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The Effects of Candidate SNPS in PKPD Pathway on Antipsychotics-Induced Amenorrhea in Female Schizophrenia Patients
Posters 1
Inje University College of Medicine, Busan, South Korea; and Inje University Busan Paik Hospital, Busan, South Korea Background: Rifampin is the most commonly used 1st line drug for the treatment of tuberculosis (active and latent infection) and linezolid in 2nd line treatment especially in MDR-TB. It is known that rifampin acts as a potent substrate and inhibitor of organic anion transporter polypeptide (OATP)-1B1 and -1B3. Recently reported, linezolid has inhibition potential on OATPs mediated drug uptake. Therefore, we aimed to investigate potential transporter mediated drug interactions (DDIs) between rifampin and linezolid in vitro. Methods: Cellular uptake of rifampin and linezolid was measured using HEK cells which were stably transfected with OATPs, OATs (organic anionic transporter) and OCTs (organic cationic transporter). Uptake/inhibition kinetics parameters were estimated using non-linear kinetic model using Phoenix software package (WinNonlin 5.1, Pharsight, USA) and DDI index (R-value) was calculated using the static modeling following FDA draft guidance for DDIs study. Results: Both OATP1B1- and OATP1B3-mediated rifampin uptakes were strongly inhibited by linezolid in a noncompetitive manner. The Ki values of linezolid were 15.5 and 10.0 µM for OATP1B1 and OATP1B3, respectively. Furthermore, the estimated drug-drug interaction (DDI) indexes (R= 1+ [I]u,inlet,max/ Ki) of linezolid were 2.65 and 3.56 (cut off ≥ 1.25) for OATP1B1 and OATP1B3, respectively, suggesting DDI interactions possibilities in vivo. The net transport activity of linezolid through SLC transporters (OATPs, OATs and OCTs) was negligible, suggesting involvement of active transport and mutual DDIs unlikely. Conclusions: The present in vitro data showed OATP1B1- and OATP1B3- mediated rifampin uptake was significantly inhibited by the linezolid with higher DDI index suggested possible drug-interaction may take place between rifampin and linezolid. 2
The Effects of Candidate SNPS in PKPD Pathway on Antipsychotics-Induced Amenorrhea in Female Schizophrenia Patients H.S. Kim1,2; J.J. Moon2; D.J. Kim1; E.Y. Kim1,2; J.C. Shim3; and J.-G. Shin1,2 1 Inje University College of Medicine, Busan, South Korea; 2 Inje University Busan Paik Hospital, Busan, South Korea; and 3 Shim JooCheol Psychiatry Clinic, Busan, South Korea Background: Amenorrhea frequently occurs in female patients taking under antipsychotic drugs (APs).It may affect drug compliance resulting treatment failure. The aim of this study was to explore the genetic effects of candidate single nucleotide polymorphisms (SNPs) in pharmacokinetics and pharmacodynamics (PKPD) pathway of APon AP-induced amenorrhea in female schizophrenia patients. Methods: Eighty-nine female schizophrenic patients (age range from 18 to 40) taking the same AP for more than 3 months were enrolled. Amenorrhea was defined as the absence of menses for three months or three periods in a row. The serum levelsof prolactin, estradiol (E2), Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) were measured. Cytochrome P450 2D6 (CYP2D6), dopamine receptor D2 (DRD2) and estrogen receptor 1 (ESR1) were genotyped. Results: Compared to the patients without amenorrhea (n= 67), prolactin level was higher (71.5 vs. 94.1 ng/mL; p= 0.044) and E2 was lower (46.7 vs. 27.0ng/mL; p= 0.007) inthe patients with amenorrhea (n= 22). There was no difference in other hormonesand baseline characteristics between the patients with and without amenorrhea. Amisulpiride, chlorpromazine, haloperidol, paliperidone, and risperidone were observed to highly increase prolactin level and categorized to drugs increasing prolactin level.
August 2017
DRD2 -141insC (OR= 0.59, 95% CI= 0.34-0.99; p= 0.049) and drugs increasing prolactin level (OR= 6.17, 95% CI= 1.28-29.64; p= 0.023) were identified as predictors for AP-induced amenorrhea using multiple logistic regression analysis identified. Conclusions: This finding is the first evidence suggesting that DRD2 -141insC might be a possible protective biomarker for AP-induced amenorrhea. Further studies to confirm the DRD2 -141insC as a biomarker for AP-induced amenorrhea are needed in larger female antipsychotic patients.
Optimal Duration of Dual Antiplatelet Therapy after Drug-Eluting Stent Implantation: A Pairwise and Network Meta-Analysis of Randomised Controlled Trials Y. Fei; M.F. Tsoi; T.T. Cheung; and B.M.Y. Cheung The University of Hong Kong, Hong Kong, China Background: The optimal duration of dual antiplatelet therapy (DAPT) after coronary drug-eluting stent (DES) implantation remains uncertain. Despite recent studies, direct comparison between shortterm (< 12 months) and extended (> 12 months) DAPT is limited. We performed a network meta-analysis to assess the risk of mortality and other cardiovascular outcomes with different DAPT durations in order to guide clinical practice. Methods: We searched for randomised controlled trials comparing different durations of DAPT after DES implantation. Those reporting frequencies of cardiovascular and bleeding events were eligible to be included. Statistic analysis was performed using frequentist approach and Bayesian framework in R. Results: We included 12 randomised controlled trials with altogether 34920 patients for analysis. Extended DAPT (> 12 months) significantly lowered the risk of myocardial infarction (OR 0.56, 95%CI 0.46-0.68 and 0.58, 0.44-0.77), and stent thrombosis (0.44, 0.30-0.65 and 0.49, 0.29-0.82) when compared to 12-month and short-term DAPT (< 12 months), respectively. However, it was associated with increased major bleeding (1.53, 1.21-1.93 and 2.58, 1.62-4.10). Compared to 12-month DAPT, extended DAPT had more all-cause death (1.27, 1.03-1.57); short-term DAPT had less major bleeds (0.59, 0.39-0.91). Conclusions: Although extending DAPT beyond 12 months after DES implantation reduced myocardial infarction and stent thrombosis, the risk of major bleeding and all-cause mortality was substantially increased. No clear superiority of extended or short-term DAPT over 12-month DAPT was identified. DAPT duration should always be tailored for different patients after considering their benefit-risk profiles.
Network Meta-Analysis of Cardiovascular Outcomes in Randomised Controlled Trials of New Antidiabetic Drugs Y. Fei; M.F. Tsoi; C.R. Kumana; T.T. Cheung; and B.M.Y. Cheung The University of Hong Kong, Hong Kong, China Background: The prevalence of cardiovascular disease is high in patients with type 2 diabetes mellitus (T2DM). However, evidence from randomised controlled trials (RCTs) that directly compared the effect of new antidiabetic drugs on cardiovascular outcomes in these patients was limited. We performed a network meta-analysis to assess the cardiovascular safety of different classes of these drugs. Methods: We searched for RCTs involving glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose co-transporter 2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors in T2DM patients with established cardiovascular risks. RCTs that reported rates of major adverse cardiovascular events and mortality
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Inje University College of Medicine, Busan, South Korea; and Inje University Busan Paik Hospital, Busan, South Korea Background: Rifampin is the most commonly used 1st line drug for the treatment of tuberculosis (active and latent infection) and linezolid in 2nd line treatment especially in MDR-TB. It is known that rifampin acts as a potent substrate and inhibitor of organic anion transporter polypeptide (OATP)-1B1 and -1B3. Recently reported, linezolid has inhibition potential on OATPs mediated drug uptake. Therefore, we aimed to investigate potential transporter mediated drug interactions (DDIs) between rifampin and linezolid in vitro. Methods: Cellular uptake of rifampin and linezolid was measured using HEK cells which were stably transfected with OATPs, OATs (organic anionic transporter) and OCTs (organic cationic transporter). Uptake/inhibition kinetics parameters were estimated using non-linear kinetic model using Phoenix software package (WinNonlin 5.1, Pharsight, USA) and DDI index (R-value) was calculated using the static modeling following FDA draft guidance for DDIs study. Results: Both OATP1B1- and OATP1B3-mediated rifampin uptakes were strongly inhibited by linezolid in a noncompetitive manner. The Ki values of linezolid were 15.5 and 10.0 µM for OATP1B1 and OATP1B3, respectively. Furthermore, the estimated drug-drug interaction (DDI) indexes (R= 1+ [I]u,inlet,max/ Ki) of linezolid were 2.65 and 3.56 (cut off ≥ 1.25) for OATP1B1 and OATP1B3, respectively, suggesting DDI interactions possibilities in vivo. The net transport activity of linezolid through SLC transporters (OATPs, OATs and OCTs) was negligible, suggesting involvement of active transport and mutual DDIs unlikely. Conclusions: The present in vitro data showed OATP1B1- and OATP1B3- mediated rifampin uptake was significantly inhibited by the linezolid with higher DDI index suggested possible drug-interaction may take place between rifampin and linezolid. 2
The Effects of Candidate SNPS in PKPD Pathway on Antipsychotics-Induced Amenorrhea in Female Schizophrenia Patients H.S. Kim1,2; J.J. Moon2; D.J. Kim1; E.Y. Kim1,2; J.C. Shim3; and J.-G. Shin1,2 1 Inje University College of Medicine, Busan, South Korea; 2 Inje University Busan Paik Hospital, Busan, South Korea; and 3 Shim JooCheol Psychiatry Clinic, Busan, South Korea Background: Amenorrhea frequently occurs in female patients taking under antipsychotic drugs (APs).It may affect drug compliance resulting treatment failure. The aim of this study was to explore the genetic effects of candidate single nucleotide polymorphisms (SNPs) in pharmacokinetics and pharmacodynamics (PKPD) pathway of APon AP-induced amenorrhea in female schizophrenia patients. Methods: Eighty-nine female schizophrenic patients (age range from 18 to 40) taking the same AP for more than 3 months were enrolled. Amenorrhea was defined as the absence of menses for three months or three periods in a row. The serum levelsof prolactin, estradiol (E2), Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) were measured. Cytochrome P450 2D6 (CYP2D6), dopamine receptor D2 (DRD2) and estrogen receptor 1 (ESR1) were genotyped. Results: Compared to the patients without amenorrhea (n= 67), prolactin level was higher (71.5 vs. 94.1 ng/mL; p= 0.044) and E2 was lower (46.7 vs. 27.0ng/mL; p= 0.007) inthe patients with amenorrhea (n= 22). There was no difference in other hormonesand baseline characteristics between the patients with and without amenorrhea. Amisulpiride, chlorpromazine, haloperidol, paliperidone, and risperidone were observed to highly increase prolactin level and categorized to drugs increasing prolactin level.
August 2017
DRD2 -141insC (OR= 0.59, 95% CI= 0.34-0.99; p= 0.049) and drugs increasing prolactin level (OR= 6.17, 95% CI= 1.28-29.64; p= 0.023) were identified as predictors for AP-induced amenorrhea using multiple logistic regression analysis identified. Conclusions: This finding is the first evidence suggesting that DRD2 -141insC might be a possible protective biomarker for AP-induced amenorrhea. Further studies to confirm the DRD2 -141insC as a biomarker for AP-induced amenorrhea are needed in larger female antipsychotic patients.
Optimal Duration of Dual Antiplatelet Therapy after Drug-Eluting Stent Implantation: A Pairwise and Network Meta-Analysis of Randomised Controlled Trials Y. Fei; M.F. Tsoi; T.T. Cheung; and B.M.Y. Cheung The University of Hong Kong, Hong Kong, China Background: The optimal duration of dual antiplatelet therapy (DAPT) after coronary drug-eluting stent (DES) implantation remains uncertain. Despite recent studies, direct comparison between shortterm (< 12 months) and extended (> 12 months) DAPT is limited. We performed a network meta-analysis to assess the risk of mortality and other cardiovascular outcomes with different DAPT durations in order to guide clinical practice. Methods: We searched for randomised controlled trials comparing different durations of DAPT after DES implantation. Those reporting frequencies of cardiovascular and bleeding events were eligible to be included. Statistic analysis was performed using frequentist approach and Bayesian framework in R. Results: We included 12 randomised controlled trials with altogether 34920 patients for analysis. Extended DAPT (> 12 months) significantly lowered the risk of myocardial infarction (OR 0.56, 95%CI 0.46-0.68 and 0.58, 0.44-0.77), and stent thrombosis (0.44, 0.30-0.65 and 0.49, 0.29-0.82) when compared to 12-month and short-term DAPT (< 12 months), respectively. However, it was associated with increased major bleeding (1.53, 1.21-1.93 and 2.58, 1.62-4.10). Compared to 12-month DAPT, extended DAPT had more all-cause death (1.27, 1.03-1.57); short-term DAPT had less major bleeds (0.59, 0.39-0.91). Conclusions: Although extending DAPT beyond 12 months after DES implantation reduced myocardial infarction and stent thrombosis, the risk of major bleeding and all-cause mortality was substantially increased. No clear superiority of extended or short-term DAPT over 12-month DAPT was identified. DAPT duration should always be tailored for different patients after considering their benefit-risk profiles.
Network Meta-Analysis of Cardiovascular Outcomes in Randomised Controlled Trials of New Antidiabetic Drugs Y. Fei; M.F. Tsoi; C.R. Kumana; T.T. Cheung; and B.M.Y. Cheung The University of Hong Kong, Hong Kong, China Background: The prevalence of cardiovascular disease is high in patients with type 2 diabetes mellitus (T2DM). However, evidence from randomised controlled trials (RCTs) that directly compared the effect of new antidiabetic drugs on cardiovascular outcomes in these patients was limited. We performed a network meta-analysis to assess the cardiovascular safety of different classes of these drugs. Methods: We searched for RCTs involving glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose co-transporter 2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors in T2DM patients with established cardiovascular risks. RCTs that reported rates of major adverse cardiovascular events and mortality
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