PURPOSE: The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin's lymphoma, and supported understanding of exposure-response relationships for efficacy and safety. METHODS: Bendamustine was administered as a 60-min 120 mg/m(2) intravenous infusion on days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined. RESULTS: Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t (1/2) (40 min) was considered the pharmacologically relevant (beta elimination) t (1/2) since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m(2) administration, except bendamustine C (max) was a significant (P value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics. CONCLUSIONS: The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t (1/2) and low concentrations of bendamustine observed by 12 h after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine C (max) increases.
PURPOSE: The pharmacokinetic profiles of bendamustine and active metabolites were defined in patients with rituximab-refractory, relapsed indolent B-cell non-Hodgkin's lymphoma, and supported understanding of exposure-response relationships for efficacy and safety. METHODS:Bendamustine was administered as a 60-min 120 mg/m(2) intravenous infusion on days 1 and 2 of six 21-day cycles. Pharmacokinetic models were developed, with covariate assessment. Correlations between bendamustine exposure and responder status or occurrence of neutropenia, thrombocytopenia, fatigue, nausea, and vomiting were examined. RESULTS: Following a single dose of bendamustine HCl, concentrations declined in a triphasic manner, with rapid distribution, intermediate, and slow terminal phases. The intermediate t (1/2) (40 min) was considered the pharmacologically relevant (beta elimination) t (1/2) since the initial phases accounted for 99% of the AUC. Age, sex, mild/moderate renal, or mild liver impairment did not alter pharmacokinetics. Metabolite concentrations were low relative to parent. No correlation was observed between exposure and safety or efficacy measures because of the limited range of exposures after 120 mg/m(2) administration, except bendamustine C (max) was a significant (P value = 0.013) predictor of the probability of nausea in patients, most of whom were pretreated with antiemetics. CONCLUSIONS: The BSA-based dosing regimen for bendamustine achieved the targeted exposure and was associated with a high incidence of therapeutic response. Given the short t (1/2) and low concentrations of bendamustine observed by 12 h after dosing, the single-dose profile for bendamustine described by these analyses is expected to be representative of the multiple-dose profile. The occurrence of nausea was significantly related to bendamustine exposure, with the probability of nausea increasing as bendamustine C (max) increases.
Authors: B D Cheson; S J Horning; B Coiffier; M A Shipp; R I Fisher; J M Connors; T A Lister; J Vose; A Grillo-López; A Hagenbeek; F Cabanillas; D Klippensten; W Hiddemann; R Castellino; N L Harris; J O Armitage; W Carter; R Hoppe; G P Canellos Journal: J Clin Oncol Date: 1999-04 Impact factor: 44.544
Authors: G von Minckwitz; I Chernozemsky; L Sirakova; P Chilingirov; R Souchon; N Marschner; U Kleeberg; C Tsekov; D Fritze; C Thomssen; N Stuart; J B Vermorken; S Loibl; Kh Merkle; M Kaufmann Journal: Anticancer Drugs Date: 2005-09 Impact factor: 2.248
Authors: Manuela A Bergmann; Maria E Goebeler; Michael Herold; Bertold Emmerich; Martin Wilhelm; Corinna Ruelfs; Lothar Boening; Michael J Hallek Journal: Haematologica Date: 2005-10 Impact factor: 9.941
Authors: Marika Rasschaert; Dirk Schrijvers; Jan Van den Brande; Joke Dyck; Johan Bosmans; Karlheinz Merkle; Jan B Vermorken Journal: Anticancer Drugs Date: 2007-06 Impact factor: 2.248
Authors: G Damaj; J Cornillon; K Bouabdallah; R Gressin; S Vigouroux; T Gastinne; F Ranchon; H Ghésquières; G Salles; I Yakoub-Agha; E Gyan Journal: Bone Marrow Transplant Date: 2017-01-23 Impact factor: 5.483
Authors: Lei He; John C Grecula; Yonghua Ling; Michael D Enzerra; Mario Ammirati; Kari Kendra; Robert Cavaliere; Nina Mayr; John McGregor; Thomas Olencki; Ewa Mrozek; Mani Matharbootham; Chima Oluigbo; Mitch A Phelps Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2012-08-16 Impact factor: 3.205
Authors: Amanda F Baker; Denise J Roe; Cynthia Laughren; Janice L Cohen; Heather M Wright; Mary C Clouser; Haiyan Cui; David S Alberts; Setsuko K Chambers Journal: Invest New Drugs Date: 2012-05-13 Impact factor: 3.850