The pharmacokinetics, pharmacodynamics, and safety of zoledronic acid (Zometa), a new-generation bisphosphonate, were evaluated in 36 patients with cancer and bone metastases. Zoledronic acid (by specific radioimmunoassay) and markers of bone turnover were determined in plasma and urine after three consecutive infusions (qx28 days) of 4 mg/5 min (n = 5),4 mg/l5 min (n = 7),8 mg/15 min (n = 12), or 16 mg/15 min (n = 12). Zoledronic plasma disposition was multiphasic, with half-lives of 0.2 and 1.4 hours representing an early, rapid decline of concentrations from the end-of-infusion C(max) to < 1% of C(max) at 24 hours postdose and half-lives of 39 and 4526 hours describing subsequent phases of very low concentrations between days 2 and 28 postdose. AUC0-24 h and C(max) were dose proportional and showed little accumulation (AUC0-24 h ratio between the third and first dose was 1.28). Prolonging the infusion from 5 to 15 minutes lowered C(max) by 34%, with no effect on AUC0-24 h. Urinary excretion of zoledronic acid was independent of infusion duration, dose, or number of doses, showing average Ae0-24 h of 38% +/- 13%, 41% +/- 14%, and 37% +/- 17%, respectively, after 4, 8, and 16 mg. Only trace amounts of drug were detectable in post 24-hour urines. Renal clearance (Ae0-24 h)/(AUC0-24 h) was on average 69 +/- 28,81 +/- 40, and 54 +/- 34 ml/min after 4,8, and 16 mg, respectively, and showed a moderate correlation (r = 0.5; p < 0.001) with creatinine clearance, which was 84 +/- 23, 82 +/- 25, and 80 +/- 40 ml/min for the dose groups at baseline. Adverse events and changes from baseline in vital signs and clinical laboratory variables showed no relationship in terms of type, frequency, or severity with zoledronic acid dose or pharmacokinetic parameters. Zoledronic acid produced significant declines from baseline in serum and/or creatinine-corrected urine C-telopeptide (by 74%), N-telopeptide (69%), pyridinium cross-links [19-33%), and calcium (62%), with an increasing trend (by 12%) in bone alkalinephosphatase. There was no relationship of the magnitude and duration of these changes with zoledronic acid dose, Ae0-24 h, AUC0-24 h or C(max). The antiresorptive effects were evident within 1 day postdose and were maintained over 28 days across all dose levels, supporting monthly dosing with 4 mg zoledronic acid.

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BACKGROUND A profound difference between cancer and normal tissues is the preferential utilization of glycolysis by cancer cells. To translate this paradigm in the clinic, we completed a phase I study of 2-deoxyglucose (2DG), and assessed 2DG uptake with fluorodeoxyglucose (FDG) positron emission tomography (PET) and the autophagy substrate p62 as a marker of 2DG resistance. METHODS Patients received 2DG orally on days 1–14 of a 21-day cycle in cohorts of three in a dose-escalating manner. Correlative assessments included PET scans at baseline and day 2 and p62 protein in peripheral blood mononuclear cells as a potential marker of 2DG resistance. RESULTS The dose of 45 mg/kg was defined as the recommended phase II dose, secondary to dose-limiting toxicity of grade 3 asymptomatic QTc prolongation at a dose of 60 mg/kg. PK evaluation of 2DG revealed linear pharmacokinetics with Cmax 45 μg/ml (277 μM), 73.7 μg/ml (449 μM), and 122 μg/ml (744 μM) in dose levels 30, 45, and 60 mg/kg, respectively. Five of eight patients assessed with FDG-PET scanning demonstrated decreased FDG uptake by day 2 of therapy, suggesting competition of 2DG with FDG. Five of six patients assessed for p62 had a decrease in p62 at 24 hr. CONCLUSIONS These data support the safety of 2DG, defined 2DG PK, demonstrated the effect of 2DG on FDG-PET imaging, and demonstrated the feasibility of assessment of p62 as an autophagic resistance marker. These data support future studies of 2DG alone or in combination with approaches to abrogate autophagy.

Drugs that target microtubules are among the most commonly prescribed anticancer therapies. Although the mechanisms by which perturbation of microtubule function leads to selective death of cancer cells remain unclear, several new microtubule-targeting compounds are undergoing clinical testing. In part, these efforts focus on overcoming some of the problems associated with taxane-based therapies, including formulation and administration difficulties and susceptibility to resistance conferred by P-glycoprotein. Epothilones have emerged from these efforts as a promising new class of anticancer drugs. Preclinical studies indicate that epothilones bind to and stabilize microtubules in a manner similar but not identical to that of paclitaxel and that epothilones are effective in paclitaxel-resistant tumor models. Clinical phase I and early phase II data are available for BMS-247550, BMS-310705, EPO906, and KOS-862. The results suggest that these compounds have a broad range of antitumor activity at doses and schedules associated with tolerable side effects.

Although there has been a significant increase in the availability and use of oral chemotherapeutic agents, the guidelines around their safe handling are still evolving. Although oral chemotherapy is associated with ease of administration, it has the same exposure risks to health care practitioners, patients, and their caregivers as intravenous formulations, and because it is administered in the home, to the families of patients. However, the general misconception appears to be that exposure risk is low and therefore oral chemotherapeutic agents present little risk and are safer to handle. In a series of three roundtable meetings, a team of international pharmacists from North America and Europe reviewed existing guidelines and identified gaps in recommendations that we believe are important for safe handling. The present article is a compilation of these gaps, especially applicable to manufacturers and distributors, storage and handling, and patient education regarding safe handling. These recommendations, on the basis of our experience and of best practices, provide an international perspective and can be adapted by institutions and practices for development of standardized procedures specific to their needs for the safe handling of oral chemotherapeutic agents.