Observational Study of the Clinical Efficacy of Voriconazole and Its Relationship to Plasma Concentrations in Patients

Abstract

ABSTRACTVoriconazole is approved for treating invasive fungal infections. We examined voriconazole exposure-response relationships for patients from nine published clinical trials. The relationship between the mean voriconazole plasma concentration (Cavg) and clinical response and between the freeCavg/MIC ratio versus the clinical response were explored using logistic regression. The impact of covariates on response was also assessed. Monte Carlo simulation was used to estimate the relationship between the trough concentration/MIC ratio and the probability of response. The covariates individually related to response were as follows: study (P< 0.001), therapy (primary/salvage,P< 0.001), primary diagnosis (P< 0.001), race (P= 0.004), baseline bilirubin (P< 0.001), baseline alkaline phosphatase (P= 0.014), and pathogen (yeast/mold,P< 0.001). TheCavgfor 72% of the patients was 0.5 to 5.0 μg/ml, with the maximum response rate (74%) at 3.0 to 4.0 μg/ml. TheCavgshowed a nonlinear relationship to response (P< 0.003), with a lower probability at the extremes. For patients withCavg< 0.5 μg/ml, the response rate was 57%. The lowest response rate (56%) was seen with aCavg≥ 5.0 μg/ml (18% of patients) and was associated with significantly lower mold infection responses compared to yeasts (P< 0.001) but not with voriconazole toxicity. Higher freeCavg/MIC ratios were associated with a progressively higher probability of response. Monte Carlo simulation suggested that a trough/MIC ratio of 2 to 5 is associated with a near-maximal probability of response. The probability of response is lower at the extremes ofCavg. Patients with higher freeCavg/MIC ratios have a higher probability of clinical response. A trough/MIC ratio of 2 to 5 can be used as a target for therapeutic drug monitoring.