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1.
CPT Pharmacometrics Syst Pharmacol ; 10(8): 953-961, 2021 08.
Article in English | MEDLINE | ID: mdl-34102029

ABSTRACT

Although the use of excipients is widespread, a thorough understanding of the drug interaction potential of these compounds remains a frequent topic of current research. Not only can excipients alter the disposition of coformulated drugs, but it is likely that these effects on co-administered drugs can reach to clinical significance leading to potential adverse effects or loss of efficacy. These risks can be evaluated through use of in silico methods of mechanistic modeling, including approaches, such as population pharmacokinetic (PK) and physiologically-based PK modeling, which require a comprehensive understanding of the compounds to ensure accurate predictions. We established a knowledgebase of the available compound (or substance) and interaction-specific parameters with the goal of providing a single source of physiochemical, in vitro, and clinical PK and interaction data of commonly used excipients. To illustrate the utility of this knowledgebase, a model for cremophor EL was developed and used to hypothesize the potential for CYP3A- and P-gp-based interactions as a proof of concept.


Subject(s)
Excipients/pharmacology , Glycerol/analogs & derivatives , Knowledge Bases , Models, Biological , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Computer Simulation , Cytochrome P-450 CYP3A/drug effects , Cytochrome P-450 CYP3A/metabolism , Drug Interactions , Glycerol/pharmacology , Humans
2.
J Clin Pharmacol ; 60(8): 1087-1098, 2020 08.
Article in English | MEDLINE | ID: mdl-32196692

ABSTRACT

Organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 are the primary hepatic transporters responsible for uptake of drugs into the liver and, as such, an area of growing research focus. Currently, evaluation of these transporters as potential mediators of drug-drug interactions (DDIs) is recommended by regulatory agencies worldwide during the drug development process. Despite the growing focus on OATP1B1/1B3 as mediators of DDIs, only 2 drugs are recommended as index inhibitors for use in clinical studies, single-dose rifampin and cyclosporine, each with limitations for the utility of the resulting data. In this study a thorough analysis of the available in vitro and clinical data was conducted to identify drugs that are clinically relevant inhibitors of OATP1B1/1B3 and, from those, to select any novel index inhibitors. A total of 13 drugs and 16 combination products were identified as clinical inhibitors of OATP1B1/1B3, showing significant changes in exposure for sensitive substrates of the transporters, with strong supporting in vitro evidence. Although none of the identified inhibitors qualified as index inhibitors, this study confirmed the utility of cyclosporine and single-dose rifampin as index inhibitors to evaluate the effect of broad, multiple-pathway inhibition and more selective OATP1B1/1B3 inhibition, respectively.


Subject(s)
Liver-Specific Organic Anion Transporter 1/antagonists & inhibitors , Solute Carrier Organic Anion Transporter Family Member 1B3/antagonists & inhibitors , Animals , Biological Transport , Cyclosporine/pharmacology , Databases, Pharmaceutical , Drug Interactions , Drug Labeling , Humans , Oocytes/drug effects , Rifampin/pharmacology , United States , United States Food and Drug Administration , Xenopus laevis
3.
Clin Transl Sci ; 13(1): 47-52, 2020 01.
Article in English | MEDLINE | ID: mdl-31468718

ABSTRACT

As the research into the organic anion transporting polypeptides (OATPs) continues to grow, it is important to ensure that the data generated are accurate and reproducible. In the in vitro evaluation of OATP1B1/1B3 inhibition, there are many variables that can contribute to variability in the resulting inhibition constants, which can then, in turn, contribute to variable results when clinical predictions (R-values) are performed. Currently, the only experimental condition recommended by the US Food and Drug Administration (FDA) is the inclusion of a pre-incubation period.1 To identify other potential sources of variability, a descriptive analysis of available in vitro inhibition data was completed. For each of the 21 substrate/inhibitor pairs evaluated, cell type and pre-incubation were found to have the greatest effect on half-maximal inhibitory concentration (IC50 ) variability. Indeed, when only HEK293 cells and co-incubation conditions were included, the observed variability for the entire data set (highest IC50 /lowest) was reduced from 12.4 to 5.2. The choice of probe substrate used in the study also had a significant effect on inhibitor constant variability. Interestingly, despite the broad range of inhibitory constants identified, these two factors showed little effect on the calculated R-values relative to the FDA evaluation cutoff of 1.1 triggering a clinical evaluation for the inhibitors evaluated. However, because of the small data set available, further research is needed to confirm these preliminary results and define best practice for the study of OATPs.


Subject(s)
Drug Evaluation, Preclinical/methods , Liver-Specific Organic Anion Transporter 1/antagonists & inhibitors , Solute Carrier Organic Anion Transporter Family Member 1B3/antagonists & inhibitors , Cell Culture Techniques/methods , Cell Culture Techniques/standards , Cyclosporine/pharmacology , Datasets as Topic , Drug Evaluation, Preclinical/standards , Drug Interactions , Gemfibrozil/pharmacology , Guidelines as Topic , HEK293 Cells , Humans , Inhibitory Concentration 50 , Liver-Specific Organic Anion Transporter 1/metabolism , Reproducibility of Results , Rifampin/pharmacology , Solute Carrier Organic Anion Transporter Family Member 1B3/metabolism , United States , United States Food and Drug Administration/standards
4.
Clin Pharmacol Ther ; 105(6): 1378-1385, 2019 06.
Article in English | MEDLINE | ID: mdl-30771252

ABSTRACT

Despite recent advances in recognizing and reducing the risk of drug-drug interactions (DDIs) in developed countries, there are still significant challenges in managing DDIs in low-income countries (LICs) worldwide. In the treatment of major infectious diseases in these regions, multiple factors contribute to ineffective management of DDIs that lead to loss of efficacy or increased risk of adverse events to patients. Some of these difficulties, however, can be overcome. This review aims to evaluate the inherent complexities of DDI management in LICs from pharmacological standpoints and illustrate the unique barriers to effective management of DDIs, such as the challenges of co-infection and treatment settings. A better understanding of comprehensive drug-related properties, population-specific attributes, such as physiological changes associated with infectious diseases, and the use of modeling and simulation techniques are discussed, as they can facilitate the implementation of optimal treatments for infectious diseases at the individual patient level.


Subject(s)
Anti-Infective Agents/therapeutic use , Communicable Diseases/drug therapy , Communicable Diseases/economics , Drug Interactions/physiology , Poverty/economics , Anti-Infective Agents/economics , Anti-Infective Agents/metabolism , Antitubercular Agents/economics , Antitubercular Agents/metabolism , Antitubercular Agents/therapeutic use , Communicable Diseases/metabolism , Humans , Poverty/trends , Treatment Outcome , Tuberculosis/drug therapy , Tuberculosis/economics , Tuberculosis/metabolism
5.
Clin Transl Sci ; 12(4): 379-387, 2019 07.
Article in English | MEDLINE | ID: mdl-30706983

ABSTRACT

Organic anion transporting polypeptides (OATPs) 1B1 and 1B3 facilitate the uptake of drugs and endogenous compounds into the liver. In recent years, the impact of these transporters on drug-drug interactions (DDIs) has become a focus of research, and the evaluation of their role in drug disposition is recommended by regulatory agencies worldwide.1-3 Although sensitive substrates of OATP1B1/1B3 have been identified in the literature and probe drugs have been proposed by regulatory agencies, there is no general consensus on the ideal in vivo substrate for clinical DDI studies as analysis may be confounded by contribution from other metabolic and/or transport pathways.1-3 A thorough analysis of the available in vitro and in vivo data regarding OATP1B1/1B3 substrates was performed using the in vitro, clinical, and pharmacogenetic modules in the University of Washington Drug Interaction Database. A total of 34 compounds were identified and further investigated as possible clinical substrates using a novel indexing system. By analyzing the compounds for in vivo characteristics, including sensitivity to inhibition by known OATP1B1/1B3 inhibitors, selectivity for OATP1B1/1B3 compared with other transport and metabolic pathways, and safety profiles, a total of six compounds were identified as potential clinical markers of OATP1B1/1B3 activity.


Subject(s)
Liver-Specific Organic Anion Transporter 1/metabolism , Solute Carrier Organic Anion Transporter Family Member 1B3/metabolism , Biomarkers/metabolism , Drug Interactions , Humans , Substrate Specificity
6.
Pharmacol Ther ; 196: 204-215, 2019 04.
Article in English | MEDLINE | ID: mdl-30557631

ABSTRACT

The importance of uptake transporters in determining drug disposition is increasingly appreciated. While the focus of regulatory agencies worldwide has been on the hepatic organic anion transporting polypeptides (OATPs)-1B1 and-1B3, there is another isoform of the OATP sub-family, OATP2B1, which should be considered equally relevant. Unlike the other members of the OATP sub-family, OATP2B1 is expressed in multiple organs in humans, including in the intestine and the liver. Similar to other OATPs, OATP2B1 mediates the hepatic and intestinal uptake of many drugs and endogenous compounds. The importance of OATP2B1 in the disposition of many drugs is highlighted by the growing recognition of its role in significant in vivo drug-drug or food-drug interactions. The dramatic changes in drug exposure attributable to inhibition of OATP2B1 highlight the importance of developing a better understanding of the clinical role of OATP2B1. This review aims to provide a thorough summary of the current understanding of the pharmacogenetics, regulation, expression and abundance of OATP2B1 in humans, as well as its clinical relevance in drug-drug and food-drug interactions.


Subject(s)
Drug Interactions , Organic Anion Transporters/metabolism , Humans , Organic Anion Transporters/antagonists & inhibitors , Organic Anion Transporters/genetics
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