The third consideration in deciding on TDM for voriconazole is whether a good relationship between drug concentration and pharmacologic response has been reported in pharmacokinetic studies conducted in humans.
Few studies to date have assessed the potential correlation between plasma concentrations of voriconazole and pharmacologic response in terms of efficacy and toxic effects (Table 2). The majority of these studies were small
observational trials with high heterogeneity in terms of patient characteristics and sampling times for the voriconazole plasma samples. Although some of the data suggested a positive correlation between concentration of voriconazole and pharmacologic response, data from other studies did not support such a relationship.
Relation Between Concentration and Efficacy
In a prospective, nonblinded, noncomparative multicentre trial, 122 random samples were drawn from 137 patients for determination of plasma voriconazole concentration; the majority of these patients were immunocompromised and were receiving voriconazole as primary or salvage therapy for proven or probable invasive aspergillosis. Five of the patients had consistently low mean concentration of voriconazole (< 0.25 mg/L). Three of these 5 patients had a failed response to therapy (defined as disease progression and death due to invasive aspergillosis, as determined by clinical, radiologic, and mycologic evidence), whereas the fourth patient had a stable response and the fifth had initial deterioration but later improvement when the dose was escalated. No difference in clinical outcomes was noted between patients with voricona- zole concentrations between 0.5 and 1 mg/L and those with voriconazole concentrations above 1 mg/L.
In a similar prospective observational study, 52 patients underwent TDM for voriconazole. A dosage adjustment scheme was followed to target trough concentrations between 1 and 5.5 mg/L. Six (46%) of the 13 patients with trough concentrations of 1 mg/L or less had no response to therapy, whereas only 5 (13%) of the 39 patients with trough concentrations above 1 mg/L had no response (p = 0.02). All 6 of the patients with no response and trough concentrations of 1 mg/L or less experienced improvement in outcomes after dose escalation. In a retrospective study, Smith and others18 used classification and regression tree modelling to determine that the pharmacokinetic-pharmacodynamic (PK-PD) break point for clinical response was 2.05 mg/L. Concentrations of voriconazole above the determined break point were associated with 100% clinical response, whereas 44% of those below the break point had disease progression.
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Contrary to the positive associations reported in these studies, Kolve and others found no correlation between trough concentrations of voriconazole and clinical outcomes in a group of 37 pediatric patients. Pfizer, the manufacturer of voriconazole, also concluded that concentrations of the drug were not predictive of clinical efficacy, on the basis of 6 of the 10 phase II and phase III therapeutic trials sponsored by the company. However, details on how the plasma samples had been collected and analyzed were not available and therefore could not be assessed by the authors of the present review.
Most of the studies evaluating a possible association between concentration of voriconazole and clinical outcomes share similar shortcomings. The observational nature of their designs renders all of the trials underpowered to establish any conclusive causal effect between concentration of the drug and pharmacologic response. Also, the studies were largely heterogeneous in terms of patient populations and the sampling time for determination of plasma voriconazole. In one trial, only about half of the patients had proven or probable invasive aspergillosis. Lack of certainty about the diagnosis at baseline, coupled with unblinded study design, made definitive and unbiased assessment of treatment response difficult.
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Furthermore, the time frame for assessment of end points and patient follow-up were not specified in some studies. In many studies, the inclusion and exclusion criteria were not well described, which may have confounded interpretation of the observations. There is also the likelihood of high variability among the blood samples collected, given that they were not consistently drawn at specified times relative to dosing time. One major limitation of these studies was the apparent selection bias for TDM. For example, in the study by Pascual and others, patients who received voriconazole and underwent TDM were followed and analyzed prospectively, whereas those who received voriconazole without drug monitoring were assessed retrospectively. In that study, it was not clear how patients were selected for drug monitoring. As such, any positive association observed might have been due to selection bias in a nonrandomized study. On the whole, thewitrials lies in the variety of pharmacokinetic parameters used to predict clinical efficacy. Although Denning and others suggested the existence of a relationship between drug concentration and pharmacologic response, the purported correlation was based on random sampling for determination of voriconazole concentration. Pascual and others found a correlation between trough concentrations of voriconazole and clinical outcomes, but that result was refuted by Kolve and others, who also investigated trough concentrations of the drug.