title: Correlation between trough plasma dabigatran concentrations and estimates of glomerular filtration rate based on creatinine and cystatin C.
abstract: OBJECTIVE
  Dabigatran is largely cleared by renal excretion. Renal function is thus a major determinant of trough dabigatran concentrations, which correlate with the risk of thromboembolic and haemorrhagic outcomes. Current dabigatran dosing guidelines use the Cockcroft-Gault (CG) equation to gauge renal function, instead of contemporary equations including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations employing creatinine (CKD-EPI_Cr), cystatin C (CKD-EPI_Cys) and both renal biomarkers (CKD-EPI_CrCys).
  
  
  METHODS
  A linear regression model including the dabigatran etexilate maintenance dose rate, relevant interacting drugs and genetic polymorphisms (including CES1), was used to analyse the relationship between the values from each renal function equation and trough steady-state plasma dabigatran concentrations.
  
  
  RESULTS
  The median dose-corrected trough steady-state plasma dabigatran concentration in 52 patients (38-94 years) taking dabigatran etexilate was 60 µg/L (range 9-279). The dose-corrected trough concentration in a patient on phenytoin and phenobarbitone was >3 standard deviations below the cohort mean. The CG, CKD-EPI_Cr, CKD-EPI_Cys and CKD-EPI_CrCys equations explained (R (2), 95 % CI) 32 % (9-55), 37 % (12-60), 41 % (16-64) and 47 % (20-69) of the variability in dabigatran concentrations between patients, respectively. One-way analysis of variance (ANOVA) comparing the R (2) values for each equation was not statistically significant (p = 0.74).
  
  
  CONCLUSIONS
  Estimates of renal function using the four equations accounted for 32-47 % of the variability in dabigatran concentrations between patients. We are the first to provide evidence that co-administration of phenytoin/phenobarbitone with dabigatran etexilate is associated with significantly reduced dabigatran exposure.
authors.affiliation: Department of Clinical Pharmacology, Christchurch Hospital, 2 Riccarton Avenue, Christchurch, 8011, New Zealand, paulc@cdhb.health.nz.
authors.forename: Paul K L
authors.initials: PK
authors.lastname: Chin
authors.forename: Daniel F B
authors.initials: DF
authors.lastname: Wright
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.forename: Mary C
authors.initials: MC
authors.lastname: Wallace
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Roberts
authors.forename: David M
authors.initials: DM
authors.lastname: Patterson
authors.forename: Berit P
authors.initials: BP
authors.lastname: Jensen
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Begg
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001562:Benzimidazoles / Q000008:administration & dosage / Q000097:blood*; D002265:Carboxylic Ester Hydrolases / Q000235:genetics; D003404:Creatinine / Q000097:blood*; D055316:Cystatin C / Q000097:blood*; D000069604:Dabigatran; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010634:Phenobarbital / Q000008:administration & dosage; D010672:Phenytoin / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D001562:Benzimidazoles; D055316:Cystatin C; D011725:Pyridines; D010672:Phenytoin; D003404:Creatinine; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D000069604:Dabigatran; D010634:Phenobarbital