Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity

b; South Texas Veterans Health Care System, San Antonio, Texas, USA c Interest in antifungal therapeutic-drug monitoring has increased due to studies demonstrating associations between concentrations and outcomes. We reviewed the antifungal drug concentration database at our institution to gain a better understanding of achievable triazole drug levels. Antifungal concentrations were measured by high-performance liquid chromatography (HPLC), ultraperformance liquid chromatography and single-quadrupole mass spectrometry (UPLC/MS), or a bioassay. For this study, only confirmed human bloodstream (serum or plasma) and cerebral spinal fluid (CSF) concentrations of voriconazole, posaconazole, and itraconazole were analyzed. The largest numbers of bloodstream and CSF samples were found for voriconazole (14,370 and 173, respectively). Voriconazole bloodstream concentrations within the range of 1 to 5.5 g/ml represented 50.6% of samples. Levels below the lower limit of quantification (0.2 g/ml) were observed in 14.6% of samples, and 10.4% of samples had levels of >5.5 g/ml. CSF voriconazole levels ranged from undetectable to 15.3 g/ml and were <0.2 g/ml in 11% of samples. Posaconazole bloodstream concentrations were >0.7 and >1.25 g/ml in 41.6% and 18.9% of samples, respectively. Posaconazole was detected in only 4 of 22 CSF samples (undetectable to 0.56 g/ml). Itraconazole levels, as measured by UPLC/MS, were >0.5 g/ml in 43.3% and were undetectable in 33.9% of bloodstream samples. In contrast, when measured by a bioassay, itraconazole/hydroxyitraconazole bloodstream concentrations were >1.0 g/ml in 72.9% of samples and were undetectable in 18% of samples. These results indicate that there is marked variability in bloodstream concentrations achieved with these three azoles. In addition, many levels within the bloodstream for each azole and for voriconazole and posaconazole in the CSF were undetectable or below thresholds associated with efficacy. O ver the last 5 years, there has been increased interest in therapeutic-drug monitoring of systemic antifungals. Much of this interest stems from clinical evidence that suggests that this practice may improve outcomes for patients treated with voriconazole and posaconazole. For both agents, studies have reported a relationship between clinical response and certain threshold concentrations (1-6). In addition, marked interpatient variability has been observed with both of these antifungals (1, 7-11). For voriconazole, a clear relationship also exists between elevated concentrations and certain toxicities (1, 12, 13). Monitoring of voriconazole concentrations has also been suggested as part of patient management in the fungal meningitis outbreak associated with contaminated steroids due to the high doses of this agent that are recommended (14, 15). Although this practice has garnered recent attention, therapeutic-drug monitoring is not new, as previous studies have suggested relationships between itraconazole and flucytosine concentrations and clinical outcomes (16)(17)(18)(19).On...

Section: Discussionsupporting

confidence: 73%

A Reference Laboratory Experience of Clinically Achievable Voriconazole, Posaconazole, and Itraconazole Concentrations within the Bloodstream and Cerebral Spinal Fluid

Wiederhold

Pennick

Dorsey

et al. 2014

“…In our center, we selected 2 to 5.5 mg/liter as the reference range for total VTCs (24-26, 43, 44). However, as there is still no clear consensus about the reference range of VTCs (24-26, 43, 45-49), the same conclusions can be drawn when simulating the worst-case scenario with an upper limit of 4 mg/liter (45)(46)(47)(48), as shown in Fig. 2.…”

Section: Discussionmentioning

confidence: 76%

Impact of Hypoalbuminemia on Voriconazole Pharmacokinetics in Critically Ill Adult Patients

Vanstraelen

Wauters

Vercammen

et al. 2014

f Setting the adequate dose for voriconazole is challenging due to its variable pharmacokinetics. We investigated the impact of hypoalbuminemia (<35 g/liter) on voriconazole pharmacokinetics in adult intensive care unit (ICU) patients treated with voriconazole (20 samples in 13 patients) as well as in plasma samples from ICU patients that had been spiked with voriconazole at concentrations of 1.5 mg/liter, 2.9 mg/liter, and 9.0 mg/liter (66 samples from 22 patients). Plasma albumin concentrations ranged from 13.8 to 38.7 g/liter. Total voriconazole concentrations in adult ICU patients treated with voriconazole ranged from 0.5 to 8.7 mg/liter. Unbound and bound voriconazole concentrations were separated using high-throughput equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Multivariate analysis revealed a positive relationship between voriconazole plasma protein binding and plasma albumin concentrations (P < 0.001), indicating higher unbound voriconazole concentrations with decreasing albumin concentrations. The correlation is more pronounced in the presence of elevated bilirubin concentrations (P ‫؍‬ 0.05). We therefore propose to adjust the measured total voriconazole concentrations in patients with abnormal plasma albumin and total serum bilirubin plasma concentrations who show adverse events potentially related to voriconazole via a formula that we developed. Assuming 50% protein binding on average and an upper limit of 5.5 mg/liter for total voriconazole concentrations, the upper limit for unbound voriconazole concentrations is 2.75 mg/liter. Alterations in voriconazole unbound concentrations caused by hypoalbuminemia and/or elevated bilirubin plasma concentrations cannot be countered immediately, due to the adult saturated hepatic metabolism. Consequently, increased unbound voriconazole concentrations can possibly cause adverse events, even when total voriconazole concentrations are within the reference range.

“…Thus, there is a growing need to develop new effective antifungal drugs to combat the increasing occurrence of Candida resistance, especially for the treatment of deep systemic infections. Because many of the marketed azole drugs are limited by a low therapeutic index (13), a drug with a higher therapeutic index might be able to combat resistant pathogens at plasma concentrations still below toxic levels.…”

mentioning

confidence: 99%

The Clinical Candidate VT-1161 Is a Highly Potent Inhibitor of Candida albicans CYP51 but Fails To Bind the Human Enzyme

Warrilow

Hull

Parker

et al. 2014

141

The binding and cytochrome P45051 (CYP51) inhibition properties of a novel antifungal compound, VT-1161, against purified recombinant Candida albicans CYP51 (ERG11) and Homo sapiens CYP51 were compared with those of clotrimazole, fluconazole, itraconazole, and voriconazole. VT-1161 produced a type II binding spectrum with Candida albicans CYP51, characteristic of heme iron coordination. The binding affinity of VT-1161 for Candida albicans CYP51 was high (dissociation constant [K d ], <39 nM) and similar to that of the pharmaceutical azole antifungals (K d , <50 nM). In stark contrast, VT-1161 at concentrations up to 86 M did not perturb the spectrum of recombinant human CYP51, whereas all the pharmaceutical azoles bound to human CYP51. In reconstitution assays, VT-1161 inhibited Candida albicans CYP51 activity in a tight-binding fashion with a potency similar to that of the pharmaceutical azoles but failed to inhibit the human enzyme at the highest concentration tested (50 M). In addition, VT-1161 (MIC ‫؍‬ 0.002 g ml ؊1 ) had a more pronounced fungal sterol disruption profile (increased levels of methylated sterols and decreased levels of ergosterol) than the known CYP51 inhibitor voriconazole (MIC ‫؍‬ 0.004 g ml ؊1 ). Furthermore, VT-1161 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. In summary, VT-1161 potently inhibited Candida albicans CYP51 and culture growth but did not inhibit human CYP51, demonstrating a >2,000-fold selectivity. This degree of potency and selectivity strongly supports the potential utility of VT-1161 in the treatment of Candida infections.