Joseph A. Sinkule

Pharmacokinetics of teniposide (VM26) and etoposide (VP16-213) in children with cancer

SummaryThe clinical pharmacokinetics of VM26 and VP16-213 were assessed in 15 children (median age 10 years) with acute leukemia, using a new high-performance liquid chromatography—electrochemical assay. Pharmacokinetic parameters were calculated by both model-dependent and compartment model-independent methods. These studies demonstrated substantial differences in the central volumes of distribution (VDc), steady-state volumes of distribution (VDss) and systemic clearances (Cls) of VM26 and VP16-213; with the VDc, VDss, and Cls all being smaller for VM26. Systemic clearances determined by model-independent methods were 5.2±1.0 ml/min/m2 (mean±SD) for VM26 and 17.8±11.2 ml/min/m2 for VP16-213. The major metabolites detected in serum and urine were the hydroxy acids. Low levels of the picro-lactone isomers were detected in some patients while the aglycones were not detected in the serum or urine of any patients.

Quantitation of daunorubicin and its metabolites by high-performance liquid chromatography with electrochemical detection

A selective and sensitive high-performance liquid chromatographic method was developed for the separation and quantitation of daunorubicin and its metabolites in serum, plasma, and other biological fluids. Daunorubicin and metabolites in human plasma were injected directly into the high-performance liquid chromatography system via a loop-column to pre-extract the drugs from the plasma, and quantitated against a multilevel calibration curve with adriamycin as the internal standard. The column effluent was monitored with an electrochemical detector at an applied oxidative potential of 0.65 V and by fluorescence. Daunorubicin and four metabolites were separated and characterized by this method. In a blinded evaluation of accuracy and precision, the mean coefficients of variation were 3.8, 3.6 and 9.8% at concentrations of 150, 75 and 15 ng/ml, respectively, and blank samples gave negligible readings. The amperometric sensitivity was greater than achieved by fluorescence detection, and offers an alternative method for quantitation of these compounds. The new method has a limit of detection of less than 2 ng on column, allowing quantitation of less than 10 ng/ml in plasma samples without organic extraction prior to chromatographic analysis.

Pharmacokinetics of Anticancer Drugs in Children

Several comprehensive reviews of the disposition of anticancer drugs in children with cancer have been published (1–7). However, recent advances in cellular and molecular biology techniques have led to the design and analysis of clinical pharmacology studies, which have increased our understanding of the age-related changes that govern drug disposition: absorption, distribution, metabolism, and elimination. Moreover, recent studies have characterized the disposition of new anticancer drugs in children, as well as contributed new insights into the use of currently available anticancer drugs. Thus, an update on pediatric pharmacokinetics of anticancer drugs in children is warranted.

High-performance liquid chromatographic assay for cytosine arabinoside, uracil arabinoside and some related nucleosides

A novel, dual-column high-performance liquid chromatographic method for determination of the anti-cancer drug cytosine arabinoside (Ara-C) and its major metabolite uracil arabinoside (Ara-U) has been developed. The analytical procedure is sensitive (25 ng/ml) and specific for Ara-C, Ara-U and the endogenous nucleosides that may influence response to Ara-C therapy, cytidine and deoxycytidine. Conventional and high dose calibration curves were linear and the method precise with the assay coefficient of variation for Ara-C and Ara-U not greater than 9.1% over the range of 0.1-10 micrograms/ml. Accuracy was determined to be within +/- 3 to 9% over this concentration range. Using this method, patient plasma samples from both conventional dose (100-200 mg/m2 per day) and high dose (3500-6500 mg/m2 per day) Ara-C can be simultaneously analyzed for Ara-C, Ara-U and nucleosides so that comparative pharmacokinetic and pharmacodynamic studies can be conducted.

Phase I clinical and pharmacokinetic study of bisantrene in refractory pediatric solid tumors

SummaryFourteen patients with pediatric malignant solid tumors, median age 15 years, received 22 courses of bisantrene in a Phase I study. Dosage escalations ranged from 10 to 120 mg/m2 daily for 5 consecutive days. Toxicity included myelosuppression and phlebitis. A sensitive (detection limit of 2 ng/ml) and specific HPLC method was developed to quantitate bisantrene in patients plasma and urine. Peak plasma concentrations at the end of 60 minute infusions ranged from 568 ng/ml at 10 mg/m2 to 6800 ng/ml at the 100 mg/m2 dosage. The elimination half life (T 1/2β) averaged about 10 hours but increased to 20 hours in a patient with liver disease. Only 2.4–10% of the bisantrene dose was eliminated in the urine suggesting that the liver may be the major route of elimination for this antineoplastic anthracene derivative.