Utilization of mechanistic modelling and simulation to analyse fenspiride proarrhythmic potency – Role of physiological and other non‐drug related parameters

Abstract

What is known and objective: Fenspiride, a drug that had been used for decades for the treatment of respiratory diseases, was recently withdrawn from the market due to the potential risk of QT prolongation and proarrhythmia. This is the first such withdrawal for many years and hence poses a question whether such risk could have been predicted and to what degree non-drug-specific parameters play a role in the reported QT prolongation and cases of TdP. The study aim was to test various 'what-if' scenarios to assess the influence of age, gender, heart rate, and plasma potassium concentration on QT interval prolongation due to various doses of fenspiride with the use of mechanistic mathematical modelling. Methods: Concentration-time profiles were simulated with the use of a PBPK model developed based on published physico-chemical data, data from in vitro ADME experiments, and in vivo PK study results. Pharmacodynamic effect, that is, drug-triggered pseudoECG signal modification was simulated using a biophysically detailed model of human cardiac myocytes. Analysis of the qNet metric was also performed to classify proarrhythmic risk related to fenspiride. Results: In the simulation study, arrhythmia was not observed even in the 'what-if' scenarios with extreme exposure, age, heart rate, and plasma potassium concentration. The qNet metric value positioned fenspiride in the intermediate risk class.What is new and conclusion: It can be hypothesized that the clinically observed arrhythmia cases were not directly caused by fenspiride alone but a combination of multiple factors, including comedications.

Synthetic Routes to Approved Drugs Containing a Spirocycle

“…For this reason, i.e. the increased risk of torsades de pointes, fenspiride was withdrawn from the pharmaceutical market in most markets around the world [19]. One of the early patents, obtained by the Italian Voghera company for the synthesis of fenspiride, describes the assembly of the target molecule starting from 1-phenethyl piperidin-4-one (43), which was involved in the Reformatsky reaction with ethyl bromoacetate.…”

“…For this reason, i.e. the increased risk of torsades de pointes, fenspiride was withdrawn from the pharmaceutical market in most markets around the world [19]. Scheme 9.…”

Synthetic Routes to Approved Drugs Containing a Spirocycle

“…Unfortunately, it does bind to this off-target and causes prolongation of QT interval. For this reason, i. e. the increased risk of torsades de pointes, fenspiride was withdrawn from the pharmaceutical market in most markets in the World [19].…”