Clinical Toxicities

Currently, 13-cis-retinoic acid is the most studied chemopreventive agent that decreases the incidence of second primary tumors in patients with head-and-neck cancer, reverses premalignant lesions, and reduces appearance of nonmelanoma skin cancer in patients with xeroderma pigmentosum. Unfortunately, this vitamin A derivative has a significant clinical toxicity, which limits its utility in a practice setting. 

Hoschele D (2006) Cell culture models for the investigation of NRTI-induced mitochondrial toxicity. Relevance for the prediction of clinical toxicity. Toxicol In Vitro 20(5) 535-546 Itescu S, Brancato LJ et al (1989) A sicca syndrome in HIV infection association with HLA-DR5 and CDS lymphocytosis. Lancet 2(8661) 466 68 Itescu S, Brancato LJ et al (1990) A diffuse infiltrative CDS lymphocytosis syndrome in human immunodeficiency virus (HIV) infection a host immune response associated with HLA-DR5. Ann Intern Med 112(1) 3-10... 

While rDNA techniques offer exciting possibilities, there are many unanswered questions about the potential toxicity that each new product represents. For example, acute clinical toxicities of interferons (IFNs) include flu-like syndrome, fever, chills, malaise, anorexia, fatigue, and headache. Chronic dose-limiting toxicities include neutropenia, thrombocytopenia, impairment of myeloid maturation, reversible dose-related hepatotoxicity, some neurological toxicity (stupor, psychosis, peripheral neuropathy) and gastrointestinal toxicity. Some of these toxicities would be difficult to ascertain in rodents, and, in fact, may be species-specific. 

In an attempt to find an in vitro assay to predict differences in the neurotoxic potential of bisindole alkaloids, an assay using cultured rat midbrain cells was developed. This system provided a qualitative measure of the effect of compounds on neuronal tissue, and when several compounds (for which clinical toxicity data were available) were evaluated using this method the results were consistent in rank order with the compounds clinical manifestation of neurotoxicity. When vinepidine was studied in this system, it was found to produce a minimal effect (Fig. 7). 

Table 8.2 gives a summary of the various toxicities and the stages at which they can occur. Also summarized are the causes for the specificity of the effect. With mutagenicity, certain pre-clinical toxicity, carcinogenicity and late clinical toxicology, the actual structure of the molecule is important and care should be taken to avoid the incorporation of toxicophores into compounds, as outlined about. Direct toxicity is addressed by ensuring the daily dose size is low, the intrinsic selectivity high and the physicochemical properties within reasonable boundaries. 

Pre-clinical and early clinical Toxicity directly related to dose size and intrinsic selectivity. Metabolites react with protein and cause cell death Overstimulation of receptor and others in superfamily. Metabolites not detoxified by glutathione etc. 

Enzyme Induction (CYP3A4) and Drug Design 1119 Tab. 8.4 Clinical toxicities and side-effects of P4503A4 inducers. 

If significant clinical toxicity is observed, extend leucovohn rescue for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. Impaired methotrexate elimination or inadvertent overdosage Beg n leucovorin rescue as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion (see Warnings). Administer leucovorin 10 mg/m IV, IM, or orally every 6 hours until the serum methotrexate level is less than 10 M. In the presence of Gl toxicity, nausea, or vomiting, administer leucovorin parenterally. 

The clinical toxicity of ganciclovir includes granulocytopenia, anemia, and thrombocytopenia. In animal studies, ganciclovir was carcinogenic, teratogenic, and caused aspermatogenesis. 

Peripheral neuropathy The major clinical toxicity is peripheral neuropathy (22% to 35%) of subjects. 

In this example, the increased unbound phenytoin concentration resulted in a larger volume of distribution (more free drug distributed to the tissues), increased clearance (more free drug available for metabolism), but no change in the drug s half-life. The paradox in this case is that the increased clearance caused the total phenytoin blood concentration to go down, while the free concentration was elevated and led to clinical toxicity. Moreover, the unchanged half-life would not have clarified the cause of the subther-apeutic phenytoin level. 

Abnormalities of fluid and electolyte imbalance are the most common forms of clinical toxicity, overdose may result in rapid reduction of blood volume, dizziness, orthostatic hypotension, headache, hypokalemia. 

Adverse effects include peripheral neuropathy which is a major clinical toxicity. Other side effects include pancreatitis, anaemia, arthralgia, headache, fever, rash, nausea, vomiting, diarrhoea, elevated transaminase values. 

The term pharmacogenetics is used here to specificy the relationship between inherited DNA variation and drug response, whereas pharmacogenomics will be used in the broader sense to encompass the relationship of DNA as well as other biological constituents (e.g., RNA, proteins) to both clinical toxicity and efficacy. 

CLINICAL TOXICITY OF THE BETA-RECEPTOR ANTAGONIST DRUGS... 

Dayan AD Albendazole, mebendazole and praziquantel. Review of non-clinical toxicity and pharmacokinetics. Acta Trop 2003 86 141. [PMID 12745134]... 

There are two separate requirements at present for measuring volatile anesthetics in blood. One is retrospect analysis of blood samples. The other is on-line monitoring of blood concentration during animal and clinical toxicity studies. Usually a method allowing analysis of samples within minutes is desired. 

Vial T, Descotes J. Clinical toxicity of interleukin-2. Drug Saf 1992 7(6) 417-33. 

Clinical Toxicity of the Beta-Receptor Antagonist Drugs... 

Finally, relationships between lapatinib plasma concentration and clinical toxicity have not been yet formally studied. 

Billemont B, et al. (2009) Correlation of sorafenib plasma concentrations and clinical toxicity a prospective population pharmacodynamic and pharmacokinetic study. J Clin Oncol 27 (No 15 S) (May 20 Suppl, el4585)... 

Eskens FA et al (2006) The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors a review. Eur J Cancer 42 3127-3139... 

A potential new drug candidate faces a well-defined clinical and product development process that has been refined over several decades. The development phase of a new dmg product usually consists of two main activities clinical evaluation (safety and efficacy), and product development (dmg substance and dosage form). As shown in Table 1.1, the process can last as long as 7-9.5 years and the cost can be approximately 50% of the entire expense for development of a new medicine.8 At this stage, some programs would be terminated for various reasons, such as lack of clinical efficacy, clinical toxicity, or dmg developability. 

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