Pharmacokinetics of vaginal versus buccal misoprostol for labor induction at term

Abstract

The IMPROVE study (NCT02408315) compared the efficacy and safety of vaginal and buccal administration of misoprostol for full-term, uncomplicated labor induction. This report compares the pharmacokinetics of misoprostol between vaginal and buccal routes. Women greater than or equal to 14 years of age undergoing induction of labor greater than or equal to 37 weeks gestation without significant complications were randomized to vaginal or buccal misoprostol 25 μg followed by 50 μg doses every 4 h. Misoprostol acid concentrations were determined using liquid chromatography-tandem mass spectrometry for the first 8 h in a subgroup of participants. A population pharmacokinetic model was developed using NONMEM. Plasma concentrations (n = 469) from 47 women were fit to a one-compartment nonlinear clearance model. The absorption rate constant (k_a ) was dependent on both route and dose of administration: buccal 25 μg 0.724 (95% confidence interval, 0.54-0.92) h^-1 ; 50 μg 0.531 (0.37-0.63) h^-1 ; vaginal 25 μg 0.507 (0. 2-1. 4) h^-1 ; and 50 μg 0.246 (0.103-0.453) h^-1 . Relative bioavailability for vaginal compared to buccal route was 2.4 (1.63-4.77). There was no effect of body mass index or age on apparent clearance 705 (431-1099) L/h or apparent volume of distribution 632 (343-1008) L. The area under the concentration-time curve to 4 h following the first 25 μg dose of misoprostol was 16.5 (15.4-17.5) pg h/ml for buccal and 34.3 (32.5-36.1) pg h/ml for vaginal administration. The rate of buccal absorption was two times faster than that of vaginal, whereas bioavailability of vaginal administration was 2.4 times higher than that of buccal. Decreased time to delivery observed with vaginal dosing may be due to higher exposure to misoprostol acid compared to buccal.

FIGURE 1

Observed misoprostol acid plasma concentration versus time profiles following vaginal (blue) or buccal (red) administration of misoprostol (25 μg followed by 50 μg at 4 h). Lines and shaded areas indicate the median and 95% confidence interval of a Loess smooth function.

FIGURE 2

Goodness‐of‐fit plots of the final parametric model: observed versus individual predictions (a), observed versus population prediction (b), conditional weighted residuals (CWRES) versus population predicted concentrations (c), or time after dose (d). Black lines indicate the line of unity a and b or zero c and d, and blue lines indicate linear trends.

FIGURE 3

Predictive check plots of misoprostol acid plasma concentrations following buccal and vaginal dosing of 25 μg of misoprostol dose. AUC_0–4h, area under the curve from 0 to 4 h; OBS indicate observed data, and SIM indicate simulated data.