Abstract
Despite substantial premarket efforts, a significant portion of approved drugs has been withdrawn from the market for safety reasons. The deleterious impact of nonsynonymous substitutions predicted by the SIFT algorithm on structure and function of drug-related proteins was evaluated for 2504 personal genomes. Both withdrawn (n = 154) and precautionary (Beers criteria (n = 90), and US FDA pharmacogenomic biomarkers (n = 96)) drugs showed significantly lower genomic deleteriousness scores (P < 0.001) compared to others (n = 752). Furthermore, the rates of drug withdrawals and precautions correlated significantly with the deleteriousness scores of the drugs (P < 0.01); this trend was confirmed for all drugs included in the withdrawal and precaution lists by the United Nations, European Medicines Agency, DrugBank, Beers criteria, and US FDA. Our findings suggest that the person-to-person genome sequence variability is a strong independent predictor of drug withdrawals and precautions. We propose novel measures of drug safety based on personal genome sequence analysis.
Highlights
The person-to-person variability in drug response is a major challenge for current clinical practice, drug development, and drug regulation.[1]
As shown in S1 Fig and S1 Table, it was consistently confirmed at all thresholds of the number of pharmacokinetics and pharmacodynamics (PK/PD) genes from 1 to 10 for study drug inclusion that the area under the curve (AUC) values of withdrawn and precautionary drugs were significantly lower than that of other drugs (P < 0.001 by ANOVA)
We have demonstrated that the person-to-person genome variability is a strong independent prognostic factor for drug withdrawals from the pharmaceutical market, which has long been considered unpredictable
Summary
The person-to-person variability in drug response is a major challenge for current clinical practice, drug development, and drug regulation.[1] A drug with proven clinical efficacy in some patients often fails to work in others and may even cause serious side effects, including death. [1,2,3] The incidence of severe adverse drug reactions (ADRs) has been estimated at 6.2–6.7% in hospitalized patients, and more than 2 million ADR cases occur annually in the United States (US), including 100,000 deaths.[3,4] As a result, many drugs causing unexpected severe ADRs are eventually withdrawn from the market. The impact and cost burden of pharmaceutical market withdrawals are enormous. Of the 548 drugs that were newly approved by the US Food and Drug Administration (FDA) between.
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