Population pharmacokinetics of imatinib and the role of α₁‐acid glycoprotein

Intracellular concentration of imatinib in leukemic cells is thought to affect the clinical efficacy of this drug in patients with chronic myeloid leukemia (CML); however, there is no report that directly indicates the relationship between intracellular concentration and clinical outcome and/or, plasma concentration. In addition, the impacts of genetic variations of drug transporters, which mediate leukocyte concentration of imatinib, are unknown. In the present study, we investigated the correlation between intracellular imatinib concentrations in leukocytes, plasma imatinib levels, and genotypes of drug transporters, including ATP binding cassette B1 (ABCB), ABCG2, solute carrier 22A1 (SLC22A1), solute carrier organic anion transporter family members 1B1 (SLCO1B1) and SLCO1B3. The imatinib levels in leukocytes were determined using HPLC in 15 patients with chronic phase CML. No significant correlation between intracellular and plasma concentrations of imatinib was observed. The intracellular concentration was comparable in both patients with or without complete cytogenetic response. The intracellular imatinib concentration was significantly higher in patients with SLCO1B3 334TT than in those with 334TG/GG ( p‫؍‬ ‫.)8810.0؍‬ Plasma concentrations were similar in both SLCO1B3 genotypes (p‫؍‬ ‫,)068.0؍‬ thereby resulting in the intracellular to plasma concentration ratio being higher in patients with SLCO1B3 334TT than those with 334 TG/GG ( p‫؍‬ ‫.)2050.0؍‬ These results suggested that the SLCO1B3 334TϾ ϾG polymorphism could have a significant impact on the intracellular concentration of imatinib in leukocytes as a promising biomarker for personalized treatment of CML patients.

Efficient antifibrotic therapies are not available for patients with systemic sclerosis (SSc). This review summarizes the current preclinical and clinical evidence for imatinib and related tyrosine kinase inhibitors as potential antifibrotic therapies for SSc and other fibrotic diseases. In experimental models of SSc, imatinib, nilotinib, and dasatinib demonstrated strong antifibrotic effects. Imatinib not only prevented fibrosis in the bleomycin-induced model of dermal fibrosis and the tight skin mouse-1 model but also reduced established fibrosis in a modified bleomycin model. Open-label, proof-of-concept trials in SSc showed moderate effects on skin fibrosis, biological measures of skin fibrosis, and lung fibrosis compared with baseline measures. However, whether this reflects the natural course of the disease or is a result of treatment effects is unclear and needs to be analyzed in larger, multicenter, randomized, placebo-controlled trials. Toxicity is expected from cancer trials with frequent mild to moderate adverse events. This review summarizes the current preclinical and clinical evidence for imatinib and related tyrosine kinase inhibitors as potential anti-fibrotic therapies in SSc and other fibrotic diseases. Tyrosine Kinase Inhibitors in the Treatment of Systemic Sclerosis: From Animal Models to Clinical Trials

Abstract-Poor adherence to medical regimen causes approximately 33% to 69% of medication-related hospitalizations and accounts for $100 billion in annual health care costs. In this paper we address the problem of unintentional non adherence, when patient fails to take a medication due to forgetfulness or carelessness. We present the safe approach to software implementation of a portable reminder device with enabled personalization of medical regimen. The presented prototype is designed for imatinib administration, a drug used to treat Chronic Myeloid Leukemia (CML). However, thanks to the component-based structure of the software, the method can be applied to other cases by replacing implementation of certain components.