Similarities Between Terodiline and Prenylamine

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Chapter: Pharmacovigilance: Withdrawal of Terodiline: A Tale of Two Toxicities

In the context of the ICH E2E guideline on Pharma-covigilance Planning, some vital pieces of information that might have presaged the potential proarrhythmic risk from terodiline were already known at the time of its re-development.


SIMILARITIES BETWEEN TERODILINE AND PRENYLAMINE

In the context of the ICH E2E guideline on Pharma-covigilance Planning, some vital pieces of information that might have presaged the potential proarrhythmic risk from terodiline were already known at the time of its re-development. The analogy between terodiline and prenylamine goes well beyond their therapeu-tic class, and extends into their chemical structures and stereoselective pharmacological and toxicological profiles (Table 10.1).


First, it was well known that the use of antianginal drugs (prenylamine and lidoflazine) might be asso-ciated with QT interval prolongation and torsade de pointes. Prenylamine was introduced in the United Kingdom in the early 1960s and lidoflazine in 1979. Secondly, both prenylamine and terodiline are highly related in their chemical structures. While terodiline is a diphenyl-propyl derivative of buty-lamine (Figure 10.1), prenylamine is a diphenyl-propyl derivative of phenylethylamine (Figure 10.2).


The presence of a chiral centre in each drug gives rise to a pair of enantiomers. It is acknowledged that even a minor modification in the structure of a molecule can dramatically alter the activity of a drug, and indeed this is the basis of metabolic inactivation of most drugs. However, notwithstanding the minor structural differences between terodiline and preny-lamine, it is intuitive that terodiline must have some cardiac effects since it was marketed originally as a cardioactive antianginal agent. Not surprisingly, both drugs share a very similar complex pharmacological profile that is discussed later. Thirdly, both preny-lamine and terodiline are chirally active and there was already evidence of stereoselectivity in the proarrhyth-mic potential of prenylamine. Fourthly, there was wide inter-individual variability in the metabolism of terodiline, with aberrant pharmacokinetic behaviour of one of the enantiomers. This is also a feature of the pharmacokinetics of prenylamine. Finally, there was evidence of stereoselectivity in the pharmaco-dynamic activities of the two enantiomers of terodi-line, and therefore the unexpectedly high frequency of anticholinergic effect observed during its use as an antianginal agent should have already suggested an unusual behaviour of one of the enantiomers (the enantiomer with predominantly anticholinergic activity).

To illustrate the regulatory deliberations at the time, frequent references will be made to prenylamine in the commentary that follows. This will highlight in detail the striking similarity between these two drugs, and hence the logic that should have supported the re-development of terodiline. Importantly, this comparison emphasizes the strengths of both a scien-tific synthesis of all the available information when evaluating the significance of even a handful of spontaneous reports of a unique drug reaction, and of formulating the most appropriate regulatory strategies for risk management.

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