Formulation substitution and other pharmacokinetic variability: underappreciated variables affecting antiarrhythmic efficacy and safety in clinical practice

Abstract

The process of treating a patient with an antiarrhythmic drug only begins when a physician chooses the drug to be employed. In the given patient, not only must the drug be chosen, but so must the dose, the formulation, and the method of follow-up. Choosing the proper dose requires an understanding of clinical trial efficacy and safety data for the agent chosen in a population of patients resembling the individual to be treated. It also requires a detailed understanding of pharmacologic principles of drug kinetics (e.g., absorption, distribution, metabolism, and excretion) that might affect the dose needed for the specific patient. The physician must be familiar with subsequent changes in clinical circumstances that might indicate a need for a change in dose or drug. Many circumstances determining drug pharmacokinetics are not under the immediate control of physicians, such as genetic patterns, organ function, and disease circumstances. One, however, is-or should always be-the selection of the drug formulation used. Although generic versions of innovator drugs exist for many agents and often are clinically acceptable, most physicians are unaware of the meager degree of testing that is necessary for the release of a generic drug, and the wide range of attained serum levels that are called bioequivalent by the US Food and Drug Administration (FDA) when one formulation is compared with another. In patients with cardiac arrhythmias, arrhythmia recurrence, proarrhythmia, and death have been reported in association with antiarrhythmic drug formulation substitution. Despite their reported bioequivalence, the generic agents involved were clearly not therapeutically equivalent. Accordingly, this article was written to educate physicians further about the above-noted important pharmacokinetic variables that can affect a patient's outcome when an antiarrhythmic drug is employed, and to provide information on the generic drug approval process and guidelines for the use of formulation substitution.