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Pharmacokinetic herb-herb and herb-drug interactions: Studies on Fufang-Danshen formula, a three-herb combination for management of angina pectoris
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Abstracts / Drug Metabolism and Pharmacokinetics 32 (2017) S1eS21
1. Yamada A., Maeda K., Kiyotani K., Mushiroda T., Nakamura Y., Sugiyama Y. Kinetic Interpretation of the Importance of OATP1B3 and MRP2 in Docetaxel-Induced Hematopoietic Toxicity. See comment in PubMed Commons below CPT Pharmacometrics Syst Pharmacol. 2014 Jul 23;3:e126. http://dx.doi.org/10.1038/psp.2014.23, Tomita Y, Maeda K, Sugiyama Y. Ethnic Variability in the Plasma Exposures of OATP1B1 Substrates Such as HMG-CoA Reductase Inhibitors: A Kinetic Consideration of Its Mechanism. Clin Pharmacol Ther. 94:37-51 (2013). 2. Chiba K., Kato M, Ito T., Suwa T., Sugiyama Y. Inter-individual Variability of In Vivo CYP2D6 Activity in Different Genotypes. Drug Metab. Pharmacokinet. 27(4):405-13 (2012). S61 THE USE OF CYNOMOLGUS MONKEYS IN PREDICTING ENZYME INDUCTION AND HUMAN DRUG-DRUG INTERACTIONS Michael Sinz. Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Wallingford, CT, USA Drug-drug interactions (DDIs), especially those related to cytochrome P450 (CYP) induction, can have significant effects on the efficacy and toxicity of co-administered CYP substrates. Several tools have been developed to screen and predict human drug-drug interactions related to enzyme induction during drug development. Early discovery screening typically employs pregnane X receptor (PXR) transactivation assays along with subsequent testing in human primary hepatocytes. Data derived from human hepatocyte cultures can then be used to predict human DDIs. These prediction methods are limited by the static nature of the hepatocyte culture system. In order to overcome the issues incumbent upon a static culture system, the monkey has been evaluated as an in vivo model to predict human DDIs related to the most common form of induction, PXRmediated CYP3A4 induction. A good correlation was found between monkey and human PXR transactivation, CYP3A4 hepatocyte induction, and in vivo AUC changes for several compounds. Overall the correlations provide confidence that, under the appropriate circumstances, monkey PXR-mediated enzyme induction can be used as an in vivo model to predict exposure changes for human DDIs. In contrast, other CYP enzymes and mechanisms of induction have not been extensively evaluated in the monkey. Limited ex vivo studies have demonstrated induction of monkey CYP1A1, 2B6 and 3A4 mRNA expression as well as corresponding enzyme activities in livers of animals treated with human inducers such as, omeprazole (OME)/CYP1A1; phenobarbital (PB); CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime and phenytoin (PHT)/CYP2B6; and rifampicin (RIF)/ CYP3A4. However, to our knowledge in vitro studies examining CYP2B6 induction in monkey hepatocyte cultures have not been reported, therefore cynomolgus monkey hepatocyte cultures were treated with wellknown inducers of human CYP enzymes to evaluate mRNA expression of PXR and constitutive androstane receptor (CAR)-mediated induction responses. Cynomolgus monkey hepatocytes treated with OME and RIF demonstrated concentration-dependent induction of CYP1A1 and UGT1A1 mRNA expression with OME treatment and CYP3A4 mRNA induction after RIF treatment. In contrast, PB, CITCO, and PHT caused no induction of CYP2B6 mRNA expression at any concentration examined. The unexpected absence of monkey CYP2B6 induction in vitro by commonly used human CYP2B6 inducers contrasts with observations found ex vivo, and suggests monkey hepatocytes are not suitable to evaluate CAR-mediated induction responses for CYP2B6. Further studies to evaluate CYP2B6 induction response in vivo and ex vivo are warranted to understand this phenomenon. S62 EVALUATION OF CYP2B6 INDUCTION AND PREDICTION OF CLINICAL DRUG-DRUG INTERACTIONS Odette A. Fahmi. Pharmacokinetics and Drug Metabolism, Pfizer, Groton, CT, USA Drug-drug interactions (DDI) due to CYP2B6 induction have recently gained prominence and clinical induction risk assessment is recommended by the regulatory agencies. The objective of this work by the
International Consortium for Innovation and Quality in Pharmaceutical Development (IQ consortium) Induction working group was to evaluate the potency of CYP2B6 vs CYP3A4 induction in vitro and from clinical studies, and to assess the predictability of efavirenz and bupropion as clinical probe substrates of CYP2B6 induction. This presentation will focus on reviewing the in-vitro induction data generated by several companies and DDI predicted values vs observed ones using various prediction models such as the R3, RIS, net effect static model and dynamic model such SimCYP. S63 PHARMACOKINETIC HERB-HERB AND HERB-DRUG INTERACTIONS: STUDIES ON FUFANG-DANSHEN FORMULA, A THREE-HERB COMBINATION FOR MANAGEMENT OF ANGINA PECTORIS Chuan Li. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China Many common diseases such as cardiovascular diseases, cancer, and mental disorders are caused by multiple molecular abnormalities, rather than being the result of a single defect. These complex diseases normally require comprehensive therapeutic approaches including multi-target drug combination therapies. The goal, in using drug combination therapies, is often to obtain synergistic and/or additive pharmacodynamic effects from the ingredients. However, the success of such combination therapies relies on the pharmacokinetic compatibility of the ingredients, i.e., the ingredients existing together with limited pharmacokinetic interaction problems after dosing. Angina pectoris represents the main symptom of established coronary artery disease, a leading cause of premature mortality; it is caused by transient myocardial ischemia, an imbalance between myocardial oxygen supply and demand. The aim of angina pectoris management is symptomatic relief and secondary prevention. In China, 30.0% outpatients with coronary heart disease concomitantly take both herbal medicines and western medicines, 3.1% of them take only herbal medicines, and 66.9% of them take only western medicines. There is a growing number of patients using herbal medicines. Fufang-Danshen formula is a three-herb combination, comprising Salvia miltiorrhiza roots (Danshen), Panax notoginseng roots (Sanqi), and Borneolum (Bingpian). Fufang-Danshen tablet and Fufang-Danshen dripping pill are two commonly used oral formulations of the formula. These herbal formulations, approved by the China Food and Drug Administration, are extensively used as add-on therapy in the conventional management of stable angina pectoris. Fufang-Danshen dripping pill is undergoing Phase III investigation in the United States after clearing Phase II clinical trials, raising the possibility that it could become the first Chinese medicinal herbal product to obtain drug approval from the U.S. Food and Drug Administration. The antianginal herbal therapies are associated with symptomatic relief and secondary prevention and appear to have low incidence of side effects in long-term use. In this presentation, the speaker will illustrate pharmacokinetic herb-herb and herb-drug interactions related to Fufang-Danshen formula mainly based on the studies by his research group. Such research facilitates the rational use of herbal therapies and enriches therapeutic approach for angina pectoris management. S64 GUT MICROBIOTA-MEDIATED DRUG-DRUG INTERACTIONS Dong-Hyun Kim. Department of Life and Nanopharmaceutical Sciences and Department of Pharmacy, Kyung-Hee University, Seoul, South Korea A drug-drug interaction is a situation in which a drug affects the activity of another drug when both are administered together: mainly the action is occurred in the absorption, distribution, metabolism, and excretion of drugs administered to living organisms including humans and animals. The action can be a synergistic, antagonistic, or new effect. Of these, xenobiotic metabolism refers to the biochemical modification of drugs and phytochemicals. The metabolism in the liver mainly converts hydrophobic drugs into more hydrophilic products (oxidation and glucuronate/sulfate conjugation), which are excretable, whereas the gut microbiota metabolism in the intestine catalyzes hydrophilic drugs such
Abstracts / Drug Metabolism and Pharmacokinetics 32 (2017) S1eS21
1. Yamada A., Maeda K., Kiyotani K., Mushiroda T., Nakamura Y., Sugiyama Y. Kinetic Interpretation of the Importance of OATP1B3 and MRP2 in Docetaxel-Induced Hematopoietic Toxicity. See comment in PubMed Commons below CPT Pharmacometrics Syst Pharmacol. 2014 Jul 23;3:e126. http://dx.doi.org/10.1038/psp.2014.23, Tomita Y, Maeda K, Sugiyama Y. Ethnic Variability in the Plasma Exposures of OATP1B1 Substrates Such as HMG-CoA Reductase Inhibitors: A Kinetic Consideration of Its Mechanism. Clin Pharmacol Ther. 94:37-51 (2013). 2. Chiba K., Kato M, Ito T., Suwa T., Sugiyama Y. Inter-individual Variability of In Vivo CYP2D6 Activity in Different Genotypes. Drug Metab. Pharmacokinet. 27(4):405-13 (2012). S61 THE USE OF CYNOMOLGUS MONKEYS IN PREDICTING ENZYME INDUCTION AND HUMAN DRUG-DRUG INTERACTIONS Michael Sinz. Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Wallingford, CT, USA Drug-drug interactions (DDIs), especially those related to cytochrome P450 (CYP) induction, can have significant effects on the efficacy and toxicity of co-administered CYP substrates. Several tools have been developed to screen and predict human drug-drug interactions related to enzyme induction during drug development. Early discovery screening typically employs pregnane X receptor (PXR) transactivation assays along with subsequent testing in human primary hepatocytes. Data derived from human hepatocyte cultures can then be used to predict human DDIs. These prediction methods are limited by the static nature of the hepatocyte culture system. In order to overcome the issues incumbent upon a static culture system, the monkey has been evaluated as an in vivo model to predict human DDIs related to the most common form of induction, PXRmediated CYP3A4 induction. A good correlation was found between monkey and human PXR transactivation, CYP3A4 hepatocyte induction, and in vivo AUC changes for several compounds. Overall the correlations provide confidence that, under the appropriate circumstances, monkey PXR-mediated enzyme induction can be used as an in vivo model to predict exposure changes for human DDIs. In contrast, other CYP enzymes and mechanisms of induction have not been extensively evaluated in the monkey. Limited ex vivo studies have demonstrated induction of monkey CYP1A1, 2B6 and 3A4 mRNA expression as well as corresponding enzyme activities in livers of animals treated with human inducers such as, omeprazole (OME)/CYP1A1; phenobarbital (PB); CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime and phenytoin (PHT)/CYP2B6; and rifampicin (RIF)/ CYP3A4. However, to our knowledge in vitro studies examining CYP2B6 induction in monkey hepatocyte cultures have not been reported, therefore cynomolgus monkey hepatocyte cultures were treated with wellknown inducers of human CYP enzymes to evaluate mRNA expression of PXR and constitutive androstane receptor (CAR)-mediated induction responses. Cynomolgus monkey hepatocytes treated with OME and RIF demonstrated concentration-dependent induction of CYP1A1 and UGT1A1 mRNA expression with OME treatment and CYP3A4 mRNA induction after RIF treatment. In contrast, PB, CITCO, and PHT caused no induction of CYP2B6 mRNA expression at any concentration examined. The unexpected absence of monkey CYP2B6 induction in vitro by commonly used human CYP2B6 inducers contrasts with observations found ex vivo, and suggests monkey hepatocytes are not suitable to evaluate CAR-mediated induction responses for CYP2B6. Further studies to evaluate CYP2B6 induction response in vivo and ex vivo are warranted to understand this phenomenon. S62 EVALUATION OF CYP2B6 INDUCTION AND PREDICTION OF CLINICAL DRUG-DRUG INTERACTIONS Odette A. Fahmi. Pharmacokinetics and Drug Metabolism, Pfizer, Groton, CT, USA Drug-drug interactions (DDI) due to CYP2B6 induction have recently gained prominence and clinical induction risk assessment is recommended by the regulatory agencies. The objective of this work by the
International Consortium for Innovation and Quality in Pharmaceutical Development (IQ consortium) Induction working group was to evaluate the potency of CYP2B6 vs CYP3A4 induction in vitro and from clinical studies, and to assess the predictability of efavirenz and bupropion as clinical probe substrates of CYP2B6 induction. This presentation will focus on reviewing the in-vitro induction data generated by several companies and DDI predicted values vs observed ones using various prediction models such as the R3, RIS, net effect static model and dynamic model such SimCYP. S63 PHARMACOKINETIC HERB-HERB AND HERB-DRUG INTERACTIONS: STUDIES ON FUFANG-DANSHEN FORMULA, A THREE-HERB COMBINATION FOR MANAGEMENT OF ANGINA PECTORIS Chuan Li. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China Many common diseases such as cardiovascular diseases, cancer, and mental disorders are caused by multiple molecular abnormalities, rather than being the result of a single defect. These complex diseases normally require comprehensive therapeutic approaches including multi-target drug combination therapies. The goal, in using drug combination therapies, is often to obtain synergistic and/or additive pharmacodynamic effects from the ingredients. However, the success of such combination therapies relies on the pharmacokinetic compatibility of the ingredients, i.e., the ingredients existing together with limited pharmacokinetic interaction problems after dosing. Angina pectoris represents the main symptom of established coronary artery disease, a leading cause of premature mortality; it is caused by transient myocardial ischemia, an imbalance between myocardial oxygen supply and demand. The aim of angina pectoris management is symptomatic relief and secondary prevention. In China, 30.0% outpatients with coronary heart disease concomitantly take both herbal medicines and western medicines, 3.1% of them take only herbal medicines, and 66.9% of them take only western medicines. There is a growing number of patients using herbal medicines. Fufang-Danshen formula is a three-herb combination, comprising Salvia miltiorrhiza roots (Danshen), Panax notoginseng roots (Sanqi), and Borneolum (Bingpian). Fufang-Danshen tablet and Fufang-Danshen dripping pill are two commonly used oral formulations of the formula. These herbal formulations, approved by the China Food and Drug Administration, are extensively used as add-on therapy in the conventional management of stable angina pectoris. Fufang-Danshen dripping pill is undergoing Phase III investigation in the United States after clearing Phase II clinical trials, raising the possibility that it could become the first Chinese medicinal herbal product to obtain drug approval from the U.S. Food and Drug Administration. The antianginal herbal therapies are associated with symptomatic relief and secondary prevention and appear to have low incidence of side effects in long-term use. In this presentation, the speaker will illustrate pharmacokinetic herb-herb and herb-drug interactions related to Fufang-Danshen formula mainly based on the studies by his research group. Such research facilitates the rational use of herbal therapies and enriches therapeutic approach for angina pectoris management. S64 GUT MICROBIOTA-MEDIATED DRUG-DRUG INTERACTIONS Dong-Hyun Kim. Department of Life and Nanopharmaceutical Sciences and Department of Pharmacy, Kyung-Hee University, Seoul, South Korea A drug-drug interaction is a situation in which a drug affects the activity of another drug when both are administered together: mainly the action is occurred in the absorption, distribution, metabolism, and excretion of drugs administered to living organisms including humans and animals. The action can be a synergistic, antagonistic, or new effect. Of these, xenobiotic metabolism refers to the biochemical modification of drugs and phytochemicals. The metabolism in the liver mainly converts hydrophobic drugs into more hydrophilic products (oxidation and glucuronate/sulfate conjugation), which are excretable, whereas the gut microbiota metabolism in the intestine catalyzes hydrophilic drugs such