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Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage

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Abstract

Cutaneous adverse reactions (CARs) from antiepileptic drugs (AEDs) are common, ranging from mild to life-threatening, including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The identification of subjects carrying the HLA-B*15:02, an inherited allelic variant of the HLA-B gene, and the avoidance of carbamazepine (CBZ) therapy in these subjects are strongly associated with a decrease in the incidence of carbamazepine-induced SJS/TEN. In spite of the strong genetic associations, the initiation of hypersensitivity for AEDs is still not very well characterized. Predicting the potential for other AEDs to cause adverse reactions will be undoubtedly beneficial to avoid CARs, which is the focus of this report. Here, we explore the use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to distinguish AEDs associated with and without CARs by examining the binding relationship of AEDs to HLA-B*15:02 and data from extensive reviews of medical records. We also evaluate the lack of benefit from a Hong Kong population policy on the effects of screening for HLA-B*15:02 and previous incorrect structure–activity hypotheses. Our analysis concludes that BDDCS class 2 AEDs are more prone to cause adverse cutaneous reactions than certain BDDCS class 1 AEDs and that BDDCS Class 3 drugs have the lowest levels of cutaneous adverse reactions. We propose that BDDCS Class 3 AEDs should be preferentially used for patients with Asian backgrounds (i.e., Han Chinese, Thai, and Malaysian populations) if possible and in patients predisposed to skin rashes.

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Acknowledgments

RC was supported in part by the American Foundation for Pharmaceutical Education Pre-Doctoral Fellowship and NIGMS grant R25 GM56847. We thank Professors Meir Bialer and Daniel Lowenstein for reviewing the manuscript and their helpful suggestions.

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Authors and Affiliations

  1. Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, 533 Parnassus Avenue, Room U-68, San Francisco, California, 94143-0912, USA

    Rosa Chan & Leslie Z. Benet

  2. Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan

    Chun-yu Wei & Yuan-tsong Chen

  3. Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, 27708, USA

    Yuan-tsong Chen

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  1. Rosa Chan
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Correspondence to Leslie Z. Benet.

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Electronic Supplementary Material

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Table S1

Parameters for the 17 most commonly prescribed AEDs. (DOCX 88 kb)

Figure S1

Biopharmaceutics Drug Disposition Classification System (BDDCS). (GIF 149 kb)

High resolution image (TIFF 406 kb)

Figure S2

Relationship between the exposure to each AED and BDDCS classification. (GIF 158 kb)

High resolution image (TIFF 971 kb)

Figure S3

Spearman correlation between the relative response to the binding of HLA-B*15:02 and incidence of AED rash. (GIF 63 kb)

High resolution image (TIFF 495 kb)

Figure S4

AED prescription patterns prior and post HLA-B*15:02 screening implementation in the first ever AED subset in the Hong Kong Population. (GIF 96 kb)

High resolution image (TIFF 598 kb)

Figure S5

AED prescription patterns prior and post HLA-B*15:02 screening implementation in the newly treated epilepsy subset in the Hong Kong Population. (GIF 86 kb)

High resolution image (TIFF 542 kb)

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Chan, R., Wei, Cy., Chen, Yt. et al. Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage. AAPS J 18, 757–766 (2016). https://doi.org/10.1208/s12248-016-9898-x

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