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Therapeutic drug monitoring of any pharmacologic agent should be considered when there is both significant pharmacokinetic variability and strong, clinically relevant, exposure-effect relationships. Many antifungal drugs exhibit marked variability in drug concentration as a result of inconsistent absorption, metabolism, elimination, or interaction with concomitant medications. For each of the available antifungal drugs, both preclinical and clinical trials have exhibited a relationship between serum concentrations and treatment efficacy. For a smaller subset of compounds, a similar relationship has been identified for the toxicity. The kinetic variability among patients falls outside the therapeutic window for a group of four antifungal compounds. This review summarizes the current literature on therapeutic drug monitoring for these antifungal agents.