Pharmacokinetics of paclitaxel administered in combination with cisplatin, etoposide and bleomycin in patients with advanced solid tumours.
OBJECTIVE
To evaluate the pharmacokinetics of paclitaxel and cisplatin administered in combination with bleomycin and etoposide and Granulocyte Colony-Stimulating Factor (G-CSF) in patients with advanced solid tumours.


METHODS
Patients were recruited to a phase I trial where escalating doses of paclitaxel (125 to 200 mg/m(2)) were administered in combination with etoposide 100 or 120 mg/m(2), and fixed dose of cisplatin 20 mg/m(2) and bleomycin 30 mg, with the concomitant use of G-CSF. Paclitaxel (3-h infusion) was followed by 1-h etoposide, 4-h cisplatin and 30-min bleomycin infusions, respectively. Pharmacokinetics sampling for paclitaxel analysis was performed in ten patients from dose levels II-V.


RESULTS
The mean paclitaxel area under the plasma concentration-versus-time curves (AUC) for the 125-mg/m(2) dose level (II) was 7.0 +/- 3.6 h micromol(-1) l(-1), for the 175-mg/m(2) dose level (III) 10.6 +/- 2. 8 h micromol(-1) l(-1), for the 200-mg/m(2) dose level (IV) it was 16.0 +/- 5.0 h micromol(-1) l(-1), and for the 175-mg/m(2) dose level (V) it was 12.5 +/- 6.1 h micromol(-1) l(-1). The mean peak plasma concentration (C(max)) values for dose levels II-V were 1.9 +/- 1.1 micromol/l, 3.4 +/- 1.2 micromol/l, 4.3 +/- 1.0 micromol/l and 3.8 +/- 1.2 h micromol/l, respectively.


CONCLUSIONS
In this study, relevant pharmacokinetic parameters of paclitaxel like AUC, C(max) and the paclitaxel plasma concentration above the pharmacologically relevant 0.1-micromol/l threshold concentration (t > 0.1 microM) when administered in combination with cisplatin, etoposide and bleomycin (PEB) were not statistically different from paclitaxel data of historical controls. However, given the trial design, pharmacokinetic interactions between the agents cannot be excluded.
Nannan Panday
V R
VR
Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. apvnp@slz.nl
de Wit
R
R
Schornagel
J H
JH
Schot
M
M
Rosing
H
H
Lieverst
J
J
ten Bokkel Huinink
W W
WW
Schellens
J H
JH
Beijnen
J H
JH
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001761:Bleomycin / Q000008:administration & dosage; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D001761:Bleomycin; D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide; D017239:Paclitaxel; D002945:Cisplatin