key determinants and the respective probability (p) in the patient population for the manifestation of liver toxicity, resulting in liver failure:
1 Determinant 1 (p1): Elevated uptake transporter activity, leading to higher than normal intracellular concentration.
2 Determinant 2 (p2): Elevated drug metabolizing enzyme activity due to prior exposure to inducers or genetic polymorphism, resulting in higher than normal T* formation.
3 Determinant 3 (p3): Suppressed UDP‐glucuronosyltransferase (UGT) and sulfotransferase (SULT) detoxification activity.
4 Determinant 4 (p4): Suppressed GST activity and/or reduced cellular GSH level.
5 Determinant 5 (p5): Hypersensitized inflammatory reactions due to previous exposure to the same drug and the associated neoantigen.
6 Determinant 6 (p6): Reduced efflux transporter activity of glucuronide and sulfate conjugates, leading to feedback inhibition of the detoxifying pathways.
In this hypothetical example, Determinant 2 (metabolic activation) is the most crucial, while the other determinants would exacerbate the hepatotoxic events. The patient who will succumb to liver failure is one with the confluence of risk factors – simultaneous occurrence of the various determinants of drug toxicity at the time of drug administration (Figure 1.1).
Based on the theory that co‐occurrence of multiple determinants are required for the manifestation of severe drug‐induced liver injuries (DILIs), the incidence of DILI in the patient population will be a product of the incidence of patients with each of the determinants at the time of drug administration as shown in the following equation:
Considering a hypothetical case that the co‐occurrence of four determinants is required for DILI, and that each determinant has an incidence of 10% of the patient population, I(DILI) will be 10% × 10% × 10% × 10% or 1 in 10 000 patients. This event therefore cannot be readily detected in the regulatory clinical trials due to the limited number of patients, but will be manifested when the drug is administered to the general patient population upon marketing.
1.4 Concluding Remarks
Transporter‐mediated drug uptake and efflux are clear determinants of intracellular concentrations of drugs and metabolites which are substrates of the transporters. Individual variations in the expression of drug metabolism enzymes and transporters due to genetic polymorphism, exposure to drugs, foods and food supplements, and various diseases have been well‐established. A thorough understanding of the role of drug metabolism and transport in the disposition of a potentially toxic drug will aid the assessment of its toxic potential and the identification of the critical determinants of events leading to the formation and accumulation of the toxic moiety. Routine evaluation of the toxicological consequence of drug metabolism and transport may therefore aid the development of drugs with lower potential of causing idiosyncratic toxicity and may eventually lead to the identification of at‐risk populations.
1.4.1 A Comprehensive Approach to Safety Evaluation in Drug Development
While the conventional preclinical and clinical safety evaluation are essential to the assessment of drug safety, additional considerations are needed to avoid the occurrence of idiosyncratic drug toxicity. I have previously proposed that drug safety assessment requires a comprehensive, multidisciplinary approach (8, 9) with input from pharmacologists, toxicologists, epidemiologists, population geneticists, and especially drug metabolism/pharmacokinetics (DMPK) experts to provide insight toward the possible risk factors discussed above.
Key parameters to be considered for drug safety evaluation based on this comprehensive approach include the following: (i) Pharmacology: Possible toxicity due to drug–target interactions, including interactions with unintended molecular targets, or with molecular targets in unintended organs. (ii) Chemistry: Chemical scaffolding and side chains with safety concerns. (iii) Toxicology: Toxicity in animals in vivo, and in relevant animal and human cells in culture. (iv) DMPK: Safety concerns due to toxification or detoxification, organ distribution, clearance, and pharmacokinetic drug–drug interactions. (v) Risk factors: Physiological, environmental, and genetic factors that may enhance a patient's susceptibility. It is proposed that this integrated, multidisciplinary approach to safety evaluation may enhance the accuracy of the prediction of drug safety and thereby the efficiency of drug development (8, 9).
1.4.2 The Dose Makes the Poison – Paracelsus Updated
A major doctrine in toxicology is the Paracelsus hypothesis:
All things are poison, and nothing is without poison; only the dose makes a thing not a poison.
When Philippus Aureolus Theophrastus Bombastus von Hohenheim (10, 11) made this statement which has become the cornerstone of the field of toxicology, he meant dose to individuals. An often cited example is that drinking too much water, a universally accepted non‐poison, can lead to fatalities due to a phenomenon known as hyponatremia, lowering of plasma sodium concentrations due to over dilution of plasma, leading to hypo‐osmolality‐related fatal events (12, 13).
Based on the Multiple Determinant Hypothesis, I would like to propose a modernization to the Paracelsus doctrine for drug toxicity:
The dose makes the poison, whilst individuals make the dose.
References
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2 2 Stepan AF, Walker DP, Bauman J, Price DA, Baillie TA, Kalgutkar AS, et al. “Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States”. Chem Res Toxicol 2011; 24(9): 1345–1410.
3 3 Li AP. “A review of the common properties of drugs with idiosyncratic hepatotoxicity and the ‘multiple determinant hypothesis’ for the manifestation of idiosyncratic drug toxicity”. Chem Biol Interact 2002; 142(1–2): 7–23.
4 4 Collins JM. “Idiosyncratic drug toxicity”. Chem Biol Interact 2002; 142(1–2): 3–6.
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7 7 Wouters OJ, McKee M, Luyten J. “Estimated research and development investment needed to bring a new medicine to market, 2009–2018”. JAMA 2020; 323(9): 844–853.
8 8 Li AP. “A comprehensive approach for drug safety assessment”. Chem Biol Interact 2004; 150(1): 27–33.
9 9 Li AP. “An integrated, multidisciplinary approach for drug safety assessment”. Drug Discov Today 2004; 9(16): 687–693.
10 10 Mann RD. “Famous names in toxicology. Paracelsus‐‐born 500 years ago”. Adverse Drug React Toxicol Rev 1993; 12(2): 81–82.
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