Utilizing physiologically based pharmacokinetic modeling to predict theoretically conceivable extreme elevation of serum flecainide concentration in an anuric hemodialysis patient with cirrhosis

European Journal of Clinical Pharmacology volume 76, pages821–831(2020)Cite this article

Abstract

Purpose

Higher drug concentrations in complex clinical scenarios in which multiple factors such as drug–drug interactions (DDIs) and comorbidities are simultaneously present are not necessarily rationalized in prospective clinical studies. Physiologically based pharmacokinetic (PBPK) modeling and simulation of the anti-arrhythmic drug flecainide, as an example, were utilized to quantitatively rationalize the higher flecainide concentration in a complex clinical case involving end-stage renal disease (ESRD), cirrhosis, and the co-administration of mexiletine, a CYP1A2 inhibitor.

Methods

The developed flecainide PBPK model was used to evaluate the DDI effect (as measured by AUC ratio before and after inhibition) of mexiletine and the combined disease effects of ESRD and cirrhosis on flecainide exposure.

Results

The predicted DDI effect of mexiletine was negligible or weak in anuric hemodialysis with cirrhosis population (mean [5th/95th percentiles], 1.23 [0.97–1.67]), although it was negligible in healthy volunteers (1.03 [1.02–1.05]). The predicted flecainide concentrations after multiple flecainide doses (50 mg BID) in the anuric hemodialysis with cirrhosis population were comparable with the observed value (3602 ng/mL), which fell between the predicted concentrations in the absence and presence of mexiletine (3043 [718–8499] and 5914 [880–20,624] ng/mL, respectively).

Conclusions

The PBPK simulation proposed a likely explanation that the observed higher flecainide concentration could be attributed to the combined effects of ESRD, cirrhosis, and a potential DDI with mexiletine. This approach provides quantitative insight into theoretically conceivable extremes in drug exposure occurring in complex clinical situations even if uncommon.

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Affiliations

  1. Department of Pharmaceutical Sciences, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8575, Japan

    Kosuke Doki & Masato Homma

  2. Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

    Keisuke Kuga, Kazutaka Aonuma & Masaki Ieda

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  1. Kosuke Doki
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  2. Keisuke Kuga
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  3. Kazutaka Aonuma
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  4. Masaki Ieda
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  5. Masato Homma
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Contributions

KD, KK, KA, MI, and MH wrote the manuscript; KD and MH designed the research; KD, KK, KA, MI, and MH performed the research; KD and KK analyzed the data.

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Correspondence to Kosuke Doki.

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Doki, K., Kuga, K., Aonuma, K. et al. Utilizing physiologically based pharmacokinetic modeling to predict theoretically conceivable extreme elevation of serum flecainide concentration in an anuric hemodialysis patient with cirrhosis. Eur J Clin Pharmacol 76, 821–831 (2020). https://doi.org/10.1007/s00228-020-02861-9

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Keywords

  • Flecainide
  • Drug–drug interaction
  • Renal impairment
  • Cirrhosis
  • Physiologically based pharmacokinetic modeling