BACKGROUND AND 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.
PATIENTS AND 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.