TY - JOUR
T1 - Effect of cytochrome p450 3a4 inducers on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib in patients with multiple myeloma or non-Hodgkins lymphoma
AU - Hellmann, Andrzej
AU - Rule, Simon
AU - Walewski, Jan
AU - Shpilberg, Ofer
AU - Feng, Huaibao
AU - Van De Velde, Helgi
AU - Patel, Hamina
AU - Skee, Donna M.
AU - Girgis, Suzette
AU - Louw, Vernon J.
N1 - Funding Information:
Drs Feng, van de Velde, Patel and Girgis and Ms Skee are employees of Johnson & Johnson Pharmaceutical Research & Development, LLC. Drs van de Velde and Patel have equity holdings in Johnson & Johnson. Professor Hellmann and Drs Rule, Walewski, Shpilberg and Louw were investigators in this study. Professor Hellmann has received research funding from Johnson & Johnson Pharmaceutical Research & Development, LLC. Dr Rule has acted as an advisor and has received research funding from Johnson & Johnson Pharmaceutical Research & Development, LLC. Dr Walewski has received research funding and honoraria from Johnson & Johnson Pharmaceutical Research & Development, LLC, and Roche. Dr Shpilberg is a consultant and advisory board member for Johnson & Johnson Pharmaceutical Research & Development, LLC, and has received honoraria from Johnson & Johnson Pharmaceutical Research & Development, LLC. Dr Louw is a consultant for Johnson & Johnson Pharmaceutical Research & Development, LLC, Novartis and Key On-cologics; has received research funding from Novartis; has received honoraria from Johnson & Johnson Pharmaceutical Research & Development, LLC, Novartis and Key Oncologics; and is an advisory board member for Johnson & Johnson Pharmaceutical Research & Development, LLC, Novartis and Key Oncologics. He has received honoraria for speaking engagements and consultancy for Johnson & Johnson Pharmaceutical Research & Development, LLC.
PY - 2011/11/21
Y1 - 2011/11/21
N2 - 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/m 2, 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 600mg 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 coadministration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40mg 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.
AB - 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/m 2, 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 600mg 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 coadministration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40mg 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.
KW - Antineoplastics
KW - Bortezomib
KW - Dexamethasone
KW - Drug-interactions
KW - Multiple-myeloma
KW - Non-Hodgkins-lymphoma
KW - Pharmacokinetics
KW - Pharmacology
KW - Rifampicin
UR - http://www.scopus.com/inward/record.url?scp=81255195686&partnerID=8YFLogxK
U2 - 10.2165/11594410-000000000-00000
DO - 10.2165/11594410-000000000-00000
M3 - Article
AN - SCOPUS:81255195686
SN - 0312-5963
VL - 50
SP - 781
EP - 791
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 12
ER -