Effect of cyclosporin A on protein binding of teniposide in cancer patients.
We investigated the effect of cyclosporin A (CSA) on protein binding of teniposide (VM26) in 16 patients with metastatic renal cell carcinoma receiving i.v. VM26 alone over 24 h (total dose, 200 mg/m2) and in association with CSA (5 mg/kg/2 h followed by 30 mg/kg/48 h i.v.). CSA was used in an attempt to overcome multidrug resistance. The unbound fraction (%fu) of VM26 was significantly (p=0.04) higher in the cycles with CSA (median 0.8; range 0.4-1.9) than in the cycles with VM26 alone (median 0.5; range 0.1-1.6). Both total VM26 area under curve concentration (AUC0-infinity) and free VM26 AUC0-infinity increased after treatment with CSA, but the median increase in free AUC0-infinity was higher (2.7-fold) than total AUC0-infinity (1.5-fold) (p = 0.04). Bilirubin was significantly (p<0.01) increased after CSA but no association was observed between bilirubin level and %fu of VM26. Albumin was in the normal range after both VM26 alone and VM26 plus CSA. The nadir of absolute neutrophil count (ANC) after VM26 plus CSA (median 700/microl, range <100-2860/microl) was lower than after VM26 alone (median 1900/microl, range 200-6000/microl) (p = 0.0007). The median percentage of ANC compared to the pretreatment value (ANC nadir/ANC pretreatment x 100) was 39.0% (range 3.1-98.8%) in the cycles with VM26 alone and 16.9% (range 1.4-97.9%) (p = 0.007) after VM26 plus CSA. Percentage change of neutrophils significantly correlated with free AUC0-infinity VM26 in the cycles with VM26 alone and VM26 plus CSA (p = 0.04, r = -0.53 and p = 0.04, r = -0.52, respectively). Only a trend which failed to reach significance was observed between total AUC0-infinity VM26 and percentage change of neutrophils in the cycles with VM26 alone and in association with CSA (p = NS, r = -0.33 and p = 0.055, r = -0.49, respectively). In conclusion, patients treated with CSA had higher systemic exposure to unbound VM26.
Toffoli
G
G
Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano (PN), Italy.
Aita
P
P
Sorio
R
R
Corona
G
G
Bertola
A
A
Colussi
A M
AM
Robieux
I
I
Boiocchi
M
M
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood* / Q000627:therapeutic use; D019540:Area Under Curve; D001663:Bilirubin / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000187:drug effects; D013713:Teniposide / Q000097:blood* / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D001798:Blood Proteins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D013713:Teniposide; D001663:Bilirubin