Journal Article

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

Walewski, Jan, Rule, Simon, Hellmann, Andrzej, Shpilberg, Ofer, van de Velde, Helgi, Girgis, Suzette, Skee, Donna M., Patel, Hamina, Feng, Huaibao, Louw, Vernon J.

2011

Overview

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 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.

• Publisher: Springer International Publishing,Adis International,Wolters Kluwer Health, Inc,Springer Nature B.V
• Subject: Adult / Aged / Aged, 80 and over / Antineoplastic Agents - blood / Antineoplastic Agents - pharmacokinetics / Antineoplastic Agents - therapeutic use / Area Under Curve / Biological and medical sciences / Boronic Acids - blood / Boronic Acids - pharmacokinetics / Boronic Acids - therapeutic use / Bortezomib / Care and treatment / Cytochrome P-450 / Cytochrome P-450 CYP3A - biosynthesis / Development and progression / Dexamethasone - pharmacology / Diagnosis / Drug Combinations / Enzyme Induction - drug effects / Female / General pharmacology / Health aspects / Hematologic and hematopoietic diseases / Humans / Immunodeficiencies. Immunoglobulinopathies / Immunoglobulinopathies / Immunopathology / Internal Medicine / Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis / Lymphoma, Non-Hodgkin - blood / Lymphoma, Non-Hodgkin - drug therapy / Male / Medical sciences / Medicine / Medicine & Public Health / Middle Aged / Multiple myeloma / Multiple Myeloma - blood / Multiple Myeloma - drug therapy / Non-Hodgkin's lymphomas / Original Research Article / Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions / Pharmacology. Drug treatments / Pharmacology/Toxicology / Pharmacotherapy / Protease Inhibitors - blood / Protease Inhibitors - pharmacokinetics / Protease Inhibitors - therapeutic use / Pyrazines - blood / Pyrazines - pharmacokinetics / Pyrazines - therapeutic use / Rifampin - pharmacology