نبذة مختصرة : Background: Understanding of TAC pharmacokinetics is required to avoid both overdosing and underdosing. VRCZ is known to increase the TAC blood concentration by inhibiting CYP3A4; however, detailed, practical information on pediatric cases is still scarce. Herein, we investigated the association between the TAC blood concentration and dosage focusing on the administration route and concomitant use of VRCZ in children.
Methods: In total, 38 children who received TAC during stem cell transplantation at our hospital between January 2013 and April 2018 were included. The ratio of the TAC blood concentration (ng/mL) to dosage (mg/kg/day) (C/D) was calculated at the last continuous intravenous infusion (C/Div) and after switching to oral administration (C/Dpo).
Results: Patients with VRCZ (n = 14) showed a higher C/D regardless of administration route (median C/Div: with VRCZ/without VRCZ = 832/643, median C/Dpo: with VRCZ/without VRCZ = 339/45). Additionally, the (C/Div)/(C/Dpo) was about one-fourth in cases with VRCZ; the median (C/Div)/(C/Dpo) was 3.3 for cases with VRCZ and 13.5 for cases without VRCZ. Interestingly, the increase in the TAC blood concentration due to VRCZ was higher when TAC was administered orally, especially in adolescent patients.
Conclusions: To obtain an optimal TAC blood concentration, dose adjustment based on multiple factors, such as administration route, concomitant use of VRCZ, and age, is required.
(© 2019 Wiley Periodicals, Inc.)
References: Watanabe N, Matsumoto K, Muramatsu H, et al. Relationship between tacrolimus blood concentrations and clinical outcome during the first 4 weeks after SCT in children. Bone Marrow Transplant. 2010;45(7):1161-1166.
Mori T, Kato J, Yamane A, et al. Drug interaction between voriconazole and tacrolimus and its association with the bioavailability of oral voriconazole in recipients of allogeneic hematopoietic stem cell transplantation. Int J Hematol. 2012;564-569.
Venkataramanan R, Jain A, Warty VS, et al. Pharmacokinetics of FK 506 in transplant patients. Transplant Proc. 1991;23(6):2736-2740.
Suetsugu K, Ikesue H, Miyamoto T, et al. Analysis of the variable factors influencing tacrolimus blood concentration during the switch from continuous intravenous infusion to oral administration after allogeneic hematopoietic stem cell transplantation. Int J Hematol. 2017;105(3):361-368.
Przepiorka D, Blamble D, Hilsenbeck S, Danielson M, Krance R, Chan KW. Tacrolimus clearance is age-dependent within the pediatric population. Bone Marrow Transpl. 2000;26(6):601-605.
Guidelines on TDM of Immunosuppressive Drugs in Organ Transplantation. 2nd edn. (The Japanese Society of Therapeutic Drug Monitoring and the Japanese Society of Transplantation, ed.). Japan: Kanehara Publishing Ltd; 2018.
Nishimura M, Yaguti H, Yoshitsugu H, Naito S, Satoh T. Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi. 2003;123(5):369-375.
Zahir H, Nand RA, Brown KF, Tattam BN, McLachlan AJ. Validation of methods to study the distribution and protein binding of tacrolimus in human blood. J Pharmacol Toxicol Methods. 2001;46(1):27-35.
Groll AH, Townsend R, Desai A, et al. Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4. Transpl Infect Dis. 2017;19(5):1-11.
Fakhoury M, Litalien C, Medard Y, et al. Localization and mRNA expression of CYP3A and P-glycoprotein in human duodenum as a function of age. Drug Metab Dispos. 2005;33(11):1603-1607.
Payne K, Mattheyse FJ, Liebenberg D, Dawes T. The pharmacokinetics of midazolam in paediatric patients. Eur J Clin Pharmacol. 1989;37(3):267-272.
Smith MT, Eadie MJ, Brophy TO. The pharmacokinetics of midazolam in man. Eur J Clin Pharmacol. 1981;19(4):271-278.
de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin Pharmacokinet. 1999;37(6):485-505.
Vanhove T, Bouwsma H, Hilbrands L, et al. Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients. Am J Transplant. 2017;17(9):2372-2380.
Hosohata K, Masuda S, Ogura Y, et al. Interaction between Tacrolimus and Lansoprazole, but not Rabeprazole in Living-Donor Liver Transplant Patients with Defects of CYP2C19 and CYP3A5. Drug Metab Pharmacokinet. 2008;23(2):134-138.
Zhou Q, Li W, Zeng S, Yu LS. Pharmacokinetic drug interaction profile of omeprazole with adverse consequences and clinical risk management. Ther Clin Risk Manag. 2013;9(1):259-271.
Sassi MB, Gaies E, Salouage I, Trabelsi S, Lakhal M, Klouz A. Involvement of CYP 3A5 In the Interaction Between Tacrolimus and Nicardipine: A Case Report. Curr Drug Saf. 2015;10(3):254-256.
Nakamura Y, Takeuchi H, Okuyama K, et al. Evaluation of appropriate blood level in continuous intravenous infusion from trough concentrations after oral administration based on area under trough level in tacrolimus and cyclosporine therapy. Transplant Proc. 2005;37(4):1725-1727.
Soda M, Fujitani M, Michiuchi R, et al. Association between tacrolimus pharmacokinetics and cytochrome P450 3A5 and multidrug resistance protein 1 Exon 21 polymorphisms. Transplant Proc. 2017;49(6):1492-1498.
Spriet I, Grootaert V, Meyfroidt G, Debaveye Y, Willems L. Switching from intravenous to oral tacrolimus and voriconazole leads to a more pronounced drug-drug interaction. Eur J Clin Pharmacol. 2013;69(3):737-738.
Processing Request
No Comments.