title: Pharmacokinetic and pharmacodynamic profile of bendamustine and its metabolites.
abstract: OBJECTIVE
  Bendamustine is a unique alkylating agent indicated for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B cell non-Hodgkin's lymphoma. Despite the extensive experience with bendamustine, its pharmacokinetic profile has only recently been described. This overview summarizes the pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and drug-drug interactions of bendamustine in adult and pediatric patients with hematologic malignancies.
  
  
  METHODS
  A literature search and data on file (including a human mass balance study, pharmacokinetic population analyses in adult and pediatric patients, and modeling analyses) were evaluated for inclusion.
  
  
  RESULTS
  Bendamustine concentrations peak at end of intravenous infusion (~1 h). Subsequent elimination is triphasic, with the intermediate t 1/2 (~40 min) as the effective t 1/2 since the final phase represents <1 % of the area under the curve. Bendamustine is rapidly hydrolyzed to monohydroxy-bendamustine and dihydroxy-bendamustine, which have little or no activity. Cytochrome P450 (CYP) 1A2 oxidation yields the active metabolites γ-hydroxybendamustine and N-desmethyl-bendamustine, at low concentrations, which contribute minimally to cytotoxicity. Minor involvement of CYP1A2 in bendamustine elimination suggests a low likelihood of drug-drug interactions with CYP1A2 inhibitors. Systemic exposure to bendamustine 120 mg/m(2) is comparable between adult and pediatric patients; age, race, and sex have been shown to have no significant effect on systemic exposure in either population. The effect of hepatic/renal impairment on bendamustine pharmacokinetics remains to be elucidated. Higher bendamustine concentrations may be associated with increased probability of nausea or infection. No clear exposure-efficacy response relationship has been observed.
  
  
  CONCLUSIONS
  Altogether, the findings support dosing based on body surface area for most patient populations.
authors.affiliation: Sci-Med Bridge, LLC, 1916 General Alexander Drive, Malvern, PA, 19355, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Darwish
authors.forename: Mary
authors.initials: M
authors.lastname: Bond
authors.forename: Edward
authors.initials: E
authors.lastname: Hellriegel
authors.forename: Philmore
authors.initials: P
authors.lastname: Robertson
authors.forename: James P
authors.initials: JP
authors.lastname: Chovan
mesh_terms: D019540:Area Under Curve; D000069461:Bendamustine Hydrochloride / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D009588:Nitrogen Mustard Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D009588:Nitrogen Mustard Compounds; C000617611:gamma-hydroxybendamustine; D000069461:Bendamustine Hydrochloride; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2
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