title: Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl.
abstract: OBJECTIVE
  In vitro work has demonstrated that cinacalcet is a strong inhibitor of cytochrome P450 isoenzyme (CYP) 2D6. The purpose of this study was to evaluate the effect of cinacalcet on CYP2D6 activity, using desipramine as a probe substrate, in healthy subjects.
  
  
  METHODS
  Seventeen subjects who were genotyped as CYP2D6 extensive metabolizers were enrolled in this randomized, open-label, crossover study to receive a single oral dose of desipramine (50 mg) on two separate occasions, once alone and once after multiple doses of cinacalcet (90 mg for 7 days). Blood samples were obtained predose and up to 72 h postdose.
  
  
  RESULTS
  Fourteen subjects completed both treatment arms. Relative to desipramine alone, mean AUC and C(max) of desipramine increased 3.6- and 1.8-fold when coadministered with cinacalcet. The t (1/2,z) of desipramine was longer when desipramine was coadministered with cinacalcet (21.0 versus 43.3 hs). The t (max) was similar between the regimens. Fewer subjects reported adverse events following treatment with desipramine alone than when receiving desipramine with cinacalcet (33 versus 86%), the most frequent of which (nausea and headache) have been reported for patients treated with either desipramine or cinacalcet.
  
  
  CONCLUSIONS
  This study demonstrates that cinacalcet is a strong inhibitor of CYP2D6. These data suggest that during concomitant treatment with cinacalcet, dose adjustment may be necessary for drugs that demonstrate a narrow therapeutic index and are metabolized by CYP2D6.
authors: Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. harrisr@amgen.com
authors: Robert Z
authors: RZ
authors: Harris
authors: Margaret
authors: M
authors: Salfi
authors: Ed
authors: E
authors: Posvar
authors: David
authors: D
authors: Hoelscher
authors: Desmond
authors: D
authors: Padhi