ABSTRACT
S-CKD602 is a pegylated liposomal formulation of CKD-602. This study is the first to evaluate the factors affecting the high interpatient variability in the pharmacokinetic disposition of S-CKD602. S-CKD602 was administered intravenously (i.v.) every 3 weeks as part of a phase I study. Pharmacokinetics studies of the liposomal encapsulated and released CKD-602 in plasma were performed. The pharmacokinetic variability of S-CKD602 is associated with both linear and nonlinear clearances. Patients > or =60 years of age have a 2.7-fold higher exposure of S-CKD602 as compared with patients <60 years of age (P = 0.02). Patients with a lean body composition have a higher plasma exposure of S-CKD602 (P = 0.02). Patients who have received prior therapy with pegylated liposomal doxorubicin (PLD) have a 2.2-fold higher exposure of S-CKD602 as compared with patients who have not received PLD (P = 0.045). Prolonged exposure of the encapsulated drug in plasma over 1-2 weeks provides significant pharmacologic advantages. The high interpatient variability in the pharmacokinetic disposition of S-CKD602 was associated with age, body composition, saturable clearance, and prior PLD therapy.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacokinetics , Camptothecin/analogs & derivatives , Neoplasms/drug therapy , Polyethylene Glycols/chemistry , Adult , Age Factors , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Body Composition/physiology , Camptothecin/administration & dosage , Camptothecin/pharmacokinetics , Female , Humans , Infusions, Intravenous , Liposomes , Male , Middle AgedABSTRACT
Pyrazofurin was administered to 21 patients with solid tumors at a dose of 200 mg/m2 iv weekly, because this dose had been shown to be well-tolerated and pharmacologic effects of a single dose at this level persisted for up to 7 days. An anemia consistent with a disturbance in rbc production was seen in most patients. Other toxic effects included stomatitis, rash, and myelosuppression. No complete or partial responses were noted, but two patients with alveolar cell carcinoma of the lung each had stable disease for 12 months. Most of the patients in this study tolerated the weekly dosage schedule well with only minimal myelosuppression, suggesting that this agent and schedule might be acceptable for use in combination chemotherapy. Several theoretic reasons favor the use of pyrazofurin in this manner. Pyrazofurin should also be evaluated more fully in patients with polycythemia vera, mycosis fungoides, and psoriasis, since other orotidylate decarboxylase inhibitors have been shown to be effective in these diseases.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Colonic Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Ribonucleosides/administration & dosage , Adult , Aged , Anemia/chemically induced , Antibiotics, Antineoplastic/adverse effects , Bone Marrow/drug effects , Clinical Trials as Topic , Drug Eruptions/etiology , Humans , Middle Aged , Orotidine-5'-Phosphate Decarboxylase/antagonists & inhibitors , Ribonucleosides/adverse effects , Stomatitis/chemically inducedSubject(s)
Leucovorin/administration & dosage , Methotrexate/administration & dosage , Neoplasms/drug therapy , Adult , Aged , Bone Marrow/drug effects , Drug Evaluation , Drug Therapy, Combination , Female , Half-Life , Humans , Infusions, Parenteral , Male , Methotrexate/adverse effects , Methotrexate/blood , Middle Aged , Neoplasms/blood , Stomatitis/chemically inducedSubject(s)
Cytidine Deaminase/metabolism , Nucleoside Deaminases/metabolism , Tetrahydrouridine/metabolism , Uridine/analogs & derivatives , Cytidine Deaminase/antagonists & inhibitors , Humans , In Vitro Techniques , Kinetics , Ligands , Liver/enzymology , Protein Binding , Tetrahydrouridine/pharmacology , ThermodynamicsABSTRACT
To correlate the pharmacokinetics and toxicity of methotrexate, we measured the drug's clearance from plasma after 395 high-dose, six-hour infusions given to 78 patients. After 375 infusions, 48 hour methotrexate levels fell within 2 standard deviations of the mean for nontoxic infusions, and myelosuppression did not occur. Methotrexate concentrations exceeded the range for nontoxic patients (mean +/- 2 standard deviations) after 20 infusions. Serious myelosuppression occurred after six of these 20 infusions, including five of 12 infusions associated with 48-hour drug concentrations above 9 X 10(-7) M. In seven patients with 48-hour concentrations above 9 X 10(-7) M, the absence of toxicity could be attributed to subsequent rapid clearance of the drug; four of these patients also received large doses of supplemental leucovorin (50 to 100 mg per square meter every six hours). Determination of methotrexate concentration in plasma thus identified patients at high risk of toxicity, a group that may benefit from supplemental leucovorin rescue.
Subject(s)
Methotrexate/toxicity , Blood Cell Count , Blood Platelets , Bone Marrow/drug effects , Creatinine/blood , Humans , Infusions, Parenteral , Kidney/drug effects , Leucovorin/administration & dosage , Leucovorin/therapeutic use , Leukocyte Count , Methotrexate/administration & dosage , Methotrexate/blood , Neoplasms/drug therapy , Time FactorsABSTRACT
Humans and rhesus monkeys receiving high-dose methotrexate (MTX) (greater than 50 mg/kg) excrete significant quantities of the metabolite, 7-hydroxy-MTX. This metabolite, though 200-fold less potent than MTX as an inhibitor of mammalian dihydrofolate reductase, is of very limited aqueous solubility, and thus may contribute to the renal toxicity of the high-dose regimen. The metabolite was not observed in previous pharmacologic studies in which conventional doses of MTX were administered (less than 10 mg/kg).
Subject(s)
Methotrexate/metabolism , Adolescent , Adult , Animals , Child , Dose-Response Relationship, Drug , Female , Haplorhini , Humans , Hydroxylation , Infusions, Parenteral , Kidney/metabolism , Liver/metabolism , Macaca mulatta , Methotrexate/administration & dosage , Methotrexate/urine , Middle AgedABSTRACT
Human subjects and rhesus monkeys receiving the antitumor agent methotrexate at the high dose levels recently introduced into clinical use (greater than 50 mg/kg) excrete significant amounts of the metabolite 7-hydroxymethotrexate. The metabolite is not detected in these species after methotrexate therapy at conventional dose levels. The evidence indicates that in primates, the in vivo conversion of methotrexate to 7-hydroxymethotrexate is a dose-dependent phenomenon, with the enzyme system(s) catalyzing the reaction having a low affinity for the drug.
Subject(s)
Methotrexate/administration & dosage , Adult , Animals , Bone Neoplasms/drug therapy , Carcinoma, Squamous Cell/drug therapy , Child , Female , Histocytochemistry , Humans , Kidney/metabolism , Lung Neoplasms/drug therapy , Macaca mulatta , Male , Methotrexate/analogs & derivatives , Methotrexate/metabolism , Methotrexate/therapeutic use , Methotrexate/urine , Middle Aged , Osteosarcoma/drug therapy , Time FactorsABSTRACT
Deoxycytidine kinase, which phosphorylates deoxycytidine (CdR) and its analog, cytosine arabinoside (ara-C), has been purified 71-fold from human leukemic cells. Biochemical properties of the partially purified enzyme included a molecular weight of 68,000, Kms of 7.8 muM for CdR and 25.6 muM for ara-C, and optimal activity with ATP and GTP as phosphate donors. Ara-C phosphorylation was strongly inhibited by CdR (Ki = 0.17 muM) and dCTP (Ki = 7.3 muM) and was weakly inhibited by ara-CTP (Ki = 0.13 mM). Purification by calcium phosphate gel elution and DEAE chromatography effectively separated this enzyme from cytidine deaminase, which deaminates both CdR and ara-C, and from uridine-cytidine kinase, the enzyme which phosphorylates 5-azacytidine. CdR kinase activity was found to decrease and cytidine deaminase to increase with maturation of normal and leukemic granulocytes. Myeloblasts purified by Ficoll sedimentation revealed an average kinase activity of 15.4 U/mg protein in acute myelocytic leukemia and 12.3 U/mg protein in blastic crisis of chronic myelocytic leukemia (CML). The average ratio of CdR kinase to deaminase activity in crude cell extracts varied from 0.197 in AML and 0.089 in blastic crisis to 0.0004 in normal granulocytes, reflecting the changes which take place with cellular maturation. The absolute levels of kinase and deaminase and the ratio of these two enzymes varied considerably among patients with AML, indicating that quantitative differences may be found in the metabolism of CdR and its analogs in leukemic cells.
Subject(s)
Granulocytes/enzymology , Leukemia/blood , Leukocytes/enzymology , Phosphotransferases/blood , Azacitidine/pharmacology , Blood Proteins/analysis , Cell Separation , Cell-Free System , Cytarabine/pharmacology , Cytidine Deaminase/blood , Deoxycytidine , Humans , Leukemia, Myeloid/blood , Leukemia, Myeloid, Acute/blood , Molecular Weight , Phosphates/metabolism , Tissue Extracts , Uridine Kinase/bloodABSTRACT
In a sibship of 5 brothers and 7 sisters, 3 sisters died from acute myelocytic leukaemia while a 4th probably had the same disease. Laboratory studies on the close relatives revealed that a 5th sister had persistently high erythrocyte sedimentation-rates and serum-IgM levels and serological evidence of acute leukaemia-associated antigens. These findings suggest a possible preleukaemic state in this patient.