Pharmacokinetic Unit

Catania, Italy

Pharmacokinetic Unit

Catania, Italy

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Russell J.A.,Foothills Hospital and Tom Baker Cancer Center | Kangarloo S.B.,Pharmacokinetic Unit | Williamson T.,Queen's University | Chaudhry M.A.,Foothills Hospital and Tom Baker Cancer Center | And 14 more authors.
Biology of Blood and Marrow Transplantation | Year: 2013

A combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Buexposures exceeding 6000μM/min may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt toidentify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50mg/m2 on days -6 to -2 and i.v. Bu 3.2mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439μM/min were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P=.014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814μM/min and >4993μM/min) had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P=.004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P=.021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P=.018). Bu exposures between 4440 and 4993μM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD. © 2013 American Society for Blood and Marrow Transplantation.


Ng E.S.M.,Pharmacokinetic Unit | Kangarloo S.B.,Pharmacokinetic Unit | Daly A.,Tom Baker Cancer Center
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2013

An improved quantitative assay was developed and validated for fludarabine in human plasma. Fludarabine and its internal standard, cladribine, were separated on a C18 analytical column after sample purification by strong anion-exchange solid-phase extraction. Quantitation was performed by electrospray triple-quadrupole mass spectrometry in positive ionization mode using multiple-reaction monitoring. This assay had excellent inter- and intra-assay precisions within 8%, and accuracies ranging from 100 to 116%. The method was linear within the concentration range of 0.2-250ng/mL using 100μL of plasma with mean R2=0.9999. The extraction recoveries were 85% for fludarabine and 95% for the internal standard, which represent a significant improvement over the previously published methods. We utilized this method for pharmacokinetic (PK) investigations in 215 patients. Interference peaks constantly observed in each blank plasma sample were well resolved from fludarabine using our optimized LC-MS/MS conditions, demonstrating the reliability of this improved assay. The validated method will be further applied to PK studies within our bone marrow transplant program, which will allow for optimal dose and scheduling of fludarabine in these patients. © 2013 Elsevier B.V.


Vitale D.C.,Pharmacokinetic Unit
European journal of drug metabolism and pharmacokinetics | Year: 2013

Isoflavones are phytoestrogens with potent estrogenic activity; genistein, daidzein and glycitein are the most active isoflavones found in soy beans. Phytoestrogens have similarity in structure with the human female hormone 17-β-estradiol, which can bind to both alpha and beta estrogen receptors, and mimic the action of estrogens on target organs, thereby exerting many health benefits when used in some hormone-dependent diseases. Numerous clinical studies claim benefits of genistein and daidzein in chemoprevention of breast and prostate cancer, cardiovascular disease and osteoporosis as well as in relieving postmenopausal symptoms. The ability of isoflavones to prevent cancer and other chronic diseases largely depends on pharmacokinetic properties of these compounds, in particular absorption and distribution to the target tissue. The chemical form in which isoflavones occur is important because it influences their bioavailability and, therefore, their biological activity. Glucose-conjugated isoflavones are highly polar, water-soluble compounds. They are hardly absorbed by the intestinal epithelium and have weaker biological activities than the corresponding aglycone. Different microbial families of colon can transform glycosylated isoflavones into aglycones. Clinical studies show important differences between the aglycone and conjugated forms of genistein and daidzein. The evaluation of isoflavone metabolism and bioavailability is crucial to understanding their biological effects. Lipid-based formulations such as drug incorporation into oils, emulsions and self-microemulsifying formulations have been introduced to increase bioavailability. Complexation with cyclodextrin also represent a valid method to improve the physicochemical characteristics of these substances in order to be absorbed and distributed to target tissues. We review and discuss pharmacokinetic issues that critically influence the biological activity of isoflavones.


Ng E.S.M.,Pharmacokinetic Unit | Kangarloo S.B.,Pharmacokinetic Unit | Konno M.,Pharmacokinetic Unit | Paterson A.,University of Calgary | And 2 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2014

Purpose: Tamoxifen is a key therapeutic option for breast cancer treatment. Understanding its complex metabolism and pharmacokinetics is important for dose optimization. We examined the possibility of utilizing archival formalin-fixed paraffin-embedded (FFPE) tissue as an alternative sample source for quantification since well-annotated retrospective samples were always limited. Methods: Six 15 μm sections of FFPE tissues were deparaffinized with xylene and purified using solid-phase extraction. Tamoxifen and its metabolites were separated and detected by liquid chromatography-tandem mass spectrometry using multiple-reaction monitoring. Results: This method was linear between 0.4 and 200 ng/g for 4-hydroxy-tamoxifen and endoxifen, and 4-2,000 ng/g for tamoxifen and N-desmethyl-tamoxifen. Inter- and intra-assay precisions were <9 %, and mean accuracies ranged from 81 to 106 %. Extraction recoveries were between 83 and 88 %. The validated method was applied to FFPE tissues from two groups of patients, who received 20 mg/day of tamoxifen for >6 months, and were classified into breast tumor recurrence and non-recurrence. Our preliminary data show that levels of tamoxifen metabolites were significantly lower in patients with recurrent cancer, suggesting that inter-individual variability in tamoxifen metabolism might partly account for the development of cancer recurrence. Nevertheless, other causes such as non-compliance or stopping therapy of tamoxifen could possibly lead to the concentration differences. Conclusions: The ability to successfully study tamoxifen metabolism in such tissue samples will rapidly increase our knowledge of how tamoxifen's action, metabolism and tissue distribution contribute to breast cancer control. However, larger population studies are required to understand the underlying mechanism of tamoxifen metabolism for optimization of its treatment. © 2014 The Author(s).


Vitale D.C.,Pharmacokinetic Unit | Piazza C.,Pharmacokinetic Unit | Melilli B.,Pharmacokinetic Unit | Drago F.,Pharmacokinetic Unit | And 2 more authors.
European Journal of Drug Metabolism and Pharmacokinetics | Year: 2012

Isoflavones are phytoestrogens with potent estrogenic activity; genistein, daidzein and glycitein are the most active isoflavones found in soy beans. Phytoestrogens have similarity in structure with the human female hormone 17-β-estradiol, which can bind to both alpha and beta estrogen receptors, and mimic the action of estrogens on target organs, thereby exerting many health benefits when used in some hormone-dependent diseases. Numerous clinical studies claim benefits of genistein and daidzein in chemoprevention of breast and prostate cancer, cardiovascular disease and osteoporosis as well as in relieving postmenopausal symptoms. The ability of isoflavones to prevent cancer and other chronic diseases largely depends on pharmacokinetic properties of these compounds, in particular absorption and distribution to the target tissue. The chemical form in which isoflavones occur is important because it influences their bioavailability and, therefore, their biological activity. Glucose-conjugated isoflavones are highly polar, water-soluble compounds. They are hardly absorbed by the intestinal epithelium and have weaker biological activities than the corresponding aglycone. Different microbial families of colon can transform glycosylated isoflavones into aglycones. Clinical studies show important differences between the aglycone and conjugated forms of genistein and daidzein. The evaluation of isoflavone metabolism and bioavailability is crucial to understanding their biological effects. Lipid-based formulations such as drug incorporation into oils, emulsions and self-microemulsifying formulations have been introduced to increase bioavailability. Complexation with cyclodextrin also represent a valid method to improve the physicochemical characteristics of these substances in order to be absorbed and distributed to target tissues. We review and discuss pharmacokinetic issues that critically influence the biological activity of isoflavones. © 2012 Springer-Verlag France.


Vitale D.C.,Pharmacokinetic Unit | Piazza C.,Pharmacokinetic Unit | Sinagra T.,Pharmacokinetic Unit | Sinagra T.,University of Catania | And 6 more authors.
Clinical Drug Investigation | Year: 2013

Background and Objective: The skeletal muscle relaxant tizanidine is approved by the US FDA and the European Medicines Agency for treating spasticity and is supplied as tablets for oral administration. However, tizanidine has a poor bioavailability, due to extensive first-pass metabolism. Therefore, the nasal route of administration, which bypasses portal circulation, may increase the bioavailability of tizanidine and, possibly, reduce the time to peak plasma concentration, thereby shorting the latency of therapeutic effect. The objective of this study was to evaluate the pharmacokinetic profile of tizanidine nasal spray and compare it to the profile of tizanidine oral tablets. Methods: This open-label, phase I study comprised two protocols: protocol 1, tizanidine HCl solution (32.73 mg/mL) intranasally at single doses of 2 and 4 mg versus 4 mg tizanidine oral tablets (randomized, three periods crossover, 12 healthy subjects); and protocol 2, tizanidine HCl solution (16.36 mg/mL) intranasally at a single dose of 1 mg vs. 4 mg tizanidine oral tablets (randomized, two periods crossover, 12 healthy subjects, one dropout). Tizanidine plasma concentrations were determined by liquid chromatography/mass spectrometry. Results: There was a linear relationship between different dosages of intranasal formulation and the area under the concentration-time curve and maximum plasma concentration (C max). The relative bioavailability of the different dosages of intranasal formulation were 1.29, 1.93, and 4.23 for 1, 2, and 4 mg intranasal administration, respectively. Comparison of C max values gave the following ratios: 0.91, 1.39, and 2.73, for 1, 2, and 4 mg intranasal administration, respectively. The mean time to C max (t max) was 0.99, 0.43, and 0.63 h for 1, 2, and 4 mg intranasal administration, respectively, whereas it was 1.13 and 1.30 h for the two series of 4 mg tizanidine oral tablets. Conclusions: The bioavailability of the tizanidine intranasal formulation was higher than that of tizanidine oral tablets. The t max was also shorter with the intranasal formulation. No serious adverse events occurred throughout the study, such that the two formulations resulted equally well-tolerated. The intranasal formulation of tizanidine results are therefore worthy of subsequent clinical testing in phase II. © 2013 Springer International Publishing Switzerland.


PubMed | Pharmacokinetic Unit
Type: Journal Article | Journal: European journal of drug metabolism and pharmacokinetics | Year: 2013

Isoflavones are phytoestrogens with potent estrogenic activity; genistein, daidzein and glycitein are the most active isoflavones found in soy beans. Phytoestrogens have similarity in structure with the human female hormone 17--estradiol, which can bind to both alpha and beta estrogen receptors, and mimic the action of estrogens on target organs, thereby exerting many health benefits when used in some hormone-dependent diseases. Numerous clinical studies claim benefits of genistein and daidzein in chemoprevention of breast and prostate cancer, cardiovascular disease and osteoporosis as well as in relieving postmenopausal symptoms. The ability of isoflavones to prevent cancer and other chronic diseases largely depends on pharmacokinetic properties of these compounds, in particular absorption and distribution to the target tissue. The chemical form in which isoflavones occur is important because it influences their bioavailability and, therefore, their biological activity. Glucose-conjugated isoflavones are highly polar, water-soluble compounds. They are hardly absorbed by the intestinal epithelium and have weaker biological activities than the corresponding aglycone. Different microbial families of colon can transform glycosylated isoflavones into aglycones. Clinical studies show important differences between the aglycone and conjugated forms of genistein and daidzein. The evaluation of isoflavone metabolism and bioavailability is crucial to understanding their biological effects. Lipid-based formulations such as drug incorporation into oils, emulsions and self-microemulsifying formulations have been introduced to increase bioavailability. Complexation with cyclodextrin also represent a valid method to improve the physicochemical characteristics of these substances in order to be absorbed and distributed to target tissues. We review and discuss pharmacokinetic issues that critically influence the biological activity of isoflavones.


PubMed | Pharmacokinetic Unit
Type: | Journal: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences | Year: 2013

An improved quantitative assay was developed and validated for fludarabine in human plasma. Fludarabine and its internal standard, cladribine, were separated on a C18 analytical column after sample purification by strong anion-exchange solid-phase extraction. Quantitation was performed by electrospray triple-quadrupole mass spectrometry in positive ionization mode using multiple-reaction monitoring. This assay had excellent inter- and intra-assay precisions within 8%, and accuracies ranging from 100 to 116%. The method was linear within the concentration range of 0.2-250ng/mL using 100L of plasma with mean R(2)=0.9999. The extraction recoveries were 85% for fludarabine and 95% for the internal standard, which represent a significant improvement over the previously published methods. We utilized this method for pharmacokinetic (PK) investigations in 215 patients. Interference peaks constantly observed in each blank plasma sample were well resolved from fludarabine using our optimized LC-MS/MS conditions, demonstrating the reliability of this improved assay. The validated method will be further applied to PK studies within our bone marrow transplant program, which will allow for optimal dose and scheduling of fludarabine in these patients.


PubMed | Pharmacokinetic Unit
Type: Clinical Trial, Phase I | Journal: Clinical drug investigation | Year: 2013

The skeletal muscle relaxant tizanidine is approved by the US FDA and the European Medicines Agency for treating spasticity and is supplied as tablets for oral administration. However, tizanidine has a poor bioavailability, due to extensive first-pass metabolism. Therefore, the nasal route of administration, which bypasses portal circulation, may increase the bioavailability of tizanidine and, possibly, reduce the time to peak plasma concentration, thereby shorting the latency of therapeutic effect. The objective of this study was to evaluate the pharmacokinetic profile of tizanidine nasal spray and compare it to the profile of tizanidine oral tablets.This open-label, phase I study comprised two protocols: protocol 1, tizanidine HCl solution (32.73 mg/mL) intranasally at single doses of 2 and 4 mg versus 4 mg tizanidine oral tablets (randomized, three periods crossover, 12 healthy subjects); and protocol 2, tizanidine HCl solution (16.36 mg/mL) intranasally at a single dose of 1 mg vs. 4 mg tizanidine oral tablets (randomized, two periods crossover, 12 healthy subjects, one dropout). Tizanidine plasma concentrations were determined by liquid chromatography/mass spectrometry.There was a linear relationship between different dosages of intranasal formulation and the area under the concentration-time curve and maximum plasma concentration (C(max)). The relative bioavailability of the different dosages of intranasal formulation were 1.29, 1.93, and 4.23 for 1, 2, and 4 mg intranasal administration, respectively. Comparison of C(max) values gave the following ratios: 0.91, 1.39, and 2.73, for 1, 2, and 4 mg intranasal administration, respectively. The mean time to C(max) (t(max)) was 0.99, 0.43, and 0.63 h for 1, 2, and 4 mg intranasal administration, respectively, whereas it was 1.13 and 1.30 h for the two series of 4 mg tizanidine oral tablets.The bioavailability of the tizanidine intranasal formulation was higher than that of tizanidine oral tablets. The t(max) was also shorter with the intranasal formulation. No serious adverse events occurred throughout the study, such that the two formulations resulted equally well-tolerated. The intranasal formulation of tizanidine results are therefore worthy of subsequent clinical testing in phase II.


PubMed | University of Rome La Sapienza, University of Catania, CNR Institute of Neurological Sciences and Pharmacokinetic Unit
Type: | Journal: Pharmacological research | Year: 2016

The ectopic re-activation of cell cycle in neurons is an early event in the pathogenesis of Alzheimers disease (AD), which could lead to synaptic failure and ensuing cognitive deficits before frank neuronal death. Cytostatic drugs that act as cyclin-dependent kinase (CDK) inhibitors have been poorly investigated in animal models of AD. In the present study, we examined the effects of flavopiridol, an inhibitor of CDKs currently used as antineoplastic drug, against cell cycle reactivation and memory loss induced by intracerebroventricular injection of A1-42 oligomers in CD1 mice. Cycling neurons, scored as NeuN-positive cells expressing cyclin A, were found both in the frontal cortex and in the hippocampus of A-injected mice, paralleling memory deficits. Starting from three days after A injection, flavopiridol (0.5, 1 and 3mg/kg) was intraperitoneally injected daily, for eleven days. Here we show that a treatment with flavopiridol (0.5 and 1mg/kg) was able to rescue the loss of memory induced by A1-42, and to prevent the occurrence of ectopic cell-cycle events in the mouse frontal cortex and hippocampus. This is the first evidence that a cytostatic drug can prevent cognitive deficits in a non-transgenic animal model of AD.

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