title: Effect of CKD and dialysis modality on exposure to drugs cleared by nonrenal mechanisms.
abstract: BACKGROUND
  Patients with kidney disease frequently experience adverse effects from medication exposure, even when drugs are cleared by nonrenal pathways. Although many studies suggest that nonrenal drug clearance is decreased in chronic kidney disease (CKD), there remains a paucity of in vivo studies in patients with varying degrees of decreased kidney function and those comparing the impact of dialysis modality (eg, hemodialysis [HD] and peritoneal dialysis [PD]).
  
  
  METHODS
  We performed in vivo clinical pharmacokinetic studies of midazolam, a nonrenally cleared specific probe for CYP3A4, and fexofenadine, a nonspecific probe for hepatic and intestinal transporters.
  
  
  METHODS
  Healthy controls (n=8), patients with non-dialysis-dependent (NDD)-CKD (n=8), and patients receiving HD (n=10) or PD (n=8).
  
  
  RESULTS
  Exposure to midazolam and fexofenadine were quantified using area under the curve (AUC). Comprehensive pharmacokinetic parameters also were calculated for both probes.
  
  
  RESULTS
  Midazolam AUC was significantly higher in the HD group (382.8 h·ng/mL) than in the healthy-control (63.0 h·ng/mL; P<0.001), NDD-CKD (84.5 h·ng/mL; P=0.002), and PD (47.4 h·ng/mL; P<0.001) groups. Fexofenadine AUC was significantly higher in each of the NDD-CKD (2,950 h·ng/mL; P=0.003), HD (2,327 h·ng/mL; P=0.01), and PD (2,095 h·ng/mL; P=0.04) groups compared with healthy controls (1,008 h·ng/mL).
  
  
  CONCLUSIONS
  Small study groups had different proportions of diabetic patients, early stages of CKD not available.
  
  
  CONCLUSIONS
  Our data suggest that selection of dialysis modality is a major determinant of exposure to the CYP3A4 probe midazolam. Exposure to the intestinal and hepatic transporter probe fexofenadine is altered in patients with NDD-CKD and PD and HD patients. Thus, drug development and licensing of nonrenally cleared drugs should include evaluation in these 3 patient groups, with these results included in approved product information labeling. This reinforces the critical need for more in vivo studies of humans that evaluate the exposure to drugs cleared by these pathways.
authors.affiliation: Department of Medicine, Western University, London, Ontario, Canada.
authors.forename: Benjamin K A
authors.initials: BK
authors.lastname: Thomson
authors.affiliation: Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Nolin
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Velenosi
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Feere
authors.affiliation: Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Knauer
authors.affiliation: Department of Medicine, Western University, London, Ontario, Canada.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Asher
authors.affiliation: Department of Medicine, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: House
authors.affiliation: Department of Medicine, Western University, London, Ontario, Canada; Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada. Electronic address: brad.urquhart@schulich.uwo.ca.
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Urquhart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018926:Anti-Allergic Agents / Q000493:pharmacokinetics; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D008875:Middle Aged; D010530:Peritoneal Dialysis; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000628:therapy*; D012720:Severity of Illness Index; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D018926:Anti-Allergic Agents; D014151:Anti-Anxiety Agents; D016593:Terfenadine; C093230:fexofenadine; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam
keywords: CYP3A4; Nonrenal drug clearance; adverse effects; chronic kidney disease (CKD); cytochrome P450; drug metabolism; hemodialysis (HD); hepatic and intestinal drug transporters; medication exposure; peritoneal dialysis (PD); pharmacokinetics