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Pharmacokinetic Studies in Pregnant Women

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Pharmacokinetics in Drug Development

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Abstract

The only way to determine appropriate medication dosing during pregnancy is to evaluate the pharmacokinetics and pharmacodynamics of individual medications in pregnant women. This type of clinical investigation can present a variety of challenges and concerns. This chapter summarizes what is known about physiologic changes in pregnancy and the impact these changes can have on drug disposition, and provides a model approach for completing pharmacokinetic studies in women during pregnancy.

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References

  • Aldridge, A., J. Bailey, et al. (1981). “The disposition of caffeine during and after pregnancy.” Semin Perinatol 5(4): 310–4.

    PubMed  CAS  Google Scholar 

  • Anderson, G. D. (2005). “Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach.” Clin Pharmacokinet 44(10): 989–1008.

    Article  PubMed  CAS  Google Scholar 

  • Andrew, M. A., T. R. Easterling, et al. (2007). “Amoxicillin pharmacokinetics in pregnant women: modeling and simulations of dosage strategies.” Clin Pharmacol Ther 81(4): 547–56.

    Article  PubMed  CAS  Google Scholar 

  • Andrew, M. A., M. F. Hebert, et al. (2008). “Physiologically based pharmacokinetic model of midazolam disposition during pregnancy.” Conf Proc IEEE Eng Med Biol Soc 2008: 5454–7.

    PubMed  Google Scholar 

  • Anger, G. J. and M. Piquette-Miller (2008). “Pharmacokinetic studies in pregnant women.” Clin Pharmacol Ther 83(1): 184–7.

    Article  PubMed  CAS  Google Scholar 

  • Assael, B. M., M. L. Como, et al. (1979). “Ampicillin kinetics in pregnancy.” Br J Clin Pharmacol 8(3): 286–8.

    PubMed  CAS  Google Scholar 

  • Bajpai, M., L. K. Roskos, et al. (1996). “Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite.” Drug Metab Dispos 24(12): 1401–3.

    PubMed  CAS  Google Scholar 

  • Bardy, A. H., V. K. Hiilesmaa, et al. (1987). “Serum phenytoin during pregnancy, labor and puerperium.” Acta Neurol Scand 75(6): 374–5.

    Article  PubMed  CAS  Google Scholar 

  • Benet, L. Z. and B. A. Hoener (2002). “Changes in plasma protein binding have little clinical relevance.” Clin Pharmacol Ther 71(3): 115–21.

    Article  PubMed  CAS  Google Scholar 

  • Blomback, M., K. Bremme, et al. (1998). “A pharmacokinetic study of dalteparin (fragmin) during late pregnancy.” Blood Coagul Fibrinolysis 9(4): 343–50.

    Article  PubMed  CAS  Google Scholar 

  • Bologa, M., B. Tang, et al. (1991). “Pregnancy-induced changes in drug metabolism in epileptic women.” J Pharmacol Exp Ther 257(2): 735–40.

    PubMed  CAS  Google Scholar 

  • Bryson, Y. J., M. Mirochnick, et al. (2008). “Pharmacokinetics and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353.” HIV Clin Trials 9(2): 115–25.

    Article  PubMed  CAS  Google Scholar 

  • Buchanan, M. L., T. R. Easterling, et al. (2009). “Clonidine pharmacokinetics in pregnancy.” Drug Metab Dispos 37(4): 702–5.

    Article  PubMed  CAS  Google Scholar 

  • Casele, H. L., S. A. Laifer, et al. (1999). “Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy.” Am J Obstet Gynecol 181(5 Pt 1): 1113–7.

    Article  PubMed  CAS  Google Scholar 

  • Chamberlain, A., S. White, et al. (1993). “Pharmacokinetics of ampicillin and sulbactam in pregnancy.” Am J Obstet Gynecol 168(2): 667–73.

    PubMed  CAS  Google Scholar 

  • Chen, S. S., E. Perucca, et al. (1982). “Serum protein binding and free concentration of phenytoin and phenobarbitone in pregnancy.” Br J Clin Pharmacol 13(4): 547–52.

    PubMed  CAS  Google Scholar 

  • Chesnutt, A. N. (2004). “Physiology of normal pregnancy.” Crit Care Clin 20(4): 609–15.

    Article  PubMed  Google Scholar 

  • Clark, S. L., D. B. Cotton, et al. (1989). “Central hemodynamic assessment of normal term pregnancy.” Am J Obstet Gynecol 161(6 Pt 1): 1439–42.

    PubMed  CAS  Google Scholar 

  • Coleman, T. (2007). “Recommendations for the use of pharmacological smoking cessation strategies in pregnant women.” CNS Drugs 21(12): 983–93.

    Article  PubMed  CAS  Google Scholar 

  • Crapo, R. O. (1996). “Normal cardiopulmonary physiology during pregnancy.” Clin Obstet Gynecol 39(1): 3–16.

    Article  PubMed  CAS  Google Scholar 

  • Davison, J. M. (1987). “Kidney function in pregnant women.” Am J Kidney Dis 9(4): 248–52.

    PubMed  CAS  Google Scholar 

  • Davison, J. M. and W. Dunlop (1980). “Renal hemodynamics and tubular function normal human pregnancy.” Kidney Int 18(2): 152–61.

    Article  PubMed  CAS  Google Scholar 

  • Davison, J. M., W. Dunlop, et al. (1980). “24-hour creatinine clearance during the third trimester of normal pregnancy.” Br J Obstet Gynaecol 87(2): 106–9.

    Article  PubMed  CAS  Google Scholar 

  • de Haan, G. J., P. Edelbroek, et al. (2004). “Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study.” Neurology 63(3): 571–3.

    PubMed  Google Scholar 

  • Dean, M., B. Stock, et al. (1980). “Serum protein binding of drugs during and after pregnancy in humans.” Clin Pharmacol Ther 28(2): 253–61.

    Article  PubMed  CAS  Google Scholar 

  • Dempsey, D., P. Jacob, III, et al. (2002). “Accelerated metabolism of nicotine and cotinine in pregnant smokers.” J Pharmacol Exp Ther 301(2): 594–8.

    Article  PubMed  CAS  Google Scholar 

  • Dunlop, W. (1981). “Serial changes in renal haemodynamics during normal human pregnancy.” Br J Obstet Gynaecol 88(1): 1–9.

    Article  PubMed  CAS  Google Scholar 

  • Dvorchik, B. H. (1982). “Drug disposition during pregnancy.” Int J Biol Res Pregnancy 3(3): 129–37.

    PubMed  CAS  Google Scholar 

  • Elkus, R. and J. Popovich, Jr. (1992). “Respiratory physiology in pregnancy.” Clin Chest Med 13(4): 555–65.

    PubMed  CAS  Google Scholar 

  • Ensom, M. H. and M. D. Stephenson (2004). “Pharmacokinetics of low molecular weight heparin and unfractionated heparin in pregnancy.” J Soc Gynecol Investig 11(6): 377–83.

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Martin, E., C. Martinez, et al. (2006). “Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals.” Mol Diagn Ther 10(1): 29–40.

    PubMed  CAS  Google Scholar 

  • Headley, J., K. Northstone, et al. (2004). “Medication use during pregnancy: data from the Avon Longitudinal Study of Parents and Children.” Eur J Clin Pharmacol 60(5): 355–61.

    Article  PubMed  CAS  Google Scholar 

  • Hebert, M. F., D. B. Carr, et al. (2005). “Pharmacokinetics and pharmacodynamics of atenolol during pregnancy and postpartum.” J Clin Pharmacol 45(1): 25–33.

    Article  PubMed  CAS  Google Scholar 

  • Hebert, M. F., T. R. Easterling, 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(2): 248–53.

    Article  PubMed  CAS  Google Scholar 

  • Heikkila, A. and R. Erkkola (1991). “Pharmacokinetics of piperacillin during pregnancy.” J Antimicrob Chemother 28(3): 419–23.

    Article  PubMed  CAS  Google Scholar 

  • Heikkila, A., K. Pyykko, et al. (1992). “The pharmacokinetics of mecillinam and pivmecillinam in pregnant and non-pregnant women.” Br J Clin Pharmacol 33(6): 629–33.

    PubMed  CAS  Google Scholar 

  • Heikkinen, T., U. Ekblad, et al. (2003). “Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation.” Clin Pharmacol Ther 73(4): 330–7.

    Article  PubMed  CAS  Google Scholar 

  • Helsby, N. A., S. A. Ward, et al. (1990). “The pharmacokinetics and activation of proguanil in man: consequences of variability in drug metabolism.” Br J Clin Pharmacol 30(4): 593–8.

    PubMed  CAS  Google Scholar 

  • Hogstedt, S., B. Lindberg, et al. (1983). “Increased oral clearance of metoprolol in pregnancy.” Eur J Clin Pharmacol 24(2): 217–20.

    Article  PubMed  CAS  Google Scholar 

  • Hogstedt, S., B. Lindberg, et al. (1985). “Pregnancy-induced increase in metoprolol metabolism.” Clin Pharmacol Ther 37(6): 688–92.

    Article  PubMed  CAS  Google Scholar 

  • Hurst, A. K., A. Shotan, et al. (1998). “Pharmacokinetic and pharmacodynamic evaluation of atenolol during and after pregnancy.” Pharmacotherapy 18(4): 840–6.

    PubMed  CAS  Google Scholar 

  • Klein, J., P. Blanchette, et al. (2004). “Assessing nicotine metabolism in pregnancy – a novel approach using hair analysis.” Forensic Sci Int 145(2–3): 191–4.

    Article  PubMed  CAS  Google Scholar 

  • Knutti, R., H. Rothweiler, et al. (1981). “Effect of pregnancy on the pharmacokinetics of caffeine.” Eur J Clin Pharmacol 21(2): 121–6.

    Article  PubMed  CAS  Google Scholar 

  • Krauer, B. and F. Krauer (1977). “Drug kinetics in pregnancy.” Clin Pharmacokinet 2(3): 167–81.

    Article  PubMed  CAS  Google Scholar 

  • Lee, E., M. K. Maneno, et al. (2006). “National patterns of medication use during pregnancy.” Pharmacoepidemiol Drug Saf 15(8): 537–45.

    Article  PubMed  Google Scholar 

  • Luxford, A. M. and G. S. Kellaway (1983). “Pharmacokinetics of digoxin in pregnancy.” Eur J Clin Pharmacol 25(1): 117–21.

    Article  PubMed  CAS  Google Scholar 

  • McBride, W. (1961). “Thalidomide and congenital abnormalities.” Lancet 278(7216): 1358.

    Article  Google Scholar 

  • McGready, R., K. Stepniewska, et al. (2003). “Pregnancy and use of oral contraceptives reduces the biotransformation of proguanil to cycloguanil.” Eur J Clin Pharmacol 59(7): 553–7.

    Article  PubMed  CAS  Google Scholar 

  • Messina, E. S., R. F. Tyndale, et al. (1997). “A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes.” J Pharmacol Exp Ther 282(3): 1608–14.

    PubMed  CAS  Google Scholar 

  • Morgan, D. J. and R. A. Smallwood (1990). “Clinical significance of pharmacokinetic models of hepatic elimination.” Clin Pharmacokinet 18(1): 61–76.

    Article  PubMed  CAS  Google Scholar 

  • Nakai, A., I. Sekiya, et al. (2002). “Assessment of the hepatic arterial and portal venous blood flows during pregnancy with Doppler ultrasonography.” Arch Gynecol Obstet 266(1): 25–9.

    Article  PubMed  CAS  Google Scholar 

  • Nathorst-Boos, J., A. Philipson, et al. (1995). “Renal elimination of ceftazidime during pregnancy.” Am J Obstet Gynecol 172(1 Pt 1): 163–6.

    Article  PubMed  CAS  Google Scholar 

  • Naylor, D. F., Jr. and M. M. Olson (2003). “Critical care obstetrics and gynecology.” Crit Care Clin 19(1): 127–49.

    Article  PubMed  Google Scholar 

  • Nordmark, A., S. Lundgren, et al. (2002). “The effect of the CYP1A2 *1F mutation on CYP1A2 inducibility in pregnant women.” Br J Clin Pharmacol 54(5): 504–10.

    Article  PubMed  CAS  Google Scholar 

  • O’Hare, M. F., W. Leahey, et al. (1983). “Pharmacokinetics of sotalol during pregnancy.” Eur J Clin Pharmacol 24(4): 521–4.

    Article  PubMed  Google Scholar 

  • Ohkita, C. and M. Goto (1990). “Increased 6-hydroxycortisol excretion in pregnant women: implication of drug-metabolizing enzyme induction.” DICP 24(9): 814–6.

    PubMed  CAS  Google Scholar 

  • Ohman, I., S. Vitols, et al. (2000). “Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation.” Epilepsia 41(6): 709–13.

    Article  PubMed  CAS  Google Scholar 

  • O’Sullivan, M. J., P. J. Boyer, et al. (1993). “The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: phase I acquired immunodeficiency syndrome clinical trials group study (protocol 082). Zidovudine Collaborative Working Group.” Am J Obstet Gynecol 168(5): 1510–6.

    PubMed  Google Scholar 

  • Pennell, P. B., D. J. Newport, et al. (2004). “The impact of pregnancy and childbirth on the metabolism of lamotrigine.” Neurology 62(2): 292–5.

    PubMed  CAS  Google Scholar 

  • Philipson, A. (1977). “Pharmacokinetics of ampicillin during pregnancy.” J Infect Dis 136(3): 370–6.

    Article  PubMed  CAS  Google Scholar 

  • Philipson, A. and G. Stiernstedt (1982). “Pharmacokinetics of cefuroxime in pregnancy.” Am J Obstet Gynecol 142(7): 823–8.

    PubMed  CAS  Google Scholar 

  • Philipson, A., G. Stiernstedt, et al. (1987). “Comparison of the pharmacokinetics of cephradine and cefazolin in pregnant and non-pregnant women.” Clin Pharmacokinet 12(2): 136–44.

    Article  PubMed  CAS  Google Scholar 

  • Prevost, R. R., S. A. Akl, et al. (1992). “Oral nifedipine pharmacokinetics in pregnancy-induced hypertension.” Pharmacotherapy 12(3): 174–7.

    PubMed  CAS  Google Scholar 

  • Rubin, J. D., C. Ferencz, et al. (1993). “Use of prescription and non-prescription drugs in pregnancy. The Baltimore-Washington Infant Study Group.” J Clin Epidemiol 46(6): 581–9.

    Article  PubMed  CAS  Google Scholar 

  • Sachse, C., U. Bhambra, et al. (2003). “Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism.” Br J Clin Pharmacol 55(1): 68–76.

    Article  PubMed  CAS  Google Scholar 

  • Schou, M., A. Amdisen, et al. (1973). “Lithium and pregnancy. II. Hazards to women given lithium during pregnancy and delivery.” Br Med J 2(5859): 137–8.

    Article  PubMed  CAS  Google Scholar 

  • Simpson, K. H., A. F. Stakes, et al. (1988). “Pregnancy delays paracetamol absorption and gastric emptying in patients undergoing surgery.” Br J Anaesth 60(1): 24–7.

    Article  PubMed  CAS  Google Scholar 

  • Thorley, K. J., J. McAinsh, et al. (1981). “Atenolol in the treatment of pregnancy-induced hypertension.” Br J Clin Pharmacol 12(5): 725–30.

    PubMed  CAS  Google Scholar 

  • Tomson, T., U. Lindbom, et al. (1994a). “Disposition of carbamazepine and phenytoin in pregnancy.” Epilepsia 35(1): 131–5.

    Article  PubMed  CAS  Google Scholar 

  • Tomson, T., U. Lindbom, et al. (1994b). “Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin.” Epilepsia 35(1): 122–30.

    Article  PubMed  CAS  Google Scholar 

  • Torgersen, K. L. and C. A. Curran (2006). “A systematic approach to the physiologic adaptations of pregnancy.” Crit Care Nurs Q 29(1): 2–19.

    PubMed  Google Scholar 

  • Tracy, T. S., R. Venkataramanan, et al. (2005). “Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A activity) during pregnancy.” Am J Obstet Gynecol 192(2): 633–9.

    Article  PubMed  CAS  Google Scholar 

  • Tran, T. A., I. E. Leppik, et al. (2002). “Lamotrigine clearance during pregnancy.” Neurology 59(2): 251–5.

    PubMed  CAS  Google Scholar 

  • Tsutsumi, K., T. Kotegawa, et al. (2001). “The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N-acetyltransferase activities in humans.” Clin Pharmacol Ther 70(2): 121–5.

    Article  PubMed  CAS  Google Scholar 

  • van Heeswijk, R. P., Y. Khaliq, et al. (2004). “The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum.” Clin Pharmacol Ther 76(6): 588–97.

    Article  PubMed  Google Scholar 

  • Ververs, F. F., H. A. Voorbij, et al. (2009). “Effect of cytochrome P450 2D6 genotype on maternal paroxetine plasma concentrations during pregnancy.” Clin Pharmacokinet 48(10): 677–83.

    Article  PubMed  CAS  Google Scholar 

  • Wadelius, M., E. Darj, et al. (1997). “Induction of CYP2D6 in pregnancy.” Clin Pharmacol Ther 62(4): 400–7.

    Article  PubMed  CAS  Google Scholar 

  • Ward, S. A., N. A. Helsby, et al. (1991). “The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism – a panel study.” Br J Clin Pharmacol 31(6): 689–92.

    PubMed  CAS  Google Scholar 

  • Watts, D. H., Z. A. Brown, et al. (1991). “Pharmacokinetic disposition of zidovudine during pregnancy.” J Infect Dis 163(2): 226–32.

    Article  PubMed  CAS  Google Scholar 

  • Wilson, C. M., J. W. Dundee, et al. (1987). “A comparison of the early pharmacokinetics of midazolam in pregnant and nonpregnant women.” Anaesthesia 42(10): 1057–62.

    Article  PubMed  CAS  Google Scholar 

  • Yerby, M. S., P. N. Friel, et al. (1990). “Pharmacokinetics of anticonvulsants in pregnancy: alterations in plasma protein binding.” Epilepsy Res 5(3): 223–8.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Indiana University School of Medicine, Indianapolis, IN, USA

    Jamie L. Renbarger

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  1. Jamie L. Renbarger
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  2. David M. Haas
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Correspondence to Jamie L. Renbarger .

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Editors and Affiliations

  1. , Pharmacokinetics, Modeling, and Simulati, Astellas Pharma, Parkway North 3, Deerfield, 60015, Illinois, USA

    Peter L. Bonate

  2. Institutes for Biomedical Research, Translational Sciences, Novartis, Health Plaza 1, East Hanover, 07936, New Jersey, USA

    Danny R. Howard

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© 2011 American Association of Pharmaceutical Scientists

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Renbarger, J.L., Haas, D.M. (2011). Pharmacokinetic Studies in Pregnant Women. In: Bonate, P., Howard, D. (eds) Pharmacokinetics in Drug Development. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7937-7_9

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