Modelling changes in the pharmacokinetics of tacrolimus during pregnancy after kidney transplantation: A retrospective cohort study.
immunosuppression
kidney transplantation
pharmacokinetics
population analysis
pregnancy
Journal
British journal of clinical pharmacology
ISSN: 1365-2125
Titre abrégé: Br J Clin Pharmacol
Pays: England
ID NLM: 7503323
Informations de publication
Date de publication:
18 Aug 2023
18 Aug 2023
Historique:
revised:
19
07
2023
received:
17
05
2023
accepted:
05
08
2023
pubmed:
19
8
2023
medline:
19
8
2023
entrez:
19
8
2023
Statut:
aheadofprint
Résumé
Pregnancy after kidney transplantation is realistic but immunosuppressants should be continued to prevent rejection. Tacrolimus is safe during pregnancy and is routinely dosed based on whole-blood predose concentrations. However, maintaining these concentrations is complicated as physiological changes during pregnancy affect tacrolimus pharmacokinetics. The aim of this study was to describe tacrolimus pharmacokinetics throughout pregnancy and explain the changes by investigating covariates in a population pharmacokinetic model. Data of pregnant women using a twice-daily tacrolimus formulation following kidney transplantation were retrospectively collected from 6 months before conception, throughout gestation and up to 6 months postpartum. Pharmacokinetic analysis was performed using nonlinear mixed effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. The final model was evaluated using goodness-of-fit plots, visual predictive checks and a bootstrap analysis. A total of 260 whole-blood tacrolimus predose concentrations from 14 pregnant kidney transplant recipients were included. Clearance increased during pregnancy from 34.5 to 41.7 L/h, by 15, 19 and 21% in the first, second and third trimester, respectively, compared to prior to pregnancy. This indicates a required increase in the tacrolimus dose by the same percentage to maintain the prepregnancy concentration. Haematocrit and gestational age were negatively correlated with tacrolimus clearance (P ≤ 0.01), explaining 18% of interindividual and 85% of interoccasion variability in oral clearance. Tacrolimus clearance increases during pregnancy, resulting in decreased exposure to tacrolimus, which is explained by gestational age and haematocrit. To maintain prepregnancy target whole-blood tacrolimus predose concentrations during pregnancy, increasing the dose is required.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Références
Murray JE, Reid DE, Harrison JH, Merrill JP. Successful pregnancies after human renal transplantation. N Engl J Med. 1963;269(7):341-343. doi:10.1056/NEJM196308152690704
Jain AB, Shapiro R, Scantlebury VP, et al. Pregnancy after kidney and kidney-pancreas transplantation under tacrolimus: a single center's experience. Transplantation. 2004;77(6):897-902. doi:10.1097/01.TP.0000117564.50117.FB
Gutiérrez MJ, Acebedo-Ribó M, García-Donaire JA, et al. Pregnancy in renal transplant recipients. Transplant Proc. 2005;37(9):3721-3722. doi:10.1016/j.transproceed.2005.09.175
Armenti VT, Moritz MJ, Cardonick EH, Davison JM. Immunosuppression in pregnancy: choices for infant and maternal health. Drugs. 2002;62(16):2361-2375. doi:10.2165/00003495-200262160-00004
Claeys E, Vermeire K. Immunosuppressive drugs in organ transplantation to prevent allograft rejection: mode of action and side effects. J Immunol Sci. 2019;3(4):14-21. doi:10.29245/2578-3009/2019/4.1178
Neuwirt H, Rudnicki M, Schratzberger P, Pirklbauer M, Kronbichler A, Mayer G. Immunosuppression after renal transplantation. memo. 2019;12(3):216-221. doi:10.1007/s12254-019-0507-4
Le HL, Francke MI, Andrews LM, de Winter BCM, van Gelder T, Hesselink DA. Usage of tacrolimus and mycophenolic acid during conception, pregnancy, and lactation, and its implications for therapeutic drug monitoring: a systematic critical review. Ther Drug Monit. 2020;42(4):518-531. doi:10.1097/FTD.0000000000000769
Thongprayoon C, Hansrivijit P, Kovvuru K, et al. Impacts of high intra- and inter-individual variability in tacrolimus pharmacokinetics and fast tacrolimus metabolism on outcomes of solid organ transplant recipients. J Clin Med. 2020;9(7):9. doi:10.3390/jcm9072193
Brunet M, van Gelder T, Åsberg A, et al. Therapeutic drug monitoring of tacrolimus-personalized therapy: second consensus report. Ther Drug Monit. 2019;41(3):261-307. doi:10.1097/FTD.0000000000000640
Kanado Y, Tsurudome Y, Omata Y, et al. Estradiol regulation of P-glycoprotein expression in mouse kidney and human tubular epithelial cells, implication for renal clearance of drugs. Biochem Biophys Res Commun. 2019;519(3):613-619. doi:10.1016/j.bbrc.2019.09.021
Alexander SPKE, Mathie A, Peters JA, Veale EL, et al. The concise guide to pharmacology 2021/22: transporters. Br J Pharmacol. 2021;178(Suppl 1):S412-S513. doi:10.1111/bph.15543
Vanhove T, Annaert P, Kuypers DR. Clinical determinants of calcineurin inhibitor disposition: a mechanistic review. Drug Metab Rev. 2016;48(1):88-112. doi:10.3109/03602532.2016.1151037
Hebert MF, Easterling TR, Kirby B, et al. 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. 2008;84(2):248-253. doi:10.1038/clpt.2008.1
Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995;29(6):404-430. doi:10.2165/00003088-199529060-00003
Hytten F. Blood volume changes in normal pregnancy. Clin Haematol. 1985;14(3):601-612. doi:10.1016/S0308-2261(21)00496-3
Zheng S, Easterling TR, Umans JG, et al. Pharmacokinetics of tacrolimus during pregnancy. Ther Drug Monit. 2012;34(6):660-670. doi:10.1097/FTD.0b013e3182708edf
Undre NA, Stevenson P, Schäfer A. Pharmacokinetics of tacrolimus: clinically relevant aspects. Transplant Proc. 1999;31(7A):21S-24S. doi:10.1016/S0041-1345(99)00788-5
Iwasaki K, Miyazaki Y, Teramura Y, et al. Binding of tacrolimus (FK506) with human plasma proteins re-evaluation and effect of mycophenolic acid. Res Commun Mol Pathol Pharmacol. 1996;94(3):251-257.
Nagase K, Iwasaki K, Nozaki K, Noda K. Distribution and protein binding of FK506, a potent immunosuppressive macrolide lactone, in human blood and its uptake by erythrocytes. J Pharm Pharmacol. 1994;46(2):113-117. doi:10.1111/j.2042-7158.1994.tb03752.x
Alexander SPFD, Kelly E, Mathie A, Peters JA, Veale EL, et al. The concise guide to pharmacology 2021/22: enzymes. Br J Pharmacol. 2021;178(Suppl 1):S313-S411. doi:10.1111/bph.15542
Hebert MF, Zheng S, Hays K, et al. Interpreting tacrolimus concentrations during pregnancy and postpartum. Transplantation. 2013;95(7):908-915. doi:10.1097/TP.0b013e318278d367
Hesselink DA, Bouamar R, Elens L, van Schaik RH, van Gelder T. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2014;53(2):123-139. doi:10.1007/s40262-013-0120-3
Bandur S, Petrasek J, Hribova P, Novotna E, Brabcova I, Viklicky O. Haplotypic structure of ABCB1/MDR1 gene modifies the risk of the acute allograft rejection in renal transplant recipients. Transplantation. 2008;86(9):1206-1213. doi:10.1097/TP.0b013e318187c4d1
Hesselink DA, van Schaik RH, van der Heiden IP, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther. 2003;74(3):245-254. doi:10.1016/S0009-9236(03)00168-1
Kuypers DR, de Jonge H, Naesens M, Lerut E, Verbeke K, Vanrenterghem Y. CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin Pharmacol Ther. 2007;82(6):711-725. doi:10.1038/sj.clpt.6100216
Elens L, Hesselink DA, Bouamar R, et al. Impact of POR*28 on the pharmacokinetics of tacrolimus and cyclosporine A in renal transplant patients. Ther Drug Monit. 2014;36(1):71-79. doi:10.1097/FTD.0b013e31829da6dd
Lunde I, Bremer S, Midtvedt K, et al. The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients. Eur J Clin Pharmacol. 2014;70(6):685-693. doi:10.1007/s00228-014-1656-3
Oneda B, Crettol S, Jaquenoud Sirot E, Bochud M, Ansermot N, Eap CB. The P450 oxidoreductase genotype is associated with CYP3A activity in vivo as measured by the midazolam phenotyping test. Pharmacogenet Genomics. 2009;19(11):877-883. doi:10.1097/FPC.0b013e32833225e7
Zhang JJ, Zhang H, Ding XL, Ma S, Miao LY. Effect of the P450 oxidoreductase 28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers. Eur J Clin Pharmacol. 2013;69(4):807-812. doi:10.1007/s00228-012-1432-1
Williams ET, Leyk M, Wrighton SA, et al. Estrogen regulation of the cytochrome P450 3A subfamily in humans. J Pharmacol Exp Ther. 2004;311(2):728-735. doi:10.1124/jpet.104.068908
McKay DB, Josephson MA. Pregnancy in recipients of solid organs-effects on mother and child. N Engl J Med. 2006;354(12):1281-1293. doi:10.1056/NEJMra050431
Shah S, Venkatesan RL, Gupta A, et al. Pregnancy outcomes in women with kidney transplant: metaanalysis and systematic review. BMC Nephrol. 2019;20(1):24. doi:10.1186/s12882-019-1213-5
Gosselink ME, van Buren MC, Kooiman J, et al. A nationwide Dutch cohort study shows relatively good pregnancy outcomes after kidney transplantation and finds risk factors for adverse outcomes. Kidney Int. 2022;102(4):866-875. doi:10.1016/j.kint.2022.06.006
Moritz MJ. Transplant Pregnancy Registry International, 2020 Annual Report. Philadelphia: Gift of Life Institute, 2020: 25.
van Buren MC, Gosselink M, Groen H, et al. Effect of pregnancy on eGFR after kidney transplantation: a national cohort study. Transplantation. 2022;106(6):1262-1270. doi:10.1097/TP.0000000000003932
Francke MI, Visser WJ, Severs D, de Mik-van Egmond AME, Hesselink DA, de Winter B. Body composition is associated with tacrolimus pharmacokinetics in kidney transplant recipients. Eur J Clin Pharmacol, submitted. 2022;78(8):1273-1287. doi:10.1007/s00228-022-03323-0
Andrews LM, Hesselink DA, van Schaik RHN, et al. A population pharmacokinetic model to predict the individual starting dose of tacrolimus in adult renal transplant recipients. Br J Clin Pharmacol. 2019;85(3):601-615. doi:10.1111/bcp.13838
Francke MI, Andrews LM, Le HL, et al. Avoiding tacrolimus underexposure and overexposure with a dosing algorithm for renal transplant recipients: a single arm prospective intervention trial. Clin Pharmacol Ther. 2021;110(1):169-178. doi:10.1002/cpt.2163
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612. doi:10.7326/0003-4819-150-9-200905050-00006
Billett HH. Hemoglobin and hematocrit. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston: Butterworths; 1990. Chapter 151. https://www.ncbi.nlm.nig.gov/books/NBK259/
Zhu L, Wang H, Sun X, et al. The population pharmacokinetic models of tacrolimus in Chinese adult liver transplantation patients. J Pharm (Cairo). 2014;2014:713650. doi:10.1155/2014/713650
Khoigani MG, Goli S, Hasanzadeh A. The relationship of hemoglobin and hematocrit in the first and second half of pregnancy with pregnancy outcome. Iran J Nurs Midwifery Res. 2012;17(2 Suppl 1):S165-S170.
Sikma MA, Van Maarseveen EM, Hunault CC, et al. Unbound plasma, Total plasma, and whole-blood tacrolimus pharmacokinetics early after thoracic organ transplantation. Clin Pharmacokinet. 2020;59(6):771-780. doi:10.1007/s40262-019-00854-1
Tracy TS, Venkataramanan R, Glover DD, Caritis SN, National Institute for Child Health and Human Development Network of Maternal-Fetal-Medicine Units. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A activity) during pregnancy. Am J Obstet Gynecol. 2005;192(2):633-639. doi:10.1016/j.ajog.2004.08.030
Hirt D, Treluyer JM, Jullien V, et al. Pregnancy-related effects on nelfinavir-M8 pharmacokinetics: a population study with 133 women. Antimicrob Agents Chemother. 2006;50(6):2079-2086. doi:10.1128/AAC.01596-05
Choi SY, Koh KH, Jeong H. Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Drug Metab Dispos. 2013;41(2):263-269. doi:10.1124/dmd.112.046276
Mlugu EM, Minzi OM, Kamuhabwa AAR, Diczfalusy U, Aklillu E. Pregnancy increases CYP3A enzymes activity as measured by the 4β-hydroxycholesterol/cholesterol ratio. Int J Mol Sci. 2022;23(23):15168. doi:10.3390/ijms232315168
Papageorgiou I, Grepper S, Unadkat JD. Induction of hepatic CYP3A enzymes by pregnancy-related hormones: studies in human hepatocytes and hepatic cell lines. Drug Metab Dispos. 2013;41(2):281-290. doi:10.1124/dmd.112.049015
Maynard SE, Thadhani R. Pregnancy and the kidney. J Am Soc Nephrol. 2009;20(1):14-22. doi:10.1681/ASN.2008050493
Piletta-Zanin A, De Mul A, Rock N, Lescuyer P, Samer CF, Rodieux F. Case report: low hematocrit leading to tacrolimus toxicity. Front Pharmacol. 2021;12:717148. doi:10.3389/fphar.2021.717148
Schijvens AM, van Hesteren FHS, Cornelissen EAM, et al. The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients. Pediatr Nephrol. 2019;34(3):507-515. doi:10.1007/s00467-018-4117-x
Størset E, Holford N, Midtvedt K, Bremer S, Bergan S, Åsberg A. Importance of hematocrit for a tacrolimus target concentration strategy. Eur J Clin Pharmacol. 2014;70(1):65-77. doi:10.1007/s00228-013-1584-7
Trull AK. Therapeutic monitoring of tacrolimus. Ann Clin Biochem. 1998;35(Pt 2):167-180. doi:10.1177/000456329803500201
Udomkarnjananun S, Francke MI, Dieterich M, et al. P-glycoprotein, FK-binding protein-12, and the intracellular tacrolimus concentration in T-lymphocytes and monocytes of kidney transplant recipients. Transplantation. 2022;107(2):382-391. doi:10.1097/TP.0000000000004287