ABSTRACT
Introduction: Despite the outstanding results generally obtained with Imatinib in the treatment of chronic myeloid leukemia, some patients show sub-optimal or no response. To evaluate the relationship between steady-state trough plasma concentration and clinical response in CML patients. The objectives of this study were to assess the variability in Imatinib pharmacokinetics and to explore the effects of several demographic and biological covariates on the disposition of Imatinib
Methods: A population pharmacokinetic analysis was performed on 170 plasma samples from 74 adult Iranian chronic myeloid leukemia patients. A population pharmacokinetics model was developed to evaluate the influence of covariates on clearance and volume of distribution
Results: A one-compartment model with first-order absorption appropriately described the data, giving a mean [+/-SEM] clearance of 14.3l [+/-1.0] and a volume of distribution of 347 l [+/-62]. Clearance was influenced by body weight, age and gender. By considering these covariates the interindividual variability decreased from 47% to 19%. A large proportion of the interindividual variability [19% of clearance and 45% of volume of distribution] remained unexplained by these demographic covariates
Discussion and Conclusion: By considering morphological and biological covariates, a unique covariate model could be used to accurately describe Imatinib pharmacokinetics in our population and because of the 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
ABSTRACT
Encapsulation of human insulin in lipid vesicular systems such as niosomes was sought as a route to protect this protein against proteolytic enzymes and to improve its oral bioavailability The purpose of this study was to assess the effect of insulin encapsulation in niosomes on oral bioavailability in diabetic rats. Recombinant human insulin was entrapped in multilamellar niosomes composed of polyoxyethylene alkyl ether surfactants [Brij 52 and Brij 92] or sorbitan monostearate [Span 60] and cholesterol. The amount of insulin released in simulated intestinal fluid [SIF] and simulated gastric fluid [SGF] were measured at 37°C. The protection of entrapped insulin against pepsin, a-chymotrypsin and trypsin were evaluated in comparison with free insulin solution. Diabetes was induced by IP injection of streptozotocin [65 mg/kg] in male wistar rats and effects of orally administered niosomes and subcutaneously injected insulin on hypoglycemia and elevation of insulin levels in serum were compared. The extent and rate of insulin release from Brij 92 and Span 60 vesicles were lower than that of Brij 52 niosomes [P<0.05]. Vesicles protected insulin in comparison with free insulin solution against proteolytic enzymes [P<0.05] significantly Animals treated with oral niosome-encapsulated insulin [100 lU/kg] showed decreased levels of blood glucose and elevated serum insulin, which in the case of Brij 92 niosomes, hypoglycemic effect was significant [P<0.05]. Niosomes were also stable in solubilizing bile salt solutions and could effectively prolong the release of insulin in both SGF and SIF. Results of this study showed that niosomes may be utilized as oral carriers of insulin; however, to increase bioavailability of insulin, further studies on the protease inhibitor co-encapsulation in niosomal formulations might be helpful
ABSTRACT
Multilamellar vesicles [noisome] of polyoxyethylene alkyl ether surfactants [Brij 52, 72, 76 and 92] were prepared using classic film hydration method. Vesicle formation ability of the surfactants was assessed in presence or absence of cholesterol. All used surfactants formed vesicles in the absence of cholesterol. Recombinant human insulin was used as a model protein drug to investigate encapsulation efficiency and release characteristics of the vesicles. The amount of insulin released in simulated intestinal fluid [SIF] and simulated gastric fluid [SGF] from Brij 92 vesicles was lower than the other ones. These vesicles also showed the highest protection of insulin against proteolytic enzymes, pepsin and trypsin. Diabetes was induced by IP injection of streptozotocin [65 mg/kg] in male wistar rats. Animals treated with oral niosome [Brij 52 and 92]-encapsulated insulin [100 IU/kg] showed decreased levels of blood glucose and elevation of serum insulin, which in the case of Brij 92 niosomes the hypoglycemic effect was significant [P< 0. 05]