S-Warfarin Limited Sampling Models to Estimate Area Under the Concentration Versus Time Curve for Cytochrome P450 2C9 Baseline Activity and After Induction

Chang, Andrew; Bertino, Joseph S.; Nafziger, Anne N.; Kashuba, Angela D. M.; Turpault, Sandrine; Lewis, Lionel D.; Joseph, D.

doi:10.1097/ftd.0000000000000277

Cited by 4 publications

(2 citation statements)

References 26 publications

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“…Consequently, the contrasting results between each study during various CYP3A conditions limit the widespread utility of these midazolam LSMs [ 23 ]. Similar findings with intravenous midazolam and oral S-warfarin (a CYP2C9 probe drug) LSMs are published elsewhere [ 25 , 26 ].…”

Section: Discussionsupporting

confidence: 83%

Limitations of fexofenadine limited sampling strategy using plasma concentrations and partial area under the concentration-time curve to estimate transporter activity in healthy adults

Liyanage¹,

Blaquera²,

Piscitelli³

et al. 2023

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Objective: Fexofenadine is a probe drug used to phenotype P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3 activities. This study evaluated a limited sampling strategy using plasma concentrations and/or partial area under the concentration versus time curves (AUCs) to estimate systemic exposure and, potentially, P-gp and OATP1B1/3 activities. Materials and methods: Plasma concentration versus time data were obtained from 53 healthy adult participants (22 females) from four published studies. Participants were administered a single oral dose (120 mg) of fexofenadine during constitutive P-gp and OATP1B1/3 conditions. Concentration-time data were divided into a training (n = 18) and validation (n = 35) set. Backwards stepwise linear regression generated single-, 2-timepoint, and partial AUC limited sampling models (LSMs). Noncompartmental analysis methods were used to determine total AUC (AUC 0–lNF ) from intensive sampling. Coefficient of determination (r 2 ) and bias and precision were assessed via relative percent mean prediction error (%MPE), relative percent mean absolute error (%MAE), and relative percent root mean square error (%RMSE). Results: The geometric mean observed AUC 0–INF was 1,680 ng×h/mL. The 2-, 5-, and 2- plus 5-hour LSMs met backwards stepwise linear regression significance (p < 0.15) to remain in the model but had unacceptable %RMSE (17 – 29%). The majority of partial AUC LSMs had unacceptable r 2 (0.21 – 0.83), with all models having unacceptable %MAE (12 – 35%). Conclusion: Fexofenadine limited sampling strategy using single-timepoint, 2-timepoint, and partial AUCs were unable to accurately estimate AUC 0–lNF and thus constitutive P-gp and OATB1B1/3 activities in healthy adults. Timepoints that were not measured or selected may have improved LSM performance.

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Section: Discussionsupporting

confidence: 83%

Limitations of fexofenadine limited sampling strategy using plasma concentrations and partial area under the concentration-time curve to estimate transporter activity in healthy adults

Liyanage¹,

Blaquera²,

Piscitelli³

et al. 2023

Self Cite

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show abstract

“…Furthermore, limited sampling can be subject to large variability due to, for example, delayed drug absorption, especially if the metric is based on the parent drug concentration only. For example, limited sampling strategies for midazolam and warfarin have shown poor correlation with full pharmacokinetic profiling . On the other hand, determination of a metabolic ratio from a single time point can be a more useful metric that accurately reflects the systemic clearance of the drug.…”

Section: Design Of Clinical Ddi Studiesmentioning

confidence: 99%

Clinical Studies on Drug–Drug Interactions Involving Metabolism and Transport: Methodology, Pitfalls, and Interpretation

Tornio

Filppula

Niemi

et al. 2019

Clin Pharma and Therapeutics

132

139

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Many drug–drug interactions ( DDI s) are based on alterations of the plasma concentrations of a victim drug due to another drug causing inhibition and/or induction of the metabolism or transporter‐mediated disposition of the victim drug. In the worst case, such interactions cause more than tenfold increases or decreases in victim drug exposure, with potentially life‐threatening consequences. There has been tremendous progress in the predictability and modeling of DDI s. Accordingly, the combination of modeling approaches and clinical studies is the current mainstay in evaluation of the pharmacokinetic DDI risks of drugs. In this paper, we focus on the methodology of clinical studies on DDI s involving drug metabolism or transport. We specifically present considerations related to general DDI study designs, recommended enzyme and transporter index substrates and inhibitors, pharmacogenetic perspectives, index drug cocktails, endogenous substrates, limited sampling strategies, physiologically‐based pharmacokinetic modeling, complex DDI s, methodological pitfalls, and interpretation of DDI information.

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S-warfarin limited sampling strategy with a population pharmacokinetic approach to estimate exposure and cytochrome P450 (CYP) 2C9 activity in healthy adults

Tran

Nikanjam

Capparelli

et al. 2021

Eur J Clin Pharmacol

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S-Warfarin Limited Sampling Models to Estimate Area Under the Concentration Versus Time Curve for Cytochrome P450 2C9 Baseline Activity and After Induction

Abstract: The differing results during CYP2C9 baseline conditions, as well as unacceptable bias and precision in patients with advanced cancer and during CYP2C9 induction, considerably limit the widespread use of previously published S-warfarin LSMs.

Cited by 4 publications

References 26 publications

Limitations of fexofenadine limited sampling strategy using plasma concentrations and partial area under the concentration-time curve to estimate transporter activity in healthy adults

Limitations of fexofenadine limited sampling strategy using plasma concentrations and partial area under the concentration-time curve to estimate transporter activity in healthy adults

Clinical Studies on Drug–Drug Interactions Involving Metabolism and Transport: Methodology, Pitfalls, and Interpretation

S-warfarin limited sampling strategy with a population pharmacokinetic approach to estimate exposure and cytochrome P450 (CYP) 2C9 activity in healthy adults

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