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The Association of the rs2108622 Single Nucleotide Polymorphism in the CYP4F2 Gene with Resistance to Clopidogrel
Clinical Therapeutics drugs with low hepatic metabolism are more frequently associated with delayed onset suggests that additional mechanism(s) outside hepatic metabolism influence the probability of delayed onset. Funding: Fondos FEDER(PI15/01440);AEMPS;CIBERehd_by_ ISCIII.
Pharmacokinetics of Fixed Dose Combination Tablets of Empagliflozin/ Metformin Compared with Individual Tablets in Healthy Subjects Under Fed Conditions Z. Blahova1; V. Endriss2; C. Lopez3; A.N. Galustyan4; and S. Hüttner5 1 Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria; 2 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 3Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; 4BioEq LLC, St. Petersburg, Russian Federation; and 5Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany Background: The aim of this study was to evaluate the bioequivalence of two empagliflozin 12.5 mg/metformin 500 mg fixed dose combination (FDC) tablets compared with individual tablets of empagliflozin 25 mg and metformin 1000 mg taken together. Methods: In a randomised, open-label, single-dose, 2-way crossover study, healthy subjects received two FDC tablets of empagliflozin 12.5 mg/metformin 500 mg and a free combination of individual tablets of empagliflozin 25 mg and metformin 1000 mg, all under fed conditions, with a washout of ≥ 5 days between treatments. Primary endpoints were the area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration (AUC0-tz) and the maximum plasma concentrations (Cmax) of empagliflozin and metformin. Secondary endpoints were AUC from time 0 extrapolated to infinity (AUC0-∞) for empagliflozin and metformin. Results: Twenty-five subjects (12 male; 22 white and 3 Asian) received study medication. One subject withdrew from the study after one treatment and was not included in these analyses. Empagliflozin and metformin exposures were bioequivalent between FDC tablets and individual tablets taken together (table). An adverse event (mild headache, not considered to be related to study drug) was reported in one subject after treatment with individual tablets. FDC vs Individual Tablets (n= 24)
Empagliflozin AUC0–tz Cmax AUC0–∞ Metformin AUC0–tz Cmax AUC0–∞
Adjusted Geometric Mean Ratio (GMR) (%)
90% confidence interval
Intra-individual Geometric Coefficient Of Variation (gCV) (%)
100.1 102.7 100.3
97.5, 102.8 97.3, 108.4 97.5, 103.1
5.4 10.9 5.7
95.5 101.1 93.6
89.3, 102.2 95.6, 106.9 82.9, 105.6
13.6 11.3 24.8
Conclusions: Two empagliflozin 12.5 mg/metformin 500 mg FDC tablets are bioequivalent to individual tablets of empagliflozin 25 mg and metformin 1000 mg taken together.
The Association of the rs2108622 Single Nucleotide Polymorphism in the CYP4F2 Gene with Resistance to Clopidogrel O.D. Konova1; K.B. Mirzaev1; K.A. Ryzhikova1; Zh.A. Sozaeva1; D.A. Andreev2; and D.A. Sychev1
e62
1
Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russia; and 2Sechenov I.M. First Moscow State Medical University, Moscow, Russia Background: Carriership of CYP4F2*3 (rs2108622, Val433Met) allelic variant can affect antiplatelet effect of clopidogrel, thus changing efficacy and safety of its standard dose. The aim of the study was to determine the impact of carriership of at least one CYP4F2*3 allele on the risk of resistance to clopidogrel in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). Methods: The study enrolled 81 patients with ACS and PCI: 64 males and 17 females, mean age 63.9 ± 10.9 years. CYP4F2 allelic variants were detected by the method of real-time polymerase chain reaction. Platelet functional activity was evaluated by a portative aggregometer - the VerifyNow P2Y12 assay. Results: Pharmacogenetic testing showed that 40 (49,4%) of ACS patients had normal genotype (CC), 38 (46,9%) patients were carriers of one associated with reduced drug metabolism allele (CT genotype), and 3 (3,7%) patients were homozygotes for T (TT genotype). Genotype and allele distribution was in the Hardy–Weinberg equilibrium (χ 2= 2,79; p= 0,095). There were no statistically significant differences in CYP4F2*3 allele frequency between patients that are resistant to clopidogrel (PRU> 208) and in patients with a normal response to clopidogrel (PRU < 208): 36,8% vs. 54,8% (р= 0,17). Average platelet reactivity units (PRU) and average platelet inhibition (%) in patients with and without T allelic variant of CYP4F2 also were not significantly different: 165,34 ± 51,03 vs. 174,8 ± 51,06 (p= 0,407) and 29,51 % ± 21,59 vs. 27,72 % ± 18,35 (p= 0,69). Conclusions: Carriership of CYP4F2*3 allelic variant does not affect antiplatelet effect of clopidogrel in ACS patients. Further research on larger samples is needed to determine the role of CYP4F2 polymorphisms in personalization of clopidogrel antiplatelet therapy.
Retrospective View on Clinical Aspects and Treatment of Nosocomial Pneumonia M.A. Chukina; M.V. Lukina; I.L. Tsarev; T.B. Andruschishina; and T.E. Morozova I.M.Sechenov First Moscow State Medical University, Moscow, Russia Background: The problem of nosocomial pneumonia (NP) development and multidrug-resistant pathogens increase dictates the need of studies to optimize antibiotic therapy and possible combined usage of inhaled antibiotics. Methods: We retrospectively reviewed all medical records of surgical patients (n= 700) in a multidisciplinary hospital for one year (201415). NP was assessed according to the criteria of American Thoracic Society. Demographic, risk factors, microbiological monitoring were analyzed. Statistical analysis was performed with R version 3.3.2. Results: In patients the incidence of NP was 17.1% (women - 46.7%, men - 53.3%, mean age 63.4 years ± 13.4 (sd)). Cancer strongly affected adverse outcome (53%; p= 0.003). The median Simplified Acute Physiology Score (SAPS II) was 39. BMI didn’t differ significantly between outcome groups (27.0 ± 4.7 vs 26.8 ± 5.7; p= 0.88). Tracheostomy patients died more frequently (60%; p= 6.964e-11). The duration of mechanical ventilation in groups with adverse and favorable outcome was 13.5 [7-26.3] and 1 day [0-6.4] accordingly (p= 4.934e-08). NP development in groups with adverse and favorable outcome was - 11.5 [7-15] and 12 [7-15] days (p= 0.9). According to microbiological results gram-negative organisms dominated: Acinetobacter baumanii KPC (14.5%), Klebsiella pneumoniae extended spectrum beta lactam (ESBL) (21.7%), Klebsiella pneumoniae carbapenemases (KPC) producing bacteria (9.5%), Ps aeruginosa KPC (10.5%). Surprisingly in patients with inhalation therapy
Volume 39 Number 8S
Pharmacokinetics of Fixed Dose Combination Tablets of Empagliflozin/ Metformin Compared with Individual Tablets in Healthy Subjects Under Fed Conditions Z. Blahova1; V. Endriss2; C. Lopez3; A.N. Galustyan4; and S. Hüttner5 1 Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria; 2 Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; 3Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut; 4BioEq LLC, St. Petersburg, Russian Federation; and 5Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany Background: The aim of this study was to evaluate the bioequivalence of two empagliflozin 12.5 mg/metformin 500 mg fixed dose combination (FDC) tablets compared with individual tablets of empagliflozin 25 mg and metformin 1000 mg taken together. Methods: In a randomised, open-label, single-dose, 2-way crossover study, healthy subjects received two FDC tablets of empagliflozin 12.5 mg/metformin 500 mg and a free combination of individual tablets of empagliflozin 25 mg and metformin 1000 mg, all under fed conditions, with a washout of ≥ 5 days between treatments. Primary endpoints were the area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration (AUC0-tz) and the maximum plasma concentrations (Cmax) of empagliflozin and metformin. Secondary endpoints were AUC from time 0 extrapolated to infinity (AUC0-∞) for empagliflozin and metformin. Results: Twenty-five subjects (12 male; 22 white and 3 Asian) received study medication. One subject withdrew from the study after one treatment and was not included in these analyses. Empagliflozin and metformin exposures were bioequivalent between FDC tablets and individual tablets taken together (table). An adverse event (mild headache, not considered to be related to study drug) was reported in one subject after treatment with individual tablets. FDC vs Individual Tablets (n= 24)
Empagliflozin AUC0–tz Cmax AUC0–∞ Metformin AUC0–tz Cmax AUC0–∞
Adjusted Geometric Mean Ratio (GMR) (%)
90% confidence interval
Intra-individual Geometric Coefficient Of Variation (gCV) (%)
100.1 102.7 100.3
97.5, 102.8 97.3, 108.4 97.5, 103.1
5.4 10.9 5.7
95.5 101.1 93.6
89.3, 102.2 95.6, 106.9 82.9, 105.6
13.6 11.3 24.8
Conclusions: Two empagliflozin 12.5 mg/metformin 500 mg FDC tablets are bioequivalent to individual tablets of empagliflozin 25 mg and metformin 1000 mg taken together.
The Association of the rs2108622 Single Nucleotide Polymorphism in the CYP4F2 Gene with Resistance to Clopidogrel O.D. Konova1; K.B. Mirzaev1; K.A. Ryzhikova1; Zh.A. Sozaeva1; D.A. Andreev2; and D.A. Sychev1
e62
1
Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russia; and 2Sechenov I.M. First Moscow State Medical University, Moscow, Russia Background: Carriership of CYP4F2*3 (rs2108622, Val433Met) allelic variant can affect antiplatelet effect of clopidogrel, thus changing efficacy and safety of its standard dose. The aim of the study was to determine the impact of carriership of at least one CYP4F2*3 allele on the risk of resistance to clopidogrel in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). Methods: The study enrolled 81 patients with ACS and PCI: 64 males and 17 females, mean age 63.9 ± 10.9 years. CYP4F2 allelic variants were detected by the method of real-time polymerase chain reaction. Platelet functional activity was evaluated by a portative aggregometer - the VerifyNow P2Y12 assay. Results: Pharmacogenetic testing showed that 40 (49,4%) of ACS patients had normal genotype (CC), 38 (46,9%) patients were carriers of one associated with reduced drug metabolism allele (CT genotype), and 3 (3,7%) patients were homozygotes for T (TT genotype). Genotype and allele distribution was in the Hardy–Weinberg equilibrium (χ 2= 2,79; p= 0,095). There were no statistically significant differences in CYP4F2*3 allele frequency between patients that are resistant to clopidogrel (PRU> 208) and in patients with a normal response to clopidogrel (PRU < 208): 36,8% vs. 54,8% (р= 0,17). Average platelet reactivity units (PRU) and average platelet inhibition (%) in patients with and without T allelic variant of CYP4F2 also were not significantly different: 165,34 ± 51,03 vs. 174,8 ± 51,06 (p= 0,407) and 29,51 % ± 21,59 vs. 27,72 % ± 18,35 (p= 0,69). Conclusions: Carriership of CYP4F2*3 allelic variant does not affect antiplatelet effect of clopidogrel in ACS patients. Further research on larger samples is needed to determine the role of CYP4F2 polymorphisms in personalization of clopidogrel antiplatelet therapy.
Retrospective View on Clinical Aspects and Treatment of Nosocomial Pneumonia M.A. Chukina; M.V. Lukina; I.L. Tsarev; T.B. Andruschishina; and T.E. Morozova I.M.Sechenov First Moscow State Medical University, Moscow, Russia Background: The problem of nosocomial pneumonia (NP) development and multidrug-resistant pathogens increase dictates the need of studies to optimize antibiotic therapy and possible combined usage of inhaled antibiotics. Methods: We retrospectively reviewed all medical records of surgical patients (n= 700) in a multidisciplinary hospital for one year (201415). NP was assessed according to the criteria of American Thoracic Society. Demographic, risk factors, microbiological monitoring were analyzed. Statistical analysis was performed with R version 3.3.2. Results: In patients the incidence of NP was 17.1% (women - 46.7%, men - 53.3%, mean age 63.4 years ± 13.4 (sd)). Cancer strongly affected adverse outcome (53%; p= 0.003). The median Simplified Acute Physiology Score (SAPS II) was 39. BMI didn’t differ significantly between outcome groups (27.0 ± 4.7 vs 26.8 ± 5.7; p= 0.88). Tracheostomy patients died more frequently (60%; p= 6.964e-11). The duration of mechanical ventilation in groups with adverse and favorable outcome was 13.5 [7-26.3] and 1 day [0-6.4] accordingly (p= 4.934e-08). NP development in groups with adverse and favorable outcome was - 11.5 [7-15] and 12 [7-15] days (p= 0.9). According to microbiological results gram-negative organisms dominated: Acinetobacter baumanii KPC (14.5%), Klebsiella pneumoniae extended spectrum beta lactam (ESBL) (21.7%), Klebsiella pneumoniae carbapenemases (KPC) producing bacteria (9.5%), Ps aeruginosa KPC (10.5%). Surprisingly in patients with inhalation therapy
Volume 39 Number 8S