Determination of Toxicity
David Woolley, Adam Woolley in Practical Toxicology, 2017
Expression of toxicity at unexpected target sites, or at unexpected intensities, by drugs or other chemicals has been a major factor in their withdrawal from the market. While clinical human toxicity at major target organs may be predicted from appropriate nonclinical studies, some target organs may be less easily predictable. For instance, cerivastatin (Baycol), a statin intended to reduce cholesterol levels, showed an unexpected risk of rhabdomyolysis (severe muscle damage) especially when used at a high dose or with gemfibrozil, another lipid-regulating agent. It is unlikely that such an effect would be predicted by any of the routinely used test systems, particularly those in vitro, as there is unlikely to be any routine test for such an endpoint. The diversity of toxicological endpoints will always be a massive hurdle to successful prediction of target organ effect in vivo from in vitro assays, covering single effects or mechanisms.
Fungi and Water
Chuong Pham-Huy, Bruno Pham Huy in Food and Lifestyle in Health and Disease, 2022
In animals, statins produce significant toxicity at high doses: increases in hepatic transaminases, atypical focal hyperplasia of the liver, cataracts, vascular lesions in the central nervous system (CNS), skeletal muscle toxicity, testicular degeneration, and more (164). Fortunately, except for rare cases of myopathy and marked but asymptomatic increases in hepatic transaminases, none of the adverse effects found in animals occur at human therapeutic doses (162–164). Muscle complaints or myalgia are common in statin users, occurring in about 7% of statin users (164). Cerivastatin was introduced in 1998 but was withdrawn in August 2001 by the manufacturer because of a large number of reports of rhabdomyolysis, of which more than 50 cases were fatal (164). In 2010, the British Medical Journal published a study that statins may raise cataract and kidney risk (164). Therefore, the use of statins must be prescribed by physicians only.
General Discussion about Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
Concomitant use of a drug that affects the activity of the same CYP responsible for biotransformation of another drug can lead to significant increases in plasma concentrations and potentially important drug–drug interactions (Ito et al. 1998). Such interactions may be associated with poor tolerability or increased risk for toxicity. On the other hand, for drugs/prodrugs requiring biotransformation via CYP enzymes from an inactive/less active parent compound to a pharmacologically active metabolite, drug interactions may manifest as a reduction in efficacy. Cases of fatal drug interactions have been reported and several prominent drugs (e.g., cerivastatin, mibefradil, sorivudine, and terfenadine) have been withdrawn from the market because of severe adverse reactions related to drug interactions (Li 2001). Both pharmacokinetic and pharmacodynamic components may be involved in these toxic drug interactions. Because of the clinical significance of drug interactions, it is important to identify drugs and compounds in development that may interact with other drugs, and timely identification of such drugs using proper in vitro and in vivo approaches has important implications for drug development (Zhou et al. 2007).
Statin use and safety concerns: an overview of the past, present, and the future
Published in Expert Opinion on Drug Safety, 2020
Rubina Mulchandani, Tanica Lyngdoh, Ashish Kumar Kakkar
The analysis of case reports from the FDA AERS database after the change in the statin drug label in 2012 also showed that the risk of cognitive dysfunction was significantly higher among patients being prescribed highly potent lipophilic statins like atorvastatin and simvastatin, compare to those on less lipophilic statins (fluvastatin, lovastatin) as well as those on hydrophilic statins such as rosuvastatin and pravastatin [122]. Results from the PRIMO study also reported that the likelihood of myalgia and other muscle ailments was the greatest among those on simvastatin – a highly lipophilic statin, when compared to other hydrophilic statins [43]. Even the cerivastatin withdrawal from the market owing to cases of severe muscle toxicity, rhabdomyolysis, and renal failure might be attributed to its potent lipophilicity.
A systematic review and meta-analysis of the effect of statin treatment on sVCAM-1 and sICAM-1
Published in Expert Review of Clinical Pharmacology, 2022
Angelo Zinellu, Arduino A Mangoni
Univariate meta-regression analyses were conducted to investigate associations between the effect size and the following study and patient characteristics: age, proportion of males, publication year, body mass index, sample size, the continent where the study was conducted, baseline concentration and the difference between baseline and post-treatment concentration (delta) of total cholesterol, low-density lipoproteins (LDL)-cholesterol, high-density lipoproteins (HDL)-cholesterol, and triglycerides, specific statin used, statin class (lipophilic: atorvastatin, simvastatin, lovastatin, fluvastatin, cerivastatin, and pitavastatin; hydrophilic: rosuvastatin, pravastatin), and treatment duration. Preplanned subgroup analyses investigated the effects of specific statins, statin classes, continent where the study was conducted, use of placebo, and presence of clinically overt atherosclerotic cardiovascular disease. Statistical analyses were performed using Stata 14 (STATA Corp., College Station, TX, USA).
Newer approaches and novel drugs for inhalational therapy for pulmonary arterial hypertension
Published in Expert Opinion on Drug Delivery, 2020
Ali Keshavarz, Hossam Kadry, Ahmed Alobaida, Fakhrul Ahsan
Phase II clinical trials [124]. Many studies have also shown that drugs entrapped in liposomes are safe for pulmonary delivery since liposomes can control the mode of drug release, hence reducing the drug amount available to exert adverse effects [132,133]. Lee et al. confirmed the safety of cerivastatin in nano-liposome formulations given via inhalation for PAH treatment. The nano-liposomes demonstrated significantly less cellular cytotoxicity as compared to free cerivastatin; furthermore, liposome delivery produced significantly lower levels of the lactone metabolite that is considered a safety risk at high statin doses. In summary, the inhaled liposomal formulation is safe to deliver the therapeutics locally to the lung [132].
Related Knowledge Centers
- Fibrate
- Gemfibrozil
- Kidney Failure
- Pharmaceutical Industry
- Statin
- Rhabdomyolysis
- Cardiovascular Disease
- Atorvastatin
- Cholesterol
- Postmarketing Surveillance