Presented virtually at ASCPT Annual Meeting, March 2021
Katie Owens, Sophie Argon, Jingjing Yu, Isabelle Ragueneau-Majlessi, and colleagues at FDA
Food-effect (FE) and gastric pH-mediated drug-drug interactions (DDIs) are absorption-related. Here. we evaluated of the Biopharmaceutical Classification System (BCS) may be correlated with FE or pH-mediated DDI observed.
Presented virtually at ASCPT Annual Meeting, March 2021
Lindsay M. Henderson, Claire Steinbronn, Jingjing Yu, Cathy Yeung, and Isabelle Ragueneau-Majlessi
This study’s objective was to evaluate the consistency in DDI labeling language of recently marketed drugs (2012-2020) when found to alter the exposure of coadministered digoxin, a clinical P-glycoprotein (P-gp) substrate and narrow therapeutic index (NTI) medication.
New drug application reviews contain critical drug interaction study results with newly approved drugs tested both as victims and as perpetrators of drug-drug interactions (DDIs). Pharmacokinetic-based DDI data for drugs approved by the US Food and Drug Administration in 2013–2017 (N = 137) were analyzed using the University of Washington Drug Interaction Database. For the largest metabolism- and transporter-based drug interactions, defined as a change in exposure ≥ 5-fold in victim drugs, the mechanisms and clinical relevance were characterized. Consistent with the major role of CYP3A in drug disposition, CYP3A inhibition and induction explained a majority of the observed interactions (new drugs as victims or as perpetrators). However, transporter-mediated interactions were also prevalent, with OATP1B1/1B3 playing a significant role. As victims, 17 and 4 new molecular entities (NMEs) were identified to be sensitive substrates of enzymes and transporters, respectively. When considered as perpetrators, three drugs showed strong inhibition of CYP3A, one was a strong CYP3A inducer, and two showed strong inhibition of transporters (OATP1B1/1B3 and/or BCRP). All DDIs with AUC changes ≥ 5-fold had labeling recommendations in their respective drug labels, contraindicating or limiting the coadministration with known substrates or perpetrators of the enzyme/transporter involved. The majority of sensitive substrates or strong inhibitors were oncology and antiviral treatments, suggesting a significant risk of DDIs in these patient populations for whom therapeutic management is already complex due to poly-therapy. Pharmacogenetic studies and physiologically based pharmacokinetic models were commonly used to assess the drug interaction potential in specific populations and clinical scenarios. Finally, absorption-based DDIs were evaluated in approximately 30% of drug applications, and 14 NMEs had label recommendations based on the results.
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.
A systematic analysis of the inhibition transporter data available in New Drug Applications of drugs approved by the US Food and Drug Administration (FDA) in 2018 (N = 42) was performed. In vitro‐to‐in vivo predictions using basic models were available for the nine transporters currently recommended for evaluation. Overall, 29 parents and 16 metabolites showed in vitro inhibition of at least one transporter, with the largest number of drugs found to be inhibitors of P‐gp followed by BCRP. The most represented therapeutic areas were oncology drugs and anti‐infective agents, each comprising 31%. Among drugs with prediction values greater than the FDA recommended cutoffs and further evaluated in vivo, 56% showed positive clinical interactions (area under the concentration‐time curve ratio (AUCRs) ≥ 1.25). Although all the observed or simulated inhibitions were weak (AUCRs < 2), seven of the nine interactions (involving five drugs) resulted in labeling recommendations. Interestingly, more than half of the drugs with predictions greater than the cutoffs had no further evaluations, highlighting that current basic models represent a useful, simple first step to evaluate the clinical relevance of in vitro findings, but that multiple other factors are considered when deciding the need for clinical studies. Four drugs had prediction values less than the cutoffs but had clinical evaluations or physiologically‐based pharmacokinetic simulations available. Consistent with the predictions, all of them were confirmed not to inhibit these transporters in vivo (AUCRs of 0.94–1.09). Overall, based on the clinical evaluations available, drugs approved in 2018 were found to have a relatively limited impact on drug transporters, with all victim AUCRs < 2.
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.
Presented at ISSX conference, June 2019, Portland, OR, USA
Jingjing Yu, Ichiko Petrie, and Isabelle Ragueneau-Majlessi
The aim of the present work was to review pharmacokinetic drug-drug interaction (DDI) data available in New Drug Applications (NDAs) for drugs approved by the US Food and Drug Administration in 2018 and analyze the mechanisms mediating interactions that triggered label recommendations.
Presented at ISSX conference, June 2019, Portland, OR, USA
Savannah J. McFeely, Yu, Tasha K. Ritchie, and Isabelle Ragueneau-Majlessi
The effect of inhibition of the organic anion transporting polypeptides (OATP) 1B1 and 1B3 has continued to grow in clinical significance and recognition. In the last five years, a signification portion of newly approved drugs in the US have been shown to be inhibitors of OATP1B1 and/or OATP1B3 in vitro. For this reason, it is critical to understand the effect of experimental variability on drug interaction predictions and how it impacts the decision for a clinical evaluation.
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.
No abstract available.