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/m(2)) 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 (AUC(0-infinity)) and free VM26 AUC(0-infinity) increased after treatment with CSA, but the median increase in free AUC(0-infinity) was higher (2.7-fold) than total AUC(0-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/mu l, range 1100-2860/mu l) was lower than after VM26 alone? (median 1900/mu l, range 200-6000/mu l) (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 AUC(0-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 AUC(0-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. [(C) 1999 Lippincott Williams & Wilkins.].