in the intravaginal pessary is much lower than the dosage used to treat malaria, and absorption of drugs in the vagina is much lower than when taken by mouth or used rectal – which is another way malaria drugs are given to children. To help answer this question of whether using low dose Artesunate pessaries for treating cervical precancer can cause resistance for malaria treatment, up to 16 female participants will be enrolled in this study. Study participants will use artesunate pessaries once daily for 5 days in the study clinic, and have blood drawn once on day 1 (prior to first pessary use), and six times on day 5 (last day of pessary use) to measure the artesunate drug levels in the blood. On day 5, participants will have a cannula placed and blood drawn from the cannula. The volume of blood drawn each time will be approximately 3 ml, less than a teaspoon. In comparison, when a person donates blood, approximately 500 ml of blood is drawn. The goal of this study is to confirm that artesunate pessaries can be used intravaginally for treatment of cervical precancer without creating resistance of the drug for treating malaria to enable studies on its use for precancer treatment.

Background: While preventable, cervical cancer is the second most common cancer among women globally, accounting for approximately 600,000 new cases and 300,000 deaths per year. Due to lack of access to primary and secondary prevention, women living in low-and middle-income countries bear a disproportionate burden of cervical cancer, accounting for 90% of new cases and 85% of deaths globally. Cervical cancer can be prevented through vaccination against Human papillomavirus (HPV), whose infection is required to develop cervical cancer. Among unvaccinated women, screening for HPV or cervical precancer allows identification of precancerous lesions – primarily cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3), that can be treated and cured, to prevent progression to cancer. Most CIN2/3 lesions that are left untreated will progress to invasive cervical cancer. Current treatments for CIN2/3 in both high- and low-resource countries (LMICs) require trained health care providers, who are often out of reach for many women, particularly in rural areas in LMICs. Lack of access to precancer treatment following screening in LMICs in part accounts for the high burden of incident cervical cancer. Preclinical data have demonstrated pro-apoptotic effects of Artesunate (AS), a commonly available drug with an excellent safety profile in oral, rectal and intravenous routes primarily used to treat malaria in LMICS. This led to a recent Phase I study in the United States that demonstrated that self-administered vaginal artesunate inserts (pessaries) are safe, well-tolerated, and demonstrate efficacy for treatment of CIN2/3. Based on the mechanism of action, the clinical safety profile, and widespread availability as a generic drug on the World Health Organization (WHO) List of Essential Medications, vaginal artesunate inserts (pessaries), if backed by data from randomized trials, may offer patient-controlled and access cervical precancer treatment method for women in LMICs who face the greatest burden of cervical cancer and have difficulty accessing skilled providers for precancer treatment. However, given that artesunate is a well-known drug used in malaria treatment, it is critical to ensure that vaginal application of the drug will not promote resistance for use in malaria treatment.

     Objectives: The proposed study seeks to investigate the pharmacokinetics of Artesunate (AS) and dihydroartemisinin (DHA), the active metabolite of artesunate, following intravaginal use at the dosing and frequency being studied for cervical precancer treatment. A secondary objective is to investigate safety among study participants.

            Methods: As a recent study demonstrated safety and tolerability of intravaginal artesunate among women with CIN2/3 and the safety of artesunate is well documented in numerous malaria studies, the proposed study will be conducted in female volunteers regardless of their HPV or cervical precancer disease status. In this single arm study, blood levels of DHA and artesunate following 5 daily applications of vaginal artesunate inserts (pessaries) will be measured. A sample size of twelve participants (N=12) are needed. Up to 16 will be consented to account for drop offs. Eligible participants will self-administer artesunate vaginal inserts (pessaries) daily in the study clinic for 5 days. Participants will undergo a blood draw prior to receiving the first dose of artesunate, and on day 5 before inserting the vaginal insert, and at 15 min, 30 mins, 1, 2, 4, 6, and 8 hours after. In each patient, pharmacokinetic parameters of artesunate and DHA will be calculated via quantitative analysis of with determination of maximum concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration versus time curve (AUC), apparent clearance, and elimination half-life (t1/2).