CC BY-NC-ND 4.0 · AJP Rep 2018; 08(02): e106-e112
DOI: 10.1055/s-0038-1639331
Case Report
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Pharmacokinetics of Hydroxyprogesterone Caproate and its Primary Metabolites during Pregnancy

Kim A. Boggess
1   University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Jeffrey B. Baker
2   Rosemark Women Care Specialists, Idaho Falls, Idaho
,
Amy P. Murtha
3   Duke University, Durham, North Carolina
,
Alan M. Peaceman
4   Northwestern University, Chicago, Illinois
,
Dinesh M. Shah
5   University of Wisconsin, Madison, Wisconsin
,
Sylvia L. Siegfried
6   Altus Research Inc., Lake Worth, Florida
,
Robert Birch
7   AMAG Pharmaceuticals, Waltham, Massachusetts
› Author Affiliations
Further Information

Publication History

09 October 2017

15 January 2018

Publication Date:
14 May 2018 (online)

Abstract

Objective To measure pharmacokinetics of hydroxyprogesterone caproate (OHPC) and its major metabolites throughout pregnancy.

Study Design Thirty women were prescribed OHPC for recurrent preterm birth prevention. Three cohorts of subjects had blood drawn for 7 consecutive days at one of three times: cohort 1 (n = 6) after the first dose (weeks 16–20), cohort 2 (n = 8) between weeks 24 and 28, and cohort 3 (n = 16) between weeks 32 and 36. We measured serum trough levels after week 1 in cohort 1 or after two consecutive weekly doses in cohorts 2 and 3. In 10 subjects, we estimated OHPC terminal half-life at 28 days after their last dose.

Results In cohorts 1, 2, and 3, the areas under curve (ng × h/mL) for OHPC were 571.4 ± 195.2, 1,269.6 ± 285.0, and 1,268.0 ± 511.6, respectively. Maximum OHPC levels (ng/mL) were 5.0 ± 1.5, 12.5 ± 3.9, and 12.3 ± 4.9, respectively. The areas under the curve for mono-hydroxylated metabolites were 208.5 ± 92.4, 157.1 ± 64.6, and 211.2 ± 113.1, and maximum concentrations were 1.9 ± 0.7, 1.5 ± 0.7, and 1.8 ± 1.0, respectively. Di-hydroxylated metabolite levels were significantly lower than mono-hydroxylated metabolites. Estimated terminal half-life of OHPC was 16.3 ± 3.6 days and 19.7 ± 6.2 days for the mono-hydroxylated metabolites.

Conclusion After the first injection, OHPC maximum serum level was approximately half steady-state level. Measurable metabolites of unknown activity were detected.

 
  • References

  • 1 Blencowe H, Cousens S, Oestergaard MZ. , et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012; 379 (9832): 2162-2172
  • 2 Martin JA, Hamilton BE, Sutton PD. , et al. Births: final data for 2006. Natl Vital Stat Rep 2009; 57 (07) 1-104
  • 3 Martin JA, Hamilton BE, Osterman MJ, Curtin SC, Matthews TJ. Births: final data for 2013. Natl Vital Stat Rep 2015; 64 (01) 1-65
  • 4 Caritis SN, Sharma S, Venkataramanan R. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetrical-Fetal Pharmacology Research Units Network. Pharmacology and placental transport of 17-hydroxyprogesterone caproate in singleton gestation. Am J Obstet Gynecol 2012; 207 (05) 398.e1-398.e8
  • 5 Caritis SN, Sharma S, Venkataramanan R. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Pharmacokinetics of 17-hydroxyprogesterone caproate in multifetal gestation. Am J Obstet Gynecol 2011; 205 (01) 40.e1-40.e8
  • 6 Meis PJ, Klebanoff M, Thom E. , et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003; 348 (24) 2379-2385
  • 7 Johnson JW, Austin KL, Jones GS, Davis GH, King TM. Efficacy of 17alpha-hydroxyprogesterone caproate in the prevention of premature labor. N Engl J Med 1975; 293 (14) 675-680
  • 8 Johnson JW, Lee PA, Zachary AS, Calhoun S, Migeon CJ. High-risk prematurity--progestin treatment and steroid studies. Obstet Gynecol 1979; 54 (04) 412-418
  • 9 Hauth JC, Gilstrap III LC, Brekken AL, Hauth JM. The effect of 17α-hydroxyprogesterone caproate on pregnancy outcome in an active-duty military population. Am J Obstet Gynecol 1983; 146 (02) 187-190
  • 10 Heyborne KD, Allshouse AA, Carey JC. Does 17-alpha hydroxyprogesterone caproate prevent recurrent preterm birth in obese women?. Am J Obstet Gynecol 2015; 213 (06) 844.e1-844.e6
  • 11 Meis PJ, Klebanoff M, Dombrowski MP. , et al. Does progesterone treatment influence risk factors for recurrent preterm delivery?. Obstet Gynecol 2005; 106 (03) 557-661
  • 12 Harper M, Thom E, Klebanoff MA. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Omega-3 fatty acid supplementation to prevent recurrent preterm birth: a randomized controlled trial. Obstet Gynecol 2010; 115 (2 Pt 1): 234-242
  • 13 Caritis SN, Venkataramanan R, Thom E. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network and Obstetric-Fetal Pharmacology Research Units Network. Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth. Am J Obstet Gynecol 2014; 210 (02) 128.e1-128.e6
  • 14 Onsrud M, Paus E, Haug E, Kjørstad K. Intramuscular administration of hydroxyprogesterone caproate in patients with endometrial carcinoma. Pharmacokinetics and effects on adrenal function. Acta Obstet Gynecol Scand 1985; 64 (06) 519-523
  • 15 DelConte A, Chidambaram N, Nachaegari S, Patel M, Venkateshwaran S. Pharmacokinetics and tolerability of oral 17-hydroxyprogesterone caproate (HPC) relative to intramuscular (IM) HPC. Am J Obstet Gynecol 2015; 212 (01) S374
  • 16 Shaik IH, Bastian JR, Zhao Y, Caritis SN, Venkataramanan R. Route of administration and formulation dependent pharmacokinetics of 17-hydroxyprogesterone caproate in rats. Xenobiotica 2016; 46 (02) 169-174
  • 17 Yan R, Nanovskaya TN, Zharikova OL, Mattison DR, Hankins GD, Ahmed MS. Metabolism of 17alpha-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons. Biochem Pharmacol 2008; 75 (09) 1848-1857
  • 18 Paulson RJ, Collins MG, Yankov VI. Progesterone pharmacokinetics and pharmacodynamics with 3 dosages and 2 regimens of an effervescent micronized progesterone vaginal insert. J Clin Endocrinol Metab 2014; 99 (11) 4241-4249