Bendamustine pharmacokinetic profile and exposure-response relationships in patients with indolent non-Hodgkin's lymphoma.
OBJECTIVE
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.
Owen
Joel S
JS
Cognigen Corporation, 395 South Youngs Road, Buffalo, NY 14221, USA.
Melhem
Murad
M
Passarell
Julie A
JA
D'Andrea
Denise
D
Darwish
Mona
M
Kahl
Bradley
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000069461:Bendamustine Hydrochloride; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000208:ethnology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D000069461:Bendamustine Hydrochloride