Confounding Issues in Estimation of Patient-Specific Pharmacokinetic Parameters and Dosage Individualization of Aminoglycosides

Abstract

Aminoglycoside antibiotics are usually administered by multiple short intravenous infusions at fixed intervals. Today, equations reported 35 years ago by Sawchuk and Zaske are still the cornerstone of methods used for determination of patient-specific pharmacokinetic parameters of aminoglycosides and individualization of drug dosage regimens in many clinical settings. Additionally, these methods are included in many clinical pharmacology curricula in pharmacy and other related fields. However, there are a few issues with regard to the application and/or modification of this method in clinical settings, which may result in some confusion among novice clinicians. For example, serum samples collected from different intervals at steady state, instead of samples obtained during the same interval, require special manipulation of sampling time before they can be used for estimation of pharmacokinetic parameters. Furthermore, there are various ways that the original equations are modified or simplified, which can result in some degree of error in the estimates of pharmacokinetic parameters and ensuing dosage regimen calculations. Simulation data presented here indicate that in some cases, these errors may be substantial, depending on the length of short infusion, half life of the drug, and the dosage interval. For instance, using equations developed for intravenous bolus mode of administration, ignoring the short infusion, may result in ≥ 25% error for a typical patient and dosing scenario. Although experts may use modified equations, understanding their error ramifications, these modifications may be confusing to the novice clinician. Therefore, it is recommended that exact equations developed specifically for multiple intravenous infusions be used without any modification, particularly in settings where clinicians are being trained.