Effects of multiple doses of voriconazole on the vision of healthy volunteers: a double-blind, placebo-controlled study.

PURPOSE: To investigate the effects, and their reversibility, of multiple oral voriconazole doses on a variety of visual tests in healthy male volunteers. METHODS: Single-center, double-blind, randomized, placebo-controlled, parallel-group study in 36 volunteers who received voriconazole (n=18, 400 mg every 12 h on day 1, then 300 mg every 12 h for 27.5 days) or matched placebo (n=18). Electroretinograms (ERGs) and ophthalmological examinations were performed at screening, throughout the study and at follow-up. RESULTS: Fifteen (83.3%) volunteers treated with voriconazole experienced ≥1 treatment-related visual adverse events (AEs); these included enhanced visual perceptions, blurred vision, color vision changes and photophobia. No serious AEs were reported. Voriconazole reduced from baseline scotopic maximal a- and b-wave amplitude, shortened implicit time and decreased oscillatory potential amplitude compared with placebo. Under photopic conditions, the 30-Hz flicker response amplitude was significantly reduced and was accompanied by a slight but nonsignificant prolongation of peak time. These effects did not progress in degree over the treatment period, and mean changes from baseline in ERG parameters were similar to placebo by day 43 (14 days after end of treatment). In the first week, color vision discrimination was impaired in the tritan axis, although this resolved by end of treatment and was similar to placebo by day 43. Mean deviation in the static visual field indicated increased sensitivity following voriconazole treatment, correlating with decreased amplitude in conjunction with shortened implicit time. CONCLUSIONS: Effects of voriconazole on altered visual perception, ERG, color vision and static visual field thresholds are nonprogressive over a treatment period and reversible. It is hypothesized that voriconazole has a pharmacological effect on rod and cone pathways including a possible mechanism of disinhibition that reversibly puts the retina in a more light-adapted state and leads to increased relative contrast sensitivity.

Pharmacokinetics of sulfobutylether-ß-cyclodextrin (SBECD) in subjects on hemodialysis.

BACKGROUND: The disposition of sulfobutylether-ß-cyclodextrin (SBECD), the solubilizing excipient in intravenous (i.v.) voriconazole, was assessed in seven male subjects with end-stage renal disease on hemodialysis and six subjects with normal renal function. METHODS: All subjects received twice-daily i.v. voriconazole at the standard voriconazole dose [6 mg/kg (96 mg/kg SBECD) every 12 h (Q12h) on Day 1 followed by 3 mg/kg (48 mg/kg SBECD) Q12h on Days 2-4, with a single i.v. dose on the morning of Day 5]. Subjects were sampled at selected pre-dose trough times, at selected times after infusions and intensively on Day 3 (non-dialysis) and Day 4 (dialysis with high-flux membranes). Compartmental analyses were performed by NONMEM. RESULTS: SBECD disposition was characterized by a two-compartment model. In renal failure, mean central (V(1)) and peripheral compartment volumes (V(2)) were 9.9 and 6.5 L, respectively. In normal subjects, V(1) and V(2) were 9.6 and 5.2 L, respectively; SBECD clearance (CL) was 130 mL/min. CL in renal failure off-dialysis was 2.6 and 48 mL/min during dialysis; mean half-life decreased from 79 to 5 h during dialysis (normal subjects: 2.1 h). CONCLUSION: Hemodialysis can significantly reduce levels of SBECD in subjects with end-stage renal disease.

Review of the basic and clinical pharmacology of sulfobutylether-beta-cyclodextrin (SBECD).

Despite its use in commercially available drugs such as intravenous voriconazole, there is little known in the medical literature about the clinical pharmacology of the solubilizing agent, sulfobutylether-beta-cyclodextrin (SBECD). This paper summarizes all known data on SBECD pharmacokinetics and safety. In animals, volume of distribution approximates extracellular water volume and clearance is determined by the glomerular filtration rate. SBECD does not have any apparent effects on cardiovascular or respiratory systems, nor on autonomic and somatic functions in animals. In 1- and 6-month studies in rats and dogs, the most noteworthy findings were renal tubular vacuolation and foamy macrophages in the liver and lungs. Mild toxicity in the kidney and liver as a consequence of vacuolation occurred in rats at the maximum dose of 3000 mg/kg, which is approximately 50-fold greater than the SBECD dose typically administered in man. Doses up to 1500 mg/kg produced no histopathological evidence of toxicity in dog kidneys. SBECD has also been studied in healthy volunteers and subjects with renal dysfunction. Whereas plasma SBECD levels accumulate in those with renal compromise, there were no deleterious effects on renal function. Nonetheless, serum creatinine levels should be monitored in subjects with renal compromise receiving multiple doses of SBECD.

Long-term visual safety of voriconazole in adult patients with paracoccidioidomycosis.

BACKGROUND: Voriconazole is an antifungal agent with in vitro activity and clinical efficacy against yeasts, molds, and dimorphic fungi (eg, Paracoccidioides brasiliensis). The safety profile of voriconazole includes transient visual adverse events (VAEs) that resolve while undergoing treatment or after its discontinuation. OBJECTIVE: The goal of this study was to assess the long-term (ie, 6-12 months) visual safety of voriconazole in adult patients with paracoccidioidomycosis. METHODS: Ophthalmic data were prospectively collected as part of a multicenter, open-label, comparative study. Patients aged ≥18 years with paracoccidioidomycosis were randomized in a 2:1 ratio to receive either voriconazole (200 mg BID orally, after the loading dose of 400 mg BID on day 1) or itraconazole (100 mg BID orally, with no loading dose). Patients were expected to receive treatment for a minimum of 6 months, or longer if needed as determined by the investigator (maximum duration, 1 year). Visual function tests and safety assessments were performed at baseline, week 12, week 24, end of treatment (EOT), and 8 weeks post-EOT. Ophthalmic examinations included visual acuity, color vision, contrast sensitivity, visual field, funduscopy, and slit lamp biomicroscopy. Treatment compliance was monitored via pill counts at each study visit. RESULTS: Thirty-five patients (mean age, 48 years; 96.2% male; 83.0% white) were randomized to receive voriconazole and 18 to receive itraconazole. Fourteen voriconazole-treated patients received >6 months of treatment (median, 169 days). Efficacy and overall safety results have been published previously. Sixteen voriconazole-treated patients and 2 itraconazole-treated patients experienced drug-related VAEs; none was considered serious or severe or led to dose reductions or resulted in discontinuation. Overall, visual examination results were not clinically significantly different between patients treated with voriconazole or itraconazole. There was no apparent relationship between changes in visual function test results and the occurrence of VAEs in either treatment group. CONCLUSION: Clinical assessment in this study found no evidence of an effect of voriconazole on long-term visual function in these adult patients with paracoccidioidomycosis.

Pharmacokinetics, safety and tolerance of voriconazole in renally impaired subjects: two prospective, multicentre, open-label, parallel-group volunteer studies.

BACKGROUND AND OBJECTIVES: Since little is known regarding the pharmacokinetics of voriconazole in renally impaired patients, two prospective, open-label, parallel-group volunteer studies were conducted to estimate the effect of renal impairment on the pharmacokinetics of oral voriconazole and intravenous voriconazole solubilized with sulphobutylether-beta-cyclodextrin (SBECD), respectively. METHODS: In study A, male subjects with no (n = 6), mild (n = 6), moderate (n = 6) or severe (n = 6) renal impairment received one 200 mg dose of oral voriconazole. Voriconazole plasma levels were periodically assessed until 48 hours post-dose. In study B, male subjects with no (n = 6) or moderate (n = 7) renal impairment received multiple doses of intravenous voriconazole solubilized with SBECD (6 mg/kg twice daily [day 1] then 3 mg/kg twice daily [days 2-6] followed by a final dose of 3 mg/kg on the morning of day 7) at an infusion rate of 3 mg/kg/h. Voriconazole plasma levels were periodically assessed until 36 hours following the final dose. Pharmacokinetics were determined by non-compartmental methods. RESULTS: The pharmacokinetics of voriconazole were unaffected in subjects with any degree of renal impairment in both studies. In study B, clearance of SBECD was proportional to creatinine clearance (r2 = 0.857). Although two subjects had >30% increase in serum creatinine from baseline, these changes did not correlate with SBECD trough levels (r2 = 0.053). The majority of subjects with moderate renal insufficiency were able to tolerate 7 days of intravenous voriconazole solubilized with SBECD. CONCLUSION: These data suggest that renal impairment does not affect the pharmacokinetics of voriconazole. Furthermore, in subjects with moderate renal impairment, there is a strong linear correlation between SBECD clearance and creatinine clearance, and elevated SBECD levels do not necessarily correlate with increased serum creatinine levels (an indicator of worsening renal function).

Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities.

This study investigated the relationship between plasma voriconazole concentrations (pVC) and risk of visual adverse events (VAEs) or liver function test (LFT) abnormalities using longitudinal logistic regression. Seven-day mean pVC were calculated from 2,925 plasma samples (1,053 patients); in each 7-day period, the presence or absence of VAEs/abnormal LFTs was analyzed as a binary outcome variable. There was a relationship between pVC and risk of VAE (P = .011) and a weaker, but statistically significant, association with risk of aspartate transaminase (AST), alkaline phosphatase (ALP), or bilirubin but not alanine transaminase (ALT) abnormalities. The odds ratios of LFT abnormalities per 1 mug/mL pVC increase ranged from 1.07 to 1.17. Maximum weekly occurrences were 10%, 8%, 5%, and 14% for AST, ALT, ALP, and bilirubin abnormalities, respectively. Receiver-operating characteristic curve analysis indicates that individual pVC cannot be used to predict subsequent LFT abnormalities.