Simulation of Metabolic Drug-Drug Interactions Perpetrated by Fluvoxamine Using Hybridized Two-Compartment Hepatic Drug-Pool-Based Tube Modeling and Estimation of In Vivo Inhibition Constants

Iga, Kanji

doi:10.1002/jps.24549

Cited by 7 publications

(4 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…If a drug is only metabolised by a single CYP (a mono-CYP substrate), meaning having a high fmCYP of more than 80%, there is a high risk for a DDI. Examples of this are the DDIs between ramelteon and fluvoxamine for CYP1A2 (Iga, 2015), and midazolam and ketoconazole for CYP3A4 (Olkkola et al, 1994) with substrate systemic (Gibbons et al, 2015)). The lowest risk of a DDI is linked to an fmCYP of less than 25% (representing a minor pathway), whereby regulatory guidelines recommend that clinical DDI studies are not required for these drugs.…”

Section: Discussionmentioning

confidence: 99%

Direct and quantitative evaluation of the major human CYP contribution (fmCYP) to drug clearance using thein vitroSilensomes™ model

et al. 2018

View full text Add to dashboard Cite

1. We have applied the concept of using MBIs to produce CYP-Silensomes to quantify the contribution of the major CYPs to drug metabolism (fmCYP). 2. The target CYPs were extensively and selectivity inhibited by the selected MBIs, while non-target CYPs were inhibited by less than 20% of the homologous control activities. Only CYP2D6-Silensomes exhibited a CYP2B6 inhibition that could be easily and efficiently encountered by subtracting the fm measured using CYP2B6-Silensomes to adjust the fm. 3. To validate the use of a panel of 6 CYP-Silensomes, we showed that the fmCYP values of mono- and multi-CYP metabolised drugs were well predicted, with 70% within ± 15% accuracy. Moreover, the correlation with observed fmCYP values was higher than that for rhCYPs, which were run in parallel using the same drugs (<45% within ±15% accuracy). Moreover, the choice of the RAF substrate in rhCYP predictions was shown to affect the accuracy of the fmCYP measurement. 4. These results support the use of CYP1A2-, CYP2B6-, CYP2C8-, CYP2C9-, CYP2D6 and CYP3A4-Silensomes to accurately predict fmCYP values during the in vitro enzyme phenotyping assays in early, as well as in development, phases of drug development.

show abstract

Section: Discussionmentioning

confidence: 99%

Direct and quantitative evaluation of the major human CYP contribution (fmCYP) to drug clearance using thein vitroSilensomes™ model

et al. 2018

View full text Add to dashboard Cite

show abstract

“…This magnitude of DDI had been deemed to be difficult to predict by any methods until we devised the mechanism. 13) The AUCR predicted by either a static method [constant unbound inhibitor (I u )-based method] as shown below, or a dynamic method (time-dependent I u -based method) employing physiologically-based pharmacokinetic (PBPK) model, wherein the well-stirred model was applied for the hepatic extraction kinetics, was no more than 5. 4) Typically, the value of AUCR estimated by a well-stirred model-based static method * To whom correspondence should be addressed.…”

Section: Unusualness Of Ramelteon (Ram)-victimizedmentioning

confidence: 99%

“…[12][13][14][15] Thus, the present review focuses on our achievements in DDI prediction by use of this method.…”

Section: Introductionmentioning

confidence: 99%

Usefulness of Two-Compartment Model-Assisted and Static Overall Inhibitory-Activity Method for Prediction of Drug–Drug Interaction

Iga

Kiriyama

2017

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

Our study of drug-drug interaction (DDI) started with the clarification of unusually large DDI observed between ramelteon (RAM) and fluvoxamine (FLV). The main cause of this DDI was shown to be the extremely small hepatic availability of RAM (vF h ). Traditional DDI prediction assuming the well-stirred hepatic extraction kinetic ignores the relative increase of vF h by DDI, while we could solve this problem by use of the tube model. Ultimately, we completed a simple and useful method for prediction of DDI. Currently, DDI prediction becomes more complex and difficult when examining issues such as dynamic changes in perpetrator level, inhibitory metabolites, etc. The regulatory agents recommend DDI prediction by use of some sophisticated methods. However, they seem problematic in requiring plural in vitro data that reduce the flexibility and accuracy of the simulation. In contrast, our method is based on the static and two-compartment models. The two-compartment model has advantages in that it uses common pharmacokinetics (PK) parameters determined from the actual clinical data, guaranteeing the simulation of the reference standard in DDI. Our studies confirmed that dynamic changes in perpetrator level do not make a difference between static and dynamic methods. DDIs perpetrated by FLV and itraconazole were successfully predicted by use of the present method where two DDI predictors [perpetrator-specific inhibitory activities toward CYP isoforms (pA i, CYP s) and victim-specific fractional CYP-isoform contributions to the clearance (vf m, CYP s)] are determined successively as shown in the graphical abstract. Accordingly, this approach will accelerate DDI prediction over the traditional methods.

show abstract

“…Subsequent research by the authors [3][4][5][6][7] revealed that the unusually large DDI was caused by the very low hepatic availability (Fh) of ramelteon, and derived the theory using the tube-based hepatic extraction model, that the magnitude of the interaction (AUCR) is determined by the overall enzymatic inhibitory activity produced by DDI (Ai,overall) and Fh of the victim drug as: AUCR = [1/Fh -1]/[exp{-Ln(Fh)/Ai,overall} -1]…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of CYP2C8-medidated drug-drug interactions produced by CYP2C8 inhibitors, gemfibrozil versus clopidogrel, focusing on the inhibition of drug distribution in UDP-glucuronosyltransferase prior to oxidation

Iga

Kiriyama

2023

Preprint

Self Cite

View full text Add to dashboard Cite

Purpose It is challenging to predict CYP2C8-mediated drug-drug interactions (DDIs) produced by clopidogrel (Clop) and gemfibrozil (Gem) by maintaining the victim’s fractional CYP2C8-mediated clearance (fm,CYP2C8) constant. The goal is to develop a comprehensive methodology for this. Method A model where UDP glucuronosyl transferase (UGT) and CYP work in pairs was devised, under the assumption that CYP2C8 substrates bind UGT before oxidation, and that Gem inhibits UGT and CYP2C8 while Clop inhibits CYP2C8 alone. Overall enzymatic inhibitory activity resulting from DDI was expressed as a function of fm,CYP2C8, fm,UGT (fractional UGT-mediated clearance), and perpetrator specific inhibitory activities against CYP2C8 and UGT (pAi,CYP2C8 and pAi,UGT(d)). Reported DDIs where Clop, Gem, or Gem + itraconazole have victimized montelukast, desloratadine, pioglitazone, repaglinide (OATP1B1 substrate) or cerivastatin (OATP1B1 substrate) were chosen for the analysis. Additionally, a method to simulate the victim’s plasma metabolite levels in response to the changes in the plasma unchanged drug levels was devised based on the previous method. Results The changes in the plasma levels of unchanged drug and metabolite produced by the DDIs were simulated successfully. The results confirmed the DDIs were not affected by the hepatic uptake transporter (OATP1B1). The pAi,CYP2C8 values for Clop and Gem were estimated to be 7 (85% inhibition) and 15 (93% inhibition). The pAi,UGT(d) values for Clop and Gem were estimated to be 1 (non-inhibition) and 2 (50% inhibition). Conclusions To predict CYP2C8 mediated DDIs, information on the victim’s fm,CYP2C8 and fm,UGT as well as the perpetrator’s pAi,CYP2C8 and pAi,UGT(d) are the most important.

show abstract

Simulation of Metabolic Drug-Drug Interactions Perpetrated by Fluvoxamine Using Hybridized Two-Compartment Hepatic Drug-Pool-Based Tube Modeling and Estimation of In Vivo Inhibition Constants

Cited by 7 publications

References 25 publications

Direct and quantitative evaluation of the major human CYP contribution (fmCYP) to drug clearance using thein vitroSilensomes™ model

Direct and quantitative evaluation of the major human CYP contribution (fmCYP) to drug clearance using thein vitroSilensomes™ model

Usefulness of Two-Compartment Model-Assisted and Static Overall Inhibitory-Activity Method for Prediction of Drug–Drug Interaction

Comparative analysis of CYP2C8-medidated drug-drug interactions produced by CYP2C8 inhibitors, gemfibrozil versus clopidogrel, focusing on the inhibition of drug distribution in UDP-glucuronosyltransferase prior to oxidation

Contact Info

Product

Resources

About