A single centre, double blind, randomised, parallel group, ascending single and multiple dose, safety and tolerability, pharmacokinetic and pharmacodynamic study of vaginal ointment in healthy women volunteers

INTERVENTION: A study to investigate the safety, tolerability, pharmacokinetic, pharmacodynamics of R131 vaginal ointment in healthy women volunteers after multiple doses of 150mg or 300mg. The study will comprise of two cohorts. Cohort 1 will involve the first period comprising of a single 150mg dose of R131 or placebo vaginal ointment with PK blood sapmling during confinement and then the second period comprising of 21 daily doses of 150mg of R131 or placebo vaginal ointment followed by PK blood sampling. Cohort 2 will be administered a 300mg dose of R131 or placebo vaginal ointment in the same dose regimen as cohort 1. Cohort 2 will commence following review and approval of DSMB. The ointment will be self‐administered into the vagina. Full instructions will be given as to its application. Participants will also be asked to provide a vaginal swabs at various intervals throughout the study. The ointment will be given to participants to take home along with the study questionnaires. A diary will also be completed by each participant. To monitor adherence to the intervention product used ointment applicators will be returned and weighed, each participant will be given a diary to complete daily, vaginal swabs will be performed on Day 1, 8, 15 and 21. Pre and post study laboratory tests will be completed to assess the health of participants. The intervention for this study is the ointment formulation of R131. CONDITION: Cervical neoplasia Condyloma acuminatum PRIMARY OUTCOME: To compare the bioavailability of Lopinavir (as summarised by Cmax and AUC) for the formulation. All plasma samples will be assayed for Lopinavir using one fully validated LC/MS/MS method. Validation will be conducted to comply with FDA guidelines. To compare the bioavailability of Ritonavir (as summarised by Cmax and AUC) for the formulation. All plasma samples will be assayed for Ritonavir using one fully validated LC/MS/MS method. Validation will be conducted to comply with FDA guidelines. To evaluate the safety (as summarised by adverse events, vital signs and ECG). SECONDARY OUTCOME: Additional Primary Outcome: To evaluate pharmacodynamics (as summarised by participant rating scores designed specifically for the study) Additional Primary Outcome: To evaluate tolerability (as summarised by participant questionnaires (vaginal irritation questionnaire)) Time to maximum peak concentration (Tmax) of R131 will be determined by plasma sample analysis. Tmax will be the time where the maximum concentration occurred in the sample points. ; ; For those participants receiving the placebo, only samples around the expected Tmax i.e. 2‐3 hours will be assayed with the pre‐dosing samples. INCLUSION CRITERIA: a) Women, 20 to 45 years old, with an intact uterus and vagina. b) Generally, in good health with no clinically significant pulmonary, cardiac, gastroenterological, pancreatic, neurologic, renal, musculoskeletal, rheumatologic, metabolic, neoplastic, or endocrine disease. c) BMI of greater than or equal to 19 and less than or equal to 30.0 d) ECG and vital signs within normal ranges e) Agree to no Alcohol from 48 hours prior to dosing in period 1 until 7 days after receiving the final dose in period 2. f) Abstain from food or beverages containing grapefruit, starfruit, pomegranate, pineapple, or pomelo for the entire study g) Able and willing to abstain from sexual intercourse +/– 6 hours around dosing within Periods 1 and 2 h) Able and willing to use stringent methods of contraception after required abstinence period through to Day 29 (7 days after receiving the final dose in period 2), including the use of a non‐latex condom (for part