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Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria.

ABSTRACT: A P-glycoprotein (P-gp) IC₅₀ working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC₅₀ determinations. Each laboratory followed its in-house protocol to determine in vitro IC₅₀ values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells--Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC₅₀ values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC₅₀ values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC₅₀ values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC₅₀ values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC₅₀ values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC₅₀ determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations are provided.

SUBMITTER: Bentz J

PROVIDER: S-EPMC3684820 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria.

Bentz Joe J O'Connor Michael P MP Bednarczyk Dallas D Coleman Joann J Lee Caroline C Palm Johan J Pak Y Anne YA Perloff Elke S ES Reyner Eric E Balimane Praveen P Brännström Marie M Chu Xiaoyan X Funk Christoph C Guo Ailan A Hanna Imad I Herédi-Szabó Krisztina K Hillgren Kate K Li Libin L Hollnack-Pusch Evelyn E Jamei Masoud M Lin Xuena X Mason Andrew K AK Neuhoff Sibylle S Patel Aarti A Podila Lalitha L Plise Emile E Rajaraman Ganesh G Salphati Laurent L Sands Eric E Taub Mitchell E ME Taur Jan-Shiang JS Weitz Dietmar D Wortelboer Heleen M HM Xia Cindy Q CQ Xiao Guangqing G Yabut Jocelyn J Yamagata Tetsuo T Zhang Lei L Ellens Harma H

Drug metabolism and disposition: the biological fate of chemicals 20130425 7

A P-glycoprotein (P-gp) IC₅₀ working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC₅₀ determinations. Each laboratory followed its in-house protocol to determine in vitro IC₅₀ values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; si ...[more]

PMID: 23620485

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Project description:Background: Increasingly, multi-criteria decision analysis has gained importance as a method by which to assess the value of orphan drugs. However, very little attention has been given to the weight (relative preferences) of the individual criteria used in a framework. Aims: This study sought to gain an understanding of the preferential weights that should be allocated in a multi-criteria decision analysis framework for orphan drugs, from a multi-stakeholder perspective. Method: Using key MCDA criteria for orphan drugs reported in the literature, we developed an interactive web-based survey tool to capture preferences for different criteria from a general stakeholder sample who were requested to assign weights from a reimbursement perspective. Each criterion could be assigned a weight on a sliding scale from 0 to 100% as long as the sum of all the criteria was 100%. We subsequently used the interactive tool with an expert focus group, followed up with a group discussion regarding each criterion and their perspectives on the weight that each criterion should be allocated when assessing an orphan drug. The expert focus group participants were then able to adjust their weights, if the group discussion had changed their perspectives. Results: The interactive tool was completed by 120 general stakeholder sample from a wide range of countries and professional backgrounds and an expert focus group of ten members. The results showed the differences in perspectives on the importance of criteria. Both groups considered Treatment efficacy to be the most important criterion. The general stakeholder sample weighted Treatment safety at 12.03% compared to the expert focus group's average of 20%. The results also demonstrated the value of the group discussion, which provided additional insights into the perspectives on the importance of criteria in assessing orphan drugs. Conclusion: This study aimed to contribute to the important aspect of preferences for different criteria in MCDA. This study sheds light on the important aspect of the preferences of the different criteria. All respondents agreed on the relative importance of Treatment efficacy and Treatment safety, criteria that are captured in conventional cost-effectiveness studies, but they also expressed the view that in addition to those, several disease-related and drug-related criteria should be included in MCDA frameworks for assessing orphan drugs.

Dataset Information

Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria.

Publications

Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria.

Similar Datasets

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