Modulation of cisplatin pharmacodynamics by Cremophor EL: experimental and clinical studies.
The paclitaxel vehicle Cremophor EL (CrEL) has been shown to selectively inhibit the accumulation of cisplatin in peripheral blood leucocytes, but not in tumour cells in vitro, and we hypothesised that this phenomenon is responsible for the improvement of the therapeutic index of cisplatin observed in combination studies with paclitaxel. Here, we report on studies assessing the interaction between CrEL and cisplatin in a murine model, and involving the potential clinical applicability of CrEL as a protector for cisplatin-associated haematological side-effects. In mice, CrEL (0.17 ml/kg, intravenous (i.v.)) given in combination with cisplatin (10 mg/kg, intraperitoneal (i.p.)) did not change the pharmacokinetics of cisplatin. Cisplatin-induced haematological toxicity, expressed as white blood cells (WBC) at nadir, was significantly reduced by CrEL from 5.05+/-0.95 to 6.50+/-1.31 x 10(9)/l (P=0.0009). Data obtained from cancer patients treated with cisplatin (70 mg/m(2), 3-h i.v.) and topotecan (0.45 or 0.60 mg/m(2)/day x 2) preceded by CrEL (12 ml, 3-h i.v.) (n=6) or without CrEL (n=10) similarly indicated significant differences in the percent decrease in WBC between the groups (46.5+/-18.7 versus 67.2+/-15.0%; P=0.029). Likewise, the percent decrease in platelet count was significantly greater in the absence of CrEL (23.9+/-5.38 versus 73.3+/-15.5%; P=0.0003). Pharmacokinetic parameters of unbound and total cisplatin and of topotecan lactone and total drug were not significantly different from historic control values (P>or=0.245). Overall, this study provides further evidence on the important role of CrEL in the pharmacological and toxicological profile of cisplatin, and implies that reformulation of cisplatin with CrEL for systemic treatment might achieve an improvement of its therapeutic index, particularly in the setting of a weekly dose-dense concept.
Gelderblom
H
H
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 EA Rotterdam, The Netherlands. a.j.gelderblom@lumc.nl
Loos
W J
WJ
Verweij
J
J
van der Burg
M E L
ME
de Jonge
M J A
MJ
Brouwer
E
E
Nooter
K
K
Stoter
G
G
Sparreboom
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006402:Hematologic Diseases / Q000139:chemically induced* / Q000517:prevention & control; D006801:Humans; D007262:Infusions, Intravenous; D007263:Infusions, Parenteral; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014677:Pharmaceutical Vehicles / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014677:Pharmaceutical Vehicles; C000515:cremophor EL; D005990:Glycerol; D002945:Cisplatin