Document Detail


Pharmacokinetics of tacrolimus during pregnancy.
MedLine Citation:
PMID:  23007747     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 (f(P)) and by 100% in blood (f(B)) 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 f(P) and f(B) contributed significantly to the observed gestational increase in tacrolimus whole-blood CL/F (r² = 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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Therapeutic drug monitoring     Volume:  34     ISSN:  1536-3694     ISO Abbreviation:  Ther Drug Monit     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-15     Completed Date:  2013-04-29     Revised Date:  2014-05-30    
Medline Journal Info:
Nlm Unique ID:  7909660     Medline TA:  Ther Drug Monit     Country:  United States    
Other Details:
Languages:  eng     Pagination:  660-70     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Biotransformation
Carbon Isotopes
Chromatography, High Pressure Liquid
Dose-Response Relationship, Drug
Female
Humans
Immunosuppressive Agents / administration & dosage,  blood,  pharmacokinetics*,  urine
Metabolic Clearance Rate
Postpartum Period
Pregnancy
Pregnancy Trimester, First
Pregnancy Trimester, Third
Serum Albumin / analysis
Tacrolimus / administration & dosage,  blood,  pharmacokinetics*,  urine
Tandem Mass Spectrometry
Young Adult
Grant Support
ID/Acronym/Agency:
R01 GM068871/GM/NIGMS NIH HHS; U10 HD047890/HD/NICHD NIH HHS; U10 HD047892/HD/NICHD NIH HHS; U10HD047890/HD/NICHD NIH HHS; U10HD047892/HD/NICHD NIH HHS; UL1 RR025014/RR/NCRR NIH HHS; UL1 RR031975/RR/NCRR NIH HHS; UL1RR025014/RR/NCRR NIH HHS; UL1RR031975/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/ALB protein, human; 0/Carbon Isotopes; 0/Immunosuppressive Agents; 0/Serum Albumin; WM0HAQ4WNM/Tacrolimus
Comments/Corrections

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