Population Pharmacokinetic Analysis of the Oral Absorption Process and Explaining Intra-Subject Variability in Plasma Exposures of Imatinib in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). The aim of this study was to investigate the absorption and distribution kinetics of imatinib in healthy Iranian volunteers using nonlinear mixed effects modeling (NLMEM) to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters after oral administration. METHODS: This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study after administering a single dose of 200 mg of each formulation. Imatinib concentrations were quantified using a validated liquid chromatography method. To simultaneously describe the imatinib pharmacokinetic profiles obtained with both formulations, a population pharmacokinetic model was applied to data using SAEM algorithm implemented in MONOLIX, whilst simulations were used by numerical solving of ordinary differential equations to calculate secondary parameters in individuals for bioequivalence studies. RESULTS: According to goodness-of-fit criteria, a two-compartment open model with sequential zero- then first-order absorption and first-order elimination was used as the structural pharmacokinetic model. Inter-individual variability (IIV) was considered for all parameters. Typical population estimates (% IIV) were fraction of the drug absorbed with a zero-order kinetic (Fr) of 0.153 (47.9 %) in period (Tk0) of 0.714 h (47.4 %), first-order absorption rate constant (k a) of 0.94 h(-1)(31.2 %), oral clearance of 19 L/h (27.9 %), central volume of distribution (V c/F) of 139 L (21.5 %), apparent peripheral volume of distribution (V p/F) of 130 L (29.7 %) and the apparent inter-compartment clearance (Q/F) of 29.6 L/h (41.8 %). Body mass index (BMI) was the only covariate found to significantly affect V p /F. The coefficient of variation for intra-individual plasma exposure (AUC0-∞) was 27.8 %. CONCLUSIONS: Analyses using NLMEM for imatinib exhibited absorption complexities such as two input rates and medium to high intra-individual variability in drug exposure.

Doxorubicin loaded folate-targeted carbon nanotubes: preparation, cellular internalization, in vitro cytotoxicity and disposition kinetic study in the isolated perfused rat liver.

The objective of this study was to use the functionalized multi-wall carbon nanotubes (CNTs) for the delivery of doxorubicin (DOX). Polyethylene glycol (PEG) chains are attached to CNTs then folate-conjugation of PEGylated CNTs was prepared. The amount of drug loading was calculated by the Multivariate Calibration Method for simultaneous quantification of DOX and CNTs. Cytotoxicity was evaluated using the folate receptor-positive HeLa cell line. To assess distribution and elimination of free DOX and drug-loaded CNTs, a recirculating rat liver perfusion system was used and pharmacokinetic parameters were calculated using non-compartmental analysis. Loading efficiency of 84.3±3.1% and 49.3±5.4% was calculated for low-PEGylated and high-PEGylated CNTs respectively. A higher release rate of DOX was achieved at a higher amount of PEGylation. Folate-targeted CNTs expressed a 3.2-fold decrease in IC50 value compared with non-targeted CNTs. The result from liver perfusion experiments revealed that DOX accumulation in the liver was higher when PEGylation was lower. There was a 2.4-fold decrease in the elimination rate constant compared to free DOX, which was attributed to the redistribution of DOX from hepatocytes in a sustained release pattern that is consistent with an increase in the mean residence time and prolonged circulation. In conclusion, folate-targeted CNTs show great potential as a targeted anticancer delivery system.

Population pharmacokinetics of imatinib in Iranian patients with chronic-phase chronic myeloid leukemia.

PURPOSE: We evaluated the population pharmacokinetics (PPK) and exposure-response relationship of imatinib mesylate in Iranian patients with chronic myeloid leukemia (CML).This study was designed to assess steady state (SS) imatinib trough concentrations (Cmin) and pharmacokinetics parameters of imatinib in patients with CML in chronic phase after at least 12-month treatment. METHODS: Plasma concentrations from a randomized controlled trial consist of 61 patients who received oral imatinib at doses ranged between 300 and 800 mg in various dosing interval, which were quantified using a validated reversed-phase high-performance liquid chromatographic method with UV detection method on different occasions at SS and evaluated using PPK model. RESULTS: A one-compartment model with zero-order absorption and a lag time was sufficient in describing the concentration-time profile. Inter-individual variability (IIV) was modeled for all parameters. Oral clearance (CL/F) and the volume of distribution (V/F) were estimated to 10.8 L/h with 30 % IIV and 265 L with 53 % IIV, respectively. Inter-occasion variability (IOV) was included in CL/F (17 %) and V/F (22 %).The proportional residual error of the model was 8 %. CONCLUSIONS: Simulation analysis from individual parameters shows exposure to imatinib is highly variable among patients. Imatinib trough plasma levels <1,257 ng/mL were associated with lower rates of major molecular response. Because of the wide IIV compared with IOV with imatinib in our study, trough levels may play a role in investigating instances of suboptimal response.