THE CONCENTRATIONS OF ITRACONAZOLE AND HYDROXYITRACONAZOLE AFTER ORAL DRUG APPLICATION IN HEALTHY SUBJECTS: THE INFLUENCE OF GENDER
Keywords:
itraconazole, hydroxy-hydroxyitraconazole, plasma concentrations, healthy subjects, gender
Abstract
The aim of our study was to investigate the influence of gender on itraconazole and hydroxyitraconazole plasma concentrations in healty humans after oral application of itraconazole in one dose.
Pharmacokinetic analysis was performed after oral administration of itraconazole in a single dose of 100 mg in 22 male and 16 female healthy volunteers. Blood samples were taken before drug administration, as well as at appropriate time intervals up to 72 hours thereafter. Itraconazole and hydroxyitraconazole concentrations were determined using a validated liquid chromatography method with mass spectrometric detection (LC-MS/MS), while their pharmacokinetic parameters were calculated by using Kinetica programme, version 5.0: Cmax,Tmax,PIK (0-72), PIK(0-∞),T1/2, and Ke.
The median values of both itraconazole and hydroxyitraconazole were lower in women in comparison to men during the whole observed period. Moreover, median values of Cmax, PIK(0-72) and PIK(0-∞) parameters were also significantly lower in women, concerning both itraconazole (p=0.005, 0.036 and 0.036, respectively) and its metabolite (p=0.004, 0.010 and 0.044, respectively). Elimination parameters - T1/2 and Ke did not differ between genders.
Women were less exposed to the itraconazole and its active metabolite than men after its oral administration, possibly as a result of less bioavailability of the drug, including more intense presystemic metabolism due to higher expression and/or activity of enzyme isoform which metabolises itraconazole, needed to be confirmed by pharmacogenomic analyzes.
References
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31. Guideline Clinical Safety Data Management: Definitions AND Standards FOR Expedited Reporting E2A. International Conference on Harmonization of Technical Requirement for Registration of Pharmaceuticals for Human use (ICH). Available from: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_Guideline.pdf
32. The use of the WHO-UMC system for standardized case causality assessment. The Uppsala Monitoring Centre. Available from: https://www.whoumc.org/media/2768/standardised-case-causality-assessment.pdf
33. Maertens JA. History of the development of azole derivatives. Clin Microbiol Infect 2004; 10(1): 1-10.
34. Davit BM, Conner DP, Fabian-Fritsch B, Haidar SH, Jiang X, Patel DT, et al. Highly Variable Drugs: Observations from Bioequivalence Data Submitted to the FDA for New Generic Drug Applications. The AAPS Journal 2008; 10(1): 148-156.
35. Hope WW, Billaud EM, Lestner J, Denning DW. Therapeutic drug monitoring for triazoles. Curr Opin Infect Dis 2008; 21(6): 580-586.
36. John J, Loo A, Mazur S, Walsh TJ. Therapeutic drug monitoring of systemic antifungal agents: a pragmatic approach for adult and pediatric patients. Expert Opin Drug Metab Toxicol 2019; 15(11): 881-895.
37. Soldin OP, Mattison DR. Sex differences in Pharmacokinetics and Pharmacodynamics. Clin Pharmacokinet 2009; 48(3): 143-157.
38. Fagiolino P, González N, Vázquez M, Eiraldi R. Itraconazole Bioequivalence Revisited: Influence of Gender on Highly Variable Drugs. The Open Drug Metabolism Journal 2007; 1(1): 7-13.
39. Yasuda K, Lan LB, Sanglard D, Furuya K, Schuetz JD, Schuetz EG. Interaction of cytochrome P450 3A inhibitors with P-glycoprotein. J Pharmacol Exp Ther 2002; 303(1): 323-332.
40. Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 1995; 275(2): 1011-1018.
41. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol 1992; 44(2): 275-283.
42. 42 George J, Byth K, Farrell GC. Age but not gender selectively affects expression of individual cytochrome P450 proteins in human liver. Biochem Pharmacol 1995; 50(5): 727-730.
43. Meffin PJ, Brooks PM, Sallustio BC. Alterations in prednisolone disposition as a result of time of administration, gender and dose. Br J Clin Pharmacol 1984; 17(4): 395-404.
44. Sakuma T, Kawasaki Y, Jarukamjorn K, Nemoto N. Sex differences of drug-metabolizing enzyme: Female Predominant Expression of Human and Mouse Cytochrome P450 3A Isoforms. Journal of Health Science 2009; 55(3): 325-337.
45. Sansone-Parsons A, Krishna G, Simon J, Soni P, Kantesaria B, Herron J, et al. Effects of Age, Gender, and Race/Ethnicity on the Pharmacokinetics of Posaconazole in Healthy Volunteers. Antimicrobial agents and chemotherapy. Antimicrob Agents Chemother 2007; 51(2): 495-502.
46. Allegra S, Fatiguso G, De Francia S, Favata F, Pirro E, Carcieri C, et al. Evaluation of Posaconazole Pharmacokinetics in Adult Patients with Invasive Fungal Infection. Biomedicines 2017; 5(4): 66.
47. Carrasco-Portugal MC, Flores-Murrieta FJ. Gender Differences in the Oral Pharmacokinetics of Fluconazole. Clin Drug Invest 2007; 27(12): 851-855.
48. Tothfalusi L, Endrenyi L, Arieta AG. Evaluation of bioequivalence for highly variable drugs with scaled average bioequivalence. Clin Pharmacokinet 2009; 48(11): 725-743.
49. Guidance for industry bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Available from: https://www.fda.gov/downloads/drugs/guidances/ucm377465.pdf.
50. Davit BM, Chen ML, Conner DP, Haidar SH, Kim S, Lee CH, et al. Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration. AAPS J 2012; 14(4): 915-924.
51. Midha K, Rawson M, Hubbard J. The bioequivalence of highly variable drugs and drug products. Int J Clin Pharmacol Ther 2005; 43(10): 485-498.
52. Public Assessment Report. Decentralised Procedure Itraconazole 100 mg Capsules. Available from: http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con046562.pdf.
53. Tucker R, Haq Y, Denning D, Stevens D. Adverse events associated with itraconazole in 189 patients on chronic therapy. J Antimicrob Chemother 1990; 26(4): 561-566.
54. Sharkey P, Rinaldi M, Dunn J, Hardin T, Fetchick R, Graybill J. High dose itraconazole in the treatment of severe mycoses . Antimicrobial agents and chemotherapy 1991; 35(4): 707-713.
55. Haneke E, Abeck D, Ring J. Safety and efficacy of intermittent therapy with itraconazole in finger- and toe nail onychomycosis: a multicentre trial. Mycoses 1998; 41(11-12): 521-527.
56. Cartledge J, Midgely J, Gazzard B. Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidosis. J Clin Pathol 1997; 50(6): 477-480.
57. Lestner J, Roberts S, Moore C, Howard S, Denning D, Hope W. Toxicodynamics of Itraconazole: Implications for Therapeutic Drug Monitoring. Clinical Infectious Diseases 2009; 49(6): 928-930.
2. Soldin OP, Chung SH, Mattison DR. Sex differences in drug disposition. J Biomed Biotechnol 2011; 2011: 187103.
3. Chu T. Gender Differences in Pharmacokinetics. US Pharm 2014; 39(9): 40-43.
4. Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol 2001; 2(6): 349-351.
5. Center for Drug Evaluation and Research. Food and Drug Administration. Guidance for Industry—Bioavailability and Bioequivalence Studies for Orally Administered Drug Products —General Considerations. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) 2002.
6. Fletcher CV, Acosta EP, Strykowski JM. Gender differences in human pharmacokinetics and pharmacodynamics. J Adolesc Health 1994; 15(8): 619-629.
7. Hutson WR, Roehrkasse RL, Wald A. Influence of gender and menopause on gastric emptying and motility. Gastroenterology 1989; 96(1): 11-17.
8. Tuo B, Wen G, Wei J, Liu X, Wang X, Zhang Y, et al. Estrogen regulation of duodenal bicarbonate secretion and sex-specific protection of human duodenum. Gastroenterology 2011; 141(3): 854-863.
9. Kim WY, Benet LZ. P-glycoprotein (P-gp/MDR1) - mediated efflux of sex-steroid hormones and modulation of P-gp expression in vitro. Pharm Res 2004; 21(7): 1284-1293.
10. Paine MF, Ludington SS, Chen ML, Stewart PW, Huang SM, Watkins PB. Do men and women differ in proximal small intestinal CYP3A or P-glycoprotein expression? Drug Metab Dispos 2005; 33(3): 426-433.
11. Baraona E, Abittan CS, Dohmen K, Moretti M, Pozzato G, Chayes ZW, et al. Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res 2001; 25(4): 502-507.
12. Brinkman-Van der Linden CM, Havenaar EC, Van Ommen CR, Van Kamp GJ, Gooren LJ, Van Dijk W. Oral estrogen treatment induces a decrease in expression of sialyl Lewis x on alpha 1-acid glycoprotein in females and male-to-female transsexuals. Glycobiology 1996; 6(4): 407-412.
13. Wiegratz I, Kutschera E, Lee JH, Moore C, Mellinger U, Winkler UH, et al. Effect of four different oral contraceptives on various sex hormones and serum-binding globulins. Contraception 2003; 67(1): 25-32.
14. Wolbold R, Klein K, Burk O, Nüssler AK, Neuhaus P, Eichelbaum M, et al. Sex is a Major Determinant of CYP3A4 Expression in Human Liver. Hepatology 2003; 38(4): 978-988.
15. Jaffe CA, Turgeon DK, Lown K, Demott-Friberg R, Watkins PB. Growth Hormone Secretion Pattern Is an Independent Regulator of Growth Hormone Actions in Humans. Am J Physiol Endocrinol Metab 2002; 283(5): E1008-E1015.
16. Handschin C, Meyer UA. Induction of drug metabolism: the role of nuclear receptors. Pharmacol Rev 2003; 55(4): 649-673.
17. Schwartz JB. The influence of sex on pharmacokinetic. Clin Pharmacokinet 2003; 42(2): 107-121.
18. Gross JL, Friedman R, Azevedo MJ, Silveiro SP, Pecis M. Effects of age and sex on glomerular filtration rate measured by 51Cr-EDTA. Braz J Med Biol Res 1992; 25(2): 129-134.
19. Cleary JD, Taylor JW, Chapman SW. Itraconazole in antifungal therapy. Ann Pharmacother 1992; 26(4): 502-509.
20. Zhou H, Goldman M, Wu J, Woestenborghs R, Hassell AE, Lee P, et al. A pharmacokinetic study of intravenous itraconazole followed by oral administration of itraconazole capsules in patients with advanced human immunodeficiency virus infection. J Clin Pharmacol 1998; 38(7): 593-602.
21. Tricot G, Joosten E, Boogaerts MA, Vande-Pitte J, Cauwenbergh G. Ketoconazole vs itraconazole for antifungal prophylaxis in patients with severe granulocytopenia: preliminary results of two nonrandomized studies. Rev Infect Dis 1987; 9(1): 94-99.
22. Jaruratanasirikul S, Kleepkaew A. Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole. Eur J Clin Pharmacol 1997; 52(3): 235-237.
23. Van Peer A, Woestenborghs R, Heykants J, Gasparini R, Gauwenbergh G. The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects. Eur J Clin Pharmacol 1989; 36(4): 423-426.
24. De Beule K, Van Gestel J. Pharmacology of Itraconazole. Drugs 2001; 61(l): 27-37.
25. Poirier JM, Cheymol G. Optimisation of Itraconazole Therapy Using Target Drug Concentrations. Clin Pharmacokinet 1998; 35(6): 461-473.
26. Blume HH, Midha KK. Bio-International 92, conference on bioavailability, bioequivalence, and pharmacokinetic studies. J Pharm Sci 1993; 82(11): 1186-1189.
27. Guideline on the investigation of bioequivalence. European Medicines Agency (EMA). Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/ WC500070039.pdf.
28. Patni AK, Monif T, Khuroo AH, Iyer SS, Tiwary AK. A comparative bioavailability study of two formulations of itraconazole 100 mg capsule in healthy human Indian subjects under fasting conditions. Clinic Res Regul Aff 2010; 27: 128-132.
29. Patni AK, Monif T, Khuroo AH, Iyer SS, Jain R, Kumar S, et al. Determination of pharmacokinetics of itraconazole in healthy Indian subjects under fed condition and incurred sample analysis using a validated liquid chromatography tandem mass spectrometric method. Clinic Res Regul Aff 2012; 29: 35-40.
30. Dragojević-Simić V, Kovačević A, Jaćević V, Rančić N, Đordjević S, Kilibarda V, et al. Bioequivalence study of two formulations of itraconazole 100 mg capsules in healthy volunteers under fed conditions: a randomized, three-period, reference-replicated, crossover study. Expert Opin Drug Metab Toxicol 2018; 14(9): 979-988.
31. Guideline Clinical Safety Data Management: Definitions AND Standards FOR Expedited Reporting E2A. International Conference on Harmonization of Technical Requirement for Registration of Pharmaceuticals for Human use (ICH). Available from: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_Guideline.pdf
32. The use of the WHO-UMC system for standardized case causality assessment. The Uppsala Monitoring Centre. Available from: https://www.whoumc.org/media/2768/standardised-case-causality-assessment.pdf
33. Maertens JA. History of the development of azole derivatives. Clin Microbiol Infect 2004; 10(1): 1-10.
34. Davit BM, Conner DP, Fabian-Fritsch B, Haidar SH, Jiang X, Patel DT, et al. Highly Variable Drugs: Observations from Bioequivalence Data Submitted to the FDA for New Generic Drug Applications. The AAPS Journal 2008; 10(1): 148-156.
35. Hope WW, Billaud EM, Lestner J, Denning DW. Therapeutic drug monitoring for triazoles. Curr Opin Infect Dis 2008; 21(6): 580-586.
36. John J, Loo A, Mazur S, Walsh TJ. Therapeutic drug monitoring of systemic antifungal agents: a pragmatic approach for adult and pediatric patients. Expert Opin Drug Metab Toxicol 2019; 15(11): 881-895.
37. Soldin OP, Mattison DR. Sex differences in Pharmacokinetics and Pharmacodynamics. Clin Pharmacokinet 2009; 48(3): 143-157.
38. Fagiolino P, González N, Vázquez M, Eiraldi R. Itraconazole Bioequivalence Revisited: Influence of Gender on Highly Variable Drugs. The Open Drug Metabolism Journal 2007; 1(1): 7-13.
39. Yasuda K, Lan LB, Sanglard D, Furuya K, Schuetz JD, Schuetz EG. Interaction of cytochrome P450 3A inhibitors with P-glycoprotein. J Pharmacol Exp Ther 2002; 303(1): 323-332.
40. Schuetz EG, Furuya KN, Schuetz JD. Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 1995; 275(2): 1011-1018.
41. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol 1992; 44(2): 275-283.
42. 42 George J, Byth K, Farrell GC. Age but not gender selectively affects expression of individual cytochrome P450 proteins in human liver. Biochem Pharmacol 1995; 50(5): 727-730.
43. Meffin PJ, Brooks PM, Sallustio BC. Alterations in prednisolone disposition as a result of time of administration, gender and dose. Br J Clin Pharmacol 1984; 17(4): 395-404.
44. Sakuma T, Kawasaki Y, Jarukamjorn K, Nemoto N. Sex differences of drug-metabolizing enzyme: Female Predominant Expression of Human and Mouse Cytochrome P450 3A Isoforms. Journal of Health Science 2009; 55(3): 325-337.
45. Sansone-Parsons A, Krishna G, Simon J, Soni P, Kantesaria B, Herron J, et al. Effects of Age, Gender, and Race/Ethnicity on the Pharmacokinetics of Posaconazole in Healthy Volunteers. Antimicrobial agents and chemotherapy. Antimicrob Agents Chemother 2007; 51(2): 495-502.
46. Allegra S, Fatiguso G, De Francia S, Favata F, Pirro E, Carcieri C, et al. Evaluation of Posaconazole Pharmacokinetics in Adult Patients with Invasive Fungal Infection. Biomedicines 2017; 5(4): 66.
47. Carrasco-Portugal MC, Flores-Murrieta FJ. Gender Differences in the Oral Pharmacokinetics of Fluconazole. Clin Drug Invest 2007; 27(12): 851-855.
48. Tothfalusi L, Endrenyi L, Arieta AG. Evaluation of bioequivalence for highly variable drugs with scaled average bioequivalence. Clin Pharmacokinet 2009; 48(11): 725-743.
49. Guidance for industry bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Available from: https://www.fda.gov/downloads/drugs/guidances/ucm377465.pdf.
50. Davit BM, Chen ML, Conner DP, Haidar SH, Kim S, Lee CH, et al. Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration. AAPS J 2012; 14(4): 915-924.
51. Midha K, Rawson M, Hubbard J. The bioequivalence of highly variable drugs and drug products. Int J Clin Pharmacol Ther 2005; 43(10): 485-498.
52. Public Assessment Report. Decentralised Procedure Itraconazole 100 mg Capsules. Available from: http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con046562.pdf.
53. Tucker R, Haq Y, Denning D, Stevens D. Adverse events associated with itraconazole in 189 patients on chronic therapy. J Antimicrob Chemother 1990; 26(4): 561-566.
54. Sharkey P, Rinaldi M, Dunn J, Hardin T, Fetchick R, Graybill J. High dose itraconazole in the treatment of severe mycoses . Antimicrobial agents and chemotherapy 1991; 35(4): 707-713.
55. Haneke E, Abeck D, Ring J. Safety and efficacy of intermittent therapy with itraconazole in finger- and toe nail onychomycosis: a multicentre trial. Mycoses 1998; 41(11-12): 521-527.
56. Cartledge J, Midgely J, Gazzard B. Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodeficiency syndrome patients with candidosis. J Clin Pathol 1997; 50(6): 477-480.
57. Lestner J, Roberts S, Moore C, Howard S, Denning D, Hope W. Toxicodynamics of Itraconazole: Implications for Therapeutic Drug Monitoring. Clinical Infectious Diseases 2009; 49(6): 928-930.
Published
2021/04/27
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