LAUSR

BACKGROUND Characterization of pharmacokinetics (PK) is lacking for vaginal progesterone in pregnancy. Dosing of vaginal progesterone for preterm birth prevention has been empirical. Due to pregnancy-related changes in vaginal and uterine blood flow, hepatic metabolism, renal clearance, and endogenously elevated serum progesterone, studies outside of pregnancy may not be applicable. The lack of the PK profile of vaginally administered progesterone in pregnancy limits the ability to define the exposure:response relationship needed to optimize dosing, which has implications for its use in research and clinical care regarding management of short cervix, prevention of recurrent preterm birth, and prevention of recurrent miscarriage. OBJECTIVE This was a study to establish the feasibility of using serum progesterone to establish basic pharmacokinetic parameters of vaginal progesterone in pregnancy for preterm birth prevention. STUDY DESIGN This is a prospective study of 6 low risk singletons 18 0/7- 23 6/7 weeks' with BMI 20-40. Exclusion criteria were current vaginitis, abnormal pap smear, prescription medication use, cervical length ≤25mm, prior preterm birth, and contraindication to progesterone. Participants received a single dose of 200mg micronized vaginal progesterone and serum progesterone levels were evaluated every two hours from 0 to 12hours and then 24 hours post-dose. Primary outcome was concentration/time profile of serum progesterone. RESULTS Median maternal age was 27 [21.5-33.3] years, median BMI was 26.5 [23.3-29.0] kg/m2, and median gestational age was 22.9 [21.0-23.4] weeks.Median baseline serum progesterone was 47[40 to 52] ng/ml, median peak concentration was 54 [48 to 68]ng/ml, median time to peak was 12 [4 to 15]hours. There was a trend in rising serum progesterone over baseline with a median ΔCmax of 11ng/ml and interquartile range 2 to 22. Median percent change from baseline was an increase by 24% IQR [4% to 53%]. However, there was no clear elimination phase and the median area under the curve was 112ng*h/ml with an IQR of -43 to 239. CONCLUSION Unlike in non-pregnant individuals, administration of vaginal progesterone in pregnant individuals only minimally impacts systemic exposure. There is a limited trend of rising serum progesterone over baseline levels with significant inter-individual variability. Serum progesterone is unlikely to be a good candidate for establishing pharmacokinetics or dosing of vaginal progesterone in pregnancy for preterm birth prevention.