tretinoin and Hypokalemia

The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children.. Vorinostat was administered orally daily starting at 180 mg/m(2)/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC).. Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m(2)/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m(2)/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m(2)/d 4 times per week and 13cRA 80 mg/m(2)/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m(2)/d for the capsule (range, 1,415 to 9,291 ng/mL x hr) and oral suspension (range, 1,186 to 4,780 ng/mL x hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination.. In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m(2)/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.

Topics: Administration, Oral; Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Humans; Hydroxamic Acids; Hypokalemia; Male; Maximum Tolerated Dose; Neoplasms; Neutropenia; Thrombocytopenia; Tretinoin; Vorinostat

A 40-year-old man was admitted with fever and purpura. He was diagnosed as having acute promyelocytic leukemia, and treated with all-trans retinoic acid. After achieving complete remission, he received consolidation therapy. During the chemotherapy, quadriplegia occurred three times. This was diagnosed as hypokalemic periodic paralysis because of the patient's low serum potassium level. Results of hormone and urine examinations showed no indication of secondary hypokalemia. However, the patient had a history of quadriplegia of unknown etiology at the age of 36. We speculated that in addition to the patient's predisposition to hypokalemic periodic paralysis, chemotherapy including prednisolone, and excessive ingestion of carbohydrate had induced his quadriplegia.

Topics: Adult; Antineoplastic Agents; Dietary Carbohydrates; Humans; Hyperinsulinism; Hypokalemia; Insulin Resistance; Leukemia, Promyelocytic, Acute; Male; Periodicity; Prednisolone; Quadriplegia; Recurrence; Tretinoin