Abstract
Abstract 3983
Background: Bortezomib is primarily metabolized by cytochrome P450 (CYP) 3A4 and 2C19 enzymes. Effects of co-administration of rifampicin (a potent CYP3A4 inducer) and dexamethasone (weak CYP3A4 inducer) on the pharmacokinetic (PK), pharmacodynamic (PD) and safety profiles of bortezomib were evaluated. Methods: Patients with relapsed or refractory multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) were enrolled in this open-label, 2-stage, parallel-group study. In stage 1, patients were randomized (1:1) to receive 3 cycles of bortezomib (1.3 mg/m2) on d 1, 4, 8, and 11 q3wk either alone or in combination with rifampicin 600 mg once-daily on d 4 to 10 of cycle 3 only. Stage 2 patients received bortezomib at same dose and schedule in combination with dexamethasone 40 mg once-daily on d 1 to 4 and d 9 to 12 of cycle 3 only. Patients could continue with bortezomib monotherapy for up to 10 cycles in case of clinical benefit. For PK/PD, blood samples were collected before and through 72 hours following bortezomib administration on d 11 of cycles 2 and 3. PK was the primary endpoint, secondary endpoints included PD (proteasome inhibition) and safety. Results: 61 patients were enrolled (39 MM, 22 NHL) in the study. 13 were treated with bortezomib + rifampicin, 18 with bortezomib + dexamethasone, and 30 with bortezomib only. Co-administration of rifampicin reduced the mean bortezomib maximum plasma concentration (Cmax) by approximately 23% (118 vs 93 ng/mL) and the mean area under plasma concentration-time curve from 0 to 72 hours (AUC72) by approximately 45% (223 vs 123 ng.h/mL). Co-administration of dexamethasone had no effect on mean AUC72 (179 vs 170 ng.h/mL). The mean bortezomib Cmax was 20% lower after co-administration of dexamethasone (140 vs 119 ng/mL); however this difference in Cmax was within the observed variability in Cmax during cycle 2 (CV=38%) and cycle 3 (CV=45%). Mean (SD) maximum percent proteasome inhibition (Emax) and area under percent proteasome inhibition-time curve from 0 to 72 hours (AUE72h) were comparable for bortezomib alone and in combination with rifampicin (Emax: 61.9 [4.56] vs. 62.3 [3.81] and AUE72h: 836 [323] vs. 777 [358]). Co-administration of dexamethasone did not affect the Emax (66.7 [4.27] vs. 61.8 [6.69]) or AUE72h (1329 [638] vs. 1157 [381]). Safety profiles were consistent with prior bortezomib experience in this population. Drug-related serious adverse events and treatment discontinuations were reported in 7/30 (23%) and 8/30 (27%) in bortezomib-only, in 3/13 (23%) and 3/13 (23%) in bortezomib + rifampicin, and 3/18 (17%) and 5/18 (28%) in bortezomib + dexamethasone subgroups. Investigator-assessed responses (CR+PR) were observed in 13/17 MM and 6/13 NHL patients in bortezomib-only, in 6/9 MM and 3/4 NHL patients in bortezomib + rifampicin, and in 10/13 MM and 2/5 NHL patients in bortezomib + dexamethasone subgroups. Conclusions: Co-administration of dexamethasone did not affect the PK or PD profiles of bortezomib. Co-administration of rifampicin reduced bortezomib exposure (AUC) by approximately 45%. Patients receiving bortezomib concomitantly with strong CYP3A4 inducers, such as rifampicin, should be monitored for reduction in clinical effect, while concomitant administration of weak CYP3A4 inducers, such as dexamethasone, is not expected to affect the bortezomib pharmacologic profile.
Disclosures:
Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Rule:Johnson & Johson: Consultancy, Speakers Bureau; Roche: Consultancy. Walewski:Johnson & Johnson: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Investigators fee. Shpilberg:Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Feng:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Patel:Johnson & Johnson: Employment, Equity Ownership. Skee:Johnson & Johnson: Employment. Girgis:Johnson & Johnson: Employment. Louw:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Key Oncologics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
Pharmacokinetics and Safety Study of Posaconazole Intravenous Solution Administered Peripherally to Healthy Subjects
