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Percutaneous absorption and pharmacokinetics of tetrabromo-o-cresol after topical administration in rats
S94
Abstracts / Drug Metabolism and Pharmacokinetics 32 (2017) S27eS107
novel thienopyridine antiplatelet agent in clinical development, is an acetate analogue of clopidogrel aiming to produce H4 more efficiently and consistently in humans than clopidogrel [3]. The aim of our study was to investigate the metabolism and pharmacokinetics of vicagrel, compared with clopidogrel, in healthy Chinese volunteers. In a randomized, double-blind, placebo-controlled, single-ascending-dose phase 1 study, 67 subjects received placebo, vicagrel 5, 10, 20, 40, 60, or 75 mg, or clopidogrel 75 mg orally, and plasma samples were collected. The samples analyzed using UHPLC-Q/TOF MS method revealed that vicagrel was extensively metabolized in humans. Vicagrel was first hydrolyzed to 2oxo-clopidogrel, and further oxidized to produce the inactive thiol isomer H3 and the active thiol isomer H4, and H3 was further S-methylated to form M9-3, whereas the hydrolysis of 2-oxo-clopidogrel produced an inactive carboxylic acid metabolite. A fast, sensitive, and reproducible UHPLC-MS/MS method was developed and validated to simultaneously determine derivatized H3 (MP-H3), derivatized H4 (MP-H4), and M9-3 in human plasma. Linear regression curves were obtained over the concentration ranges of 0.100e200 ng/mL for MP-H3/MP-H4 and 1.00e1000 ng/mL for M9-3, respectively. The validated method was successfully applied in pharmacokinetic study of vicagrel. Vicagrel was rapidly absorbed with median tmax 0.5-1 h for active H4. Plasma concentrations of M9-3 were the highest among the three matabolites. For all the three matabolites, mean Cmax and AUC increased approximately proportionally with the dose of vicagrel from 5 to 75 mg, demonstrating a linear and predictable pharmacokinetic profile. For active H4, compared with the clopidogrel 75 mg group, median tmax was significantly shorter [0.50 (0.25-1.00) vs. 0.75 (0.50-2.00) h, P ¼ 0.0396], whereas mean Cmax was higher (13.5 ± 4.52 vs. 9.95 ± 4.74 ng/ml, P ¼ 0.910) with no significant difference, and mean AUC0-t was similar (11.7 ± 4.52 vs. 11.8 ± 4.94 ng/ ml, P ¼ 0.820) in the vicagrel 5 mg group. These results indicated that compared with clopidogrel 75 mg, vicagrel 5 mg would result in comparable but more consistent platelet inhibition with more rapid onset, whereas did not increase the risk of bleeding. 1. Dansette P.M., Rosi J., et al. Cytochromes P450 catalyze both steps of the major pathway of clopidogrel bioactivation, whereas paraoxonase catalyzes the formation of a minor thiol metabolite isomer. Chem Res Toxicol 2012; 25: 348-56. 2. Zhang H., Lauver D.A., et al. Formation, reactivity, and antiplatelet activity of mixed disulfide conjugates of clopidogrel. Mol Pharmacol 2013; 83: 848-56. 3. Shan J., Zhang B., et al. Overcoming clopidogrel resistance: discovery of vicagrel as a highly potent and orally bioavailable antiplatelet agent. J Med Chem 2012; 55: 3342-52. P235 MODELING AND SIMULATION ANALYSIS OF A NOVEL ENGINEERED THERAPEUTIC ANTIBODY WITH PH-DEPENDENT BINDING TO TARGET ANTIGEN Kenta Haraya 1, Tatsuhiko Tachibana 1, Junichi Nezu 1, Masaki Ishigai 2, Tomoyuki Igawa 3. 1 Chugai Pharmabody Research Pte. Ltd., Singapore, Singapore; 2 Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan; 3 Chugai Pharmaceutical Co., Ltd., Gotemba, Japan Antibody-mediated accumulation of soluble target antigens has been reported in preclinical and clinical studies, because the clearance of a complex formed from an antibody and a target antigen is much lower than that of the target antigen. To overcome this issue, our group has reported novel engineered therapeutic antibodies with pH-dependent binding to the target antigen (recycling antibody) and with both pH-dependent binding to target antigen and increased binding to FcRn at neutral pH (sweeping antibody). The aim of this work is to better understand the potential applications of these recycling and sweeping antibodies as therapeutics by simulating the pharmacokinetics and pharmacodynamics in a modeling and simulation study. Pharmacokinetic parameters for the antibody and target antigen dynamics were estimated from the results of a pharmacokinetic study in human FcRn transgenic mice that used human soluble IL-6 receptor as a model target antigen and antiehuman IL-6 receptor antibodies. A modeling and simulation study was performed using the target-mediated disposition with recycling model and the estimated pharmacokinetic parameters with various target antigen profiles
(clearance, endogenous concentration, binding affinity to antibody). In the pharmacokinetic study, the recycling antibody enhanced the target-antigen clearance by 3 fold compared to a conventional antibody, while the sweeping antibody accelerated the target-antigen clearance by 10 fold. Modeling and simulation results showed that recycling and sweeping antibodies can improve dosage frequency and reduce the required dosage for target antigens with various levels of clearance, endogenous concentration, or binding affinity to antibody. Moreover, the results showed the importance of the association rate constant in enhancing the beneficial effect of antibodies. These results demonstrated that recycling and sweeping antibodies can be applied to various target antigens with different profiles, and thus will expand the number of antigens that therapeutic antibodies can target. P236 PERCUTANEOUS ABSORPTION AND PHARMACOKINETICS OF TETRABROMO-O-CRESOL AFTER TOPICAL ADMINISTRATION IN RATS Youngsung Lee, Hyeon Gwan Choi, Sungwook Park. Sungkyunkwan University, Suwon, South Korea
Park,
Junwoo
Tetrabromo-o-cresol (TOC) is a preservative used in a variety of consumer products such as cosmetics, personal care products and surgical cleaning treatments. Given the widespread use of these products, there is a possibility of systemic exposure to this chemical. To our knowledge, however, limited information is available on absorption and disposition of TOC in animals and humans [1]. The present study was conducted to characterize the absorption, distribution and elimination of TOC after topical application and intravenous injection in rats. Two reference formulations of lotion and cream containing 0.8 and 1.2% of TOC, respectively, were prepared. Approximately 1 day prior to topical application, the back skin of rats was shaved, and each formulation (amount 234 mg/kg) was evenly applied to the shaved area. Jugular venous blood samples were collected at 0, 0.5, 1, 2, 4, 8 and 12 hr. At this time, the applied area was carefully rinsed with alcohol swaps to remove unabsorbed TOC remaining on the skin. Then, additional blood samples were collected at 0.25, 0.5, 1 and 2 hr. After collection of the last blood sample, the rats were sacrificed and the stratum corneum (30 times of tape strips) and combined epidermis and dermis were collected. Concentrations of TOC were determined by a validated HPLC-MS/MS method. The average plasma Cmax, tmax and AUC were 18.5 ± 2.6 ng/ml, 10.0 ± 4.0 hr and 202.5 ± 35.4 ng.hr/ml, respectively, for lotion and 28.6 ± 6.9 ng/ml, 10.0 ± 2.3 hr, 316.8 ± 81.1 ng.hr/ml, respectively, for cream. Average percentages of the applied dose found in the stratum corneum, combined epidermis and dermis, and alcohol swaps were 1.9 ± 0.5%, 1.4 ± 0.2% and 53.3 ± 6.9%, respectively, for lotion and 1.9 ± 0.6%, 1.4 ± 0.4% and 54.9 ± 6.4%, respectively, for cream. In a separate study, TOC was intravenously injected to rats (dose 2 mg/kg) to characterize the pharmacokinetic disposition and to determine the absolute topical bioavailability. Venous blood samples were collected at 0, 2, 5, 15, 30 min, 1, 2, 4 and 6 hr. The pharmacokinetic parameters of Cl, Vdss, AUC and t1/2 were 52.2 ± 7.0 ml/min/kg, 2.3 ± 0.7 l/kg, 649.3 ± 100.5 ng.hr/ml and 1.7 ± 0.5 hr, respectively. The absolute topical bioavailability was 33.3 ± 5.8% for lotion and 34.7 ± 8.9% for cream. TOC was found to be absorbed in the systemic circulation in significant amounts after topical application. 1. Reports of the Scientific Committee on Cosmetology Concerning the Use of Preservatives in Cosmetic Products (sixth series), Commission of the European Communities, 1987. P237 PHARMACOKINETIC CHARACTERISTICS OF KAURENOIC ACID AFTER USUAL ORAL DOSE OF ARALIAE CONTINENTALIS RADIX EXTRACT FROM A PHASE I TRIAL IN KOREAN SUBJECTS Dong-Seok Lee 1, Sook-Jin Kim 1, Seong-Ho Ham 2, Jung-Hee Cho 2, SeungJung Yang 3, Yong-Bok Lee 4, Hea-Young Cho 1. 1 College of Pharmacy, CHA University, Seongnam, South Korea; 2 Jeonnam Development Institute for Korean Traditional Medicine, Jeollanam-do, South Korea; 3 Department of Korean Obestetrics and Gynecology, Dong-shin University, Naju-si, South Korea; 4 Department of Pharmaceutics, College of Pharmacy, Chonnam National University, Gwangju, South Korea
Abstracts / Drug Metabolism and Pharmacokinetics 32 (2017) S27eS107
novel thienopyridine antiplatelet agent in clinical development, is an acetate analogue of clopidogrel aiming to produce H4 more efficiently and consistently in humans than clopidogrel [3]. The aim of our study was to investigate the metabolism and pharmacokinetics of vicagrel, compared with clopidogrel, in healthy Chinese volunteers. In a randomized, double-blind, placebo-controlled, single-ascending-dose phase 1 study, 67 subjects received placebo, vicagrel 5, 10, 20, 40, 60, or 75 mg, or clopidogrel 75 mg orally, and plasma samples were collected. The samples analyzed using UHPLC-Q/TOF MS method revealed that vicagrel was extensively metabolized in humans. Vicagrel was first hydrolyzed to 2oxo-clopidogrel, and further oxidized to produce the inactive thiol isomer H3 and the active thiol isomer H4, and H3 was further S-methylated to form M9-3, whereas the hydrolysis of 2-oxo-clopidogrel produced an inactive carboxylic acid metabolite. A fast, sensitive, and reproducible UHPLC-MS/MS method was developed and validated to simultaneously determine derivatized H3 (MP-H3), derivatized H4 (MP-H4), and M9-3 in human plasma. Linear regression curves were obtained over the concentration ranges of 0.100e200 ng/mL for MP-H3/MP-H4 and 1.00e1000 ng/mL for M9-3, respectively. The validated method was successfully applied in pharmacokinetic study of vicagrel. Vicagrel was rapidly absorbed with median tmax 0.5-1 h for active H4. Plasma concentrations of M9-3 were the highest among the three matabolites. For all the three matabolites, mean Cmax and AUC increased approximately proportionally with the dose of vicagrel from 5 to 75 mg, demonstrating a linear and predictable pharmacokinetic profile. For active H4, compared with the clopidogrel 75 mg group, median tmax was significantly shorter [0.50 (0.25-1.00) vs. 0.75 (0.50-2.00) h, P ¼ 0.0396], whereas mean Cmax was higher (13.5 ± 4.52 vs. 9.95 ± 4.74 ng/ml, P ¼ 0.910) with no significant difference, and mean AUC0-t was similar (11.7 ± 4.52 vs. 11.8 ± 4.94 ng/ ml, P ¼ 0.820) in the vicagrel 5 mg group. These results indicated that compared with clopidogrel 75 mg, vicagrel 5 mg would result in comparable but more consistent platelet inhibition with more rapid onset, whereas did not increase the risk of bleeding. 1. Dansette P.M., Rosi J., et al. Cytochromes P450 catalyze both steps of the major pathway of clopidogrel bioactivation, whereas paraoxonase catalyzes the formation of a minor thiol metabolite isomer. Chem Res Toxicol 2012; 25: 348-56. 2. Zhang H., Lauver D.A., et al. Formation, reactivity, and antiplatelet activity of mixed disulfide conjugates of clopidogrel. Mol Pharmacol 2013; 83: 848-56. 3. Shan J., Zhang B., et al. Overcoming clopidogrel resistance: discovery of vicagrel as a highly potent and orally bioavailable antiplatelet agent. J Med Chem 2012; 55: 3342-52. P235 MODELING AND SIMULATION ANALYSIS OF A NOVEL ENGINEERED THERAPEUTIC ANTIBODY WITH PH-DEPENDENT BINDING TO TARGET ANTIGEN Kenta Haraya 1, Tatsuhiko Tachibana 1, Junichi Nezu 1, Masaki Ishigai 2, Tomoyuki Igawa 3. 1 Chugai Pharmabody Research Pte. Ltd., Singapore, Singapore; 2 Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan; 3 Chugai Pharmaceutical Co., Ltd., Gotemba, Japan Antibody-mediated accumulation of soluble target antigens has been reported in preclinical and clinical studies, because the clearance of a complex formed from an antibody and a target antigen is much lower than that of the target antigen. To overcome this issue, our group has reported novel engineered therapeutic antibodies with pH-dependent binding to the target antigen (recycling antibody) and with both pH-dependent binding to target antigen and increased binding to FcRn at neutral pH (sweeping antibody). The aim of this work is to better understand the potential applications of these recycling and sweeping antibodies as therapeutics by simulating the pharmacokinetics and pharmacodynamics in a modeling and simulation study. Pharmacokinetic parameters for the antibody and target antigen dynamics were estimated from the results of a pharmacokinetic study in human FcRn transgenic mice that used human soluble IL-6 receptor as a model target antigen and antiehuman IL-6 receptor antibodies. A modeling and simulation study was performed using the target-mediated disposition with recycling model and the estimated pharmacokinetic parameters with various target antigen profiles
(clearance, endogenous concentration, binding affinity to antibody). In the pharmacokinetic study, the recycling antibody enhanced the target-antigen clearance by 3 fold compared to a conventional antibody, while the sweeping antibody accelerated the target-antigen clearance by 10 fold. Modeling and simulation results showed that recycling and sweeping antibodies can improve dosage frequency and reduce the required dosage for target antigens with various levels of clearance, endogenous concentration, or binding affinity to antibody. Moreover, the results showed the importance of the association rate constant in enhancing the beneficial effect of antibodies. These results demonstrated that recycling and sweeping antibodies can be applied to various target antigens with different profiles, and thus will expand the number of antigens that therapeutic antibodies can target. P236 PERCUTANEOUS ABSORPTION AND PHARMACOKINETICS OF TETRABROMO-O-CRESOL AFTER TOPICAL ADMINISTRATION IN RATS Youngsung Lee, Hyeon Gwan Choi, Sungwook Park. Sungkyunkwan University, Suwon, South Korea
Park,
Junwoo
Tetrabromo-o-cresol (TOC) is a preservative used in a variety of consumer products such as cosmetics, personal care products and surgical cleaning treatments. Given the widespread use of these products, there is a possibility of systemic exposure to this chemical. To our knowledge, however, limited information is available on absorption and disposition of TOC in animals and humans [1]. The present study was conducted to characterize the absorption, distribution and elimination of TOC after topical application and intravenous injection in rats. Two reference formulations of lotion and cream containing 0.8 and 1.2% of TOC, respectively, were prepared. Approximately 1 day prior to topical application, the back skin of rats was shaved, and each formulation (amount 234 mg/kg) was evenly applied to the shaved area. Jugular venous blood samples were collected at 0, 0.5, 1, 2, 4, 8 and 12 hr. At this time, the applied area was carefully rinsed with alcohol swaps to remove unabsorbed TOC remaining on the skin. Then, additional blood samples were collected at 0.25, 0.5, 1 and 2 hr. After collection of the last blood sample, the rats were sacrificed and the stratum corneum (30 times of tape strips) and combined epidermis and dermis were collected. Concentrations of TOC were determined by a validated HPLC-MS/MS method. The average plasma Cmax, tmax and AUC were 18.5 ± 2.6 ng/ml, 10.0 ± 4.0 hr and 202.5 ± 35.4 ng.hr/ml, respectively, for lotion and 28.6 ± 6.9 ng/ml, 10.0 ± 2.3 hr, 316.8 ± 81.1 ng.hr/ml, respectively, for cream. Average percentages of the applied dose found in the stratum corneum, combined epidermis and dermis, and alcohol swaps were 1.9 ± 0.5%, 1.4 ± 0.2% and 53.3 ± 6.9%, respectively, for lotion and 1.9 ± 0.6%, 1.4 ± 0.4% and 54.9 ± 6.4%, respectively, for cream. In a separate study, TOC was intravenously injected to rats (dose 2 mg/kg) to characterize the pharmacokinetic disposition and to determine the absolute topical bioavailability. Venous blood samples were collected at 0, 2, 5, 15, 30 min, 1, 2, 4 and 6 hr. The pharmacokinetic parameters of Cl, Vdss, AUC and t1/2 were 52.2 ± 7.0 ml/min/kg, 2.3 ± 0.7 l/kg, 649.3 ± 100.5 ng.hr/ml and 1.7 ± 0.5 hr, respectively. The absolute topical bioavailability was 33.3 ± 5.8% for lotion and 34.7 ± 8.9% for cream. TOC was found to be absorbed in the systemic circulation in significant amounts after topical application. 1. Reports of the Scientific Committee on Cosmetology Concerning the Use of Preservatives in Cosmetic Products (sixth series), Commission of the European Communities, 1987. P237 PHARMACOKINETIC CHARACTERISTICS OF KAURENOIC ACID AFTER USUAL ORAL DOSE OF ARALIAE CONTINENTALIS RADIX EXTRACT FROM A PHASE I TRIAL IN KOREAN SUBJECTS Dong-Seok Lee 1, Sook-Jin Kim 1, Seong-Ho Ham 2, Jung-Hee Cho 2, SeungJung Yang 3, Yong-Bok Lee 4, Hea-Young Cho 1. 1 College of Pharmacy, CHA University, Seongnam, South Korea; 2 Jeonnam Development Institute for Korean Traditional Medicine, Jeollanam-do, South Korea; 3 Department of Korean Obestetrics and Gynecology, Dong-shin University, Naju-si, South Korea; 4 Department of Pharmaceutics, College of Pharmacy, Chonnam National University, Gwangju, South Korea