Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 73, Issue 4, pp 789–797 | Cite as

Pharmacokinetics of doxorubicin in pregnant women

  • Rachel J. Ryu
  • Sara Eyal
  • Henry G. Kaplan
  • Arezoo Akbarzadeh
  • Karen Hays
  • Kristin Puhl
  • Thomas R. Easterling
  • Stacey L. Berg
  • Kathleen A. Scorsone
  • Eric M. Feldman
  • Jason G. Umans
  • Menachem Miodovnik
  • Mary F. HebertEmail author
Original Article

Abstract

Purpose

Our objective was to evaluate the pharmacokinetics (PK) of doxorubicin during pregnancy compared to previously published data from non-pregnant subjects.

Methods

During mid- to late-pregnancy, serial blood and urine samples were collected over 72 h from seven women treated with doxorubicin for malignancies. PK parameters were estimated using non-compartmental techniques. Pregnancy parameters were compared to those previously reported non-pregnant subjects.

Results

During pregnancy, mean (±SD) doxorubicin PK parameters utilizing 72 h sampling were: clearance (CL), 412 ± 80 mL/min/m2; steady-state volume of distribution (Vss), 1,132 ± 476 L/m2; and terminal half-life (T1/2), 40.3 ± 8.9 h. The BSA-adjusted CL was significantly decreased (p < 0.01) and T1/2 was not different compared to non-pregnant women. Truncating our data to 48 h, PK parameters were: CL, 499 ± 116 ml/min/m2; Vss, 843 ± 391 L/m2; and T1/2, 24.8 ± 5.9 h. The BSA-adjusted CL in pregnancy compared to non-pregnant data was significantly decreased in 2 of 3 non-pregnant studies (p < 0.05, < 0.05, NS). Vss and T1/2 were not significantly different.

Conclusions

In pregnant subjects, we observed significantly lower doxorubicin CL in our 72 h and most of our 48 h sampling comparisons with previously reported non-pregnant subjects. However, the parameters were within the range previously reported in smaller studies. At this time, we cannot recommend alternate dosage strategies for pregnant women. Further research is needed to understand the mechanism of doxorubicin pharmacokinetic changes during pregnancy and optimize care for pregnant women.

Keywords

Doxorubicin Doxorubicinol Adriamycin Pregnancy Pharmacokinetics 

Abbreviations

Terminal half-life

T1/2

AUC

Area under the concentration–time curve

BSA

Body surface area

P-gp

P-glycoprotein

Vd

Volume of distribution

Vss

Volume of distribution at steady state

CL

Clearance

SD

Standard deviation

CBR1

Carbonyl reductase 1

Notes

Acknowledgments

S. Eyal, T. R. Easterling, S. L. Berg, K. A. Scorsone and M. F. Hebert: Grant Number U10HD047892 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health and National Center for Research Resources Grant Numbers M01RR00037 and RR023256. J.G. Umans and M. Miodovnik: Grant Number U10HD047891 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the National Institutes of Health.

Conflict of interest

None of the authors have a conflict of interest.

References

  1. 1.
    Cardonick E, Iacobucci A (2004) Use of chemotherapy during human pregnancy. Lancet Oncol 5:283–291PubMedCrossRefGoogle Scholar
  2. 2.
    Lycette JL, Dul CL, Munar M et al (2006) Effect of pregnancy on the pharmacokinetics of paclitaxel: a case report. Clin Breast Cancer 7:322–324CrossRefGoogle Scholar
  3. 3.
    Van Calsteren K, Verbesselt R, Ottevanger N et al (2010) Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study. Acta Obstet Gynecol Scand 89:1338–1345PubMedCrossRefGoogle Scholar
  4. 4.
    Doll DC, Ringenberg QS, Yarbro JW (1988) Management of cancer during pregnancy. Arch Intern Med 148:2058–2064PubMedCrossRefGoogle Scholar
  5. 5.
    Donegan WL (1983) Cancer and pregnancy. CA Cancer J Clin 33:194–214PubMedCrossRefGoogle Scholar
  6. 6.
    Speth PA, van Hoesel QG, Haanen C (1988) Clinical pharmacokinetics of doxorubicin. Clin Pharmacokinet 15:15–31PubMedCrossRefGoogle Scholar
  7. 7.
    Chassany O, Urien S, Claudepierre P, Bastian G, Tillement JP (1996) Comparative serum protein binding of anthracycline derivatives. Cancer Chemother Pharmacol 38:571–573PubMedCrossRefGoogle Scholar
  8. 8.
    Eksborg S, Ehrsson H, Ekqvist B (1982) Protein binding of anthraquinone glycosides, with special reference to adriamycin. Cancer Chemother Pharmacol 10:7–10PubMedCrossRefGoogle Scholar
  9. 9.
    Greene RF, Collins JM, Jenkins JF, Speyer JL, Myers CE (1983) Plasma pharmacokinetics of adriamycin and adriamycinol: implications for the design of in vitro experiments and treatment protocols. Cancer Res 43:3417–3421PubMedGoogle Scholar
  10. 10.
    Robert J, Bui NB, Vrignaud P (1987) Pharmacokinetics of doxorubicin in sarcoma patients. Eur J Clin Pharmacol 31:695–699PubMedCrossRefGoogle Scholar
  11. 11.
    Piscitelli SC, Rodvold KA, Rushing DA, Tewksbury DA (1993) Pharmacokinetics and pharmacodynamics of doxorubicin in patients with small cell lung cancer. Clin Pharmacol Ther 53:555–561PubMedCrossRefGoogle Scholar
  12. 12.
    Rodvold KA, Rushing DA, Tewksbury DA (1988) Doxorubicin clearance in the obese. J Clin Oncol 6:1321–1327PubMedGoogle Scholar
  13. 13.
    Hochster H, Liebes L, Wadler S et al (1992) Pharmacokinetics of the cardioprotector ADR-529 (ICRF-187) in escalating doses combined with fixed-dose doxorubicin. J Natl Cancer Inst 84:1725PubMedCrossRefGoogle Scholar
  14. 14.
    Kassner N, Huse K, Martin HJ et al (2008) Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver. Drug Metab Dispos 36:2113–2120PubMedCrossRefGoogle Scholar
  15. 15.
    Robert J (1998) Anthracyclines. In: Grochow LB, Ames MM (eds) A clinician’s guide to chemotherapy pharmacokinetics and pharmacodynamics. Williams & Wilkins, Baltimore, pp 93–173Google Scholar
  16. 16.
    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229PubMedCrossRefGoogle Scholar
  17. 17.
    Takanashi S, Bachur NR (1976) Adriamycin metabolism in man. Evidence from urinary metabolites. Drug Metab Dispos 4:79–87PubMedGoogle Scholar
  18. 18.
    d’Incalci M, Broggini M, Buscaglia M, Pardi G (1983) Transplacental passage of doxorubicin. Lancet 1:75PubMedCrossRefGoogle Scholar
  19. 19.
    Karp GI, von Oeyen P, Valone F et al (1983) Doxorubicin in pregnancy: possible transplacental passage. Cancer Treat Rep 67:773–777PubMedGoogle Scholar
  20. 20.
    Lambert J, Wijermans PW, Dekker GA, Ossenkoppele GJ (1991) Chemotherapy in non-Hodgkin’s lymphoma during pregnancy. Neth J Med 38:80–85PubMedGoogle Scholar
  21. 21.
    García L, Valcárcel M, Santiago-Borrero PJ (1999) Chemotherapy during pregnancy and its effects on the fetus–neonatal myelosuppression: two case reports. J Perinatol 19:230–233PubMedCrossRefGoogle Scholar
  22. 22.
    Thompson PA, Rosner GL, Matthay KK et al (2009) Impact of body composition on pharmacokinetics of doxorubicin in children: a glaser pediatric research network study. Cancer Chemother Pharmacol 64:243–251PubMedCrossRefGoogle Scholar
  23. 23.
    Hebert MF, Roberts JP, Prueksaritanont T, Benet LZ (1992) Bioavailability of cyclosporine with concomitant rifampin administraiton is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 52:453–457PubMedCrossRefGoogle Scholar
  24. 24.
    Hebert MF, Carr DB, Anderson GD, Blough D, Green GE, Brateng DA, Kantor E, Benedetti TJ, Easterling TR (2005) Pharmacokinetics and pharmacodynamics of atenolol during pregnancy and postpartum. J Clin Pharmacol 45:25–33PubMedCrossRefGoogle Scholar
  25. 25.
    Benjamin RS, Riggs CE, Bachur NR (1973) Pharmacokinetics and metabolism of adriamycin in man. Clin Pharmacol Ther 14:592–600PubMedGoogle Scholar
  26. 26.
    Riggs CE, Benjamin RS, Serpick AA, Bachur NR (1977) Bilary disposition of adriamycin. Clin Pharmacol Ther 22:234–241PubMedGoogle Scholar
  27. 27.
    WHO (2013) Weight for age chart—Birth to 6 months girl’s percentiles. http://www.who.int/childgrowth/standards/cht_wfa_girls_p_0_6.pdf. Accessed 05 May 2013
  28. 28.
    Dobbs NA, Twelves CJ, Gillies H, James CA, Harper PG, Rubens RD (1995) Gender affects doxorubicin pharmacokinetics in patients with normal liver biochemistry. Cancer Chemother Pharmacol 36:473–476PubMedCrossRefGoogle Scholar
  29. 29.
    Rudek MA, Sparreboom A, Garrett-Mayer ES, Armstrong DK, Wolff AC, Verweij J, Baker SD (2004) Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer 40(8):1170–1178PubMedCrossRefGoogle Scholar
  30. 30.
    Dodion P, Riggs CE, Akman SR et al (1984) Interactions between cyclophosphamide and adriamycin metabolism in rats. J Pharmacol Exp Ther 229:51PubMedGoogle Scholar
  31. 31.
    Nakai A, Sekiya I, Oya A, Koshino T, Araki T (2002) Assessment of the hepatic arterial and portal venous blood flows during pregnancy with Doppler ultrasonography. Arch Gynecol Obstet 266:25–29PubMedCrossRefGoogle Scholar
  32. 32.
    Oppermann U (2007) Carbonyl reductases: the complex relationships of mammalian carbonyl- and quinone-reducing enzymes and their role in physiology. Annu Rev Pharmacol Toxicol 47:293–322PubMedCrossRefGoogle Scholar
  33. 33.
    Iwata N, Inazu N, Satoh T (1990) Changes and localization of ovarian carbonyl reductase during pseudopregnancy and pregnancy in rats. Biol Reprod 43:397–403PubMedCrossRefGoogle Scholar
  34. 34.
    Waclawik A, Jabbour HN, Blitek A, Ziecik AJ (2009) Estradiol-17beta, prostaglandin E2 (PGE2), and the PGE2 receptor are involved in PGE2 positive feedback loop in the porcine endometrium. Endocrinology 150:3823–3832PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Jacquet JM, Bressolle F, Galtier M et al (1990) Doxorubicin and doxorubicinol: intra and inter-individual variations of pharmacokinetic parameters. Cancer Chemother Pharmacol 39:507Google Scholar
  36. 36.
    Hebert MF, Easterling TR, Kirby B et al (2008) Effects of pregnancy on CYP3A and P-glycoprotein activities as measured by disposition of midazolam and digoxin: a University of Washington specialized center of research study. Clin Pharmacol Ther 84:248–253PubMedCrossRefGoogle Scholar
  37. 37.
    Davison JM, Dunlop W (1980) Renal hemodynamics and tubular function normal human pregnancy. Kidney Int 18:152–161PubMedCrossRefGoogle Scholar
  38. 38.
    Elis A, Lishner M, Walker S, Atias D, Korenberg A, Koren G (2010) Doxorubicin in lymphoma: association between pharmacokinetic variability and clinical response. Ther Drug Monit 32:50–52PubMedCrossRefGoogle Scholar
  39. 39.
    Cardonick E, Dougherty R, Grana G, Gilmandyar D, Ghaffar S, Usmani A (2010) Breast cancer during pregnancy: maternal and fetal outcomes. Cancer J 16:76–82PubMedCrossRefGoogle Scholar
  40. 40.
    Legha SJ, Benjamin RS, McKay B (1982) Reduction of doxorubicin cardiotoxicity by prolonged continuous infusion. Ann Intern Med 96:133PubMedCrossRefGoogle Scholar
  41. 41.
    Olson L, Bedja D, Alvey S, Cardounel A, Gabrielson K, Reeves R (2003) Protection from doxorubicin-induced cardiac toxicity in mice with a null allele of carbonyl reductase 1. Cancer Res 63:6602–6606PubMedGoogle Scholar
  42. 42.
    Lukaski H, Skiers W, Nielsen E, Hall C (1994) Total body water in pregnancy: assessment by using bioelectrical impedance. Am J Clin Nutr 59:578–585PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Rachel J. Ryu
    • 1
  • Sara Eyal
    • 1
    • 7
  • Henry G. Kaplan
    • 2
  • Arezoo Akbarzadeh
    • 1
  • Karen Hays
    • 1
  • Kristin Puhl
    • 1
  • Thomas R. Easterling
    • 1
    • 3
  • Stacey L. Berg
    • 4
  • Kathleen A. Scorsone
    • 4
  • Eric M. Feldman
    • 5
  • Jason G. Umans
    • 6
  • Menachem Miodovnik
    • 5
  • Mary F. Hebert
    • 1
    • 3
    Email author
  1. 1.Department of PharmacyUniversity of WashingtonSeattleUSA
  2. 2.Swedish Medical CenterSeattleUSA
  3. 3.Obstetrics and GynecologyUniversity of WashingtonSeattleUSA
  4. 4.Texas Children’s Cancer CenterHoustonUSA
  5. 5.Group Health Capitol Hill CampusWashingtonUSA
  6. 6.MedStar Research InstituteWashington Hospital Center and Georgetown University Medical CenterWashingtonUSA
  7. 7.Institute for Drug ResearchThe Hebrew UniversityJerusalemIsrael

Personalised recommendations