- Email: [email protected]
Population Pharmacokinetics Of Propranolol in Patients with Liver Cirrhosis
Posters symptoms, hyperprolactinemia and weight gain) had serum concentrations higher than 60 ng/ml. Conclusions: These preliminary findings indicate that serum concentrations of paliperidone after intramuscular administration of paliperidone pamitate are closely correlated with the given dose, but are not affected by sex and age. As with the oral formulations, serum concentrations above 60 ng/ml are more frequently associated with adverse effects.
Increased Expression of P-Glycoprotein (P-gp) In Human Macrophages by Rifampin May Reduce Efficacy of the P-gp Substrate Anti-Tuberculosis Drugs M. Hasanuzzaman1; Y. Myeongjin1; C. Munju1; M.M. Parvez1; S.J. Lee1; and J.-G. Shin1,2 1 Inje University College of Medicine, Busan, South Korea; and 2 Inje University Busan Paik Hospital, Busan, South Korea Background: Treatment of drug resistance tuberculosis (TB) is a global problem due to reduced drug efficacy. The host cell mediated tolerance of Mycobacterium tuberculosis to anti-tuberculosis (anti-TB) drugs affects the treatment success, particularly of anti-TB drugs that are substrates for drug efflux transporter in immune cells. Methods: THP1 monocytes were stimulated to THP1 macrophages by treating with 100 nM of phorbol 12-myristate 13-acetate (PMA) for 72 h. Quantitative RT-PCR was used to detect the mRNA expression of MDR1 and PXR gene in RIF treated and untreated (control) THP1 macrophages. The P-gp and PXR protein expression was evaluated by Western blot; relative quantification was done by imageJ software and protein level was normalized to GAPDH. Intracellular Rhodamine-123 fluorescence and prothionamide accumulation were determined by Victor3 Multilabel Counter and LC-MS/MS method, respectively. The data were analyzed by GraphPad Prism software. Results: At 100 µM, RIF significantly induced MDR1 protein (~2 fold) and mRNA (~4 fold) in PMA-stimulated THP1 macrophages (P < 0.001 and 0.01, respectively). The pregnane X receptor (PXR) was involved in the induction of P-gp protein expression in RIF-treated THP1 macrophages. The PXR activation inhibitors resveratrol and ketoconazole significantly suppressed RIF-induced P-gp expression in THP1 macrophages (P < 0.05). RIF-treated THP1 macrophages also exhibited strong efflux of P-gp substrate, resulting in a reduced intracellular fluorescence concentration of rhodamine-123 and the anti-TB drug prothionamide (P < 0.01 and 0.05, respectively). In contrast; the P-gp inhibitor cyclosporine A significantly increased intracellular accumulation of rhodamine-123 and prothionamide (P < 0.001 and 0.05, respectively) in RIF-treated THP1 macrophages. Conclusions: The present results suggest that use of RIF together with P-gp–substrate drugs to treat drug-resistant TB may lead to treatment failure due to the lower intracellular drug concentration caused by P-gp induction. Further studies should assess the contribution of this mechanism to clinical outcomes.
Effect of P-Amino Salicylic Acid (PAS) on the Pharmacokinetics of Tenofovir in Korean Healthy Subjects M.M. Parvez1; S. Kalkishm2; H.-K. Choi3; J.G. Park3; J.A. Jung3; M. Babaoglu2; and J.-G. Shin1,3 1 Inje University College of Medicine, Busan, South Korea; 2 Hacettepe University Faculty of Medicine, Ankara, Turkey; and 3 Inje University Busan Paik Hospital, Busan, South Korea Background: Multidrug-resistant tuberculosis is growing and may be threat among patients infected with human immunodeficiency virus (HIV). Tenofovir, used for the treatment of hepatitis B virus and HIV, are eliminated mainly through the kidneys which are mediated by OAT1/ OAT3 and multidrug resistance-associated protein 4. Para-amino
August 2017
salicylic acid (PAS), a second line anti-tuberculosis drug, is the inhibitor of organic anion transporters. Therefore, we aimed to investigate the effect of PAS on tenofovir pharmacokinetics in healthy Korean male subjects. Methods: Using cell system in vitro transport interaction study was done initially for PAS and tenofovir. An open-label, randomized, crossover study was conducted among healthy Korean male subjects. In brief, 18 subjects received a single dose 300 mg tenofovir disproxil fumarate tablet alone (R) or with 5.28 g PAS-Ca twice-daily (T) multiple dose following a 7 days washout period. Blood samples were collected for tenofovir up to 72 h when alone 84 h with PAS-Ca and 12 h for PAS, respectively. To evaluate urinary excretion amount of tenofovir urine sample was collected up to 24 h. Results: PAS inhibited OAT1- and OAT3-mediated uptake of tenofovir (P= 0.001) in vitro and the drug interaction index of PAS were 2.70±0.41 for OAT1 and 3.30±0.62for OAT3 mediated tenofovir uptake inhibition. In the clinical validation study for tenofovir among the 18 subjects, the geometric mean ratios for T/R (90% confidence intervals) of Cmax and AUCinf were 0.33 (0.28-0.38) and 0.29 (0.260.33), respectively without significant altering renal clearance and secretory clearance.There was no PAS in plasma after 6 h among all subjects. Suggesting, tenofovir pharmacokinetics greatly affected by PAS which may alter pharmacological response. Conclusions: There was significant pharmacokinetic interactions when tenofovir and PAS were co-administered but renal transporterinvolvement was unlikely.
Population Pharmacokinetics Of Propranolol in Patients with Liver Cirrhosis S. Park; S. Ryu; W. Yong Oh; I. Yeong Hwang; J. Gu Lee; Z. Won Park; and S. Eun Choi National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju, Korea Background: Since propranolol, a nonselective β -blocker, is known to a high extraction drug and mainly metabolized in the liver after oral administration, the pharmacokinetics may be markedly affected by the hepatic function. The aim of this study is to develop a population pharmacokinetic model and evaluate the effects of covariates including hepatic impairment. Methods: Single oral dose of 40mg propranolol was administered and plasma concentrations of propranolol and metabolite concentrations were measured over 8h after dosing. The population pharmacokinetics was analyzed using NONMEM for 468 plasma concentrations of propranolol and metabolite from 42 noncirrhotic and 36 cirrhotic subjects. Volume of distribution of parent drug (Vp/F) was set equal to volume of distribution of metabolite. The parameters were estimated using the first-order conditional estimation method with interaction. Covariates were tested with exponential relationship by stepwise covariate model building. Results: The final model was a one-compartment for both parent and metabolite model with two depot compartments: the dose enters not only into the parent compartment at a rate Ka with a fraction F1(0.25 fix) but also into the metabolite compartment at a rate Kam with a fraction F2(0.315 fix). Final parameter estimates (%inter-individual variability, IIV) were as follows; Vp/F = 14.8 L (187.8%), clearance of propranolol (CL) = 44.8 L/hr (130.4%), clearance of 4-OH propranolol (CLm) = 1060 L/hr (75.6%), and the metabolic rate constant of propranolol to 4-OH propranolol (Km) = 0.215 hr-1 (47.6%). The platelet count showed an influence on propranolol PK parameters; Vp/F, CL, CLm and Km. The visual predictive check and the fits of a bootstrap with 1000 replicates of the data set demonstrated the adequateness and robustness of the developed model.
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Clinical Therapeutics Conclusions: A population PK model reflecting the first-pass effect was successfully developed and we evaluated the effects of covariates on the pharmacokinetic parameters.
Comparison Between Likelihood and Bayesian Approaches in Small-Sized Bioequivalence Dataset B.H. Kim1; S.V. Yim1; E.J. Song2; and W. Lee2 1 Kyung Hee University College of Medicine and Hospital, Seoul, Republic of Korea; and 2Inha University, Incheon, Republic of Korea Background: This study was planned to assess the changes of statistical power in small-sized datasets from actual bioequivalence datasets with various intra-subject coefficient variations of pharmacokinetic parameters, using the bioequivalence tests based on likelihood versus Bayesian approaches. Methods: Three bioequivalence studies of baclofen, omeprazole and simvastatin were selected based on the number of subject and their degree of inter-subject variability. To obtain the 1000 small-sized bioequivalence datasets in each subsample, the number of subjects in the original dataset was randomly and repeatedly reduced by 2 subjects until 8, 12 or 24 subjects for baclofen, omeprazole, and simvastatin studies. The bioequivalence were repeated assessed in all the 1000 small-sized datasets for each subsample, based on the mixed model with fixed effects (formulation, period, and sequence) and random effects (subjects). All the parameters for the mixed model were estimated using the R and WinBUGS, based on likelihood versus Bayesian approaches. Results: In the small-sized datasets of three drugs with various sample sizes, the statistical power for bioequivalence generally decreased according to the reduction in sample size. Also, the statistical powers for baclofen and omeprazole with regards to the sample size were similar between REML and Bayesian approaches. In the case of simvastatin, all the powers of Bayesian approach were lower than those of REML method. Conclusions: The statistical powers with regards to the reduction of sample size decreased with similar tendency between REML and Bayesian approaches in bioequivalence studies with relatively small intra-subject coefficient variations of pharmacokinetic parameters.
Pharmacokinetic Modeling and Simulation Analysis of LCB01-0371, A New Oxazolidinone Antibiotic Under Clinical Development Y.-S. Cho1; Y. Han Kim1,2; H. Youn Choi1,2; Y. Zu Kim3; Y. Lag Cho3; H. Sook Nam3; K.-S. Bae1,2; and H.-S. Lim1,2 1 Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu Seoul 138-736, Korea; 2University of Ulsan College of Medicine, Seoul, Korea; and 3LegoChem Biosciences, Inc, Daedeok-gu, Daejeon, Korea Background: LCB01-0371, a new oxazolidinone with cyclic amidrazone under clinical development, has been shown to have a superior animal safety profile and better efficacy than those of linezolid. It works by binding to the 23S ribosomal RNA of the 50S subunit, thereby preventing the formation of the 70S initiation complex and inhibiting protein synthesis. The aims of this study were to develop a population pharmacokinetics (PPK) model for oral LCB01-0371 in healthy Korean volunteers and to predict the plasma LCB01-0371 concentration over time on various dosing regimens of LCB01-0371 via Monte-Carlo simulation Methods: Pharmacokinetics (PK) data were collected from 110 healthy, Korean, male subjects in three Phase 1 studies for LCB010371. LCB01-0371 was administered at single or multiple oral doses of 50 ~ 3,200 mg, and blood and urine samples were collected
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serially for PK. Plasma and urine concentrations of LCB01-0371 were measured by validated LC/MS-MS. PPK analysis were performed using nonlinear mixed effect modeling software NONMEM (version 7.3) with the first-order conditional estimation with interaction (FOCE-I) method. Results: Plasma LCB01-0371 was absorbed fast after oral administration with followed by rapid decline in plasma concentration. The LCB01-0371 concentration in plasma and amount excreted in urine over time were best described by two-compartment model (central Vd, 82.4 L; peripheral Vd, 8.59 L) with absorption lag (ALAG1, 0.212 hour) and mixed zero (D1, 0.286 hour) and first order absorption (Ka, 80.7 /hour) process. Basic goodness of fit plots, visual predictive check plots exhibited that the final plasma and urine PPK model describe the data reasonably well. Conclusions: The current modeling and simulation analysis adequately characterized the pharmacokinetics of LCB01-0371 in Korean healthy adult male subjects, which will be a valuable tool in the search for the optimal dosing regimens of LCB01-0371.
Serum Beta-2 Microglobulin Level is Elevated in Patients with Acute Coronary Syndrome B. Cheung1; F. Tam2; C. Cheung1; S. Lee2; S. Tsui2; and E. Chan1 University of Hong Kong, Hong Kong; and 2Queen Mary Hospital, Hong Kong Background: Beta-2 microglobulin (B2M) is a marker of renal dysfunction and immune activation. We previously reported that serum B2M is related to age, renal function, cardiovascular and all-cause mortality in Americans. Acute coronary syndrome (ACS) is a common cause of hospital admission and cardiovascular mortality. We tested the hypothesis that the serum level of B2M is elevated in ACS in a prospective study. Methods: We recruited 167 Chinese patients (118 men and 49 women; mean age±SD, 64±13 years), of whom 88 had ACS and 79 were controls matched for age and sex. Serum B2M was measured in an accredited laboratory using a latex-enhanced immunoassay (intra-assay coefficient of variation 3.4%). Results: In our patients, the serum B2M level (mean±SE) was 2.27±0.12 µg/mL. Because the upper reference level of serum B2M in our laboratory is 1.42 µg/mL, only 24 subjects (14%) had a serum B2M within the reference range. Serum B2M levels (mean±SE) were 2.52±0.21 in ACS patients and 1.99±0.06 µg/mL in controls (p= 0.02). There was no significant correlation between serum B2M and troponin level. Serum B2M correlated with serum creatinine (ρ = 0.62, p< 0.001), age (Spearman’s ρ = 0.52, p< 0.001) and male gender (ρ = 0.19, p= 0.01). Conclusions: Serum B2M level is increased in ACS patients. It is also related to age and gender, and the serum level of creatinine but not troponin. Our study shows for the first time that serum B2M is a cardiovascular risk marker in Chinese as it is in Americans. B2M is an established prognostic marker in multiple myeloma and so the test is widely available. A prospective study with long follow-up is warranted to evaluate B2M as a prognostic marker after ACS. 1
Patterns of Use of Pregabalin and Gabapentin in France: A Cohort Study of New Users on a French Representative Sample D. Driot1,2; A. Palmaro1,2,3; J. Dupouy1,2; S. Oustric1,2; E. Jouanjus1,2,3; and M. Lapeyre-Mestre1,2,3 1 Université Paul Sabatier Toulouse 3, Toulouse, France; 2Unité Mixte de Recherche 1027 Inserm-Université, Toulouse, France; and 3Centre Hospitalier Universitaire de Toulouse, Toulouse, France
Volume 39 Number 8S
Increased Expression of P-Glycoprotein (P-gp) In Human Macrophages by Rifampin May Reduce Efficacy of the P-gp Substrate Anti-Tuberculosis Drugs M. Hasanuzzaman1; Y. Myeongjin1; C. Munju1; M.M. Parvez1; S.J. Lee1; and J.-G. Shin1,2 1 Inje University College of Medicine, Busan, South Korea; and 2 Inje University Busan Paik Hospital, Busan, South Korea Background: Treatment of drug resistance tuberculosis (TB) is a global problem due to reduced drug efficacy. The host cell mediated tolerance of Mycobacterium tuberculosis to anti-tuberculosis (anti-TB) drugs affects the treatment success, particularly of anti-TB drugs that are substrates for drug efflux transporter in immune cells. Methods: THP1 monocytes were stimulated to THP1 macrophages by treating with 100 nM of phorbol 12-myristate 13-acetate (PMA) for 72 h. Quantitative RT-PCR was used to detect the mRNA expression of MDR1 and PXR gene in RIF treated and untreated (control) THP1 macrophages. The P-gp and PXR protein expression was evaluated by Western blot; relative quantification was done by imageJ software and protein level was normalized to GAPDH. Intracellular Rhodamine-123 fluorescence and prothionamide accumulation were determined by Victor3 Multilabel Counter and LC-MS/MS method, respectively. The data were analyzed by GraphPad Prism software. Results: At 100 µM, RIF significantly induced MDR1 protein (~2 fold) and mRNA (~4 fold) in PMA-stimulated THP1 macrophages (P < 0.001 and 0.01, respectively). The pregnane X receptor (PXR) was involved in the induction of P-gp protein expression in RIF-treated THP1 macrophages. The PXR activation inhibitors resveratrol and ketoconazole significantly suppressed RIF-induced P-gp expression in THP1 macrophages (P < 0.05). RIF-treated THP1 macrophages also exhibited strong efflux of P-gp substrate, resulting in a reduced intracellular fluorescence concentration of rhodamine-123 and the anti-TB drug prothionamide (P < 0.01 and 0.05, respectively). In contrast; the P-gp inhibitor cyclosporine A significantly increased intracellular accumulation of rhodamine-123 and prothionamide (P < 0.001 and 0.05, respectively) in RIF-treated THP1 macrophages. Conclusions: The present results suggest that use of RIF together with P-gp–substrate drugs to treat drug-resistant TB may lead to treatment failure due to the lower intracellular drug concentration caused by P-gp induction. Further studies should assess the contribution of this mechanism to clinical outcomes.
Effect of P-Amino Salicylic Acid (PAS) on the Pharmacokinetics of Tenofovir in Korean Healthy Subjects M.M. Parvez1; S. Kalkishm2; H.-K. Choi3; J.G. Park3; J.A. Jung3; M. Babaoglu2; and J.-G. Shin1,3 1 Inje University College of Medicine, Busan, South Korea; 2 Hacettepe University Faculty of Medicine, Ankara, Turkey; and 3 Inje University Busan Paik Hospital, Busan, South Korea Background: Multidrug-resistant tuberculosis is growing and may be threat among patients infected with human immunodeficiency virus (HIV). Tenofovir, used for the treatment of hepatitis B virus and HIV, are eliminated mainly through the kidneys which are mediated by OAT1/ OAT3 and multidrug resistance-associated protein 4. Para-amino
August 2017
salicylic acid (PAS), a second line anti-tuberculosis drug, is the inhibitor of organic anion transporters. Therefore, we aimed to investigate the effect of PAS on tenofovir pharmacokinetics in healthy Korean male subjects. Methods: Using cell system in vitro transport interaction study was done initially for PAS and tenofovir. An open-label, randomized, crossover study was conducted among healthy Korean male subjects. In brief, 18 subjects received a single dose 300 mg tenofovir disproxil fumarate tablet alone (R) or with 5.28 g PAS-Ca twice-daily (T) multiple dose following a 7 days washout period. Blood samples were collected for tenofovir up to 72 h when alone 84 h with PAS-Ca and 12 h for PAS, respectively. To evaluate urinary excretion amount of tenofovir urine sample was collected up to 24 h. Results: PAS inhibited OAT1- and OAT3-mediated uptake of tenofovir (P= 0.001) in vitro and the drug interaction index of PAS were 2.70±0.41 for OAT1 and 3.30±0.62for OAT3 mediated tenofovir uptake inhibition. In the clinical validation study for tenofovir among the 18 subjects, the geometric mean ratios for T/R (90% confidence intervals) of Cmax and AUCinf were 0.33 (0.28-0.38) and 0.29 (0.260.33), respectively without significant altering renal clearance and secretory clearance.There was no PAS in plasma after 6 h among all subjects. Suggesting, tenofovir pharmacokinetics greatly affected by PAS which may alter pharmacological response. Conclusions: There was significant pharmacokinetic interactions when tenofovir and PAS were co-administered but renal transporterinvolvement was unlikely.
Population Pharmacokinetics Of Propranolol in Patients with Liver Cirrhosis S. Park; S. Ryu; W. Yong Oh; I. Yeong Hwang; J. Gu Lee; Z. Won Park; and S. Eun Choi National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju, Korea Background: Since propranolol, a nonselective β -blocker, is known to a high extraction drug and mainly metabolized in the liver after oral administration, the pharmacokinetics may be markedly affected by the hepatic function. The aim of this study is to develop a population pharmacokinetic model and evaluate the effects of covariates including hepatic impairment. Methods: Single oral dose of 40mg propranolol was administered and plasma concentrations of propranolol and metabolite concentrations were measured over 8h after dosing. The population pharmacokinetics was analyzed using NONMEM for 468 plasma concentrations of propranolol and metabolite from 42 noncirrhotic and 36 cirrhotic subjects. Volume of distribution of parent drug (Vp/F) was set equal to volume of distribution of metabolite. The parameters were estimated using the first-order conditional estimation method with interaction. Covariates were tested with exponential relationship by stepwise covariate model building. Results: The final model was a one-compartment for both parent and metabolite model with two depot compartments: the dose enters not only into the parent compartment at a rate Ka with a fraction F1(0.25 fix) but also into the metabolite compartment at a rate Kam with a fraction F2(0.315 fix). Final parameter estimates (%inter-individual variability, IIV) were as follows; Vp/F = 14.8 L (187.8%), clearance of propranolol (CL) = 44.8 L/hr (130.4%), clearance of 4-OH propranolol (CLm) = 1060 L/hr (75.6%), and the metabolic rate constant of propranolol to 4-OH propranolol (Km) = 0.215 hr-1 (47.6%). The platelet count showed an influence on propranolol PK parameters; Vp/F, CL, CLm and Km. The visual predictive check and the fits of a bootstrap with 1000 replicates of the data set demonstrated the adequateness and robustness of the developed model.
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Clinical Therapeutics Conclusions: A population PK model reflecting the first-pass effect was successfully developed and we evaluated the effects of covariates on the pharmacokinetic parameters.
Comparison Between Likelihood and Bayesian Approaches in Small-Sized Bioequivalence Dataset B.H. Kim1; S.V. Yim1; E.J. Song2; and W. Lee2 1 Kyung Hee University College of Medicine and Hospital, Seoul, Republic of Korea; and 2Inha University, Incheon, Republic of Korea Background: This study was planned to assess the changes of statistical power in small-sized datasets from actual bioequivalence datasets with various intra-subject coefficient variations of pharmacokinetic parameters, using the bioequivalence tests based on likelihood versus Bayesian approaches. Methods: Three bioequivalence studies of baclofen, omeprazole and simvastatin were selected based on the number of subject and their degree of inter-subject variability. To obtain the 1000 small-sized bioequivalence datasets in each subsample, the number of subjects in the original dataset was randomly and repeatedly reduced by 2 subjects until 8, 12 or 24 subjects for baclofen, omeprazole, and simvastatin studies. The bioequivalence were repeated assessed in all the 1000 small-sized datasets for each subsample, based on the mixed model with fixed effects (formulation, period, and sequence) and random effects (subjects). All the parameters for the mixed model were estimated using the R and WinBUGS, based on likelihood versus Bayesian approaches. Results: In the small-sized datasets of three drugs with various sample sizes, the statistical power for bioequivalence generally decreased according to the reduction in sample size. Also, the statistical powers for baclofen and omeprazole with regards to the sample size were similar between REML and Bayesian approaches. In the case of simvastatin, all the powers of Bayesian approach were lower than those of REML method. Conclusions: The statistical powers with regards to the reduction of sample size decreased with similar tendency between REML and Bayesian approaches in bioequivalence studies with relatively small intra-subject coefficient variations of pharmacokinetic parameters.
Pharmacokinetic Modeling and Simulation Analysis of LCB01-0371, A New Oxazolidinone Antibiotic Under Clinical Development Y.-S. Cho1; Y. Han Kim1,2; H. Youn Choi1,2; Y. Zu Kim3; Y. Lag Cho3; H. Sook Nam3; K.-S. Bae1,2; and H.-S. Lim1,2 1 Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu Seoul 138-736, Korea; 2University of Ulsan College of Medicine, Seoul, Korea; and 3LegoChem Biosciences, Inc, Daedeok-gu, Daejeon, Korea Background: LCB01-0371, a new oxazolidinone with cyclic amidrazone under clinical development, has been shown to have a superior animal safety profile and better efficacy than those of linezolid. It works by binding to the 23S ribosomal RNA of the 50S subunit, thereby preventing the formation of the 70S initiation complex and inhibiting protein synthesis. The aims of this study were to develop a population pharmacokinetics (PPK) model for oral LCB01-0371 in healthy Korean volunteers and to predict the plasma LCB01-0371 concentration over time on various dosing regimens of LCB01-0371 via Monte-Carlo simulation Methods: Pharmacokinetics (PK) data were collected from 110 healthy, Korean, male subjects in three Phase 1 studies for LCB010371. LCB01-0371 was administered at single or multiple oral doses of 50 ~ 3,200 mg, and blood and urine samples were collected
e52
serially for PK. Plasma and urine concentrations of LCB01-0371 were measured by validated LC/MS-MS. PPK analysis were performed using nonlinear mixed effect modeling software NONMEM (version 7.3) with the first-order conditional estimation with interaction (FOCE-I) method. Results: Plasma LCB01-0371 was absorbed fast after oral administration with followed by rapid decline in plasma concentration. The LCB01-0371 concentration in plasma and amount excreted in urine over time were best described by two-compartment model (central Vd, 82.4 L; peripheral Vd, 8.59 L) with absorption lag (ALAG1, 0.212 hour) and mixed zero (D1, 0.286 hour) and first order absorption (Ka, 80.7 /hour) process. Basic goodness of fit plots, visual predictive check plots exhibited that the final plasma and urine PPK model describe the data reasonably well. Conclusions: The current modeling and simulation analysis adequately characterized the pharmacokinetics of LCB01-0371 in Korean healthy adult male subjects, which will be a valuable tool in the search for the optimal dosing regimens of LCB01-0371.
Serum Beta-2 Microglobulin Level is Elevated in Patients with Acute Coronary Syndrome B. Cheung1; F. Tam2; C. Cheung1; S. Lee2; S. Tsui2; and E. Chan1 University of Hong Kong, Hong Kong; and 2Queen Mary Hospital, Hong Kong Background: Beta-2 microglobulin (B2M) is a marker of renal dysfunction and immune activation. We previously reported that serum B2M is related to age, renal function, cardiovascular and all-cause mortality in Americans. Acute coronary syndrome (ACS) is a common cause of hospital admission and cardiovascular mortality. We tested the hypothesis that the serum level of B2M is elevated in ACS in a prospective study. Methods: We recruited 167 Chinese patients (118 men and 49 women; mean age±SD, 64±13 years), of whom 88 had ACS and 79 were controls matched for age and sex. Serum B2M was measured in an accredited laboratory using a latex-enhanced immunoassay (intra-assay coefficient of variation 3.4%). Results: In our patients, the serum B2M level (mean±SE) was 2.27±0.12 µg/mL. Because the upper reference level of serum B2M in our laboratory is 1.42 µg/mL, only 24 subjects (14%) had a serum B2M within the reference range. Serum B2M levels (mean±SE) were 2.52±0.21 in ACS patients and 1.99±0.06 µg/mL in controls (p= 0.02). There was no significant correlation between serum B2M and troponin level. Serum B2M correlated with serum creatinine (ρ = 0.62, p< 0.001), age (Spearman’s ρ = 0.52, p< 0.001) and male gender (ρ = 0.19, p= 0.01). Conclusions: Serum B2M level is increased in ACS patients. It is also related to age and gender, and the serum level of creatinine but not troponin. Our study shows for the first time that serum B2M is a cardiovascular risk marker in Chinese as it is in Americans. B2M is an established prognostic marker in multiple myeloma and so the test is widely available. A prospective study with long follow-up is warranted to evaluate B2M as a prognostic marker after ACS. 1
Patterns of Use of Pregabalin and Gabapentin in France: A Cohort Study of New Users on a French Representative Sample D. Driot1,2; A. Palmaro1,2,3; J. Dupouy1,2; S. Oustric1,2; E. Jouanjus1,2,3; and M. Lapeyre-Mestre1,2,3 1 Université Paul Sabatier Toulouse 3, Toulouse, France; 2Unité Mixte de Recherche 1027 Inserm-Université, Toulouse, France; and 3Centre Hospitalier Universitaire de Toulouse, Toulouse, France
Volume 39 Number 8S