| Pharmacokinetics of Tacrolimus During Pregnancy. | |
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MedLine Citation:
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PMID: 23007747 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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BACKGROUND:: Information on the pharmacokinetics of tacrolimus during pregnancy is limited to case reports despite the increasing number of pregnant women being prescribed tacrolimus for immunosuppression. METHODS:: Blood, plasma, and urine samples were collected over 1 steady-state dosing interval from women treated with oral tacrolimus during early to late pregnancy (n = 10) and postpartum (n = 5). Total and unbound tacrolimus as well as metabolite concentrations in blood and plasma were assayed by a validated liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method. A mixed-effect linear model was used for comparison across gestational age and using postpartum as the reference group. RESULTS:: The mean oral clearance (CL/F) based on whole-blood tacrolimus concentration was 39% higher during mid-pregnancy and late pregnancy compared with postpartum (47.4 ± 12.6 vs. 34.2 ± 14.8 L/h, P < 0.03). Tacrolimus-free fraction increased by 91% in plasma (fP) and by 100% in blood (fB) during pregnancy (P = 0.0007 and 0.002, respectively). Increased fP was inversely associated with serum albumin concentration (r = -0.7, P = 0.003), which decreased by 27% during pregnancy. Pregnancy-related changes in fP and fB contributed significantly to the observed gestational increase in tacrolimus whole-blood CL/F (r = 0.36 and 0.47, respectively, P < 0.01). In addition, tacrolimus whole-blood CL/F was inversely correlated with both hematocrit and red blood cell counts, suggesting that binding of tacrolimus to erythrocytes restricts its availability for metabolism. Treating physicians increased tacrolimus dosages in study participants during pregnancy by an average of 45% to maintain tacrolimus whole-blood trough concentrations in the therapeutic range. This led to striking increases in unbound tacrolimus trough concentrations and unbound area under the concentration-time curve, by 112% and 173%, respectively, during pregnancy (P = 0.02 and 0.03, respectively). CONCLUSIONS:: Tacrolimus pharmacokinetics are altered during pregnancy. Dose adjustment to maintain whole-blood tacrolimus concentration in the usual therapeutic range during pregnancy increases circulating free drug concentrations, which may impact clinical outcomes. |
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Authors:
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Songmao Zheng; Thomas R Easterling; Jason G Umans; Menachem Miodovnik; Justina C Calamia; Kenneth E Thummel; Danny D Shen; Connie L Davis; Mary F Hebert |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-9-21 |
Journal Detail:
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Title: Therapeutic drug monitoring Volume: - ISSN: 1536-3694 ISO Abbreviation: Ther Drug Monit Publication Date: 2012 Sep |
Date Detail:
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Created Date: 2012-9-25 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7909660 Medline TA: Ther Drug Monit Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Departments of *Pharmaceutics †Obstetrics and Gynecology ‡Pharmacy; and §Medicine, University of Washington, Seattle, WA ¶MedStar Health Research Institute ‖Washington Hospital Center **Georgetown University Medical Center ††Georgetown-Howard Universities Center for Clinical and Translational Science, Washington, DC. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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