title: Pharmacokinetics of tacrolimus during pregnancy.
abstract: 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.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98195-7630, USA.
authors.forename: Songmao
authors.initials: S
authors.lastname: Zheng
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Easterling
authors.forename: Jason G
authors.initials: JG
authors.lastname: Umans
authors.forename: Menachem
authors.initials: M
authors.lastname: Miodovnik
authors.forename: Justina C
authors.initials: JC
authors.lastname: Calamia
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Thummel
authors.forename: Danny D
authors.initials: DD
authors.lastname: Shen
authors.forename: Connie L
authors.initials: CL
authors.lastname: Davis
authors.forename: Mary F
authors.initials: MF
authors.lastname: Hebert
mesh_terms: D000328:Adult; D001711:Biotransformation; D002247:Carbon Isotopes; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008657:Metabolic Clearance Rate; D049590:Postpartum Period; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011263:Pregnancy Trimester, Third; D012709:Serum Albumin / Q000032:analysis; D000075462:Serum Albumin, Human; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: C422455:ALB protein, human; D002247:Carbon Isotopes; D007166:Immunosuppressive Agents; D012709:Serum Albumin; D016559:Tacrolimus; D000075462:Serum Albumin, Human