Advertisement

Effects of Sex Differences in the Pharmacokinetics of Drugs and Their Impact on the Safety of Medicines in Women

Chapter

Abstract

Inclusion of women in clinical trials and analysis of clinical trial data for sex/gender effects have been an integral component of the US FDA’s consideration for approval of pharmaceutical products since the mid-1980s (1993). The study of sex differences is now a routine component of drug development because of existing data in drug exposure and response differences between men and women and the need to understand such differences for proper dosing. The resulting expanding knowledge of sex differences in the exposure and responses to drugs has led to a better understanding of the mechanisms contributing to these differences and improved pharmacotherapy for men and women.

Keywords

Lower Glomerular Filtration Rate Ceftaroline Fosamil Body Weight Difference Influence Drug Disposition Olanzapine Clearance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Aarons L, Hopkins K, Rowland M et al (1989) Route of administration and sex differences in the pharmacokinetics of aspirin, administered as its lysine salt. Pharm Res 6:660–666PubMedCrossRefGoogle Scholar
  2. Abad-Santos F, Novalbos J, Galvez-Mugica MA et al (2005) Assessment of sex differences in pharmacokinetics and pharmacodynamics of amlodipine in a bioequivalence study. Pharmacol Res 51:445–452PubMedCrossRefGoogle Scholar
  3. Ambien® CR (zolpidem tartrate) US FDA drug product labeling. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=404c858c-89ac-4c9d-8a96-8702a28e6e76. Accessed 16 June 2014
  4. Ambien® (zolpidem tartrate) US FDA drug product labeling. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c36cadf4-65a4-4466-b409-c82020b42452. Accessed 16 June 2014
  5. Anderson GD (2005) Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. J Womens Health 14(1):19–29CrossRefGoogle Scholar
  6. Ashiru DA, Patel R, Basit AW (2008) Polyethylene glycol 400 enhances the bioavailability of a BCS class III drug (ranitidine) in male subjects but not females. Pharm Res 25:2327–2333PubMedCrossRefGoogle Scholar
  7. Baraona E, Abittan CS, Dohmen K et al (2001) Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res 25:502–507PubMedCrossRefGoogle Scholar
  8. Bebia Z, Buch SC, Wilson JW et al (2004) Bioequivalence revisited: influence of age and sex on CYP enzymes. Clin Pharmacol Ther 76(6):618–627PubMedCrossRefGoogle Scholar
  9. Beierle I, Meibohm B, Derendorf H (1999) Gender differences in pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther 37:529–547PubMedGoogle Scholar
  10. Berg UB (2006) Differences in decline in GFR with age between males and females: reference data on clearances of inulin and PAH in potential kidney donors. Nephrol Dial Transplant 21(9):2577–2582PubMedCrossRefGoogle Scholar
  11. Bigos KL, Pollock BG, Stankevich BA et al (2009) Sex differences in the pharmacokinetics and pharmacodynamics of antidepressants: an updated review. Gend Med 6(4):522–543PubMedCrossRefGoogle Scholar
  12. Chen ML, Lee SC, Ng MJ et al (2000) Pharmacokinetics analysis of bioequivalence trials: implications for sex-related issues in clinical pharmacology and biopharmaceutics. Clin Pharmacol Ther 68(5):510–521PubMedCrossRefGoogle Scholar
  13. Cheng X, Buckley D, Klaassen CD (2007) Regulation of hepatic bile acid transporters Ntcp and Bsep expression. Biochem Pharmacol 74:1665–1676PubMedCentralPubMedCrossRefGoogle Scholar
  14. Chetty M, Mattison D, Rostami-Hodjegan A (2012) Sex differences in the clearance of CYP3A4 substrates: exploring possible reasons for the substrate dependency and lack of consensus. Curr Drug Metab 13(6):778–786PubMedCrossRefGoogle Scholar
  15. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41PubMedCrossRefGoogle Scholar
  16. Copeland V, Parekh A (2011) FDA approved drug labels 2007–10: dose adjustments for women based on exposure. Drug Information Association 2011 47th annual meeting, 19–23 June 2011, Chicago. Poster Presentation. www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm201358.htm. Accessed 16 June 2014
  17. Costantine MM (2014) Physiologic and pharmacokinetic changes in pregnancy. Front Pharmacol 5:65. doi: 10.3389/fphar.2014.00065 PubMedCentralPubMedCrossRefGoogle Scholar
  18. Ernstgård L, Sjögren B, Warholm M et al (2003) Sex differences in the toxicokinetics of inhaled solvent vapors in humans 2.2-propanol. Toxicol Appl Pharmacol 193:158–167PubMedCrossRefGoogle Scholar
  19. Farkas RH, Unger EF, Temple R (2013) Zolpidem and driving impairment-identifying persons at risk. N Engl J Med 369(8):689–691. doi: 10.1056/NEJMp1307972. Epub 2013 Aug 7 PubMedCrossRefGoogle Scholar
  20. FDA drug safety communication: FDA approves new label changes and dosing for zolpidem products and a recommendation to avoid driving the day after using Ambien CR http://www.fda.gov/Drugs/DrugSafety/ucm352085.htm. Accessed 16 June 2014
  21. FDA drug safety communication: risk of next-morning impairment after use of insomnia drugs; FDA requires lower recommended doses for certain drugs containing zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist) http://www.fda.gov/Drugs/DrugSafety/ucm334033.htm. Accessed 16 June 2014
  22. FDA Guidance for Industry (1993) Guidance for the study and evaluation of gender differences in the clinical evaluation of drugs. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072044.pdf. Accessed 15 Aug 2014
  23. FDA Guidance for Industry: Population Pharmacokinetics, 1999. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072137.pdf. Accessed 16 June 2014
  24. FDA Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drug Submitted Under an ANDA (Draft) 2013. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM377465.pdf. Accessed 16 June 2014
  25. Franconi F, Campesi I (2014) Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women. Br J Pharmacol 171(3):580–594PubMedCrossRefGoogle Scholar
  26. Franconi F, Brunelleschi S, Steardo L et al (2007) Gender differences in drug responses. Pharmacol Res 55:81–95PubMedCrossRefGoogle Scholar
  27. Freire AC, Basit AW, Choudhary R et al (2011) Does sex matter? The influence of gender on gastrointestinal physiology and drug delivery. Int J Pharm 415:15–28PubMedCrossRefGoogle Scholar
  28. Frezza M, di Padova C, Pozzato G et al (1990) High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med 322(2):95–99PubMedCrossRefGoogle Scholar
  29. Gandhi M, Aweeka F, Greenblatt RM et al (2004) Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol 44:499–523PubMedCrossRefGoogle Scholar
  30. Gaudry SE, Sitar DS, Smyth DD et al (1993) Gender and age as factors in the inhibition of renal clearance of amantadine by quinine and quinidine. Clin Pharmacol Ther 54(1):23–27PubMedCrossRefGoogle Scholar
  31. Giacomini KM, Huang SM (2013) Transporters in drug development and clinical pharmacology. Clin Pharmacol Ther 94(1):3–9. doi: 10.1038/clpt.2013.86 PubMedCrossRefGoogle Scholar
  32. Giacomini KM, Sugiyama Y (2006) In: Brunton LL, Lazo JS, Parker RL (eds) Goodman & Gilman’s the pharmacological basis of therapeutics. McGraw-Hill, New York, pp 41–70Google Scholar
  33. Gleichmann W, Bachmann G, Dengler H et al (1973) Effects of hormonal contraceptives and pregnancy on serum protein pattern. Eur J Clin Pharmacol 5:218–225CrossRefGoogle Scholar
  34. Greenblatt DJ, von Moltke LL (2008) Gender has a small but statistically significant effect on clearance of CYP3A substrate drugs. J Clin Pharmacol 48:1350–1355PubMedCrossRefGoogle Scholar
  35. Greenblatt D, Allen M, Harmatz J et al (1980) Diazepam disposition determinants. Clin Pharmacol Ther 27:301–312PubMedCrossRefGoogle Scholar
  36. Greenblatt DJ, Abernethy DR, Lochniskai A et al (1985) Age, sex and nitrazepam kinetics: relation to antipyrene disposition. Clin Pharmacol Ther 38:697–703PubMedCrossRefGoogle Scholar
  37. Gurwitz JH (2005) The age/gender interface in geriatric pharmacotherapy. J Womens Health (Larchmt) 14:68–72CrossRefGoogle Scholar
  38. Harris RZ, Benet LZ, Schwartz JB (1995) Gender effects in pharmacokinetics and pharmacodynamics. Drugs 50:222–239PubMedCrossRefGoogle Scholar
  39. Hu ZY, Zhao YS (2010) Sex-dependent differences in cytochrome P450 3A activity as assessed by midazolam disposition in humans: a meta-analysis. Drug Metab Dispos 38(5):817–823PubMedCrossRefGoogle Scholar
  40. Huang SM, Rowland M (2012) The role of physiologically based pharmacokinetic modeling in regulatory review. Clin Pharmacol Ther 91(3):542–549. doi: 10.1038/clpt.2011.320. Epub 2012 Feb 8 PubMedCrossRefGoogle Scholar
  41. Huang SM, Miller M, Toigo T et al (2007) Evaluation of drugs in women. In: Lagato MJ (ed) Principles of gender specific medicine, vol 2. Elsevier Academic Press, Oxford, pp 848–859Google Scholar
  42. Institute of Medicine (US) (2001) Committee on understanding the biology of sex and gender differences. In: Wizemann TM, Pardue ML (eds) Exploring the biological contributions to human health: does sex matter? National Academy Press, Washington, DC. Available at http://www.nap.edu/books/0309072816/html. Accessed 28 May 2014
  43. Intermezzo® (zolpidem tartrate) US FDA drug product labeling. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022328s001lbl.pdf. Accessed 16 June 2014
  44. Jann MW, ZumBrunnen TL, Tenjarla SN et al (1998) Relative bioavailability of ondansetron 8-mg oral tablets versus two extemporaneous 16-mg suppositories: formulation and gender differences. Pharmacotherapy 18:288–294PubMedGoogle Scholar
  45. Kahan BD, Kramer WG, Wideman C et al (1986) Demographic factors affecting the pharmacokinetics of cyclosporine estimated by radioimmunoassay. Transplantation 41:459–464PubMedCrossRefGoogle Scholar
  46. Kashuba ADM, Nafziger AN (1998) Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin Pharmacokinet 34(3):203–218PubMedCrossRefGoogle Scholar
  47. Keefe D, Yee Y, Kates R (1981) Verapamil protein binding in patients and normal subjects. Clin Pharmacol Ther 29:21–26PubMedCrossRefGoogle Scholar
  48. Kharasch ED, Mautz D, Senn T et al (1999) Menstrual cycle variability in midazolam pharmacokinetics. J Clin Pharmacol 39(3):275–280PubMedGoogle Scholar
  49. Kim JS, Nafziger AN (2000) Is it sex or is it gender? Clin Pharmacol Ther 68(1):1–3PubMedCrossRefGoogle Scholar
  50. Kishino S, Nomura A, Di Z et al (1995) Alpha-1acid glycoprotein concentration and the protein binding of diopyramide in healthy subjects. J Clin Pharmacol 35:510–514PubMedCrossRefGoogle Scholar
  51. Klaassen CD, Aleksunes LM (2010) Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev 62(1):1–96PubMedCentralPubMedCrossRefGoogle Scholar
  52. Knight V, Yu C, Gilbert B et al (1988) Estimating the dosage of ribavirin aerosol according to age and other variables. J Infect Dis 158:443–447PubMedCrossRefGoogle Scholar
  53. Kristensen CB (1983) Imipramine serum protein binding in healthy subjects. Clin Pharmacol Ther 34(5):689–694PubMedCrossRefGoogle Scholar
  54. Labbé L, Sirois C, Pilote S et al (2000) Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metabolic ratios of marker substrates. Pharmacogenetics 10(5):425–438PubMedCrossRefGoogle Scholar
  55. Lane HY, Chang YC, Chang WH et al (1999) Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry 60(1):36–40PubMedCrossRefGoogle Scholar
  56. Loebstein R, Lalkin A, Koren G (1997) Pharmacokinetic changes during pregnancy and their clinical relevance. Clin Pharmacokinet 33(5):328–343PubMedCrossRefGoogle Scholar
  57. Manjunath G, Sarnak M, Levy A (2001) Prediction equations to estimate glomerular filtration rate: an update. Curr Opin Nephrol Hypertens 10:785–792PubMedCrossRefGoogle Scholar
  58. Mattison DR (2013) Pharmacokinetics in real life: sex and gender differences. J Popul Ther Clin Pharmacol 20(3):e340–e349Google Scholar
  59. Mattison DR, Blann E, Malek A (1991) Physiological alterations during pregnancy: impact on toxicokinetics. Fundam Appl Toxicol 16(2):215–218PubMedCrossRefGoogle Scholar
  60. Meibohm B, Beierle I, Derendorf H (2002) How important are gender differences in pharmacokinetics? Clin Pharmacokinet 41(5):329–342PubMedCrossRefGoogle Scholar
  61. Merino G, van Herwaarden AE, Wagenaar E et al (2005) Sex-dependent expression and activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP/ABCG2) in liver. Mol Pharmacol 67(5):1765–1771PubMedCrossRefGoogle Scholar
  62. Mojaverian P, Rocci ML Jr, Corner DP et al (1987) Effect of food on the absorption of enteric-coated aspirin: correlation with gastric residence time. Clin Pharmacol Ther 41:11–17PubMedCrossRefGoogle Scholar
  63. Nicolas JM, Espie P, Molimard M (2009) Gender and interindividual variability in pharmacokinetics. Drug Metab Rev 41(3):408–421. doi: 10.1080/10837450902891485 PubMedCrossRefGoogle Scholar
  64. Norvasc® (amlodipine) US FDA drug product labeling. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=44e5ad27-e062-461a-bdf4-192d852fbc49. Accessed 16 June 2014
  65. Ochs H, Greenblatt D, Divoll M et al (1981) Diazepam kinetics in relation to age and sex. Pharmacology 23:24–30PubMedCrossRefGoogle Scholar
  66. Paine M, Ludington SS, Chen ML et al (2005) Do men and women differ in proximal small intestinal CYP3A or P-glycoprotein expression? Drug Metab Dispos 33:426–433PubMedCrossRefGoogle Scholar
  67. Parekh A, Fadiran EO, Uhl K et al (2011) Adverse effects in women: implications for drug development and regulatory policies. Expert Rev Clin Pharmacol 4(4):453–466PubMedCrossRefGoogle Scholar
  68. Piafsky K, Borga O (1977) Plasma protein binding of basic drugs. Importance of α 1-acid glycoprotein for interindividual variation. Clin Pharmacol Ther 22:545–549PubMedGoogle Scholar
  69. Potter JM, McWhinney BC, Sampson L et al (2004) Area-under-the-curve monitoring of prednisolone for dose optimization in a stable renal transplant population. Ther Drug Monit 26(4):408–414PubMedCrossRefGoogle Scholar
  70. Prasad B, Evers R, Gupta A et al (2014) Interindividual variability in hepatic organic anion-transporting polypeptides and P-glycoprotein (ABCB1) protein expression: quantification by liquid chromatography tandem mass spectroscopy and influence of genotype, age, and sex. Drug Metab Dispos 42(1):78–88. doi: 10.1124/dmd.113.053819. Epub 2013 Oct 11 PubMedCentralPubMedCrossRefGoogle Scholar
  71. Rademaker M (2001) Do women have more adverse drug reactions? Am J Clin Dermatol 2(6):349–369351PubMedCrossRefGoogle Scholar
  72. Rhatagi S, Calic F, Harding N et al (2000) Pharmacokinetics, pharmacodynamics, and safety of inhaled cyclosporin A (AD1628) after single and repeated administration healthy male and female subjects and asthmatics patients. J Clin Pharmacol 40:1211–1226Google Scholar
  73. Roberts RK, Desmond PV, Wilkinson GR et al (1979) Disposition of chlordiazepoxide: sex differences and effects of oral contraceptives. Clin Pharmacol Ther 25:826–831PubMedGoogle Scholar
  74. Rolan PE (1994) Plasma protein binding displacement interactions – why are they still regarded as clinically important? Br J Clin Pharmacol 37(2):125–128PubMedCentralPubMedCrossRefGoogle Scholar
  75. Rowland M, Peck C, Tucker G (2011) Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol 51:45–73. doi: 10.1146/annurev-pharmtox-010510-100540 PubMedCrossRefGoogle Scholar
  76. Schuetz EG, Furuya KN, Schuetz JD (1995) Interindividual variation in expression of p-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 275(2):1011–1018PubMedGoogle Scholar
  77. Schwartz JB (2003) The influence of sex on pharmacokinetics. Clin Pharmacokinet 42(2):107–121PubMedCrossRefGoogle Scholar
  78. Schwartz JB (2007) The current state of the knowledge on age, sex and their interactions on clinical pharmacology. Clin Pharmacol Ther 82(1):87–89PubMedCrossRefGoogle Scholar
  79. Shah AK, Laboy-Goral L, Scott N et al (2001) Pharmacokinetics and safety of oral eletriptan during different phases of the menstrual cycle in healthy volunteers. J Clin Pharmacol 41(12):1339–1344PubMedCrossRefGoogle Scholar
  80. Soldin OP, Mattison DR (2009) Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 48(3):114–157CrossRefGoogle Scholar
  81. Sun H, Fadiran EO, Jones CD et al (1999) Population pharmacokinetics: a regulatory perspective. Clin Pharmacokinet 37(1):41–58PubMedCrossRefGoogle Scholar
  82. Tran C, Knowleges SR, Liu BA et al (1988) Gender differences in adverse drug reactions. J Clin Pharmacol 38:1003–1009CrossRefGoogle Scholar
  83. Vahl N, Moller N, Lauritzen T et al (1998) Metabolic effects and pharmacokinetics of a growth hormone pulse in healthy adults: relation to age, sex, and body composition. J Clin Endocrinol Metab 82:3612–3618CrossRefGoogle Scholar
  84. Verbeeck R, Cardinal JA, Wallace S (1984) Effect of age and sex on the plasma binding of acidic and basic drugs. Eur J Clin Pharmacol 27:91–97PubMedCrossRefGoogle Scholar
  85. Vukovich RA, Brannick LJ, Sugerman AA et al (1975) Sex differences in the intramuscular absorption and bioavailability of cephradine. Clin Pharmacol Ther 18(2):215–220PubMedGoogle Scholar
  86. Waxman DJ, Holloway MG (2009) Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol 76:215–228PubMedCentralPubMedCrossRefGoogle Scholar
  87. Yang Y, Lai J, Lee C et al (2011) Increased risk of hospitalization related to motor vehicle accidents among people taking zolpidem: a case–crossover study. J Epidemiol 21(1):37–43. doi: 10.2188/jea.JE20090195 PubMedCentralPubMedCrossRefGoogle Scholar
  88. Zofran® (ondansetron) US FDA product labeling. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=c7d61d98-fe86-4340-9b86-47eb92acaa0e. Accessed 16 June 2014
  89. Zyprexa® (olanzapine) US FDA product labeling. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d5051fbc-846b-4946-82df-341fb1216341. Accessed 16 June 2014

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Office of Women’s Health, Office of the Commissioner, Food and Drug AdministrationSilver SpringUSA
  2. 2.Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringUSA

Personalised recommendations