cgp-74588 and Gastrointestinal-Stromal-Tumors

A 63-year-old woman underwent living donor liver transplantation for hepatic metastases of an extragastrointestinal stromal tumor (EGIST) originating from the rectovaginal space. Due to a multifocal extrahepatic tumor recurrence, treatment with imatinib mesylate was started after extensive pharmacokinetic studies to rule out possible interactions with immunosuppressives. We performed several re- resections for EGIST recurrence thereafter. At the last follow-up, 17 years after primary tumor resection and 10 years after living donor liver transplantation, the patient is symptom-free under immunosuppressive and imatinib mesylate treatments with a 2-cm stable recurrent pararectal EGIST. To our knowledge, this is the only report published on a patient who underwent transplantation for hepatic EGIST metastases with a posttransplantation follow-up of 10 years and the first report on living donor liver transplantation for metastasized EGIST. This is the first description of pharmacokinetics of imatinib and its main active metabolite CGP74588 in a liver transplant recipient.

Topics: Antineoplastic Agents; Benzamides; Female; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Living Donors; Middle Aged; Neoplasm Recurrence, Local; Piperazines; Pyrimidines; Rectal Neoplasms; Time Factors; Treatment Outcome; Vaginal Neoplasms

Imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor approved for use in the management of chronic myeloid leukemia in adults and children and in gastrointestinal stromal tumors in adults. Population pharmacokinetic (PPK) studies evaluating the effect of population covariates on the pharmacokinetics of imatinib and its active metabolite have been developed in adults with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, this still remains to be described in children.. The objectives of the analysis were to develop a PPK model of imatinib and its active metabolite, CGP74588, to describe exposure in children and young adults and to identify covariates that are predictors of variability in disposition.. Plasma concentrations from 26 subjects with Philadelphia (Ph+) leukemia (Phase I study) and 15 subjects with refractory solid tumors (Phase II study), who received oral imatinib at doses ranging from 260 to 570 mg/m(2), were available for the PPK analysis in NONMEM. Blood samples were drawn prior to dosing and over 24-48 h on days 1 and 8 of the studies. Covariates studied included weight, age, albumin, alanine aminotransferase and the study population.. The pharmacokinetics of imatinib and CGP 74588 were well described by one and two compartment models, respectively. Total body weight was the only covariate found to significantly affect Cl/F and V/F. The final imatinib-CGP 74588 model is summarized as follows: CL/F (imatinib) (L/h) = 10.8 x (WT/70)(0.75), V/F (imatinib) (L) = 284 x (WT/70) and D1(duration of zero order absorption,imatinib) (h) = 1.67 and CL/F (CGP 74588) (L/h) = 9.65 x (WT/70)(0.75), V1/F (CGP 74588) (L) = 11.6 x (WT/70), Q (CGP 74588) (L/h) = 2.9 x (WT/70)(0.75) and V2/F (CGP 74588) (L) = 256*(WT/70). Model evaluation indicated that the final model was robust and satisfactory.. Current imatinib dosing guidelines in pediatrics is based on the achievement of exposures consistent with doses known to be safe and efficacious in adults. Dose adjustments in children are guided empirically by the observance of drug-related toxicities. While, the pharmacokinetics of imatinib and its active metabolite, CGP 74588 in children are consistent with prior knowledge in adults, the model will form the basis to support the design of future trials, particularly with a view to managing toxicities and exploring dosing in this population.

Topics: Administration, Oral; Adolescent; Aging; Antineoplastic Agents; Benzamides; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Models, Biological; Multivariate Analysis; Piperazines; Pyrimidines; Young Adult

Topics: Aged; Antineoplastic Agents; Benzamides; Bile; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Liver Diseases; Male; Piperazines; Pyrimidines; Severity of Illness Index

The aim of this study was to explore the effect of several demographic, biological, and pharmacogenetic covariates on the disposition of imatinib and its main metabolite (CGP74588) in both adults and children.. Thirty-three children with solid malignancies included in a phase II exploratory study and 34 adults with gastrointestinal stromal tumors received 340 mg/m(2) and 400 mg imatinib, respectively. Plasma imatinib and CGP74588 concentrations observed on day 1 and at steady-state were analyzed by a population pharmacokinetic method (NONMEM) to evaluate the effect of age, body weight, age, sex, albuminemia, plasma alpha1-acid glycoprotein (AGP), and eight polymorphisms corresponding to ABCB1, ABCG2, CYP3A4, CYP3A5, and AGP (pharmacogenetic data available for 46 of 67 patients).. Analysis of the whole data set in 67 patients showed that apparent clearance (CL/F) of imatinib was positively correlated with body weight and albuminemia and negatively with AGP. By considering these three covariates, the interindividual variability on CL/F decreased from 47% to 19%. The apparent clearance of CGP74588 was similarly dependent on both body weight and AGP and significantly lower (30% reduction) at steady-state. By adding genotype status to the final covariate imatinib model, a 22% reduction in CL/F was observed in heterozygous compared with wild-type patients corresponding to ABCG2 c.421C>A (P<0.05).. By considering morphologic and biological covariates, a unique covariate model could be used to accurately describe imatinib pharmacokinetics in patients ages 2 to 84 years. Morphologic and biological characteristics have a stronger influence than pharmacogenetics on imatinib pharmacokinetics.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Benzamides; Blood Proteins; Body Weight; Child; Child, Preschool; Gastrointestinal Stromal Tumors; Glycoproteins; Humans; Imatinib Mesylate; Metabolic Clearance Rate; Middle Aged; Pharmacogenetics; Piperazines; Polymorphism, Genetic; Population Groups; Pyrimidines; Serum Albumin; Sex Factors; Young Adult

Imatinib mesylate, licensed to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, is metabolized by cytochrome P450 3A and undergoes little renal excretion, but its biliary excretion by humans is uncharacterized. Liquid chromatography-mass spectrometry was used to quantitate imatinib and its metabolite CGP 74588 in the bile of two patients with biliary stents; the ratio of imatinib:CGP 74588 in each was approximately 9:1. In the first patient, who was receiving long-term therapy with imatinib 400 mg/day and had normal liver function tests, biliary imatinib accounted for 17.7% of the daily dose and CGP 74588 accounted for 2.1%. In the second patient, who had elevated liver function tests and was studied after his first dose of imatinib 300 mg, biliary imatinib accounted for only 1.8% of the daily dose and CGP 74588 accounted for 0.2%. These data show both the qualitative similarities and the quantitative variability in biliary excretion of imatinib and its principal metabolite.

Topics: Adenocarcinoma; Adult; Antineoplastic Agents; Benzamides; Bile; Gastrointestinal Stromal Tumors; Humans; Imatinib Mesylate; Male; Middle Aged; Piperazines; Pyrimidines; Stents