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Article ; Online: Physiologically-based pharmacokinetic modeling of prominent oral contraceptive agents and applications in drug-drug interactions.

Lewis, Gareth J / Ahire, Deepak / Taskar, Kunal S

CPT: pharmacometrics & systems pharmacology

2024 Volume 13, Issue 4, Page(s) 563–575

Abstract: Considerable interest remains across the pharmaceutical industry and regulatory landscape in capabilities to model oral contraceptives (OCs), whether combined (COCs) with ethinyl estradiol (EE) or progestin-only pill. Acceptance of COC drug-drug ... ...

Abstract	Considerable interest remains across the pharmaceutical industry and regulatory landscape in capabilities to model oral contraceptives (OCs), whether combined (COCs) with ethinyl estradiol (EE) or progestin-only pill. Acceptance of COC drug-drug interaction (DDI) assessment using physiologically-based pharmacokinetic (PBPK) is often limited to the estrogen component (EE), requiring further verification, with extrapolation from EE to progestins discouraged. There is a paucity of published progestin component PBPK models to support the regulatory DDI guidance for industry to evaluate a new chemical entity's (NCE's) DDI potential with COCs. Guidance recommends a clinical interaction study to be considered if an investigational drug is a weak or moderate inducer, or a moderate/strong inhibitor, of CYP3A4. Therefore, availability of validated OC PBPK models within one software platform, will be useful in predicting the DDI potential with NCEs earlier in the clinical development. Thus, this work was focused on developing and validating PBPK models for progestins, DNG, DRSP, LNG, and NET, within Simcyp, and assessing the DDI potential with known CYP3A4 inhibitors (e.g., ketoconazole) and inducers (e.g., rifampicin) with published clinical data. In addition, this work demonstrated confidence in the Simcyp EE model for regulatory and clinical applications by extensive verification in 70+ clinical PK and CYP3A4 interaction studies. The results provide greater capability to prospectively model clinical CYP3A4 DDI with COCs using Simcyp PBPK to interrogate the regulatory decision-tree to contextualize the potential interaction by known perpetrators and NCEs, enabling model-informed decision making, clinical study designs, and delivering potential alternative COC options for women of childbearing potential.
MeSH term(s)	Humans ; Female ; Progestins ; Cytochrome P-450 CYP3A ; Contraceptives, Oral ; Drug Interactions ; Ethinyl Estradiol ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; Models, Biological
Chemical Substances	Progestins ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Contraceptives, Oral ; Ethinyl Estradiol (423D2T571U) ; Cytochrome P-450 CYP3A Inhibitors
Language	English
Publishing date	2024-01-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13101
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Article ; Online: Innovations, Opportunities, and Challenges for Predicting Alteration in Drug-Metabolizing Enzyme and Transporter Activity in Specific Populations.

Chothe, Paresh P / Arya, Vikram / Prasad, Bhagwat / Ramsden, Diane / Taskar, Kunal

Drug metabolism and disposition: the biological fate of chemicals

2023 Volume 51, Issue 12, Page(s) 1547–1550

Abstract: Drug-metabolizing enzymes and transporters (DMETs) are key regulators of the pharmacokinetics, efficacy, and toxicity of therapeutics. Over the past two decades, significant advancements in in vitro methodologies, targeted proteomics, in vitro to in vivo ...

Abstract	Drug-metabolizing enzymes and transporters (DMETs) are key regulators of the pharmacokinetics, efficacy, and toxicity of therapeutics. Over the past two decades, significant advancements in in vitro methodologies, targeted proteomics, in vitro to in vivo extrapolation methods, and integrated computational approaches such as physiologically based pharmacokinetic modeling have unequivocally contributed to improving our ability to quantitatively predict the role of DMETs in absorption, distribution, metabolism, and excretion and drug-drug interactions. However, the paucity of data regarding alterations in DMET activity in specific populations such as pregnant individuals, lactation, pediatrics, geriatrics, organ impairment, and disease states such as, cancer, kidney, and liver diseases and inflammation has restricted our ability to realize the full potential of these recent advancements. We envision that a series of carefully curated articles in a special supplementary issue of
MeSH term(s)	Pregnancy ; Female ; Humans ; Child ; Membrane Transport Proteins/metabolism ; Liver Diseases ; Drug Interactions ; Inflammation ; Metabolic Clearance Rate
Chemical Substances	Membrane Transport Proteins
Language	English
Publishing date	2023-09-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.123.001453
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Article ; Online: Physiologically-based Pharmacokinetic (PBPK) Modelling of Transporter Mediated Drug Absorption, Clearance and Drug-drug Interactions.

Taskar, Kunal S / Harada, Isobel / Alluri, Ravindra V

Current drug metabolism

2021 Volume 22, Issue 7, Page(s) 523–531

Abstract: Membrane transporters play an important role in intestinal absorption, distribution and clearance of drugs. Additionally transporters along with enzymes regulate tissue exposures (e.g. liver, kidney and brain), which are important for safety and efficacy ...

Abstract	Membrane transporters play an important role in intestinal absorption, distribution and clearance of drugs. Additionally transporters along with enzymes regulate tissue exposures (e.g. liver, kidney and brain), which are important for safety and efficacy considerations. Early identification of transporters involved guides generation of in vitro and in vivo data needed to gain mechanistic understanding on the role of transporters in organ clearance, tissue exposures and enables development of physiological-based pharmacokinetic (PBPK) models. A lot of progress has been made in developing several in vitro assay systems and mechanistic in silico models to determine kinetic parameters for transporters, which are incorporated into PBPK models. Although, intrinsic clearance and inhibition data from in vitro systems generally tend to underpredict in vivo clearance and magnitude of drug-drug interactions (DDIs), empirical scaling factors derived from a sizable dataset are often used to offset underpredictions. PBPK models are increasing used to predict the impact of transporters on intestinal absorption, clearance, victim and perpetrator DDIs prior to first in human clinical trials. The models are often refined when clinical data is available and are used to predict pharmacokinetics in untested scenarios such as the impact of polymorphisms, ontogeny, ethnicity, disease states and DDIs with other perpetrator drugs. The aim of this review is to provide an overview of (i) regulatory requirements around transporters, (ii) in vitro systems and their limitations in predicting transporter mediated drug disposition and DDIs, (iii) PBPK modelling tactics and case studies used for internal decision making and/or for regulatory submissions.
MeSH term(s)	Animals ; Drug Elimination Routes ; Drug Interactions ; Humans ; Intestinal Absorption ; Membrane Transport Proteins/drug effects ; Membrane Transport Proteins/metabolism ; Models, Biological ; Pharmacokinetics
Chemical Substances	Membrane Transport Proteins
Language	English
Publishing date	2021-01-05
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2064815-7
ISSN	1875-5453 ; 1389-2002
ISSN (online)	1875-5453
ISSN	1389-2002
DOI	10.2174/1389200221999210101233340
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Article ; Online: Development of a physiologically based pharmacokinetic model of fostemsavir and its pivotal application to support dosing in pregnancy.

Salem, Farzaneh / Nguyen, Dung / Bush, Mark / Moore, Katy P / Mudunuru, Jennypher / Stamatopoulos, Konstantinos / Thakkar, Nilay / Taskar, Kunal S

CPT: pharmacometrics & systems pharmacology

2024

Abstract: It is critical to understand the impact of significant physiological changes during pregnancy on the extent of maternal and fetal drug exposure. Fostemsavir (FTR) is a prodrug of temsavir (TMR) and is approved in combination with other antiretrovirals ... ...

Abstract	It is critical to understand the impact of significant physiological changes during pregnancy on the extent of maternal and fetal drug exposure. Fostemsavir (FTR) is a prodrug of temsavir (TMR) and is approved in combination with other antiretrovirals for multi-drug-resistant human immunodeficiency virus (HIV) infections. This physiologically based pharmacokinetic model (PBPK) study was used to estimate TMR PK in pregnant populations during each trimester of pregnancy to inform FTR dosing. A PBPK model was developed and validated for TMR using PK data collected following intravenous TMR and oral FTR dosing (immediate-release and extended-release tablets) in healthy volunteers. Predicted TMR concentration-time profiles accurately predicted the reported clinical data and variability in healthy (dense data) and pregnant (sparse data) populations. Predicted versus observed TMR geometric mean (CV%) clearance following intravenous administration was 18.01 (29) versus 17 (21) (L/h). Predicted versus observed TMR AUC
Language	English
Publishing date	2024-05-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.13156
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Article ; Online: When special populations intersect with drug-drug interactions: Application of physiologically-based pharmacokinetic modeling in pregnant populations.

Sychterz, Caroline / Galetin, Aleksandra / Taskar, Kunal S

Biopharmaceutics & drug disposition

2021 Volume 42, Issue 4, Page(s) 160–177

Abstract: Pregnancy results in significant physiological changes that vary across trimesters and into the postpartum period, and may result in altered disposition of endogenous substances and drug pharmacokinetics. Pregnancy represents a unique special population ... ...

Abstract	Pregnancy results in significant physiological changes that vary across trimesters and into the postpartum period, and may result in altered disposition of endogenous substances and drug pharmacokinetics. Pregnancy represents a unique special population where physiologically-based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms without subjecting pregnant women or their fetuses to extensive clinical studies. A critical review of applications of pregnancy PBPK models (pPBPK) was conducted to understand its current status for prediction of drug exposure in pregnant populations and to identify areas of further expansion. Evaluation of existing pPBPK modeling efforts highlighted improved understanding of cytochrome P450 (CYP)-mediated changes during pregnancy and identified knowledge gaps for non-CYP enzymes and the physiological changes of the postpartum period. Examples of the application of pPBPK beyond simple dose regimen recommendations are limited, particularly for prediction of drug-drug interactions (DDI) or differences between genotypes for polymorphic drug metabolizing enzymes. A raltegravir pPBPK model implementing UGT1A1 induction during the second and third trimesters of pregnancy was developed in the current work and verified against clinical data. Subsequently, the model was used to explore UGT1A1-related DDI risk with atazanavir and rifampicin along with the effect of enzyme genotype on raltegravir apparent clearance. Simulations of pregnancy-related induction of UGT1A1 either exacerbated UGT1A1 induction by rifampicin or negated atazanavir UGT1A1 inhibition. This example illustrated the advantages of pPBPK modeling for mechanistic evaluation of complex interplays of pregnancy- and drug-related effects in support of model-informed approaches in drug development.
MeSH term(s)	Computer Simulation ; Cytochrome P-450 Enzyme System/metabolism ; Dose-Response Relationship, Drug ; Drug Development/methods ; Drug Interactions ; Female ; Genotype ; Glucuronosyltransferase/genetics ; Glucuronosyltransferase/metabolism ; Humans ; Models, Biological ; Pharmaceutical Preparations/administration & dosage ; Pharmaceutical Preparations/metabolism ; Pregnancy/metabolism ; Pregnancy Trimesters
Chemical Substances	Pharmaceutical Preparations ; Cytochrome P-450 Enzyme System (9035-51-2) ; UGT1A1 enzyme (EC 2.4.1.-) ; Glucuronosyltransferase (EC 2.4.1.17)
Language	English
Publishing date	2021-04-26
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	603014-2
ISSN	1099-081X ; 0142-2782
ISSN (online)	1099-081X
ISSN	0142-2782
DOI	10.1002/bdd.2272
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Zs.A 1520: Show issues

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Article ; Online: Robust physiologically based pharmacokinetic model of rifampicin for predicting drug-drug interactions via P-glycoprotein induction and inhibition in the intestine, liver, and kidney.

Asaumi, Ryuta / Nunoya, Ken-Ichi / Yamaura, Yoshiyuki / Taskar, Kunal S / Sugiyama, Yuichi

CPT: pharmacometrics & systems pharmacology

2022 Volume 11, Issue 7, Page(s) 919–933

Abstract: P-glycoprotein (P-gp) is an efflux transporter that plays an important role in the pharmacokinetics of its substrate, and P-gp activities can be altered by induction and inhibition effects of rifampicin. This study aimed to establish a physiologically ... ...

Abstract	P-glycoprotein (P-gp) is an efflux transporter that plays an important role in the pharmacokinetics of its substrate, and P-gp activities can be altered by induction and inhibition effects of rifampicin. This study aimed to establish a physiologically based pharmacokinetic (PBPK) model of rifampicin to predict the P-gp-mediated drug-drug interactions (DDIs) and assess the DDI impact in the intestine, liver, and kidney. The induction and inhibition parameters of rifampicin for P-gp were estimated using two of seven DDI cases of rifampicin and digoxin and incorporated into our previously constructed PBPK model of rifampicin. The constructed rifampicin model was verified using the remaining five DDI cases with digoxin and five DDI cases with other P-gp substrates (talinolol and quinidine). Based on the established PBPK model, following repeated dosing of 600 mg rifampicin, the deduced net effect was an approximately threefold induction in P-gp activities in the intestine, liver, and kidney. Furthermore, in all 12 cases the predicted area under the plasma concentration-time curve ratios of the P-gp substrates were within the predefined acceptance criteria with various dosing regimens. Intestinal effects of P-gp-mediated DDIs had their greatest impact on the pharmacokinetics of digoxin and talinolol, with a minimal impact on the liver and kidney. For quinidine, predicted intestinal P-gp/cytochrome P450 3A-mediated DDIs were slightly underestimated because of the complexity of nonlinearity and transporter-enzyme interplay. These findings demonstrate that our rifampicin model can be applicable to quantitatively predict the net impact of P-gp induction and/or inhibition on diverse P-gp substrates and investigate the magnitude of DDIs in each tissue.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Cytochrome P-450 CYP3A/metabolism ; Digoxin/pharmacology ; Drug Interactions ; Humans ; Intestines ; Kidney/metabolism ; Liver/metabolism ; Membrane Transport Proteins ; Models, Biological ; Quinidine/pharmacology ; Rifampin/pharmacokinetics
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Membrane Transport Proteins ; Digoxin (73K4184T59) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Quinidine (ITX08688JL) ; Rifampin (VJT6J7R4TR)
Language	English
Publishing date	2022-06-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12807
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Article ; Online: Physiologically based pharmacokinetic modeling for development and applications of a virtual celiac disease population using felodipine as a model drug.

Salem, Farzaneh / Nimavardi, Ali / Mudunuru, Jennypher / Tompson, Debra / Bloomer, Jackie / Turner, David B / Taskar, Kunal S

CPT: pharmacometrics & systems pharmacology

2023 Volume 12, Issue 6, Page(s) 808–820

Abstract: In celiac disease (CeD), gastrointestinal CYP3A4 abundance and morphology is affected by the severity of disease. Therefore, exposure to CYP3A4 substrates and extent of drug interactions is altered. A physiologically-based pharmacokinetic (PBPK) ... ...

Abstract	In celiac disease (CeD), gastrointestinal CYP3A4 abundance and morphology is affected by the severity of disease. Therefore, exposure to CYP3A4 substrates and extent of drug interactions is altered. A physiologically-based pharmacokinetic (PBPK) population for different severities of CeD was developed. Gastrointestinal physiology parameters, such as luminal pH, transit times, morphology, P-gp, and CYP3A4 expression were included in development of the CeD population. Data on physiological difference between healthy and CeD subjects were incorporated into the model as the ratio of celiac to healthy. A PBPK model was developed and verified for felodipine extended-release tablet in healthy volunteers (HVs) and then utilized to verify the CeD populations. Plasma concentration-time profile and PK parameters were predicted and compared against those observed in both groups. Sensitivity analysis was carried out on key system parameters in CeD to understand their impact on drug exposure. For felodipine, the predicted mean concentration-time profiles and 5th and 95th percentile intervals captured the observed profile and variability in the HV and CeD populations. Predicted and observed clearance was 56.9 versus 56.1 (L/h) in HVs. Predicted versus observed mean ± SD area under the curve for extended release felodipine in different severities of CeD were values of 14.5 ± 9.6 versus 14.4 ± 2.1, 14.6 ± 9.0 versus 17.2 ± 2.8, and 28.1 ± 13.5 versus 25.7 ± 5.0 (ng.h/mL), respectively. Accounting for physiology differences in a CeD population accurately predicted the PK of felodipine. The developed CeD population can be applied for determining the drug concentration of CYP3A substrates in the gut as well as for systemic levels, and for application in drug-drug interaction studies.
MeSH term(s)	Humans ; Felodipine/pharmacokinetics ; Cytochrome P-450 CYP3A/metabolism ; Celiac Disease ; Drug Interactions ; Cytochrome P-450 CYP3A Inhibitors ; Models, Biological
Chemical Substances	Felodipine (OL961R6O2C) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Cytochrome P-450 CYP3A Inhibitors
Language	English
Publishing date	2023-04-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2697010-7
ISSN	2163-8306 ; 2163-8306
ISSN (online)	2163-8306
ISSN	2163-8306
DOI	10.1002/psp4.12954
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Article ; Online: Considerations for Industry-Preparing for the FDA Model-Informed Drug Development (MIDD) Paired Meeting Program.

Galluppi, Gerald R / Ahamadi, Malidi / Bhattacharya, Souvik / Budha, Nageshwar / Gheyas, Ferdous / Li, Chi-Chung / Chen, Yuan / Dosne, Anne-Gaëlle / Kristensen, Niels Rode / Magee, Mindy / Samtani, Mahesh N / Sinha, Vikram / Taskar, Kunal / Upreti, Vijay V / Yang, Jianning / Cook, Jack

Clinical pharmacology and therapeutics

2024

Abstract: A recent industry perspective published in this journal describes the benefits received by drug companies from participation in the MIDD Pilot Program. Along with the primary objectives of supporting good decision-making in drug development, there were ... ...

Abstract	A recent industry perspective published in this journal describes the benefits received by drug companies from participation in the MIDD Pilot Program. Along with the primary objectives of supporting good decision-making in drug development, there were substantial savings in time and development costs. Furthermore, many sponsors reported qualitative benefits such as new learnings and clarity on MIDD strategies and methodology that could be applied to other development programs. Based on the success of the Pilot Program, the FDA recently announced the continuation of the MIDD Paired Meeting Program as part of the Prescription Drug User Fee Act (PDUFA VII). In this report, we describe the collective experiences of industry participants in the MIDD Program to date, including all aspects of the process from meeting request submission to follow-up actions. The purpose is to provide future participants with information to optimize the value of the MIDD Program.
Language	English
Publishing date	2024-03-22
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.3245
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Article ; Online: Importance of Hepatic Transporters in Clinical Disposition of Drugs and Their Metabolites.

Patel, Mitesh / Taskar, Kunal S / Zamek-Gliszczynski, Maciej J

Journal of clinical pharmacology

2016 Volume 56 Suppl 7, Page(s) S23–39

Abstract: This review provides a practical clinical perspective on the relevance of hepatic transporters in pharmacokinetics and drug-drug interactions (DDIs). Special emphasis is placed on transporters with clear relevance to clinical DDIs, efficacy, and safety. ... ...

Abstract	This review provides a practical clinical perspective on the relevance of hepatic transporters in pharmacokinetics and drug-drug interactions (DDIs). Special emphasis is placed on transporters with clear relevance to clinical DDIs, efficacy, and safety. Basolateral OATP1B1 and 1B3 emerged as important hepatic drug uptake pathways, sites for systemic DDIs, and sources of pharmacogenetic variability. As the first step in hepatic drug removal from the circulation, OATPs are an important determinant of systemic pharmacokinetics, specifically influencing systemic absorption, clearance, and hepatic distribution for subsequent metabolism and/or excretion. Biliary excretion of parent drugs is a less prevalent clearance pathway than metabolism or urinary excretion, but BCRP and MRP2 are critically important to biliary/fecal elimination of drug metabolites. Inhibition of biliary excretion is typically not apparent at the level of systemic pharmacokinetics but can markedly increase liver exposure. Basolateral efflux transporters MRP3 and MRP4 mediate excretion of parent drugs and, more commonly, polar metabolites from hepatocytes into blood. Basolateral excretion is an area in need of further clinical investigation, which will necessitate studies more complex than just systemic pharmacokinetics. Clinical relevance of hepatic uptake is relatively well appreciated, and clinical consequences of hepatic excretion (biliary and basolateral) modulation remain an active research area.
MeSH term(s)	ATP Binding Cassette Transporter, Sub-Family G, Member 2/metabolism ; Animals ; Biological Transport/drug effects ; Biological Transport/physiology ; Drug Interactions/physiology ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Humans ; Liver/drug effects ; Liver/metabolism ; Membrane Transport Proteins/metabolism ; Multidrug Resistance-Associated Proteins/metabolism ; Neoplasm Proteins/metabolism ; Organic Anion Transporters/metabolism ; Pharmaceutical Preparations/administration & dosage ; Pharmaceutical Preparations/metabolism
Chemical Substances	ABCG2 protein, human ; ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; Membrane Transport Proteins ; Multidrug Resistance-Associated Proteins ; Neoplasm Proteins ; Organic Anion Transporters ; Pharmaceutical Preparations
Language	English
Publishing date	2016
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	188980-1
ISSN	1552-4604 ; 0091-2700 ; 0021-9754
ISSN (online)	1552-4604
ISSN	0091-2700 ; 0021-9754
DOI	10.1002/jcph.671
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Article ; Online: Clinical Implications of Altered Drug Transporter Abundance/Function and PBPK Modeling in Specific Populations: An ITC Perspective.

Chu, Xiaoyan / Prasad, Bhagwat / Neuhoff, Sibylle / Yoshida, Kenta / Leeder, James Steven / Mukherjee, Dwaipayan / Taskar, Kunal / Varma, Manthena V S / Zhang, Xinyuan / Yang, Xinning / Galetin, Aleksandra

Clinical pharmacology and therapeutics

2022 Volume 112, Issue 3, Page(s) 501–526

Abstract: The role of membrane transporters on pharmacokinetics (PKs), drug-drug interactions (DDIs), pharmacodynamics (PDs), and toxicity of drugs has been broadly recognized. However, our knowledge of modulation of transporter expression and/or function in the ... ...

Abstract	The role of membrane transporters on pharmacokinetics (PKs), drug-drug interactions (DDIs), pharmacodynamics (PDs), and toxicity of drugs has been broadly recognized. However, our knowledge of modulation of transporter expression and/or function in the diseased patient population or specific populations, such as pediatrics or pregnancy, is still emerging. This white paper highlights recent advances in studying the changes in transporter expression and activity in various diseases (i.e., renal and hepatic impairment and cancer) and some specific populations (i.e., pediatrics and pregnancy) with the focus on clinical implications. Proposed alterations in transporter abundance and/or activity in diseased and specific populations are based on (i) quantitative transporter proteomic data and relative abundance in specific populations vs. healthy adults, (ii) clinical PKs, and emerging transporter biomarker and/or pharmacogenomic data, and (iii) physiologically-based pharmacokinetic modeling and simulation. The potential for altered PK, PD, and toxicity in these populations needs to be considered for drugs and their active metabolites in which transporter-mediated uptake/efflux is a major contributor to their absorption, distribution, and elimination pathways and/or associated DDI risk. In addition to best practices, this white paper discusses current challenges and knowledge gaps to study and quantitatively predict the effects of modulation in transporter activity in these populations, together with the perspectives from the International Transporter Consortium (ITC) on future directions.
MeSH term(s)	Adult ; Biological Transport ; Child ; Drug Interactions ; Humans ; Membrane Transport Proteins/metabolism ; Models, Biological ; Proteomics
Chemical Substances	Membrane Transport Proteins
Language	English
Publishing date	2022-06-21
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.2643
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