ABSTRACT
The prescribed dose of anticancer agents is most commonly calculated using body surface area as the only independent variable, and it has been shown that this approach still results in large interpatient variability in drug exposure. Here, we retrospectively assessed the pharmacokinetics of 33 investigational agents tested in phase I trials from 1991 through 2001, as a function of body surface area in 1650 adult cancer patients. Twelve of the drugs were administered orally, 19 were administered intravenously, and two were administered by both routes. Body surface area-based dosing was statistically significantly associated with a reduction in interpatient variability in drug clearance for only five of the 33 agents: docosahexaenoic acid (DHA)-paclitaxel, 5-fluorouracil/eniluracil, paclitaxel, temozolomide, and troxacitabine. These results do not support the use of body surface area in dose calculations and suggest that alternate dosing strategies should be evaluated. We conclude that body surface area should not be used to determine starting doses of investigational agents in future phase I studies.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Body Surface Area , Cytosine/analogs & derivatives , Dacarbazine/analogs & derivatives , Uracil/analogs & derivatives , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Clinical Trials, Phase I as Topic , Cytosine/administration & dosage , Cytosine/pharmacokinetics , Dacarbazine/administration & dosage , Dacarbazine/pharmacokinetics , Dioxolanes/administration & dosage , Dioxolanes/pharmacokinetics , Docosahexaenoic Acids/administration & dosage , Docosahexaenoic Acids/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Drugs, Investigational/administration & dosage , Drugs, Investigational/pharmacokinetics , Female , Fluorouracil/administration & dosage , Fluorouracil/pharmacokinetics , Humans , Infusions, Intravenous , Male , Paclitaxel/administration & dosage , Paclitaxel/pharmacokinetics , Retrospective Studies , Temozolomide , Uracil/administration & dosage , Uracil/pharmacokineticsSubject(s)
Busulfan/administration & dosage , Bone Marrow Transplantation/adverse effects , Bone Marrow Transplantation/methods , Busulfan/adverse effects , Busulfan/pharmacokinetics , Drug Monitoring , Hepatic Veno-Occlusive Disease/chemically induced , Hepatic Veno-Occlusive Disease/prevention & control , Humans , Infusions, Parenteral , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapyABSTRACT
The aromatic fatty acid sodium phenylbutyrate (PB) promotes cytostasis and differentiation in a wide variety of tumor types; among several molecular activities, inhibition of histone deacetylase (HDAC) may account for many of its pharmacodynamic effects. A Phase I study demonstrated promising preliminary evidence of clinical activity in acute myeloid leukemia and myelodysplastic syndrome; however, plasma concentrations achieved at the maximum tolerated dose were less than those targeted based on in vitro studies. Because prolonged exposure to suboptimal concentrations of PB in vitro led to pharmacodynamic changes similar to a more brief exposure to higher concentrations, a study of the feasibility of prolonged administration of sodium PB was performed. Selected patients with acute myeloid leukemia and myelodysplastic syndrome were treated with sodium PB as a continuous i.v. infusion via ambulatory infusion pump. Sequential cohorts were treated for 7 consecutive days out of 14 or with 21 consecutive days out of 28. Prolonged infusions were well tolerated; dose-limiting central nervous system toxicity developed in 1 of 23 patients treated. End-of-infusion plasma concentrations were maintained within a range sufficient to inhibit HDAC. Two patients on the 21/28 schedule developed hematological improvement. Prolonged infusions of PB are well tolerated making this an attractive platform for the clinical investigation of HDAC inhibition.
Subject(s)
Leukemia, Myeloid/drug therapy , Myelodysplastic Syndromes/drug therapy , Phenylbutyrates/therapeutic use , Acute Disease , Aged , Apoptosis/drug effects , Bone Marrow Cells/drug effects , Bone Marrow Cells/immunology , Cell Cycle/drug effects , Colony-Forming Units Assay , Diarrhea/chemically induced , Drug Administration Schedule , Female , Fetal Hemoglobin/drug effects , Fetal Hemoglobin/metabolism , Fever/chemically induced , Humans , Infusions, Intravenous , Male , Middle Aged , Nausea/chemically induced , Phenylbutyrates/adverse effects , Phenylbutyrates/pharmacokinetics , Time Factors , Treatment Outcome , Vomiting/chemically inducedABSTRACT
Paclitaxel was administered as a 24-h continuous infusion at 250 mg/m(2) in this Phase II trial in patients with adenocarcinoma of the colon or rectum. Nineteen patients were evaluated for toxity and 15 were assessable for response. There were no complete or partial responses, and toxicity present was primarily neutropenia. This study found that paclitaxel as a single agent does not have activity in adenocarcinoma of the colon or rectum.
