Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein
| Autor: | Widmer N, La, Decosterd, Chantal Csajka, Leyvraz S, Ma, Duchosal, Rosselet A, Rochat B, Cb, Eap, Henry H, Biollaz J, Buclin T |
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| Předmět: |
Adult
Male Gastrointestinal Stromal Tumors Body Weight Age Factors Administration Oral Antineoplastic Agents Orosomucoid Original Articles Middle Aged Piperazines Pyrimidines Sex Factors Intestinal Absorption Leukemia Myelogenous Chronic BCR-ABL Positive Benzamides Imatinib Mesylate Humans Female Aged |
| Zdroj: | Europe PubMed Central |
| Popis: | The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma alpha1-acid glycoprotein concentrations.A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients.A one-compartment model with first-order absorption appropriately described the data, giving a mean (+/-SEM) oral clearance of 14.3 l h-1 (+/-1.0) and a volume of distribution of 347 l (+/-62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma alpha1-acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells.Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating alpha1-acid glycoprotein concentrations or free imatinib concentrations. |
| Databáze: | OpenAIRE |
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