ABSTRACT
INTRODUCTION: The effect of standing on heart rate and QT is well known but its impact on QTc is less clear. METHODS: Serial supine and standing 12-lead ECGs (seven pairs each day) were recorded from 54 healthy volunteers each day of a three-day period. ECGs were captured digitally and over-read by a cardiologist. RESULTS: A statistically significant shortening of RR (216 ms), QT (40 ms), and decreases in QTc-F (Fridericia) and QTc-LR (Framingham) were demonstrated on standing (8.3 and 6.9 ms, respectively). In contrast, QTc-B (Bazett's) significantly increased by 9.6 ms. Two subject-individualized correction methods were derived using each subject's supine measurements. Both showed significant decreases in QTc of approximately 13-14 ms upon standing. Using the bin analysis method, comparisons between positions using 25 ms interval RR bins revealed significant QT shortening of up to 15 ms upon standing. CONCLUSION: We have demonstrated a postural effect on cardiac repolarization independent of heart rate using two individualized correction methods, as well as QTc-F and QTc-LR, and the bin method. Characterization of postural differences in QT/QTc (other than QTc-B) may provide a safe and inexpensive physiological control to validate the ECG methodology used in clinical trials to assess potential drug-induced QT interval changes.
Subject(s)
Electrocardiography , Heart Rate/physiology , Posture/physiology , Female , Follow-Up Studies , Humans , Male , Reference ValuesABSTRACT
PURPOSE: To evaluate safety, tolerability, and pharmacokinetics of a new nucleoside analogue, tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC)] in patients with refractory solid tumors. EXPERIMENTAL DESIGN: Seventy patients were enrolled in four separate Phase I trials. Patients had metastatic or relapsed cancer of the colon, breast, pancreas, gastrointestinal tract, lung, and other sites. FMdC was administered by i.v. infusion over 30 min in one of four dose schedules--from once every 3 weeks to twice a week for 3 weeks, with dose escalation in each. Maximum doses ranged from 630 to 16 mg/m(2). RESULTS: Myelotoxicity, especially neutropenia, was the dominant toxicity and was generally dose-related. Grade 3 or 4 neutropenia occurred in 53% of patients but was of relatively short duration (1-8 days) in all of the patients. One patient experienced grade 3 thrombocytopenia and one patient grade 4 (duration 15 and 11 days, respectively). Transient febrile episodes were reported in 82% of patients with drug administration but were easily controlled. Drug-related gastrointestinal events were mild and appeared unrelated to dose. Pharmacokinetics were linear with dose, not appreciably affected by schedules, and not different after single or multiple doses. Terminal half-life was 3-4 h, and 23% of the administered drug was recovered in the urine as unchanged drug. The uridine analogue (FMdU), the deaminated metabolite of FMdC, was the primary metabolite. Objective antitumor activity was observed in eight patients: one exhibited a partial response and seven exhibited stable disease. CONCLUSIONS: In general, FMdC was well tolerated. On the basis of the time to recovery from neutropenia, the recommended schedule for Phase II studies is one treatment every 2 weeks, at a minimum dose of 270 mg/m(2).
Subject(s)
Antimetabolites, Antineoplastic/therapeutic use , Deoxycytidine/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/pharmacokinetics , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Resistance, Neoplasm , Female , Half-Life , Humans , Infections/etiology , Infusions, Intravenous , Male , Middle Aged , Molecular Structure , Neoplasm Metastasis , Neoplasm Recurrence, Local/drug therapy , Neoplasms/mortality , Neoplasms/pathology , Neutropenia/chemically induced , Thrombocytopenia/chemically inducedABSTRACT
PURPOSE: Preclinical studies indicate that the cyclin-dependent kinase inhibitor flavopiridol potentiates the induction of apoptosis by paclitaxel, provided paclitaxel is followed by flavopiridol. We therefore designed a phase I clinical trial of sequential paclitaxel and flavopiridol. PATIENTS AND METHODS: Paclitaxel was administered at a fixed dose, as either a 24- or 3-hour infusion on day 1, followed by a 24-hour infusion of flavopiridol on day 2. Doses of flavopiridol were escalated in successive cohorts according to a modified Fibonacci design. Flavopiridol pharmacokinetics were obtained on all patients. RESULTS: Dose-limiting neutropenia developed with 24-hour paclitaxel doses of 135 and 100 mg/m(2) and flavopiridol doses of 10 and 20 mg/m(2), respectively. With 3-hour paclitaxel at 100 mg/m(2), flavopiridol could be escalated to 70 mg/m(2) without dose-limiting toxicity. With 3-hour paclitaxel next escalated to 135 mg/m(2), dose-limiting neutropenia and pulmonary toxicity occurred when flavopiridol was escalated to 94 mg/m(2). This did not correlate with any change in flavopiridol or paclitaxel pharmacokinetics. At a 3-hour paclitaxel dose of 175 mg/m(2), dose-limiting pulmonary toxicity occurred in only one patient at flavopiridol doses under 94 mg/m(2). Clinical activity was observed in patients with esophagus, lung, and prostate cancer, including patients who had progressed on paclitaxel. CONCLUSION: The recommended phase II doses will be a 3-hour infusion of paclitaxel at 175 mg/m(2) on day 1 followed by a 24-hour infusion of flavopiridol at 70 mg/m(2) on day 2. Flavopiridol dose escalations to 80 mg/m(2) are possible. At these doses, toxicities are manageable and clinical activity is promising.
