1. Deutscher Kongress für Patientensicherheit bei medikamentöser Therapie, April 19th ­ 20th, Congresshal e, Saarbrücken, Germany

Deductive, Systematic Signal Validation as Method for Efficacy Improvement in Pharmaco- and Chemo-Vigilance

by Information Organization

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Background: Death by Medication

Example: Benzene Toxicity and crossing metabolic pathways

The actual pharmacovigilance crisis is obvious, structural y As an example, we analyze the metabolic pathways of benzene in humans. Benzene is hydroxylated in several steps leading to more bioactive

caused, and manifested by market withdrawals of drugs as wel and critical compounds before its clearance8,15. Ether bridge opening is a frequently observed process in human metabolism of xenobiotics.

as statements of regulatory authorities (EMEA, FDA). The pictures below show information screens in the ADRIS solution SafeBaseTM. The connecting lines (i.e., relations) in light grey represent

Fundamental limitations in clinical trials have been recognized as the scientific status "hypothetical" while the black lines represent proven information. Wave­form connections show statistical coincidences,

responsible (FDA)1. An enormously high incidence of Adverse whereas straight lines or arrows stand for causal, mechanistic, and semantic relations.

Drug Reactions (ADRs) leading to death have been calculated by

meta-analysis. ADRs represent the 4th to 6th leading cause of

death (approx. 100,000 per year in the US alone). Overal 23,8 %

(95% CI 18.6%-29.0%) are type B reactions (i.e. not dose

dependent, idiosyncratic)3. Since the frequency is about 1:20′000

or even more rare it is not possible to detect them in clinical trials1

or early enough after approval.

Method: Signal matching with pre-assessed Pattern

We show how the interrelation of known facts in appropriate

ontology (ADRIS)2 in suitable visual interfaces leads to the

recognition of principles and final y the formulation of a theory of

possible ADRs. A recent publication shows, that the ADRIS

approach using SafeBaseTM could have led to the identification of

hidden risk factors, related to the later observed ADRs in the

Troglitazone (RezulinTM) case14. Possibly one would have paid

more attention to metabolic steps that could be critical. Using

such methods beforehand is possible and results in a pre-

assessment of likely problems in predisposed people. This

deductive approach directs the attention in vigilance towards

particular events, already before they become statistical y

significant based on their frequency. Through that they can be

subject of careful analysis, which leads, if the theory is confirmed,

Figure 1:

to an earlier recognition of underlying pattern, i.e. signal

A variety of substances are potentially able to converge in the metabolic pathway of benzene. All human beings are benzene exposed, for example when handling fuel at a gas
station. Benzene exposure risks are possibly amplified if the formation of HHQ (here stated to be the critical molecule in the benzene toxification / metabolic activation9) is

validation. A typical principle is based on metabolic pathways to

increased by such metabolic conversion. The pre-assessment indicates to be aware of benzene specific clinical endpoints in the vigilance of such compounds and, in
addition, to investigate cases of coincidence for specific individual predisposition. Such predisposition is likely (but not limited to) genetic properties causing changes in the

metabolites, which can be assessed on the base of available

metabolism of compounds resulting in higher amounts of HHQ formation. If such facts are found it is possible to identify risk populations for those molecules and one can
protect individuals from exposure.

evidence.

Results: First Validation steps empower the Theory

Our example is the toxicity of benzene, related to the occurrence

of hydroxyhydroquinone and particularly its spontaneously formed

quinone15 as critical molecule. Conclusions based on analogies

show some likelihood of the occurrence of this metabolite in not

completely elucidated pathways of medications and other

substances, some of them are related to clinical endpoints

associated with the exposure of human individuals to benzene.

Figure 2:

Conclusion: Signal Validation can lead Vigilance

The proven metabolism of the approved drug paroxetine shows in one of the metabolic steps
a dealkylation reaction resulting in metabolite III. Even if HHQ occurrence has not been

Just single ADRs relating the known benzene - toxicologic

proven by analysis it is considered that the second part of the molecule is in analogy to all
such human processes leading to HHQ. Leukocytosis is an infrequent, Leukopenia a rare

endpoints (leukemia, breast cancer) and these substances are

ADR of paroxetine6 and they are symptoms of the benzene typical leukemia. Such findings

Figure 3:

worth to be investigated completely, since they enable risk

support the validation of a suspected synergism in some patients.

Tobacco smoke is known to contain catechol and to induce higher rates
of breast cancer. The benzene metabolite HHQ is formed from catechol in

assessments based on predisposition and epidemiology much

humans by a minor metabolic pathway8. HHQ has been found to induce in
vitro characteristic processes which are known to play a role in cancer

earlier. The need of intel igence tools to deal with such

and especially AML9 development (Aneuploidy12 and DNA single strands

heterogeneous data is obvious. The paradoxical situation that

break11). Linking this information visualizes that individual SNP′s
changing this minor pathway to a major one can increase the risk for the

often arises is characterized by information overload but

related endpoints. Such findings in single case investigation would
substantially improve the knowledge.

knowledge deficiency, and the need for intel ectual involvement in

information assimilation4. IT tools for intel igence are designed to

assess risks in situations when only bits and pieces of knowledge

are available but the situation forces to find the trace of future and

past events (like it is the case in criminology, counter-terrorism,

and military intel igence).

Figure 4:

Benefits:

It has been found in a case control study that paroxetine exposure results in an increased
risk of breast cancer if compared with other antidepressants5. Some single cases are

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Improve patients safety.

published ("survivor story"). But antidepressant exposure generally seems to be related

Figure 5:

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Avoid financial damage to

with higher breast cancer rates7. On the other hand have the rare condition of male breast

Sesamol is a food component and also used in cosmetics. It has been stated

cancer been observed in relation with Selective Serotonin Reuptake Inhibitor prescription13.

to be related to a higher risk of cancer10, but has as well properties that

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health insurance,

The statistically weak signal of paroxetine is validated by the above shown likely

could protect people from cancer and it has been recommended for cancer

convergence with benzene metabolism. Again - individual predisposition must be explored

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pharmaceutical companies,

prevention. Among other mechanisms, the cancer induction by sesamol

to find a common pattern of such events. Otherwise, they will remain single observations

could be explained with the ability of the compound to converge with

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market-risk (re)-insurers,

without impact.

benzene metabolism.

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investors.

References:

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Early identification and validation of serious risk

2. FDA, Stephen et al. (1995) Clinical Therapeutics and the Recognition of Drug-Induced Disease. - A MedWatch Continuing Education Article, June
3. Hug et al. (2003) ADRIS - The adverse drug reactions information scheme. - Pharmacogenetics 12: 767-772.

factors through

4. Lazarou et al 1998 Incidence of Adverse Drug Reactions in Hospitalized Patients - JAMA 279:1200-1205

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holistic integration of all risk factors which

5. Abbott (2004) Integration and Structuring for Enhanced Knowledge Management - Drug Information Journal, Vol. 38, pp. 187­196
6. Cotterchio et al. (2000) Antidepressant medication use and breast cancer risk. - Am J Epidemiol. 151(10):951-7.

are potentially relevant for ADRs,

7. Prescribing Information PaxilTM, Jan. 2005, GlaxoSmithKline, USA

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integration of individual-based data,

8. Steingart et al. (2003) Antidepressant medication use and breast cancer risk: a case-control study - Int J Epidemiol. 32(6):961-6.
9. Clayton, G. D. and F. E. Clayton (eds.). Patty′s Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3273, cited in

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library of quality-reviewed public domain

NATIONAL PARK SERVICE, FORT COLLINS, COLORADO, USA, ENVIRONMENTAL CONTAMINANTS ENCYCLOPEDIA - BENZENE ENTRY, USA, July 1, 19

10. Zhang et al. (1998) Benzene metabolites induce the loss and long arm deletion of chromosomes 5 and 7 in human lymphocytes. - Leuk Res. ;22(2):105-13.

data,

11. Hirose (1998) Carcinogenicity of antioxidants BHA, caffeic acid, sesamol, 4-methoxyphenol and catechol ... - Carcinogenesis 19(1):207-12.

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retro- and prospective risk analyses.

12. Hiramoto et al. (1998) Identification of hydroxyhydroquinone in coffee as a generator of reactive oxygen species that break DNA single strands. - Mutat Res. 419(1-3):43-51.
13. Chung & Kim (2002) Detection of chromosome-specific aneusomy and translocation by benzene metabolites in human lymphocytes ... - J Toxicol Environ Health A. 65(5-6):365-72.
14. Wallace et al. (2001) Male breast neoplasia in association with selective serotonin re-uptake inhibitor therapy: a report of three cases. - Eur J Surg Oncol. 27(4):429-31.
15. Hug et al. (2004) Ontology-based knowledge management of troglitazone-induced hepatotoxicity. - Drug Discov Today. 9(22):948-54.
16. NATIONAL TOXICOLOGY PROGRAM (NTP) (1986) TOXICOLOGY AND CARCINOGENESIS STUDIES OF BENZENE ... - Technical Report NTP TR 289, NIH Publication No. 86-2545

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