Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide

Abstract

Purpose: The therapeutic index (TI) is the range of doses at which a medication is effective without unacceptable adverse events. Drugs with a narrow TI (NTIDs) have a narrow window between their effective doses and those at which they produce adverse toxic effects. Generic drugs may be substituted for brand-name drugs provided that they meet the recommended bioequivalence (BE) limits. However, an appropriate range of BE for NTIDs is essential to define due to the potential for ineffectiveness or adverse events. Flecainide is an antiarrhythmic agent that has the potential to be considered an NTID. This review aims to evaluate the literature surrounding guidelines on generic substitution for NTIDs and to evaluate the evidence for flecainide to be considered an NTID.

Methods: A review of recommendations from various regulatory authorities regarding BE and NTIDs, and publications regarding the NTID characteristics of flecainide, was carried out.

Results: Regulatory authorities generally recommend reduced BE limits for NTIDs. Some, but not all, regulatory authorities specify flecainide as an NTID. The literature review demonstrated that flecainide displays NTID characteristics including a steep drug dose-response relationship for safety and efficacy, a need for therapeutic drug monitoring of pharmacokinetic (PK) or pharmacodynamics measures and intra-subject variability in its PK properties.

Conclusions: There is much evidence for flecainide to be considered an NTID based on both preclinical and clinical data. A clear understanding of the potential of proarrhythmic effects or lack of efficacy, careful patient selection and regular monitoring are essential for the safe and rational administration of flecainide.

Fig. 1

Plasma levels and side effects of flecainide acetate. a Flecainide plasma levels, per cent suppression of VPCs from pretreatment and per cent of plasma levels associated with cardiovascular side effects for flecainide plasma levels grouped in 250-ng/mL increments. b The probability of cardiovascular side effects compared with the change in ECG intervals from baseline (n = 40 for PR and n = 36 for QRS interval). Bundle branch block was excluded from analysis for comparison of change in QRS interval with cardiovascular side effects. c The probability of cardiovascular side effects occurring is compared with trough plasma flecainide levels by use of the Kaplan–Meier product limit estimator for all 43 patients (open circles). The efficacy/plasma concentration curve for 90 % suppression of VEDs is also shown for those 33 patients with available data for both efficacy and flecainide levels (closed symbols). Twenty-eight of the 33 patients achieved at least 90 % suppression of VEDs. RBBB right bundle branch block, CHF congestive heart failure, LBBB left bundle branch block, VPBs premature ventricular beats, VT ventricular trachycardia (taken from Salerno et al.) [57]

Fig. 2

Concentration–response curves for flecainide proarrhythmia in dogs with acute myocardial ischaemia (AMI) or chronic myocardial infarction (CMI) 72 h after coronary artery ligation (taken from Nattel) [60]