Comparison of pharmacokinetics and pharmacodynamics of docetaxel and Cisplatin in elderly and non-elderly patients: why is toxicity increased in elderly patients?
OBJECTIVE
Following phase I studies of docetaxel and cisplatin in patients with non-small-cell lung cancer, the recommended doses of docetaxel were different for elderly (> or = 75 years) and non-elderly (< 75 years) patients. To elucidate the mechanism of the difference, the pharmacokinetics of docetaxel and cisplatin were investigated in two phase II studies separately conducted in elderly and non-elderly patients.


METHODS
Twenty-seven elderly and 25 non-elderly patients were treated with three weekly administrations of docetaxel and cisplatin every 4 weeks. Doses of docetaxel were 20 and 35 mg/m(2) for elderly and non-elderly patients, respectively. All patients received 25 mg/m(2) of cisplatin. The pharmacokinetics and pharmacodynamics of docetaxel and cisplatin were compared in elderly and non-elderly patients.


RESULTS
There were no differences in pharmacokinetics of docetaxel or cisplatin between elderly versus non-elderly patients with regard to clearance and volume of distribution. In the pharmacodynamic analysis, neutropenia was positively correlated with the area under the concentration-time curve for docetaxel but not for cisplatin. In evaluating the relationship between neutropenia and the area under the concentration-time curve of docetaxel, elderly patients experienced greater neutropenia than those predicted by a pharmacodynamic model developed in non-elderly patients; the residual for prediction of the percent change in neutrophil count was -11.2% (95% CI, -21.8 to -0.5%).


CONCLUSIONS
The pharmacokinetics of docetaxel and unchanged cisplatin were not different between elderly and non-elderly patients. The elderly patients were more sensitive to docetaxel exposure than the non-elderly patients, resulting in the different recommended doses for the phase II studies.
Minami
Hironobu
H
Division of Oncology/Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa 277-8577, Japan. hminami@east.ncc.go.jp
Ohe
Yuichi
Y
Niho
Seiji
S
Goto
Koichi
K
Ohmatsu
Hironobu
H
Kubota
Kaoru
K
Kakinuma
Ryutaro
R
Nishiwaki
Yutaka
Y
Nokihara
Hiroshi
H
Sekine
Ikuo
I
Saijo
Nagahiro
N
Hanada
Kazuhiko
K
Ogata
Hiroyasu
H
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002945:Cisplatin / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D043823:Taxoids / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin