Bharat Damle

Phase I Trial and Pharmacokinetic Study of BMS-247550, an Epothilone B Analog, Administered Intravenously on a Daily Schedule for Five Days

PURPOSE The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. PATIENTS AND METHODS Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m2/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both. RESULTS One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m2 of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m2/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 +/- 6.0 hours, the volume of distribution at steady-state was 798 +/- 375 L, and the clearance was 712 +/- 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer. CONCLUSION The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m2/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.

Phase I and Pharmacokinetic Study of the Oral Fluoropyrimidine S-1 on a Once-Daily-for-28-Day Schedule in Patients with Advanced Malignancies

Purpose: The oral fluoropyrimidine S-1, which consists of a mixture of a 5-fluorouracil (5-FU) prodrug (tegafur), a dihydropyrimidine dehydrogenase inhibitor [5-chloro-2,4-dihydroxypyrimidine (CDHP)], and an inhibitor of orotate phosphoribosyltransferase [potassium oxonate (oxonic acid)], was developed to increase the feasibility and therapeutic index of 5-FU administered orally. The principal objective of this study was to assess the feasibility of administering S-1 on a once-daily-for-28-day schedule every 5 weeks, determine the maximum tolerated dose, characterize the pharmacokinetics of S-1, and seek evidence of anticancer activity. Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of S-1 on a once-daily oral schedule for 28 days every 5 weeks. The maximum tolerated dose was defined as the highest dose in which fewer than two of the first six new patients experienced dose-limiting toxicity. The pharmacokinetic profiles of the tegafur, CDHP, and oxonic acid constituents were characterized. Results: Twenty patients were treated with 72 courses of S-1 at three dose levels ranging from 50 to 70 mg/m2/day. Diarrhea, which was often associated with abdominal discomfort and cramping, was the principal dose-limiting toxicity of S-1 on this protracted schedule. Nausea, vomiting, mucositis, fatigue, and cutaneous effects were also observed but were rarely severe. Myelosuppression was modest and uncommon. A partial response and a 49% reduction in tumor size were observed in patients with fluoropyrimidine- and irinotecan-resistant colorectal carcinoma. The pharmacokinetic data suggested potent inhibition of 5-FU clearance by CHDP, with resultant 5-FU exposure at least 10-fold higher than that reported from equitoxic doses of tegafur modulated by uracil in the oral fluoropyrimidine UFT. Conclusions: The recommended dose for Phase II studies of S-1 administered once daily for 28 consecutive days every 5 weeks is 50 mg/m2/day. The pharmacokinetic data indicate substantial modulation of 5-FU clearance by CDHP. Based on these pharmacokinetic data, the predictable toxicity profile of S-1, and the low incidence of severe adverse effects at the recommended Phase II dose, evaluations of S-1 on this schedule are warranted in malignancies that are sensitive to the fluoropyrimidines.

Effect of Food on the Oral Bioavailability of Didanosine from Encapsulated Enteric-Coated Beads

The objective of this study was to assess the effect of food and timing of meals on the bioavailability of didanosine from encapsulated enteric‐coated beads. Four different independent, open‐label, single‐dose, randomized, crossover studies were conducted in healthy subjects (n = 20–30). Didanosine (400 mg) was given concomitantly with a high‐fat meal, light meal, yogurt, and applesauce. In addition, didanosine was given 1, 1.5, 2, and 3 hours before and 2 hours after a light meal. Statistical comparison with fasting conditions was made using the equivalence approach for Cmax (70%‐143%) and AUC (80%‐125%). The high‐fat meal, light meal, yogurt, and applesauce decreased the Cmax by 46%, 22%, 30%, and 24%, respectively, and lowered the AUC by 19%, 27%, 20%, and 18%, respectively; statistical analyses indicated an indeterminate food effect, except for the Cmax for the high‐fat meal. For 1 hour before meal, Cmax and AUC were lower by 15% and 24% and, for 2 hours after meal, were lower by 15% and 10%, respectively. There was an indeterminate food effect for 1 hour before the meal treatment; in addition, 2 hours after the meal, treatment approached statistical equivalence, missing narrowly on the lower bounds. For 1.5, 2, and 3 hours before meal treatments, Cmax values were unchanged, but AUC was lower by 10%, 4%, and 0%, respectively; lack of food effect was observed for all three treatments. Across studies, median time to Cmax ranged from 1.67 to 2.67 hours but was delayed by 2.5 to 3 hours with high‐fat and light meals compared to fasting conditions. The half‐life of didanosine was 1.5 to 2 hours. It was concluded that the bioavailability of didanosine from encapsulated enteric‐coated beads was reduced by approximately 20% to 25% with food, which can be circumvented by taking didanosine on an empty stomach. The clinical significance of such moderate reductions in didanosine exposure with food, especially as part of a highly active antiretroviral therapy, is not clear.

Bioequivalence of Two Formulations of Didanosine, Encapsulated Enteric‐Coated Beads and Buffered Tablet, in Healthy Volunteers and HIV‐Infected Subjects

Didanosine is an acid labile drug and hence has been given with buffering agents. To avoid the need for concurrent administration with antacids, an encapsulated enteric‐coated bead formulation of didanosine was developed. The objective of this study was to assess the bioequivalence of the encapsulated enteric‐coated beads compared to the buffered tablet. Two separate open‐label, randomized, two‐way crossover studies were conducted, one in healthy subjects and the other in HIV‐infected subjects (with CD4 cell counts > 200 cells/mm3). All subjects received a 400‐mg dose of the buffered tablet (reference formulation) and the encapsulated enteric‐coated beads (test formulation). Blood samples were collected over 12 hours, and plasma levels of didanosine were determined using a validated assay. The 90% confidence interval (CI) of the ratio of the geometric means of log‐transformed Cmax and AUC∞ values were used to assess bioequivalence between the two formulations using the equivalence interval of 0.80 and 1.25. In healthy volunteers (n = 46), the point estimate and 90% CI of the ratios of Cmax and AUC∞ values were 0.58 (0.52, 0.64) and 1.02 (0.95, 1.01), respectively. In HIV‐infected subjects (n = 30), the point estimate and 90% CI of the ratios of Cmax and AUC∞ values were 0.64 (0.56, 0.72) and 0.95 (0.86, 1.06), respectively. Median tmax value increased significantly from 0.67 hours for the buffered tablet in both studies to 2.33 hours (in healthy subjects) or 2.0 hours (in HIV‐infected subjects) for the enteric‐coated beads. The mean half‐life of didanosine was similar between treatments and ranged between 1.60 and 1.70 hours across healthy and HIV‐infected subjects. It was concluded that the encapsulated enteric‐coated bead formulation of didanosine is equivalent to the buffered tablet in the extent of exposure but differs in the rate of absorption. The pharmacokinetic profile of the enteric formulation appears to be similar in healthy and HIV‐infected subjects.

Influence of Immunogenicity on the Pharmacokinetics of BMS‐191352, a Pseudomonas Exotoxin Immunoconjugate, in Rats and Dogs

BMS‐191352 is an immunotoxin construct of modified Pseudomonas exotoxin conjugated to a fragment of the BR96 monoclonal antibody. We have investigated the potential for immunogenicity of BMS‐191352 and its influence on the pharmacokinetics in rats and dogs.