Time-Dependent Inhibition and Estimation of CYP3A Clinical Pharmacokinetic Drug-Drug Interactions Using Plated Human Cell Systems

Albaugh, Daniel; Fullenwider, Cody L.; Fisher, Michael B.; Hutzler, J. Matthew

doi:10.1124/dmd.112.044644

Cited by 21 publications

(18 citation statements)

References 33 publications

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“…The ratio of k inact /K I also suggests that mibefradil and troleandomycin are the most potent time-dependent inhibitors in the set, with respective inactivation ratios of 1400 and 345 ml/min·mmol. These values are in agreement with what was determined by Albaugh et al (2012), who similarly evaluated a plated hepatocyte assay, but used midazolam as probe substrate. Verapamil and clarithromycin were observed to have relatively moderate inactivation potential.…”

Section: Resultssupporting

confidence: 90%

“…The inactivation constants for the validation set derived using the pooled donor HH8004 are reported in Table 2, including the ratio of k inact /K I . These values are in agreement with what was determined by Albaugh et al (2012) using a similar approach. In vitro parameters of inactivation were used to predict DDI and were compared with published clinical study data.…”

Section: Discussionsupporting

confidence: 92%

“…One major advantage of this is that the lots can be validated using known TDIs with clinically observed DDIs (Tables 2 and 4), which also provides the opportunity to assess the risk of DDIs with compounds in development compared with known TDIs in the clinic. Similar to Albaugh et al (2012), the AUC changes predicted across different lots resulted in fairly similar outcomes (Fig. 8).…”

Section: Discussionmentioning

confidence: 64%

“…Earlier, we described the DDIs observed between gemfibrozil and cerivastatin as well as bupropion and dextromethorphan, where the involvement of transporters in the observed DDI cannot be excluded (Parkinson et al, 2010). Albaugh et al (2012) assessed the utility of freshly prepared plated hepatocytes, cryopreserved plated hepatocytes, and plated HepaRG cells for the estimation of TDI parameters using a subset of compounds with clinically observed DDIs due to CYP3A4 TDI. In general, the estimated DDIs derived from each of the tested systems agreed with the clinically reported DDI within approximately 2-fold.…”

Section: Discussionmentioning

confidence: 99%

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VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions

Zetterberg

Maltais

Laitinen

et al. 2016

Drug Metabolism and Disposition

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(R)-2-((2-(1H-pyrrolo [2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide decernotinib) is an oral Janus kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis. Patients with rheumatoid arthritis often receive multiple medications, such as statins and steroids, to manage the signs and symptoms of comorbidities, which increases the chances of drug-drug interactions (DDIs). Mechanism-based inhibition is a subset of time-dependent inhibition (TDI) and occurs when a molecule forms a reactive metabolite which irreversibly binds and inactivates drug-metabolizing enzymes, potentially increasing the systemic load to toxic concentrations. Traditionally, perpetrating compounds are screened using human liver microsomes (HLMs); however, this system may be inadequate when the precipitant is activated by a non-cytochrome P450 (P450)-mediated pathway. Even though studies assessing competitive inhibition and TDI using HLM suggested a low risk for CYP3A4-mediated DDI in the clinic, VX-509 increased the area under the curve of midazolam, atorvastatin, and methyl-prednisolone by approximately 12.0-, 2.7-, and 4.3-fold, respectively. Metabolite identification studies using human liver cytosol indicated that VX-509 is converted to an oxidative metabolite, which is the perpetrator of the DDIs observed in the clinic. As opposed to HLM, hepatocytes contain the full complement of drug-metabolizing enzymes and transporters and can be used to assess TDI arising from non-P450-mediated metabolic pathways. In the current study, we highlight the role of aldehyde oxidase in the formation of the hydroxylmetabolite of VX-509, which is involved in clinically significant TDIbased DDIs and represents an additional example in which a system-dependent prediction of TDI would be evident.

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Section: Resultssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions

Zetterberg

Maltais

Laitinen

et al. 2016

Drug Metabolism and Disposition

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“…3B). The simulated and observed shifted IC 50 curves were shifted to left (more a Reference values compiled from the following sources: Mayhew et al, 2000;Bertelsen et al, 2003;Ito et al, 2003;Zhao et al, 2005Zhao et al, , 2007Obach et al, 2007;Watanabe et al, 2007;Berry and Zhao, 2008;Perloff et al, 2009;Li et al, 2009;Mori et al, 2009;Xu et al, 2009;Kirby et al, 2011;Albaugh et al, 2012;Kenny et al, 2012; Amgen in-house data; University of Washington Drug Interaction Database (www.druginteractioninfo.org). dmd.aspetjournals.org potent) relative to the simulated and observed IC 50 curves, indicating time-dependent inactivation of CYP3A4.…”

Section: Downloaded Frommentioning

confidence: 99%

Dynamic Modeling of Cytochrome P450 Inhibition In Vitro: Impact of Inhibitor Depletion on IC₅₀ Shift

2013

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The impact of inhibitor depletion on the determination of shifted IC 50 (IC 50 determined after 30 minutes of preincubation with inhibitor) is examined. In addition, IC 50 -shift data are analyzed using a mechanistic model that incorporates the processes of inhibitor depletion, as well as reversible and time-dependent inhibition. Anomalies such as a smaller-than-expected shift in IC 50 and even increases in IC 50 with preincubation were explained by the depletion of inhibitor during the preincubation. The IC 50 -shift assay remains a viable approach to characterizing a wide range of reversible and time-dependent inhibitors. However, as with more traditional time-dependent inactivation methods, it is recommended that IC 50 -shift experimental data be interpreted with some knowledge of the magnitude of inhibitor depletion. For the most realistic classification of time-dependent inhibitors using IC 50 -shift methods, shifted IC 50 should be calculated using observed inhibitor concentrations at the end of the incubation rather than nominal inhibitor concentrations. Finally, a mechanistic model that includes key processes, such as competitive inhibition, enzyme inactivation, and inhibitor depletion, can be used to describe accurately the observed IC 50 and shifted IC 50 curves. For compounds showing an IC 50 fold shift >1.5 based on the observed inhibitor concentrations, reanalyzing the IC 50 -shift data using the mechanistic model appeared to allow for reasonable estimation of K i , K I , and k inact directly from the IC 50 shift experiments.

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Assessment of CYP3A4 Time-Dependent Inhibition in Plated and Suspended Human Hepatocytes

Zhang

Stresser

2013

Methods in Pharmacology and Toxicology

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Time-Dependent Inhibition and Estimation of CYP3A Clinical Pharmacokinetic Drug-Drug Interactions Using Plated Human Cell Systems

Cited by 21 publications

References 33 publications

VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions

VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions

Dynamic Modeling of Cytochrome P450 Inhibition In Vitro: Impact of Inhibitor Depletion on IC₅₀ Shift

Assessment of CYP3A4 Time-Dependent Inhibition in Plated and Suspended Human Hepatocytes

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Time-Dependent Inhibition and Estimation of CYP3A Clinical Pharmacokinetic Drug-Drug Interactions Using Plated Human Cell Systems

Cited by 21 publications

References 33 publications

VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions

VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions

Dynamic Modeling of Cytochrome P450 Inhibition In Vitro: Impact of Inhibitor Depletion on IC50 Shift

Assessment of CYP3A4 Time-Dependent Inhibition in Plated and Suspended Human Hepatocytes

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Dynamic Modeling of Cytochrome P450 Inhibition In Vitro: Impact of Inhibitor Depletion on IC₅₀ Shift