title: Effect of cytochrome P450 3A4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or non-Hodgkin's lymphoma.
abstract: OBJECTIVE
  Bortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect these enzymes may therefore have an impact on the pharmacological profile of bortezomib. This study evaluated the effects of co-administration of a potent CYP3A4 inducer (rifampicin [rifampin]) and a weak CYP3A4 inducer (dexamethasone) on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib.
  
  
  METHODS
  Patients aged ≥18 years with relapsed or refractory multiple myeloma or non-Hodgkin's lymphoma received intravenous bortezomib 1.3 mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles. In stage 1, patients were randomized (1 : 1) to receive bortezomib alone or in combination with oral rifampicin 600 mg once daily on days 4-10 during cycle 3 only. If the mean area under the plasma concentration-time curve (AUC) of bortezomib was reduced by ≥30% during rifampicin co-administration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40 mg once daily on days 1-4 and days 9-12 during cycle 3 only. Blood samples were collected on days 11 through 14 of cycles 2 and 3 before and after bortezomib administration, at prespecified time points, for pharmacokinetic and pharmacodynamic (proteasome inhibition) assessments.
  
  
  RESULTS
  Twelve patients in the bortezomib-alone arm, six patients in the bortezomib plus rifampicin arm and seven patients in the bortezomib plus dexamethasone arm were included in the pharmacokinetics-evaluable set. Rifampicin reduced the mean AUC from 0 to 72 hours (AUC(72h)) of bortezomib by approximately 45% (223 ng · h/mL in cycle 2 vs 123 ng · h/mL in cycle 3), while dexamethasone had no effect (mean AUC(72h): 179 ng · h/mL in cycle 2 vs 170 ng · h/mL in cycle 3). Proteasome inhibition parameters in peripheral blood were unaffected by rifampicin or dexamethasone. Safety profiles were similar across the treatment arms and consistent with previous experience of bortezomib.
  
  
  CONCLUSIONS
  In patients with multiple myeloma or non-Hodgkin's lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles. Concomitant administration of bortezomib with strong CYP3A4 inducers such as rifampicin is not recommended, as it may result in a reduction of the clinical effect, whereas concomitant administration of weak CYP3A4 inducers such as dexamethasone does not affect the pharmacological profile of bortezomib.
authors.affiliation: Medical University of Gdansk, Poland. klhem@gumed.edu.pl
authors.forename: Andrzej
authors.initials: A
authors.lastname: Hellmann
authors.forename: Simon
authors.initials: S
authors.lastname: Rule
authors.forename: Jan
authors.initials: J
authors.lastname: Walewski
authors.forename: Ofer
authors.initials: O
authors.lastname: Shpilberg
authors.forename: Huaibao
authors.initials: H
authors.lastname: Feng
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.forename: Hamina
authors.initials: H
authors.lastname: Patel
authors.forename: Donna M
authors.initials: DM
authors.lastname: Skee
authors.forename: Suzette
authors.initials: S
authors.lastname: Girgis
authors.forename: Vernon J
authors.initials: VJ
authors.lastname: Louw
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001897:Boronic Acids / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000069286:Bortezomib; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D004338:Drug Combinations; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood* / Q000188:drug therapy; D011480:Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011719:Pyrazines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012293:Rifampin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D004338:Drug Combinations; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D012293:Rifampin
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