Tag Archives: pharmacokinetics

The Statistical Analysis of Pharmacokinetic Parameters in the Context of Bioequivalence Testing of Two Anthelmintic Formulas Based on Ivermectine and Triclabendazole in Sheep

Lenard Farczadi1, Laurian Vlase2, Orsolya Melles3, Ramona Tolomeiu4, Octavia Tamas-Krumpe4, Andreea Buta4, Laurentiu Ognean4

1. University of Medicine, Pharmacy, Science and Technology of Targu Mures, Romania
2. “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
3. Clinical and Analytical Research Center Vim Spectrum
4. University of Agricultural Science and Veterinary Medicine Cluj-Napoca, Romania

DOI: 10.2478/amma-2019-0015

Conducting bioequivalence studies is an essential step during the market authorization process of generic pharmaceutical formulations, for both human or veterinary use. The aim of the present study was to evaluate the pharmacokinetics of triclabendazole sulphoxide, the main metabolite of triclabendazole, and ivermectin in order to evaluate the bioavailability and bioequivalence of a novel sheep anthelmintic formulation of oral suspension for sheep treatment containing triclabendazole 50 mg/mL and ivermectin 1 mg/mL compared to the reference product. In order to determine relative bioavailability of the test product with respect to the reference product the study was conducted on 36 clinically healthy sheep, following an unicentric, randomized, cross-over, two-sequence, two-treatment and 14-day wash-out study design. For the determination of triclabendazole sulphoxide and ivermectin sheep plasma concentrations, two rapid, selective high performance liquid chromatography coupled with mass spectrometry (LC-MS/MS) methods were developed and validated. The measured plasma concentrations of triclabendazole sulphoxide and ivermectin were used for the pharmacokinetic analysis and the determination of bioequivalence between the test product with regards to the reference product. The noncompartmental analysis of the pharmacokinetic data for both triclabendazole sulphoxide and ivermectin showed similarities between first-order kinetics of the test and reference product. The relevant pharmacokinetic parameters (Cmax, AUClast, AUCtot) were determined and the bioequivalence between the test and reference product could be concluded.

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Effect of Food on the Pharmacokinetics of Gliclazide 60 mg Modified Release Tablet in Healthy Caucasian Volunteers

Diana Pop1, Ana-Maria Gheldiu1, Monica Oroian1,2, Adriana Marcovici2, Sandeep Bhardwaj2, Arshad Khuroo3, Ravi Kochhar4, Laurian Vlase1

1. Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, Romania
2. Clinical Pharmacology and Pharmacokinetics Department, Terapia S.A-Sun Pharma Company, Cluj-Napoca, Romania
3. Clinical Pharmacology and Pharmacokinetics Department, Gurugram, India
4. R&D Formulation Development, Gurugram, India

DOI: 10.2478/amma-2018-0022

Objective: To evaluate the food effect on glicazide disposition in clinical trials conducted on healthy Caucasian volunteers who were given a new modified release oral formulation of Gliclazide 60 mg developed by Sun Pharmaceutical Industries, India.
Methods: The studies were designed as open-label, randomized, single-dose, crossover studies that consisted of two periods. During each study, venous blood samples were taken before and after drug administration up to 96 hours. Subsequently, individual plasma profiles were determined and non-compartmental method was employed for the assessment of food effect on the pharmacokinetic profile of gliclazide. The statistical significance of differences for the main pharmacokinetic parameters was evaluated by ANOVA test, for p < 0.05 statistical significance was decided. The relative profiles of absorption of gliclazide were obtained by mathematical deconvolution. All calculations were performed by Phoenix WinNonlin®.
Results: High-fat, high-calorie meal decreased gliclazide exposure. The mean maximum plasma concentration decreased with 14%, while the mean total area under the plasma concentration-time profile registered a 17% decrease. The elimination half-lives under fasted and fed conditions were comparable and the time to maximum plasma concentration was shortened under fed condition. Safety evaluation showed that overall gliclazide was well tolerated under both fasted and fed condition.
Conclusions: The statistical analysis revealed the lack of food effect on the new modified release tablets of Gliclazide 60 mg. However, before stating a definite conclusion regarding the food effect on gliclazide pharmacokinetic profile, additional studies on patients with type 2 diabetes mellitus should be conducted.

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The Influence of CYP2D6 Phenotype on the Pharmacokinetic Profile of Atomoxetine in Caucasian Healthy Subjects

Ioana Todor1, Dana Muntean1, Maria Neag2, Corina Bocsan2, Anca Buzoianu2, Laurian Vlase1, Daniel Leucuta3, Ana-Maria Gheldiu1, Adina Popa4, Corina Briciu4

1 University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics, Cluj-Napoca, Romania
2 University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Medicine, Department of Pharmacology, Toxicology and Clinical Pharmacology, Cluj- Napoca, Romania
3 University of Medicine and Pharmacy “Iuliu Hatieganu”, Department of Medical Informatics and Biostatistics, Cluj-Napoca, Romania
4 University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Pharmacy, Department of Clinical Pharmacy, Cluj-Napoca, Romania

DOI: 10.1515/amma-2017-0023

Objective: To analyze a potential phenotypic variation within the studied group based on the pharmacokinetic profile of atomoxetine and its active metabolite, and to further investigate the impact of CYP2D6 phenotype on atomoxetine pharmacokinetics.
Methods: The study was conducted as an open-label, non-randomized clinical trial which included 43 Caucasian healthy volunteers. Each subject received a single oral dose of atomoxetine 25 mg. Subsequently, atomoxetine and 4-hydroxyatomoxetine-O-glucuronide (glucuronidated active metabolite) plasma concentrations were determined and a noncompartmental method was used to calculate the pharmacokinetic parameters of both compounds. Further on, the CYP2D6 metabolic phenotype was assessed using the area under the curve (AUC) metabolic ratio (atomoxetine/ 4-hydroxyatomoxetine-O-glucuronide) and specific statistical tests (Lilliefors (Kolgomorov-Smirnov) and Anderson-Darling test). The phenotypic differences in atomoxetine disposition were identified based on the pharmacokinetic profile of the parent drug and its metabolite.
Results: The statistical analysis revealed that the AUC metabolic ratio data set did not follow a normal distribution. As a result, two different phenotypes were identified, respectively the poor metabolizer (PM) group which included 3 individuals and the extensive metabolizer (EM) group which comprised the remaining 40 subjects. Also, it was demonstrated that the metabolic phenotype significantly influenced atomoxetine pharmacokinetics, as PMs presented a 4.5-fold higher exposure to the parent drug and a 3.2-fold lower exposure to its metabolite in comparison to EMs.
Conclusions: The pharmacokinetic and statistical analysis emphasized the existence of 2 metabolic phenotypes: EMs and PMs. Furthermore, it was proved that the interphenotype variability had a marked influence on atomoxetine pharmacokinetic profile.

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Determination of Valproic Acid in Human Plasma by High-Performance Liquid Chromatography with Mass Spectrometry Detection

Vancea Szende1, Imre Silvia1, Vari C1, Dogaru Maria Titica1, Muntean Daniela-Lucia1, Căldăraru Carmen2, Dogaru G2, Donáth-Nagy Gabriella1

1 Faculty of Pharmacy, University of Medicine and Pharmacy, Tîrgu Mureş, Romania
2 Faculty of Medicine, University of Medicine and Pharmacy, Tîrgu Mureș, Romania

Background: Free valproic acid is shows no characteristic absorption in the ultraviolet region (above 235 nm), therefore its direct quantification and also the quantification of the corresponding metabolites from human plasma has proven to be challenging. Aim: The aim of our study was to develop and validate an effective LC-MS method for the determination of valproic acid in human plasma without using solid phase extraction as sample preparation, with a short analysis time and high sensitivity.
Materials and methods: Valproic acid was analyzed on a reversed – phase column (Zorbax SB – C18, 100 mm x 3 mm I.D., 3.5 μm) under isocratic conditions using a mobile phase of a 40:60 (v/v) mixture of acetonitrile and 0.1% (v/v) acetic acid in water. The flow rate was 1 mL/min and the column temperature 45 ºC. In these chromatographic conditions, the retention time was 2.3 minute for valproic acid. The detection of the analyte was in single ion monitoring mode using a triple quadrupole mass spectrometer with electrospray negative ionization. The monitored ion was 143.1 m/z derived from 144.2 m/z valproic acid. The sample preparation was very simple and consisted in plasma protein precipitation from 0.2 mL plasma using 0.6 mL methanol.
Results: Calibration curves were generated over the range of 2–200 µg/mL with values for coefficient of determination greater than 0.996 and by using a weighted (1/x) quadratic regression. The values of precision and accuracy for valproic acid at quantification limit were less than 3.3% and 7.2%, for within- and between-run assays, respectively. The mean recovery of the analyte was 104%. Valproic acid samples demonstrated good short-term, post-preparative and freeze-thaw stability.
Conclusion: The method is very simple and allows obtaining a very good recovery of the analyte. The validated LC-MS/MS method could be applied to pharmacokinetics and therapeutic drug monitoring study regarding valproic acid in humans.

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The Monitoring of Immunosuppressive Therapy with Tacrolimus in Patients with Kidney Transplant, Based on the Pharmacokinetic Criteria

Stoica Ciprian Mihai1, Căldăraru Carmen Denise2*, Vari Camil Eugen3, Tarța Dorin Ionuț1, Dogaru Maria Titica3, Carașca Emilian4, Dogaru Grigore Aloiziu1

1 Department of Nephrology, University of Medicine and Pharmacy, Târgu-Mureş, România
2 Department of Physiology, University of Medicine and Pharmacy, Târgu-Mureş, România
3 Department of Pharmacology and Clinical Pharmacy, University of Medicine and Pharmacy, Târgu-Mureş, România
4 Department of Internal Medicine IV, University of Medicine and Pharmacy, Târgu-Mureş, România

DOI: 10.1515/amma-2015-0082

Background: Therapeutic drug monitoring (TDM) in patients with Chronic Kidney Disease (CKD) with kidney transplant, represents a major post transplant concern due to the characteristics of this special category of patients, particularities which can generate changes of the pharmacokinetic profile of the administered medication.
Material and methods: The current study is a retrospective pharmacokinetic study, over a period of 50 months, including a group of 36 kidney transplanted patients with CKD. Tacrolimus blood concentration was determined by a validated high-performance liquid chromatography method (HPLC), at a 12 hour time interval from the last administration of the immunosuppressive medication and before the following dose (Residual concentration, Cmin(trough)).
Results: During the monitoring of therapy, based on the pharmacokinetic criteria, 252 measurements of blood concentration were determined, 58 of these being outside the therapeutic window.
Conclusions: The results obtained show that it is mandatory to continue to monitor closely medical therapy based on the pharmacokinetic criteria in view of improving drug administration. The other ways of monitoring therapy: the clinical and biochemical criteria should not be overlooked. In addition, the interindividual variability of patients should be considered, as well as drug interaction which can alter the pharmacokinetics of tacrolimus.

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