CYCLOSPORINE-A AS A MULTIDRUG-RESISTANT MODULATOR IN PATIENTS WITH RENAL-CELL CARCINOMA TREATED WITH TENIPOSIDE

Patients with refractory metastatic renal cell carcinoma (RCC) were en rolled in a phase II study with teniposide (VM26) and cyclosporin A (C SA) to investigate (1) the effect of CSA on the response rate to VM26; and (2) the effect of CSA on the pharmacokinetics and pharmacodynamic s of VM26. Sixteen patients initially received VM26 alone (200 mg m(-2 ) day(-1) i.v.). No objective responses were observed and all patients crossed over to receive at least an additional two courses (range 2-5 ) of VM26 plus CSA (5 mg kg(-1) 2h(-1) followed by 30 mg kg(-1) 48h(-1 ) i.v.). At the end of the 2-h loading dose of CSA, whole-blood CSA le vels ranged from 2250 to 3830 ng ml(-1), whereas at the end of the 48- h CSA infusion, CSA ranged from 1830 to 4501 ng ml(-1). CSA significan tly (P<0.01) increased the area under the curve (AUG) of VM26. The var iation in the paired AUC of VM26 was 50%. Terminal half-life of VM26 w as significantly (P<0.01) increased (1.72-fold) after CSA administrati on, whereas the systemic clearance of VM26 was decreased by 1.4-fold ( P<0.01). The nadir neutrophil count after VM26 plus CSA (median 700 mu l(-1), range <100 to 2860 mu l(-1)) was lower than after VM26 alone ( median 1900 mu l(-1), range 200 to 6000 mu l(-1)). Increased haematolo gical toxicity after CSA could be explained by the increase in the VM2 6 AUC and by inhibition of P-glycoprotein (P-gp) activity in haematopo ietic precursor cells. Bilirubin concentrations in the serum were incr eased after VM26 plus CSA compared with VM26 alone (P<0.01). Among the 15 patients evaluable for response, one had a minor response, eight h ad stable disease, and six had progressive disease. In conclusion, the dose of CSA we used achieved plasma concentrations within the effecti ve range for P-gp inhibition. CSA affected both the pharmacokinetics a nd pharmacodynamics of VM26 in the patients, principally by increasing the plasma concentrations of the antineoplastic drug and VM26 haemopo ietic toxicity.