CLINICAL AND PHARMACOKINETIC STUDY OF ORAL NK611, A NEW PODAPHYLLATOXIN DERIVATIVE

NK611 is a novel water-soluble podophyllotoxin derivative that has com parable antitumour activity but higher potency and better bioavailabil ity in animals as compared with etoposide. The primary objectives of t his study were to determine, after both oral and intravenous administr ation in the same patient, the bioavailability and the pharmacokinetic profile of NK611. Secondary objectives involved evaluation of the tox icity and the antitumor activity. Patients were randomly assigned to r eceive oral or intravenous (30-min infusion) doses of 5, 10, and 20 mg /m(2) on day 1, when pharmacokinetic studies were performed. A daily o ral dose of 20 mg/m(2) was then given from day 4 through day 7 for res pective total doses of 85, 90, and 100 mg/m(2). NK611 and its metaboli tes were determined in plasma and urine by two different high-performa nce liquid chromatography (HPLC) methods with UV detection. A total of 21 adult patients entered the study and received the complete first c ycle and at least the Ist day of cycle 2; 17 of them received at least 2 complete cycles of treatment. After intravenous administration, the plasma decay curve of NK611 followed a two-exponential model, and aft er oral administration it declined monoexponentially in most cases. At all dose levels, bioavailability values were around 100%. At concentr ations between 10 and 20 mg/m(2) after both routes of administration, the pharmacokinetics were nonlinear; the terminal half-life, plasma cl earance, and volume of distribution were significantly different; and the area under the plasma concentration-time curve was not correlated to the dose. The urinary excretion of NK611 corresponded to 10-15% of the dose after administration by both routes, whereas that of N-demeth yl NK611 and its picroform was highly variable. The features of neutro penia were comparable with those noted for etoposide involving a high degree of interpatient variability and recovery within 1 month after t reatment. A daily dose of 20 mg/m(2) for 5 consecutive days every 4 we eks is the recommended regimen for phase II studies in patients who ha ve never been treated or have undergone previous chemotherapy only onc e.