Dvoprostorni farmakokinetički model itrakonazola nakon oralne primene jedne doze leka – razlike među polovima
Sažetak
Uvod/Cilj. Itrakonazol (ITZ) je široko korišćen antimikotik koji ima veoma varijabilnu farmakokinetiku (FK), što je rezultat same prirode molekula leka, kao i uticaja više faktora. Jedan od faktora uticaja je pol, ali njegov značaj još uvek nije potvrđen. Cilj rada bio je da se ispita uticaj pola na FK ITZ-a primenom dvoprostornog modela, koji je dobijen nakon primene leka per os, u jednoj dozi, na pun želudac kod zdravih ispitanika oba pola. Metode. Prethodno sprovedena studija bioekvivalencije dve oralne farmaceutske formulacije ITZ-a od 100 mg kod 38 zdravih učesnika (22 muškarca i 16 žena) rezultirala je sa 114 setova plazma koncentracija ITZ-a. Od toga је u ovoj studiji analizirano 64 seta (40 od muškaraca i 24 od žena) korišćenjem softvera Kinetica, jer je njihovom primenom dobijen dvoprostorni model. Koncentracije ITZ-a u plazmi bile su određene prethodno validiranom metodom tečne hromatografije sa masenom spektrometrijskom detekcijom. Statističke analize u SPSS-u obuhvatale su Mann-Whitney U i Fisher-ov egzaktni test za poređenje grupa, kao i Spearman-ovu korelacionu analizu odnosa parametara. Rezultati. Slabija resorpcija ITZ-a otkrivena je kod ženskog pola u odnosu na muškarce, a praćena je i razlikama koje su se pojavile u procesu distribucije leka iz centralnog u periferni prostor i obrnuto. Šta više, postoje razlike i u eliminaciji ITZ-a među polovima, koja je efektivnija kod žena. Ovo nije samo rezultat izraženijeg efekta prvog prolaza, već je povezano i sa terminalnom fazom eliminacije nakon oralne primene leka. Zaključak. Primena dvoprostornog modela ITZ-a nakon njegove primene u jednoj dozi per os kod zdravih učesnika u istraživanju omogućila je detaljniji uvid u varijabilnu FK ovog leka, kao i u razlike koje postoje među polovima.
Reference
Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Infectious Diseases Society of America. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008; 46(3): 327–60.
Rogers D, Krysan D. Antifungal Agents. In: Brunton LL, Hilal-Dandan R, Knollmann BC, editors. Goodman and Gilman’s The pharmacological basis of therapeutics. 13th ed. New-York: McGraw-Hill Education; 2018. p. 1087–104.
Frazier WT, Santiago-Delgado ZM, Stupka KC 2nd. Onychomy-cosis: Rapid Evidence Review. Am Fam Physician 2021; 104(4): 359–67.
Armstrong-James D. Antifungal chemotherapies and immuno-therapies for the future. Parasite Immunol 2023; 45(2): e12960.
Hardin TC, Graybill JR, Fetchick R, Woestenborghs R, Rinaldi MG, Kuhn JG. Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob Agents Chemother 1988; 32(9): 1310–3.
De Beule K, Van Gestel J. Pharmacology of itraconazole. Drugs 2001; 61 Suppl 1: 27–37.
Sweetman SC. Martindale: the complete drug reference. 36th ed. Book & CD-ROM Package. London: Pharmaceutical Press; 2009. p. 3712.
Abuhelwa AY, Mudge S, Hayes D, Uptona NR, Foster JRD. Pop-ulation in vitro-in vivo correlation model linking gastrointes-tinal transit time, pH, and pharmacokinetics. Itraconazole as model drug. Pharm Res 2016; 33(7): 1782–94.
Rowland M, Tozer T. Clinical Pharmacokinetics and pharmaco-dynamics: Concepts and Applications. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2011. p. 864.
Cross LJ, Bagg J, Oliver D, Warnock D. Serum itraconazole con-centrations and clinical responses in Candida-associated den-ture stomatitis patients treated with itraconazole solution and itraconazole capsules. J Antimicrob Chemother 2000; 45(1): 95–9.
Fagiolino P, González N, Vázquez M, Eiraldi R. Itraconazole bi-oequivalence revisited: Influence of gender on highly variable drugs. Open Drug Metab J 2007; 1: 7–13.
Thompson GR 3rd, Lewis P, Mudge S, Patterson TF, Burnett BP. Open-Label Crossover Oral Bioequivalence Pharmacokinetics Comparison for a 3-Day Loading Dose Regimen and 15-Day Steady-State Administration of SUBA-Itraconazole and Con-ventional Itraconazole Capsules in Healthy Adults. Antimi-crob Agents Chemother 2020; 64(8): e00400–20.
Heykants J, Van Peer A, Van de Velde V, Van Rooy P, Meulder-mans W, Lavrijsen K, et al. The clinical pharmacokinetics of itraconazole: an overview. Mycoses 1989; 32 Suppl 1: 67–87.
Prentice AG, Glasmacher A. Making sense of itraconazole pharmacokinetics. J Antimicrob Chemiother 2005; 56 Suppl 1: i17–22.
Bellmann R, Smuszkiewicz P. Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of pa-tients. Infection 2017; 45(6): 737–79.
European Medicines Agency. Guideline on the investigation of bioequivalence [Internet]. London: EMA; 2010 [cited 2023 Sep 29; accessed 2024 April 24]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf
Dragojević-Simić V, Kovačević A, Jaćević V, Rančić N, Djordjević 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): 979–88.
Sweetman SC. Martindale: The Complete Drug Reference. 37th ed. London: Pharmaceutical Press; 2011. p. 562–99.
McEvoy GK. AHFS drug information 2016. Bethesda, Mary-land: American Society of Health-System Pharmacists (ASHP); 2016. p. 498–507.
Ibarra М, Vázquez M, Fagiolino P. Sex Effect on Average Bioe-quivalence. Clin Ther 2017; 39(1): 23–33.
Anderson GD. Sex and racial differences in pharmacological re-sponse: Where is the evidence? Pharmacogenetics, pharmaco-kinetics, and pharmacodynamics. J Womens Health (Larchmt) 2005; 14(1): 19–29.
Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2009; 48(3): 143–57.
Van Peer A, Woestenborghs R, Heykants J, Gasparini R, Gauwen-bergh G. The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects. Eur J Clin Pharmacol 1989; 36(4): 423–6.
Puttick MP, Phillips P. Itraconazole: Precautions regarding drug interactions and bioavailability. Can J Infect Dis 1994; 5(4): 179–83.
Zimmermann T, Yeates RA, Laufen H, Pfaff G, Wildfeuer A. In-fluence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole. Eur J Clin Pharmacol 1994; 46(2): 147–50.
Van de Velde VJ, Van Peer AP, Heykants JJ, Woestenborghs RJ, Van Rooy P, De Beule KL, et al. Effect of food on the pharma-cokinetics of a new hydroxypropyl-beta-cyclodextrin formula-tion of itraconazole. Pharmacotherapy 1996; 16(3): 424–8.
Cartledge JD, Midgely J, Gazzard BG. Itraconazole solution: higher serum drug concentrations and better clinical response rates than the capsule formulation in acquired immunodefi-ciency syndrome patients with candidiosis. J Clin Pathol 1997; 50(6): 477–80.
Abdel-Rahman SM, Jacobs RF, Massarella J, Kauffman RE, Brad-ley JS, Kimko HC, et al. Single-dose pharmacokinetics of intra-venous itraconazole and hydroxypropyl-beta-cyclodextrin in infants, children, and adolescents. Antimicrob Agents Chemother 2007; 51(8): 2668–73.
Abuhelwa AY, Foster DJ, Mudge S, Hayes D, Upton RN. Popula-tion pharmacokinetic modeling of itraconazole and hydroxy-itraconazole for oral SUBA-itraconazole and sporanox capsule formulations in healthy subjects in fed and fasted states. An-timicrob Agents Chemother 2015; 59(9): 5681–96.
Czyrski A, Resztak M, Świderski P, Brylak J, Główka FK. The Overview on the Pharmacokinetic and Pharmacodynamic In-teractions of Triazoles. Pharmaceutics 2021; 13(11): 1961.
Bury D, Tissing WJE, Muilwijk EW, Wolfs TFW, Brüggemann RJ. Clinical Pharmacokinetics of Triazoles in Pediatric Pa-tients. Clin Pharmacokinet 2021; 60(9): 1103–47.
Naqvi SMH, Gala MYN, Muchhala S, Arumugam A, Panigrahi D, Patil D, et al. Pharmacokinetics/Pharmacodynamics study of Fixtral SB as compared to supra bioavailable itraconazole and conventional itraconazole. World J Pharmacol 2023; 12(1): 1–11.
Miljković MN, Rančić N, Kovačević A, Cikota-Aleksić B, Skadrić I, Jaćević V, et al. Influence of Gender, Body Mass Index, and Age on the Pharmacokinetics of Itraconazole in Healthy Sub-jects: Non-Compartmental Versus Compartmental Analysis. Front Pharmacol 2022; 13: 796336.
Yun HY, Baek MS, Park IS, Choi BK, Kwon KI. Comparative analysis of the effects of rice and bread meals on bioavailabil-ity of itraconazole using NONMEM in healthy volunteers. Eur J Clin Pharmacol 2006; 62(12): 1033–9.
Bae SK, Park SJ, Shim EJ, Mun JH, Kim EY, Shin JG, et al. In-creased oral bioavailability of itraconazole and its active me-tabolite, 7-hydroxyitraconazole, when coadministered with a vitamin C beverage in healthy participants. J Clin Pharmacol 2011; 51(3): 444–51.
Prieto Garcia L, Janzén D, Kanebratt KP, Ericsson H, Lennernäs H, Lundahl A. Physiologically based pharmacokinetic model of itraconazole and two of its metabolites to improve the predic-tions and the mechanistic understanding of CYP3A4 drug-drug interactions. Drug Metab Dispos 2018; 46(10): 1420–33.
Thummel K, Shen D, Isoherranen N. Design and Optimization of Dosage Regimens: Pharmacokinetic Data. In: Brunton LL, Hi-lal-Dandan R, Knollman BC. Goodman and Gilman’s The Pharmacological Basis of therapeutics. 13th ed. New York: McGraw-Hill Education; 2018. p. 1325–78.
Nakamura Y, Matsumoto K, Sato A, Morita K. Effective plasma concentrations of itraconazole and its active metabolite for the treatment of pulmonary aspergillosis. J Infect Chemother 2020; 26(2): 170–4.
Patni AK, Monif T, Khuroo AH, Tiwary AK. Validated Liquid chromatography tandem mass spectrometric method for quan-tification of Itraconazole and Hydroxy Itraconazole in human plasma for pharmacokinetic study. Der Pharmacia Lettre 2010; 2(2): 41–53.
Liu F, Yi H, Wang L, Cheng Z, Zhang G. A novel method to estimate the absorption rate constant for two compartment model fitted drugs without intravenous pharmacokinetic data. Front. Pharmacol 2023; 14: 1087913.
Ben Mansour G, Kacem A, Ishak M, Grélot L, Ftaiti F. The ef-fect of body composition on strength and power in male and female students. BMC Sports Sci Med Rehabil 2021; 13(1): 150.
Bredella MA. Sex Differences in Body Composition. In: Mau-vais-Jarvis F, editor. Sex and Gender Factors Affecting Meta-bolic Homeostasis, Diabetes and Obesity. Advances in Exper-imental Medicine and Biology, vol 1043. New York: Springer; 2017. p. 9–27.
Karastergiou K, Smith SR, Greenberg AS, Fried SK. Sex differ-ences in human adipose tissues - the biology of pear shape. Bi-ol Sex Differ 2012; 3(1): 13.
Shargel L, Wu-Pong S, Yu A. Applied biopharmaceutics & pharmacokinetics. 6th ed. New York: The McGraw-Hill Companies; 2012. p. 811.
Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmaco-kinetics and pharmacodynamics. Drugs 1995; 50(2): 222–39.
Pollock BG. Gender differences in psychotropic drug metabo-lism. Psychopharmacol Bull 1997; 33(2): 235–41.
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): 978–88.
Sakuma T, Kawasaki Y, Jarukamjorn K, Nemoto N. Sex differ-ences of drug-metabolizing enzyme: Female Predominant Ex-pression of Human and Mouse Cytochrome P450 3A Isoforms. J Health Sci 2009; 55(3): 325–37.
Waxman DJ, O’Connor C. Growth hormone regulation of sex-dependent liver gene expression. Mol Endocrinol 2006; 20(11): 2613–29.
Jaffe CA, Turgeon DK, Lown K, Demott-Friberg R, Watkins PB. Growth hormone secretion pattern is an independent regula-tor of growth hormone actions in humans. Am J Physiol En-docrinol Metab 2002; 283(5): E1008–15.
Yáñez JA, Remsberg CM, Sayre CL, Forrest ML, Davies NM. Flip-flop pharmacokinetics – delivering a reversal of disposi-tion: challenges and opportunities during drug development. Ther Deliv 2011; 2(5): 643–72.
Dvorchik BH, Vessell ES. Significance of error associated with use of the one-compartment formula to calculate clearance of thirty-eight drugs. Clin Pharmacol Ther 1978; 23(6): 617–23.
Loughnan PM, Sitar DS, Ogilvie RI, Neims AH. The two-compartment open-system kinetic model: A review of its clin-ical implications and applications. J Pediatr 1976; 88(5): 869–73.
Wagner JG. Application of the Wagner-Nelson absorption method to the two-compartment open model. J Pharmacoki-net Biopharm 1974; 2(6): 469–86.
Qusai U, Hameed A, Hameed Rasheed K. Compartmental and Non-Compartmental Pharmacokinetic Analysis of Extended Release Diclofenac Sodium Tablet. NUCEJ 2016; 19(1): 161–5.