Effect of the Cytochrome P450 2C19 Inhibitor Omeprazole on the Pharmacokinetics and Safety Profile of Bortezomib in Patients with Advanced ... View Full Text


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Article Info

DATE

2009-03

AUTHORS

David I. Quinn, John Nemunaitis, Jyotsna Fuloria, Carolyn D. Britten, Nashat Gabrail, Lorrin Yee, Milin Acharya, Kai Chan, Nadine Cohen, Assen Dudov

ABSTRACT

Background and objective: Bortezomib, an antineoplastic for the treatment of relapsed multiple myeloma and mantle cell lymphoma, undergoes metabolism through oxidative deboronation by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2C19. Omeprazole, a proton-pump inhibitor, is primarily metabolized by and demonstrates high affinity for CYP2C19. This study investigated whether coadministration of omeprazole affected the pharmacokinetics, pharmacodynamics and safety profile of bortezomib in patients with advanced cancer. The variability of bortezomib pharmacokinetics with CYP enzyme polymorphism was also investigated.Patients and methods: This open-label, crossover, pharmacokinetic drug-drug interaction study was conducted at seven institutions in the US and Europe between January 2005 and August 2006. Patients who had advanced solid tumours, non-Hodgkin’s lymphoma or multiple myeloma, were aged ≥18 years, weighed ≥50 kg and had a life expectancy of ≥3 months were eligible. Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 for two 21-day cycles, plus omeprazole 40 mg in the morning of days 6–10 and in the evening of day 8 in either cycle 1 (sequence 1) or cycle 2 (sequence 2). On day 21 of cycle 2, patients benefiting from therapy could continue to receive bortezomib for six additional cycles. Blood samples for pharmacokinetic/ pharmacodynamic evaluation were collected prior to and at various timepoints after bortezomib administration on day 8 of cycles 1 and 2. Blood samples for pharmacogenomics were also collected. Pharmacokinetic parameters were calculated by noncompartmental analysis of plasma concentration-time data for bortezomib administration on day 8 of cycles 1 and 2, using WinNonlin™ version 4.0. 1.a software. The pharmacodynamic profile was assessed using a whole-blood 20S proteasome inhibition assay.Results: Twenty-seven patients (median age 64 years) were enrolled, 12 in sequence 1 and 15 in sequence 2, including eight and nine pharmacokinetic-evaluable patients, respectively. Bortezomib pharmacokinetic parameters were similar when bortezomib was administered alone or with omeprazole (maximum plasma concentration 120 vs 123 ng/mL; area under the plasma concentration-time curve from 0 to 72 hours 129 vs 135 ng · h/mL). The pharmacodynamic parameters were also similar (maximum effect 85.8% vs 93.7%; area under the percent inhibition-time curve over 72 hours 4052 vs 3910 % × h); the differences were not statistically significant. Pharmacogenomic analysis revealed no meaningful relationships between CYP enzyme polymorphisms and pharmacokinetic/pharmacodynamic parameters. Toxicities were generally similar between patients in sequence 1 and sequence 2, and between cycle 1 and cycle 2 in both treatment sequences. Among 26 evaluable patients, 13 (50%) were assessed as benefiting from bortezomib at the end of cycle 2 and continued to receive treatment.Conclusions: No impact on the pharmacokinetics, pharmacodynamics and safety profile of bortezomib was seen with coadministration of omeprazole. Concomitant administration of bortezomib and omeprazole is unlikely to cause clinically significant drug-drug interactions and is unlikely to have an impact on the efficacy or safety of bortezomib. More... »

PAGES

199-209

Identifiers

URI

http://scigraph.springernature.com/pub.10.2165/00003088-200948030-00006

DOI

http://dx.doi.org/10.2165/00003088-200948030-00006

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1043605865

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19385713


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34 schema:description Background and objective: Bortezomib, an antineoplastic for the treatment of relapsed multiple myeloma and mantle cell lymphoma, undergoes metabolism through oxidative deboronation by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2C19. Omeprazole, a proton-pump inhibitor, is primarily metabolized by and demonstrates high affinity for CYP2C19. This study investigated whether coadministration of omeprazole affected the pharmacokinetics, pharmacodynamics and safety profile of bortezomib in patients with advanced cancer. The variability of bortezomib pharmacokinetics with CYP enzyme polymorphism was also investigated.Patients and methods: This open-label, crossover, pharmacokinetic drug-drug interaction study was conducted at seven institutions in the US and Europe between January 2005 and August 2006. Patients who had advanced solid tumours, non-Hodgkin’s lymphoma or multiple myeloma, were aged ≥18 years, weighed ≥50 kg and had a life expectancy of ≥3 months were eligible. Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 for two 21-day cycles, plus omeprazole 40 mg in the morning of days 6–10 and in the evening of day 8 in either cycle 1 (sequence 1) or cycle 2 (sequence 2). On day 21 of cycle 2, patients benefiting from therapy could continue to receive bortezomib for six additional cycles. Blood samples for pharmacokinetic/ pharmacodynamic evaluation were collected prior to and at various timepoints after bortezomib administration on day 8 of cycles 1 and 2. Blood samples for pharmacogenomics were also collected. Pharmacokinetic parameters were calculated by noncompartmental analysis of plasma concentration-time data for bortezomib administration on day 8 of cycles 1 and 2, using WinNonlin™ version 4.0. 1.a software. The pharmacodynamic profile was assessed using a whole-blood 20S proteasome inhibition assay.Results: Twenty-seven patients (median age 64 years) were enrolled, 12 in sequence 1 and 15 in sequence 2, including eight and nine pharmacokinetic-evaluable patients, respectively. Bortezomib pharmacokinetic parameters were similar when bortezomib was administered alone or with omeprazole (maximum plasma concentration 120 vs 123 ng/mL; area under the plasma concentration-time curve from 0 to 72 hours 129 vs 135 ng · h/mL). The pharmacodynamic parameters were also similar (maximum effect 85.8% vs 93.7%; area under the percent inhibition-time curve over 72 hours 4052 vs 3910 % × h); the differences were not statistically significant. Pharmacogenomic analysis revealed no meaningful relationships between CYP enzyme polymorphisms and pharmacokinetic/pharmacodynamic parameters. Toxicities were generally similar between patients in sequence 1 and sequence 2, and between cycle 1 and cycle 2 in both treatment sequences. Among 26 evaluable patients, 13 (50%) were assessed as benefiting from bortezomib at the end of cycle 2 and continued to receive treatment.Conclusions: No impact on the pharmacokinetics, pharmacodynamics and safety profile of bortezomib was seen with coadministration of omeprazole. Concomitant administration of bortezomib and omeprazole is unlikely to cause clinically significant drug-drug interactions and is unlikely to have an impact on the efficacy or safety of bortezomib.
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40 schema:keywords CYP-enzyme polymorphisms
41 CYP2C19
42 CYP3A4
43 Europe
44 Hodgkin's lymphoma
45 P450
46 WinNonlin
47 additional cycles
48 administration
49 advanced cancer
50 advanced solid tumors
51 affinity
52 analysis
53 antineoplastics
54 background
55 blood samples
56 bortezomib
57 bortezomib administration
58 bortezomib pharmacokinetics
59 cancer
60 cell lymphoma
61 coadministration
62 coadministration of omeprazole
63 concentration-time data
64 concomitant administration
65 crossover
66 cycle
67 cycle 1
68 cycle 2
69 cytochrome P450
70 data
71 day 1
72 day 21
73 day 6
74 day 8
75 deboronation
76 differences
77 drug-drug interaction studies
78 drug-drug interactions
79 effect
80 efficacy
81 end
82 enzyme polymorphisms
83 evaluable patients
84 evaluation
85 evening
86 expectancy
87 high affinity
88 impact
89 inhibition
90 inhibitor omeprazole
91 inhibitors
92 institutions
93 interaction
94 interaction studies
95 life expectancy
96 lymphoma
97 m2
98 mantle cell lymphoma
99 meaningful relationships
100 metabolism
101 method
102 months
103 morning
104 multiple myeloma
105 myeloma
106 non-Hodgkin lymphoma
107 noncompartmental analysis
108 objective
109 omeprazole
110 oxidative deboronation
111 parameters
112 patients
113 pharmacodynamic evaluation
114 pharmacodynamic parameters
115 pharmacodynamic profile
116 pharmacodynamics
117 pharmacogenomic analysis
118 pharmacogenomics
119 pharmacokinetic drug-drug interaction study
120 pharmacokinetic parameters
121 pharmacokinetics
122 plasma concentration-time data
123 polymorphism
124 profile
125 proteasome inhibition
126 proton pump inhibitors
127 relationship
128 safety
129 safety of bortezomib
130 safety profile
131 samples
132 sequence
133 sequence 1
134 sequence 2
135 significant drug-drug interactions
136 software
137 solid tumors
138 study
139 therapy
140 timepoints
141 toxicity
142 treatment
143 treatment sequence
144 tumors
145 uses
146 variability
147 version 4.0
148 years
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