Practice guidelines for therapeutic drug monitoring of voriconazole: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring

Tan et al. [4] mentioned that routine monitoring of VRCZ concentration to prevent elevated liver function and visual disturbances was unlikely to add any clinical value. This conclusion was based on the premise that regular monitoring of liver function while patients are receiving VRCZ may be sufficient and visual disturbances represent, in general, a transient and mild effect that rarely necessitates discontinuation of VRCZ therapy. In addition, lower and upper target thresholds for VRCZ have been suggested, but studies to date have not been appropriately designed or powered to reveal any definitive association with its efficacy and toxicity [5]. Therefore, routine assessment of TDM in VRCZ cannot be recommended as a mandatory maneuver except in certain circumstances in this guideline. The committee defined particular indications for TDM in several situations, such as lack of response to therapy or evidence of toxicity, in which case the selective indication for TDM is clinically useful.

VRCZ is associated with adverse events, including visual disturbance and hepatic enzyme elevation with drug overdosing. The steady-state blood concentration of VRCZ has large interpersonal variability because it can be affected by several factors, including patient age, race, drug–drug interactions, route of administration, cytochrome P450 (CYP) polymorphism (mainly CYP2C19), and race because of the polymorphism [5‐12]. Several observational studies have demonstrated that the blood trough level was associated with adverse events [8, 10, 13‐15].

Examination of weekly plasma concentration data from patients in ten studies suggested that patients who reported visual adverse events (VAE) had higher VRCZ plasma concentrations [12]. Kakuda et al. [16] mentioned that coadministration of etravirine with VRCZ resulted in higher etravirine exposure, with an area under the plasma concentration–time curve during 0–12 h (AUC_12h) that was 1.36 fold larger. The VRCZ plasma concentrations were slightly raised, but no grade 3 or 4 adverse events were observed during treatment. Park et al. [17] conducted a randomized controlled trial to investigate the efficacy of TDM of VRCZ against invasive fungal infections. Although the proportion of VRCZ discontinuation due to adverse events was significantly lower in the TDM group than in the non-TDM group, routine TDM of VRCZ did not reduce the incidence of drug-related adverse events because of the early occurrence of adverse events compared with the time needed for optimizing VRCZ levels based on TDM.

Variability in the plasma concentration of VRCZ both within and between individuals is high, especially in pediatric patients. The in vitro metabolism of VRCZ by liver microsomes mirrored the in vivo clearance differences in children versus adults, with VRCZ clearance being approximately threefold higher in children than in adults [18]. The VRCZ pharmacokinetics in children are highly variable, particularly for oral formulations [19]. In an open-label study of 12 immunocompromised children, wide intra- and interindividual variations in the plasma VRCZ levels were confirmed [20]. Karlsson et al. [21] suggested that children are especially at risk because VRCZ exhibits markedly reduced oral bioavailability in children compared with adults (44.6 vs. 96 %). Driscoll et al. [22] conducted a study of children who were switched from intravenous to oral treatment. In the study, large intersubject variability was observed. In the steady state during oral treatment, children had higher average exposure than adults. In adolescents who were switched from intravenous to oral treatment, large intersubject variability was observed; however, VRCZ exposure in the majority of adolescents was comparable to that in adults [23].

Several studies have demonstrated that the blood trough level was associated with not only adverse events but also treatment response. Smith et al. [8] retrospectively researched patients treated with VRCZ for invasive aspergillosis. Classification and regression tree (CART) analysis showed a relationship (P < 0.025) between disease progression and drug concentration. Park et al. [17] confirmed the beneficial effect of routine TDM in a randomized, controlled trial. A clinical response was observed in 81 % of patients in the TDM group compared to 57 % in the non-TDM group, with a significant difference. Among allograft recipients receiving VRCZ for the prevention of fungal infections, 6 candidiasis cases were seen among the 43 patients with VRCZ levels ≤2 μg/mL, whereas none was seen among the 24 cases with higher levels (P = 0.061) [6]. Trifilio et al. [24] conducted a retrospective study of VRCZ concentrations in recipients who had undergone allogeneic HSCT and received VRCZ for the prophylaxis of invasive fungal infection. Their data suggested that VRCZ concentrations were unpredictable, despite standard dosing, and the acceptability of a concentration on one occasion could not be extrapolated to future concentrations in the same patient. Trifilio et al. [13] measured the steady-state plasma trough VRCZ level and found that VRCZ was undetectable in 15 % of the patients in their series.

In an animal experiment using a neutropenic murine model of disseminated Candida albicans infection, the treatment efficacy supported the use of the AUC/MIC ratio as a PK–PD parameter that was predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of the treatment outcomes [25]. Andes [26] suggested that a free AUC/MIC value <25 was associated with a half-maximal antifungal effect in murine models of disseminated candidiasis.

Monte Carlo simulation can be used to assess the relationship between the VRCZ trough concentration/MIC ratio and the clinical response. The probability of a clinical response is near maximum when the trough/MIC ratio is between 2 and 5. A previous study suggested that the trough concentration is more clinically tractable [14]. Johnson and Kauffman [27] reported that the bioavailability of the oral formulation was >90 % when administered either 1 h before or 1 h after a meal, and similar PK to intravenous administration was obtained in patients with oral administration.

Mikus et al. [28] conducted a randomized controlled trial to investigate interactions with VRCZ. The coadministration of a potent CYP3A4 inhibitor led to higher and prolonged exposure to VRCZ that might have increased the risk of the development of adverse drug reactions on a short-term basis, particularly in CYP2C19 PM patients. In gene analysis of a Japanese population, the frequency of poor metabolizers was 18.8 % [29]. The genotype status of CYP2C19 and/or the coadministration of drugs that modulate CYP2C19 or CYP3A4 activities might influence VRCZ plasma levels. The influence of the genotype on VRCZ exposure is confounded by drug–drug and drug–disease interactions in the population; thus, no dose adjustments based on genotype are recommended [30]. In gene analysis in an Asian population, the frequency of the CYP2C19 PM was similar to that in the Japanese population [31]. In this study, subsequent studies have used a combination of phenotyping and genotyping tests and have confirmed marked interethnic variation in the frequency of the PM phenotype: there is a higher frequency of the trait in Asian (12–23 %) than Caucasian (1–6 %) or Black African (1–7.5 %) populations, and African-American and Arab populations appear to be similar to Caucasians. Kimura et al. [32] reported that the pharmacokinetics of VRCZ were comparatively unstable and that the concentration of VRCZ varied among individuals, regardless of the CYP2C19 genotype.

Purkins et al. [33] suggested that steady-state levels were achieved by the 5th to 6th day of multiple dosing, and Lazarus et al. [34] suggested that steady-state levels were achieved by the 4th to 7th day. The majority of these pharmacokinetic estimates are based upon single trough concentrations. It would be interesting to determine whether the use of additional monitoring time points to reflect the AUC more accurately might further enhance the strength of these concentration–outcome relationships. Because of the high bioavailability (>90 %) of the oral formulation [27], TDM can be performed using the same timing in patients receiving the oral administration.

Ueda et al. [6] and Trifilio et al. [7] concluded that trough VRCZ levels >2 μg/mL were associated with clinical efficacy. Smith et al. [8] found that favorable responses were observed at concentrations >2.05 μg/mL. Miyakis et al. [11] reported that successful outcomes were more likely among patients with a median trough VRCZ concentration >2.2 μg/mL.

Pascual et al. [9] reported that a lack of response to therapy was more frequent among patients with VRCZ ≤1 μg/mL than in patients with VRCZ >1 μg/mL. Okuda et al. [10] found a significant difference (P < 0.05) in average trough blood concentrations between patients in whom VRCZ was effective and those in whom VRCZ was ineffective (8.21 ± 2.19 vs. 1.01 ± 0.86 μg/mL). Hamada et al. [12] reported that for graded cutoff values within the range of 1.0–3.0 μg/mL, VRCZ >1.0 μg/mL was used as the VRCZ trough blood concentration (P < 0.0001). Because of the small number of PK–PD analyses concerning clinical efficacy in each study, target serum concentrations were not demonstrated according to the type of infections and causative organisms.

Ueda et al. [6] reported that elevation of hepatic enzymes was frequently observed when the VRCZ concentration was >6 μg/mL. Pascual et al. [9] found that none of the patients in their series with levels ≤5.5 μg/mL presented with neurological toxicity (P = 0.002). Okuda et al. [10] found a significant difference (P < 0.05) in the average trough blood concentrations between patients presenting with adverse events and those with no adverse events (7.64 ± 2.84 vs. 1.49 ± 1.79 μg/mL). Hagiwara et al. [35] reported that the average VRCZ trough level of patients with neurological adverse events was 3.2 μg/mL and that the troughs of all the patients requiring discontinuation because of hepatic disorder were >4.0 μg/mL. Trifilio et al. [36] found that the VRCZ concentrations were correlated with aspartate aminotransferase (AST) (P = 0.0009) and alkaline phosphatase (ALP) (P = 0.03) levels. As a result of logistic analysis, the probability of hepatotoxicity at VRCZ trough concentrations of 2 and 4 μg/mL was 1.6 and 21.6 %, respectively [37]. Lutsar et al. [38] showed a 7–17 % increase in the odds of an abnormal alanine aminotransferase (ALT), AST, ALP, or bilirubin level for every 1 μg/mL increase in the plasma concentration of VRCZ. Denning et al. [39] reported that five of six patients with VRCZ concentrations >10 μg/mL developed adverse events requiring discontinuation from the study. For neurological adverse effects, the increased incidence for values >4.0 μg/mL was significant when examined in a meta-analysis (P = 0.02) [12]. However, many neurological adverse events have been reported to be transient and to disappear after the discontinuation of VRCZ treatment; therefore, for safety purposes, caution with regard to liver function is recommended when the trough level exceeds 4–5 μg/mL.

VRCZ exhibited nonlinear pharmacokinetics in healthy volunteers. This deviation from linear pharmacokinetics was confirmed by linearity ratios of >1 and decreasing kel (elimination rate constant) values for multiple dosing, with a consequent increase in the terminal phase t _1/2 [33]. Purkins et al. [40] found that VRCZ exhibited nonlinear pharmacokinetics and that both the C _max and the area under the concentration–time curve within the dosage interval (AUC_τ) increased disproportionately with the dose for both intravenous (IV) and oral dosing. With oral administration, patient compliance can be monitored using TDM [2, 41].

Table 2 Initial administration regimen (B-II).

VRCZ is available in both intravenous and oral formulations. In adults, steady-state plasma levels after intravenous infusion of 3–6 mg/kg twice daily range from 3 to 6 μg/mL [42]. Steady-state concentrations are achieved only after 5–6 days but, if a loading dose is given, earlier steady-state concentrations are obtained [39]; therefore, a loading dose of 6 mg/kg every 12 h for 2 doses in patients with intravenous administration and 300 mg every 12 h for 2 doses in oral administration is required.

Purkins et al. [43] conducted a randomized controlled trial of 12 healthy volunteers. In the trial, the bioavailability of twice-daily 200 mg VRCZ was reduced by approximately 22 %, as measured by AUC_τ, after multiple dosing taken with food, compared with fasting. The results of this study suggest that to maximize bioavailability, VRCZ should not be administered immediately following a meal.

For patients under the following clinical conditions and for children, particular consideration is required because of unstable pharmacokinetic parameters.

Mikus et al. [28] reported that the coadministration of a potent CYP3A4 inhibitor leads to higher and prolonged exposure to VRCZ, possibly increasing the risk of adverse drug reactions. In a trial to study the interactions between VRCZ and omeprazole, omeprazole was found to have no clinically relevant effect on VRCZ exposure, suggesting that no VRCZ dosage adjustment is necessary for patients in whom omeprazole therapy is initiated [58]. Purkins et al. [59] conducted two studies pertinent to the interactions between VRCZ and phenytoin. Consequently, repeated dose administration of phenytoin was shown to decrease the mean steady-state C _max and AUC_τ of VRCZ by approximately 50 and 70 %, respectively. The repeated dose administration of 400 mg VRCZ twice daily increased the mean steady-state C _max and AUC_τ of phenytoin by approximately 70  and 80 %, respectively. Consequently, the plasma phenytoin concentrations should be monitored.

Takashima et al. [60] conducted a retrospective study of HSCT patients treated with tacrolimus. The oral administration of VRCZ increased the blood concentration/dose (C/D) ratio of tacrolimus by 2.7 fold, and the IV administration of VRCZ increased the C/D ratio by 2 fold. Considering these results, the dosages of calcineurin inhibitors should be reduced by 50–65 % when concomitantly administered with VRCZ. Trifilio et al. [61] suggested that the dosage of tacrolimus may need to be reduced by 30–40 %. When VRCZ and calcineurin inhibitors are coadministered, close and periodic monitoring of the tacrolimus and cyclosporine concentrations is necessary in each patient to minimize dose-related toxicity and to maximize efficacy [62, 63].

High performance liquid chromatography (HPLC) is recommended to measure blood concentrations. No factors affecting such measurements have been reported (B-III).

To perform TDM, a validated analytical method must be available to determine VRCZ plasma concentrations. The various methods employed include HPLC with ultraviolet or mass spectrometric and bioassays; however, for the treatment of invasive antifungal infection, bioassays lack sensitivity and specificity compared with HPLC, when combination therapy is being used. Thus, HPLC may be the most suitable assay for measuring VRCZ concentrations [64‐83].