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. 2011 Jul;205(1):40.e1-8.
doi: 10.1016/j.ajog.2011.03.028. Epub 2011 Mar 22.

Pharmacokinetics of 17-hydroxyprogesterone caproate in multifetal gestation

Steve N Caritis  1 , Shringi Sharma, Raman Venkataramanan, Dwight J Rouse, Alan M Peaceman, Anthony Sciscione, Catherine Y Spong, Michael W Varner, Fergal D Malone, Jay D Iams, Brian M Mercer, John M Thorp Jr, Yoram Sorokin, Marshall Carpenter, Julie Lo, Susan Ramin, Margaret Harper; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network
Collaborators, Affiliations

Pharmacokinetics of 17-hydroxyprogesterone caproate in multifetal gestation

Steve N Caritis et al. Am J Obstet Gynecol. 2011 Jul.

Abstract

Objective: The purpose of this study was to define the pharmacokinetic parameters of 17-hydroxyprogesterone caproate (17-OHPC) in multifetal gestation.

Study design: Blood was obtained at 24-28 weeks' gestation and at 32-35 weeks gestation in 97 women with twin and 26 women with triplet gestation who were receiving 17-OHPC. Six of the women with twins had daily blood sampling for 7 days between 24 and 28 weeks' gestation, and pharmacokinetic parameters were estimated with the use of noncompartmental analysis. Modeling was applied to estimate the population parameters and to simulate various treatment scenarios.

Results: The apparent half-life of 17-OHPC was 10 days. Body mass index significantly impacted 17-OHPC concentrations, but fetal number and parity did not. Apparent clearance was significantly greater in African American than in white women (P = .025).

Conclusion: This is the first pharmacokinetic analysis of 17-OHPC in pregnant women. Determination of half-life, covariates that affect plasma 17-OHPC concentrations, and the modeling of drug behavior provide insights into this drug's pharmacologic properties during multifetal pregnancy.

Trial registration: ClinicalTrials.gov NCT00099164.

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Figures

Figure 1
Figure 1. Mean Plasma Concentration of 17-OHPC Following IM Injection of 250mg
17-OHPC concentration–time profiles for 6 subjects with twins who had sampling done before and then daily for seven days after an injection. Values are mean (±) standard deviation.
Figure 2
Figure 2. Mean Plasma Concentrations of 17-OHPC in Twin and Triplet Gestation During Two Gestational Epochs
Mean (±sd) 17-OHPC concentrations in the 70 subjects with twins and the 12 subjects with triplets who had blood obtained during epoch 1 at 24–28 weeks and epoch 2 at 32–35 weeks. Single asterisk indicates significant difference (p<0.002) between epoch1 and epoch 2 in twins. Concentrations in twins vs triplets were statistically similar (p>0.05) both in epoch 1 and 2. Mann-Whitney test was used for the comparisons.
Figure 3
Figure 3. 17-OHPC Clearance According to Race
A boxplot depicting the median 17-OHPC clearance (individual) estimates associated with different ethnicities. The bars represent 25th (lower bar) and 75th (upper bar) percentile. AA – African Americans (n=14), CA – Caucasians (n=46) and HIS – Hispanics (n=9). The mean clearance in the Caucasians was significantly lower than that of African Americans (p<0.05). The individual estimates were obtained with the final model which included BMI as the covariate. Kruskal-Wallis one-way analysis of variance with Dunn’s post test was used for the comparison.
Figure 4
Figure 4. Simulated Plasma 17-OHPC Concentrations
Simulated plasma concentration time profiles of 17-OHPC in pregnant subjects. The bold indicates the simulated plasma concentration utilizing a dose of 250 mg IM once weekly of 17-OHPC. The lighter line indicates simulated concentrations under various scenarios.

  1. effect of BMI (18, 45 and 27) on plasma concentration time profiles,

  2. effect of adding a loading dose of 1000 mg to the currently recommended regimen, and

  3. effect of changing the dosing schedule from 250 mg once weekly to 500 mg every 2 weeks.

See this image and copyright information in PMC

References

    1. Meis, et al. for the NICHD Maternal-Fetal Medicine Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348:2379–2385. - PubMed
    1. Rouse DJ, et al. for the NICHD Maternal-Fetal Medicine Units Network. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N. Engl J Med. 2007;357:454–461. - PubMed
    1. Caritis SN, et al. for the NICHD Maternal-Fetal Medicine Units Network. Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate a randomized controlled trial. Obstet & Gynecol. 2009;113:285–292. - PMC - PubMed
    1. Combs CA, Carite T, Maurel K, Das A, Porto M. Obstetrix Collaborative Network. Failure of 17-hydroxyprogesterone to reduce neonatal morbidity or prolong triplet pregnancy: a double-blind, randomized clinical trial. Am J Obstet Gynecol. 2010 Sep;203(3):248.e1–248.e9. - PubMed
    1. Berghella V, Figueroa D, Szychowski JM, Owen J, Hankins GD, Iams JD, Sheffield JS, Perez-Delboy A, Wing DA, Guzman ER. Vaginal Ultrasound Trial Consortium. 17-alpha-hydroxyprogesterone caproate for the prevention of preterm birth in women with prior preterm birth and a short cervical length. Am J Obstet Gynecol. 2010 Apr;202(4):351.e1–351.e6. - PMC - PubMed

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