Pharmacokinetics of vaginal progesterone in pregnancy

Abstract

Characterization of pharmacokinetics is lacking for vaginal progesterone in pregnancy. Dosing of vaginal progesterone for preterm birth prevention has been empirical. Owing 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 pharmacokinetics 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. 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. This is a prospective study of 6 low-risk singletons at 18 0/7 to 23 6/7 weeks' gestation with body mass index 20-40. Exclusion criteria were current vaginitis, abnormal Pap smear, prescription medication use, cervical length ≤25 mm, prior preterm birth, and contraindication to progesterone. Participants received a single dose of 200 mg micronized vaginal progesterone and serum progesterone levels were evaluated every 2 hours from 0 to 12 hours and then 24 hours postdose. Primary outcome was concentration/time profile of serum progesterone. Median (range) maternal age was 27 (21.5-33.3) years, median body mass index 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 (40-52) ng/mL, median peak concentration was 54 (48-68) ng/mL, and median time to peak was 12 (4-15) hours. There was a trend in rising serum progesterone over baseline with a median change in peak concentration of 11 ng/mL and interquartile range of 2-22. Median percent change from baseline was an increase by 24% (interquartile range, 4%-53%). However, there was no clear elimination phase and the median area under the curve was 112 ng*h/mL with an interquartile range of -43 to239. Unlike in nonpregnant 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.