Drug Safety

, Volume 25, Issue 10, pp 735–750 | Cite as

A New Poisson and Bayesian-Based Method to Assign Risk and Causality in Patients with Suspected Hepatic Adverse Drug Reactions

A Report of Two New Cases of Ticlopidine-Induced Hepatotoxicity
  • Pedro Zapater
  • José Such
  • Miguel Pérez-Mateo
  • José Francisco Horga
Original Research Article


Objective: The diagnosis of drug-induced hepatotoxicity is based on circumstantial evidence and is often inaccurate. We have designed a method based on published data to assign causality to suspected cases of drug-induced hepatotoxicity.

Design: Forty-seven published cases of ticlopidine-induced hepatotoxicity were identified by a Medline-based literature search. Data regarding abnormal liver function in patients receiving ticlopidine were obtained from the only published placebo-ticlopidine clinical trial (the Canadian American Ticlopidine Study; CATS). Thus, we calculated the maximum number of expected hepatotoxicity cases in patients exposed to ticlopidine and those not exposed to the drug by means of the Poisson distribution. The calculated odds ratio was used as a prior odd for subsequent quantification, using a Bayesian-based approach, of individual ticlopidine-induced hepatotoxicity likelihood. Concretely, the prior odd is modified by several separate likelihood ratios: age; sex; AST level; ALT level; alkaline phosphatase level; total bilirubin level; latent period of adverse reaction appearance; and period of remission of adverse reaction. This methodology was applied to two new cases of suspected ticlopidine-induced hepatotoxicity.

Results: The prior probability of ticlopidine-induced hepatotoxicity derived from CATS data is 61.29%. This is in contrast with the 28.83% incidence rate of drug-induced liver alterations in the general population. Alkaline phosphatase levels and total bilirubin levels were six times the normal values among individuals with ticlopidine-induced hepatotoxicity than in the general population. They were the most relevant likelihood ratios of the Bayesian model to establish a high level of causality relationship between a hepatotoxicity event and ticlopidine use.

Conclusions: The proposed method, which links information from clinical trials with the profile of clinical hepatotoxicity of a drug defined from published cases reported after a drug is marketed, can be a useful tool for drug postmarketing surveillance research.


Total Bilirubin Ticlopidine Selegiline Abnormal Liver Function Alkaline Phosphatase Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors are grateful to Professor Asunción Martínez Mayoral (Department of Statistics and Applied Mathematics, University Miguel Hernández) for her helpful commentaries and assistance.

No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.


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Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Pedro Zapater
    • 1
  • José Such
    • 2
  • Miguel Pérez-Mateo
    • 2
  • José Francisco Horga
    • 1
  1. 1.Clinical Pharmacology UnitUniversity General Hospital of Alicante and Department of Pharmacology and Therapeutics, Faculty of Medicine, University Miguel HernándezSan Juan de AlicanteSpain
  2. 2.Liver Unit, Department of MedicineUniversity General Hospital of Alicante and Department of Medicine, Faculty of Medicine, University Miguel HernándezSan Juan de AlicanteSpain

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