Suarez-Torres Jose D, Orozco Camilo A, Ciangherotti Carlos E
Department of Pharmacy, Faculty of Sciences, Universidad Nacional de Colombia, Bogotá, Colombia.
Department of Toxicology, Faculty of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia.
Fundam Clin Pharmacol. 2021 Dec;35(6):1069-1089. doi: 10.1111/fcp.12674. Epub 2021 Apr 27.
The nonclinical branch of regulatory pharmacology has traditionally relied on the sensitivity and specificity of regulatorily recommended bioassays. Nonetheless, any predictive testing (eg, safety pharmacology) with less than 100% sensitivity or 100% specificity is prone to deliver false positive or negative results (namely, outcomes discordant to the clinical gold standard). It was recently suggested that the statistics-based and regulatory pertinent "predictive values approach" (PVA) might help to reach a more predictive use of preclinical testing data. To resolve the associated probability of carcinogenicity to humans, the PVA was applied to 37 pharmaceuticals bearing inadequate epidemiological evidence of carcinogenicity, but identifiable as unequivocal mutagens. According to current knowledge, a 98.9% (or more) probability of carcinogenicity to humans was reckoned for those 37 genotoxic drugs. Accordingly, these pharmaceutical drugs might be either scientifically or regulatorily regarded as "carcinogenic to humans." In the USA, European Union, or Canada as examples, the great majority of these 37 pharmaceuticals are authorized for medical use in humans. From the results of the present appraisal, the following is suggested (1) for the pharmaceuticals listed in this report, to include significant carcinogenicity warnings in their prescribing information; (2) to conduct pharmacoepidemiology studies or risk-benefit analyses (if warranted), and (3) based on the respective risk-benefit analyses, to re-evaluate the authorization of hydralazine and phenoxybenzamine as antihypertensives, oxcarbazepine as an anticonvulsant, and phenazopyridine as a urinary tract antimicrobial or analgesic. For the four latter drugs (eg, phenoxybenzamine), a 99.5% probability of carcinogenicity to humans was estimated.
传统上，监管药理学的非临床分支依赖于监管机构推荐的生物测定的敏感性和特异性。然而，任何敏感性低于100%或特异性低于100%的预测性测试（如安全药理学）都容易产生假阳性或假阴性结果（即与临床金标准不一致的结果）。最近有人提出，基于统计学且与监管相关的“预测值方法”（PVA）可能有助于更具预测性地利用临床前测试数据。为了解决对人类致癌性的相关概率问题，PVA被应用于37种药物，这些药物致癌性的流行病学证据不足，但可明确鉴定为明确的诱变剂。根据目前的知识，估计这37种基因毒性药物对人类致癌的概率为98.9%（或更高）。因此，这些药物在科学或监管方面可能被视为“对人类致癌”。以美国、欧盟或加拿大为例，这37种药物中的绝大多数已被批准用于人类医疗用途。根据本次评估结果，建议如下：（1）对于本报告中列出的药物，在其处方信息中纳入重大致癌性警告；（2）进行药物流行病学研究或风险效益分析（如有必要），以及（3）根据各自的风险效益分析，重新评估肼屈嗪和酚苄明作为抗高血压药、奥卡西平作为抗惊厥药以及非那吡啶作为尿路抗菌药或镇痛药的批准情况。对于后四种药物（如酚苄明），估计对人类致癌的概率为99.5%。
