Pharmacokinetics of high-dose teniposide.

This paper describes the pharmacokinetics of teniposide (VM-26) after being administered iv in high doses to eight cancer patients (maximum dose, 1.0 g/m2). VM-26 levels in plasma, urine, saliva, duodenal fluid, and cerebrospinal fluid were determined using high-performance liquid chromatography in combination with electrochemical detection. The plasma concentration-time curve of VM-26 showed a triphasic decay with a slow third phase in five patients, whereas in two patients the plasma concentration decay was biphasic. The plasma pharmacokinetics of VM-26 proved to be linear and could be fitted to a three-compartment model (five patients) and to a two-compartment model (two). The steady-state volume of distribution varied from 13.2 to 24.7 L/m2. The total-body clearance ranged from 5.84 to 10.18 ml/minute/m2. Low concentrations of VM-26 were found in saliva, duodenal fluid, cerebrospinal fluid, and urine. Excretion of unchanged VM-26 into the urine varied from 8.8% to 13.9% of the administered dose. No glucuronide of VM-26 could be detected in plasma or other biological fluid.

Pharmacokinetics of high dose etoposide (VP 16-213).

This paper describes the pharmacokinetics of etoposide in cancer patients after high dose administration (up to 3.5 g/m2). High performance liquid chromatography with electrochemical detection was used to determine etoposide, cis etoposide and the glucuronide of etoposide in plasma, bile, cerebro-spinal fluid, urine, saliva and ascites, the detection limit being 2 ng etoposide/ml plasma. The plasma concentration time curve shows a tri-phasic decay. The terminal phase is very slow. It was concluded that etoposide is strongly bound in the peripheral compartment. The volume of the central compartment varied from 7.4 to 20.1 l and the steady state volume of distribution from 3.1 to 7.8 l/m2. Relatively high concentrations of etoposide were found in saliva, bile, ascites and urine and low concentrations in cerebro-spinal fluid. The total body clearance varied from 12.0 to 26.8 ml/min/m2, and 26.2 to 53.4% was excreted as unchanged etoposide into the urine and 8.3 to 17.3% as glucuronide into the urine. Very low amounts of the trans hydroxy acid of etoposide and the cis etoposide were detected in the urine. Glucuronides were found in urine and duodenal fluid but not in plasma.

Pharmacokinetic evaluation of increasing dosages of etoposide in a chronic hemodialysis patient.

A chronic hemodialysis patient was treated for small cell lung cancer with a combination therapy consisting of doxorubicin, cyclophosphamide, and etoposide. The dose of etoposide was increased to normal in five steps because of the possible accumulation and higher plasma peak levels due to terminal renal failure. In order to study this phenomenon, plasma, urine, and dialysate levels of etoposide were determined during five treatment courses with a high-performance liquid chromatographic method combined with electrochemical detection; this proved that the pharmacokinetic curves for etoposide fit a two-compartment model. Peak plasma levels were 7.96, 10.84, 18.24, 21.0, and 24.0 micrograms/ml for dosages of etoposide of 75, 100, 150, 200, and 250 mg, respectively. No accumulation occurred, half-life times of the elimination phase were between 8.7 and 23.0 hours, apparent distribution volumes of the central compartment were between 9.2 and 14.5 L, and the total-body clearances were between 2.1 and 2.8 L/hour. Thus, pharmacokinetic parameters were comparable with those obtained in patients with normal renal function. Hemodialysis did not disturb the exponential decay of plasma etoposide concentration during the elimination phase. No etoposide was found in the dialysate and only minimal etoposide was recovered from the urine. The data presented here indicate that renal clearance is not indispensable for eliminating etoposide.