Fungal infections in cats may respond poorly to treatment with commonly used azole antifungal drugs (itraconazole and fluconazole), and use of these drugs as well as amphotericin B can be limited by expense and toxic effects.1 One newer alternative is voriconazole, a synthetic triazole antifungal agent available in IV and oral formulations.2,3 Voriconazole inhibits fungal 14-alpha-sterol-demethylase (a CYP-dependent enzyme) and disrupts the fungal cell membrane and halts fungal growth. In humans, the drug is extensively transported across the blood-brain and blood-retinal barriers. Voriconazole is recommended as a first-line treatment for acute invasive aspergillosis in humans4 and is also used to treat serious and refractory fungal infections caused by Scedosporium spp, Paecilomyces spp, Fusarium spp, and Candida spp.2,5 Voriconazole also has activity against Cryptococcus spp and endemic fungi such as Blastomyces spp, Histoplasma capsulatum, and Coccidioides spp.2 In vitro experiments have revealed that fungal isolates obtained from cats (Cryptococcus spp, Candida spp, and Aspergillus fumigatus) are susceptible to voriconazole.5 Cryptococcosis is the most common systemic mycosis in cats, and the organism has a propensity to invade the CNS; therefore, voriconazole represents an attractive antifungal drug for cats that fail to respond adequately to fluconazole treatment. Voriconazole also has properties that make it desirable for treatment of sino-orbital and sinonasal aspergillosis in cats, and the drug may be useful for treatment of histoplasmosis and opportunistic mold infections.
Voriconazole has been used with some success to treat systemic mold and yeast infections in dogs.3,6 However, when a dosage used to treat humans and dogs (5 mg/kg, PO, q 12 h) was administered to cats with naturally occurring fungal infections, severe adverse events were reported, including death of some cats.7–10 Signs of toxicosis in cats include visual abnormalities, mydriasis, ataxia, hypokalemia, and arrhythmias. Signs resolve after the drug is discontinued. Plasma concentrations of voriconazole were not measured in these studies,7–10 and pharmacokinetics of voriconazole in cats was not known. This suggests that cats are inherently more sensitive to adverse effects of voriconazole or the pharmacokinetics of voriconazole in cats differs from those in humans and dogs.
In healthy human volunteers, oral bioavailability of voriconazole in 1 study11 was > 90%, but it may be < 20% when given with food. The CSF and vitreous humor concentrations are > 50% and 40% of serum concentrations, respectively.2 In humans, voriconazole undergoes extensive metabolism by hepatic CYP isoenzymes, with < 2% to 5% eliminated unchanged in the urine.2,3 Large variability in voriconazole trough plasma concentrations has been observed in human therapeutic drug monitoring studies, and there is an association between voriconazole concentrations and adverse effects.4
Voriconazole pharmacokinetic properties have also been studied in dogs, guinea pigs, rats, rabbits,12 horses,13 alpacas,14 and Amazon parrots.15 In most species, including dogs and humans, pharmacokinetics of voriconazole is nonlinear, which indicates that enzymes for metabolism become saturated. Therefore, drug clearance is lower with high doses, with an increased risk of toxicosis.4,15 Saturable nonlinear pharmacokinetics can be species-specific and cannot be extrapolated to other species, such as cats.12–15 Extrapolation of doses is further complicated because repeated administration of voriconazole to mice, rats, and dogs,12 and sometimes humans,16–18 results in induction of metabolizing enzymes, which lowers plasma drug concentrations. Hence, single-dose experiments may not accurately predict pharmacokinetics when multiple doses are administered.12,15
Because toxicosis for voriconazole in humans is a concentration-dependent phenomenon, it is possible that voriconazole can be administered to cats if concentrations can be maintained within a safe range. To avoid toxic effects in humans, it is recommended that doses be adjusted to achieve trough concentrations no higher than 4 to 6 μg/mL.19 If voriconazole can be administered safely to cats and concurrently maintain therapeutic plasma drug concentrations, it would be an attractive treatment option because of its activity against important fungal pathogens of cats and reduced cost (because of the reduced quantity of drug required).
The purpose of the study reported here was to characterize pharmacokinetics and adverse effects after IV or oral administration of a single dose of voriconazole to healthy cats and after oral administration to healthy cats for 14 days. We intended to use the resulting pharmacokinetic information to determine whether an oral dose of voriconazole could be identified for cats that would maintain plasma drug concentrations within a safe and effective range.
Materials and Methods
Animals
Six 1-year-old, specific pathogen–free, sexually intact domestic shorthair cats were included in the study. Body weight ranged from 4.6 to 6.0 kg (mean, 5.5 kg). The cats had no history of illness. Prior to the start of the study, cats were assessed as healthy on the basis of results of a physical examination conducted by a veterinarian board-certified in internal medicine (PV) and results for a CBC, serum biochemical analysis, and urinalysis within respective reference ranges. Cats were housed in research animal facilities at the University of California-Davis and fed a maintenance diet.a The study was approved by the Institutional Animal Care and Use Committee at the University of California-Davis.
Study design
The study was divided into 3 consecutive phases. Food was withheld from all cats for 12 hours before the start of the study, and anesthesia was induced by IV administration of ketamine hydrochloride (5 mg/kg) and diazepam (0.2 mg/kg) and maintained with isoflurane. A 5.5F, 13-cm triple-lumen catheterb was placed percutaneously into a jugular vein of each cat for collection of blood samples. Catheters were maintained for the duration of the study.
In phase 1, all 6 cats were treated with voriconazole (1 mg/kg, IV). Plasma samples obtained at various time points from 0 to 24 hours after administration were analyzed by use of HPLC, and pharmacokinetic variables were calculated. In phase 2, cats were treated by oral administration of voriconazole at a range of doses determined with data obtained from phase 1. Plasma samples were again obtained from 0 to 24 hours after administration and analyzed by use of HPLC; pharmacokinetic variables were again calculated. In phase 3, cats were treated by oral administration of voriconazole for 14 days by use of a dosage determined with data obtained from phase 2. Each phase was separated by a washout period of at least 3 weeks. A CBC, serum biochemical analysis, and urinalysis were performed on each cat at the end of phases 2 and 3. Cats were examined by a veterinarian board-certified in internal medicine (PV or JES) daily during the study, and a 2-minute ECG was obtained daily during phase 3. Appetite was monitored daily throughout the study by weighing the food offered in the morning and any food remaining 12 hours later; body weight of each cat was determined daily.
Drug administration and blood sample collection
A commercially available injectable formulation of voriconazolec was used for phase 1. A 20-gauge catheter was placed in a cephalic vein of each cat, and voriconazole was administered over a period of 2 to 3 minutes (the end of the voriconazole injection was designated as time 0). Blood samples (5 mL) were collected at 0, 10, 20, 40, 60, and 90 minutes and 2, 4, 6, 12, 18, and 24 hours.
For phase 2, voriconazole (commercially available suspensiond or 50-mg tabletse) was used. The powdered suspension was reconstituted by the addition of water to achieve a final concentration of 40 mg/mL, in accordance with the manufacturer's instructions. Food was withheld for 12 hours, voriconazole was orally administered, and a bolus of 5 mL of water was then orally administered. Two cats received each dose of the suspension (4, 5, and 6 mg/kg, respectively). Blood samples (5 mL) were collected at 0, 30, 60, and 90 minutes and 2, 4, 6, 12, 18, and 24 hours after administration. Subsequently, 4 of the 6 cats received voriconazole tablets (25 mg/cat; 4.1 to 4.78 mg/kg), and the remaining 2 cats received the oral suspension (4 mg/kg). Blood samples were collected at 0 and 30 minutes and 1, 2, 4, 12, 24, 48, and 72 hours after administration.
The dosage regimen for phase 3 was developed from simulations constructed with data obtained from phase 2 of the study. On day 0 of phase 3, all cats received a loading dose of the tablet formulation (25 mg/cat) followed 48 hours later by administration of the tablet formulation at 12.5 mg/cat every 48 hours for 14 days. We predicted that a 48-hour dosing interval would maintain plasma drug concentrations in the desired range as determined on the basis of the long t1/2 calculated in the pharmacokinetic analysis of data obtained from phase 2. Blood samples were collected 48 hours after administration of the loading dose (ie, plasma trough concentration) and on days 2, 4, 8, and 15.
Determination of plasma voriconazole concentrations
All blood samples were collected into heparinized glass tubes. Blood samples were kept on ice and centrifuged (2,000 × g for 10 minutes) within 2 hours after collection. The resulting plasma was harvested and stored at −80°C for up to 4 weeks until used for analysis. Samples were shipped on dry ice via overnight courier to the Clinical Pharmacology Laboratory at North Carolina State University and were processed immediately on receipt.
Drug concentration was determined by use of HPLC with UV detection at 263 nm. This method was also expected to clearly differentiate between the parent drug and metabolites because investigators of a previous study12 found that voriconazole was the major component in all species evaluated and other metabolites were minor and appeared in another region of the chromatogram. The assay had been validated by the laboratory for use on samples obtained from dogs, birds, and horses.20 A partial validation for samples obtained from cats was conducted in accordance with established guidelines21,22 to enable us to complete the present study.
All plasma samples were subjected to solid-phase extraction by use of cyano-bonded cartridgesf and then injected into the HPLC system in accordance with a slightly modified method described in a previous study.13 An aliquot (200 μL) of a sample was added to the solid-phase extraction cartridge. Wash steps were performed, and the drug was eluted with 1 mL of methanol. Eluent was evaporated under compressed air at 40°C for 30 minutes. Samples were reconstituted with 200 μL of mobile phase, which consisted of double-deionized water and HPLC-grade acetonitrile (50:50 [vol/vol]). A reverse-phase C8 columng was used for separation. Flow rate was 1.0 mL/min, and sample injection volume was 25 μL. Samples for calibration curves and quality control samples were prepared fresh for each day's assays by fortifying a pooled sample of plasma (obtained from the 6 study cats before commencement of the study) with known concentrations of voriconazole reference standardh (99% pure). A blank sample was processed and analyzed at the beginning of each assay to assess for interfering peaks. Calibration curves were linear (R2 > 0.99) between the concentrations of 0.05 and 10 μg/mL, and all values were within 15% of the expected range. The lower limit of quantification was defined as the lowest concentration on the linear portion of the calibration curve as determined on the basis of linear regression analysis and meeting acceptance criteria for the signal-to-noise ratio. For these conditions, the lower limit of quantification for voriconazole in plasma was 0.05 μg/mL
Pharmacokinetic analysis
Plasma concentration–time plots were examined to determine possible pharmacokinetic models. The model that best fit the data for IV administration was a 2-compartment model with first-order elimination. The model that best fit the data after oral administration was a 1-compartment model with first-order input (absorption) and elimination. Oral administration experiments were performed with different groups of cats and doses ranging from 4 to 6 mg/kg, and both tablets and suspension were administered. Results for each dose and each formulation were analyzed. However, because there were no apparent differences in pharmacokinetic parameters as a consequence of the dose or formulation, all results were combined in the final analysis into 1 robust summary.
A computer program with a nonlinear modeli was used to determine the drug disposition for each cat by use of standard pharmacokinetic methods. Plasma drug concentrations weighted by a factor of 1/(predicted Y)2, where Y is the plasma concentration, were used for pharmacokinetic analysis. The specific model (eg, 1- or 2-compartment model) was determined for best fit on the basis of a smaller value for the Akaike information criterion.23 For the 2-compartment, biexponential analysis, the corresponding equation was as follows:
where C is the plasma drug concentration, A is the y-axis intercept for the distribution phase of the curve, e is the base of the natural logarithm, α is the slope of the distribution phase of the curve, t is time, B is the y-axis intercept for the elimination phase of the curve, and β is the slope of the elimination phase of the curve. Other compartmental pharmacokinetic parameters were calculated in accordance with equations reported elsewhere.24
For oral administration, pharmacokinetic parameters were calculated by use of the following equation:
where K01 is the non-IV absorption rate (assuming first-order absorption), D is the orally administered dose, V is the apparent volume of distribution, and K10 is the elimination rate constant. Secondary parameters from the model included Cmax, Tmax, CL/F, AUC, absorption t1/2, and t1/2 for the terminal phase.
Systemic availability for a non-IV dose was calculated by use of the following equation:
where AUCoral and AUCIV are the AUC after oral and IV administration, respectively, and DoseIV and Doseoral are the doses for IV and oral administration, respectively.
Results
Phase 1
No adverse effects were detected after IV administration of voriconazole. Plasma voriconazole Cmax was attained immediately after IV injection and then decreased, with an initial rapid distribution phase (t1/2, 0.20 hours; CV, 26.4%) and slower elimination (t1/2, 12.4 hours; CV, 37.7%; Figure 1; Table 1). The apparent volume of distribution at steady state was large (1.3 L/kg) and relatively consistent among cats (CV, 10%). The CL was 1.37 mL/kg/min (CV, 36.3%).
Mean ± SD plasma concentrations of voriconazole in 6 healthy cats after IV administration at a dose of 1 mg/kg. Voriconazole was administered over a period of 2 to 3 minutes; the end of voriconazole injection was designated as time 0.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Mean ± SD plasma concentrations of voriconazole in 6 healthy cats after IV administration at a dose of 1 mg/kg. Voriconazole was administered over a period of 2 to 3 minutes; the end of voriconazole injection was designated as time 0.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Mean ± SD plasma concentrations of voriconazole in 6 healthy cats after IV administration at a dose of 1 mg/kg. Voriconazole was administered over a period of 2 to 3 minutes; the end of voriconazole injection was designated as time 0.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Pharmacokinetic values after IV administration of voriconazole (1 mg/kg) to 6 healthy cats.
| Parameter | Mean ± SD | Range | CV (%) |
|---|---|---|---|
| A (µg/mL) | 0.90 ± 0.24 | 0.52–1.17 | 26.756 |
| α (1/h) | 3.68 ± 0.84 | 2.45–4.43 | 22.741 |
| α t1/2 (h) | 0.20 ± 0.05 | 0.16–0.28 | 26.425 |
| AUC (h•µg/mL) | 13.63 ± 4.87 | 8.01–20.75 | 35.709 |
| B (µg/mL) | 0.75 ± 0.09 | 0.63–0.87 | 11.818 |
| β (1/h) | 0.06 ± 0.02 | 0.03–0.09 | 32.529 |
| β t1/2 (h) | 12.43 ± 4.68 | 7.69–20.67 | 37.683 |
| CL (mL/h/kg) | 81.91 ± 29.73 | 48.19–124.84 | 36.291 |
| K12 (1/h) | 1.88 ± 0.53 | 1.02–2.43 | 28.116 |
| K21 (1/h) | 1.72 ± 0.42 | 1.05–2.15 | 24.134 |
| MRT (h) | 17.60 ± 6.80 | 10.77–29.51 | 38.627 |
| Vd1 (mL/kg) | 620.67 ± 107.06 | 552.01–824.60 | 17.249 |
| Vdss (mL/kg) | 1,294.70 ± 130.93 | 1,116.92–1,443.80 | 10.113 |
A = Distribution intercept. α = Distribution rate constant. α t1/2 = Distribution t1/2. B = Elimination phase intercept. β = Elimination rate constant. β t1/2 = Elimination t1/2. K12 = Microdistribution rate constant from the central compartment to the peripheral compartment. K21 = Microdistribution rate constant from the peripheral compartment to the central compartment. MRT = Mean residence time. Vd1 = Apparent volume of distribution of the central compartment. Vdss = Apparent volume of distribution at steady state.
Phase 2
Within seconds after oral administration of the suspension, 3 cats had marked ptyalism that lasted 1 to 3 minutes. Approximately 30 minutes later, 1 cat that received a dose of 5 mg/kg and 2 cats that received a dose of 6 mg/kg developed severe miosis. One of these 3 cats also had blepharospasm and apparent photophobia and was reluctant to move. In all cats, profound miosis was evident for approximately 2 hours, and partial miosis persisted for an additional 46 hours. Cats did not have abnormal behavior; they responded to human interactions, walked without abnormalities, and jumped from platform to platform within their enclosures. All cats ate well 2 hours after administration of the medication, and no loss of appetite, vomiting, or diarrhea was detected over the course of the study. Rectal temperatures remained within reference limits.
Analysis of plasma voriconazole concentrations revealed rapid absorption of voriconazole after oral administration (mean ± SD absorption t1/2, 0.14 ± 0.11 hours) with Tmax at approximately 1.1 ± 0.72 hours (Figure 2). Mean systemic availability was > 260%, compared with that for the IV dose (Table 2). Severe ptyalism in 1 cat led to failure of drug absorption; therefore, data for that cat were not included in the analysis. The t1/2 after administration of the oral suspension was as great as 80 to 90 hours in some cats (mean ± SD, 40.5 ± 6.9 hours). Miosis was not associated with peak voriconazole concentrations and was observed in cats with Cmax as low as 2.5 μg/mL. Cats that received a dose of 4 mg/kg had peak voriconazole concentrations of 2.0 and 2.3 μg/mL, respectively, and no adverse effects were detected. Plasma concentrations at 24 hours for those 2 cats were 1.0 and 1.6 μg/mL, respectively.
Plasma voriconazole concentrations for 6 healthy cats after oral administration of voriconazole suspension at a dose of 4 mg/kg (dashed line), 5 mg/kg (dotted line), or 6 mg/kg (solid line). Each symbol represents results for 1 cat.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Plasma voriconazole concentrations for 6 healthy cats after oral administration of voriconazole suspension at a dose of 4 mg/kg (dashed line), 5 mg/kg (dotted line), or 6 mg/kg (solid line). Each symbol represents results for 1 cat.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Plasma voriconazole concentrations for 6 healthy cats after oral administration of voriconazole suspension at a dose of 4 mg/kg (dashed line), 5 mg/kg (dotted line), or 6 mg/kg (solid line). Each symbol represents results for 1 cat.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Pharmacokinetic values after oral administration of suspension and tablet formulations of voriconazole to healthy cats.
| Suspension (4–6 mg/kg; n = 7) | Tablets (4.1–4.78 mg/kg; n = 4) | All cats (n = 11) | |
|---|---|---|---|
| Parameter | Mean ± SD | Mean ± SD | Mean ± SD |
| AUC (h•µg/mL) | 132.33 ± 42.13 | 177.93 ± 43.46 | 148.91 ± 46.49 |
| CL/F (mL/h/kg) | 38.69 ± 13.93 | 25.39 ± 5.65 | 33.85 ± 13.08 |
| Cmax (µg/mL) | 2.20 ± 0.49 | 2.52 ± 0.41 | 2.31 ± 0.47 |
| K01 (1/h) | 7.48 ± 3.43 | 6.78 ± 6.25 | 7.27 ± 4.08 |
| K01 t1/2 (h) | 0.12 ± 0.07 | 0.20 ± 0.19 | 0.14 ± 0.11 |
| K10 (1/h) | 0.02 ± 0.00 | 0.01 ± 0.00 | 0.02 ± 0.00 |
| K10 t1/2 (h) | 40.50 ± 6.90 | 48.27 ± 11.16 | 43.33 ± 9.02 |
| Tmax (h) | 0.99 ± 0.52 | 1.46 ± 1.14 | 1.13 ± 0.72 |
| Vd/F (mL/kg) | 2,150.79 ± 396.84 | 1,709.31 ± 176.17 | 1,990.25 ± 391.68 |
| Dose (mg/kg) | 4.71 ± 0.95 | 4.34 ± 0.31 | 4.58 ± 0.78 |
| F (%) | 2.51 ± 1.28 | 2.89 ± 0.69 | 2.64 ± 1.08 |
K01 = Absorption rate constant. K01 t1/2 = Absorption t1/2. K10 = Terminal rate constant. K10 t1/2 = Terminal t1/2. Vd/F = Apparent volume of distribution per fraction absorbed.
When results for the tablet formulation were compared with results for the oral suspension, the 2 cats that received the oral suspension had moderate ptyalism immediately after administration; ptyalism was not observed in cats that received the tablet formulation. Three of 4 cats that received the tablet formulation and 1 of 2 cats that received the oral suspension developed mild and transient miosis. Voriconazole pharmacokinetics after tablet administration resembled that of the oral suspension (Figure 3; Table 2). Plasma voriconazole concentrations remained consistently > 1 μg/mL for almost 72 hours after tablet administration.
Plasma voriconazole concentrations in 6 healthy cats after oral administration of a 25-mg tablet (black circles and solid line) or 22 or 23 mg in a voriconazole suspension (white circles and dotted line). Each symbol represents results for 1 cat.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Plasma voriconazole concentrations in 6 healthy cats after oral administration of a 25-mg tablet (black circles and solid line) or 22 or 23 mg in a voriconazole suspension (white circles and dotted line). Each symbol represents results for 1 cat.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Plasma voriconazole concentrations in 6 healthy cats after oral administration of a 25-mg tablet (black circles and solid line) or 22 or 23 mg in a voriconazole suspension (white circles and dotted line). Each symbol represents results for 1 cat.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Phase 3
A physical examination, ECG, CBC, biochemical analysis, and urinalysis were performed at the beginning of phase 3 (repeated dose administration). None of the 6 cats had abnormalities, and voriconazole was undetectable in the plasma. Appetite, amount of activity, body weight, and ECG findings remained unaffected throughout the 14-day treatment period for all cats. Mild miosis was detected in 3 of 6 cats; it was most pronounced during the first 1 to 3 days of the 14-day treatment period. No abnormalities were detected for the CBC, biochemical analysis, and urinalysis performed at the end of the treatment period.
Plasma voriconazole concentrations remained within the target range recommended for humans (1 to 5 μg/mL) during the entire treatment period. However, plasma concentrations gradually increased over time (Figure 4). This indicated drug accumulation, which was not anticipated on the basis of results of earlier phases of the study or evaluation of a simulated curve in which cats received a loading dose of 5 mg/kg followed by 2.5 mg/kg every 48 hours (Figure 5).
Plasma voriconazole concentrations in 6 healthy cats after oral administration of an induction dose of 25 mg/cat (4.1 to 5.4 mg/kg) followed by 12.5 mg/cat, PO, every 48 hours for 14 days during phase 3. Each symbol represents results for 1 cat.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Plasma voriconazole concentrations in 6 healthy cats after oral administration of an induction dose of 25 mg/cat (4.1 to 5.4 mg/kg) followed by 12.5 mg/cat, PO, every 48 hours for 14 days during phase 3. Each symbol represents results for 1 cat.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Plasma voriconazole concentrations in 6 healthy cats after oral administration of an induction dose of 25 mg/cat (4.1 to 5.4 mg/kg) followed by 12.5 mg/cat, PO, every 48 hours for 14 days during phase 3. Each symbol represents results for 1 cat.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Simulated plasma drug concentrations (line) determined on the basis of pharmacokinetic results after oral administration in phase 1 and calculated for a loading dose of 5 mg/kg, PO, followed by 2.5 mg/kg, PO, every 48 hours. The mean ± SD concentration (circles) represents concentrations in 6 healthy cats after administration of a loading dose of 25 mg/cat (4.3 ± 0.11 mg/kg) followed by a dose of 12.5 mg/cat (2.2 ± 0.08 mg/kg), PO, every 48 hours for 14 days during phase 3.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Simulated plasma drug concentrations (line) determined on the basis of pharmacokinetic results after oral administration in phase 1 and calculated for a loading dose of 5 mg/kg, PO, followed by 2.5 mg/kg, PO, every 48 hours. The mean ± SD concentration (circles) represents concentrations in 6 healthy cats after administration of a loading dose of 25 mg/cat (4.3 ± 0.11 mg/kg) followed by a dose of 12.5 mg/cat (2.2 ± 0.08 mg/kg), PO, every 48 hours for 14 days during phase 3.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Simulated plasma drug concentrations (line) determined on the basis of pharmacokinetic results after oral administration in phase 1 and calculated for a loading dose of 5 mg/kg, PO, followed by 2.5 mg/kg, PO, every 48 hours. The mean ± SD concentration (circles) represents concentrations in 6 healthy cats after administration of a loading dose of 25 mg/cat (4.3 ± 0.11 mg/kg) followed by a dose of 12.5 mg/cat (2.2 ± 0.08 mg/kg), PO, every 48 hours for 14 days during phase 3.
Citation: American Journal of Veterinary Research 77, 9; 10.2460/ajvr.77.9.931
Discussion
In the study reported here, oral administration of low doses of voriconazole to cats every 48 hours resulted in plasma concentrations at or above the target concentrations for humans.19 There were minimal adverse effects. Both tablet and suspension formulations of voriconazole were absorbed rapidly in cats after oral administration, with concentrations reaching a mean ± SD Cmax of 2.31 ± 0.45 μg/mL approximately 1 hour after administration. The longer t1/2 of voriconazole after oral administration (> 43 hours) when compared with the t1/2 after IV administration (12 hours) was unexpected. One possible explanation for this finding was that the higher orally administered dose may have been responsible for nonlinear pharmacokinetics of voriconazole in which higher doses were cleared and eliminated more slowly than were lower doses. A dose-ranging study after oral administration would be needed to investigate this possibility. The second possibility was a flip-flop effect25 caused when the terminal slope t1/2 resulted from slow absorption rather than slow elimination. Thus, absorption (rather than elimination) would dictate the shape of the plasma concentration–time profile, which might explain the inflated bioavailability of 260%. Slow absorption leading to a flip-flop effect occurs with extended-release or controlled-release oral formulations; however, a formulation effect was unlikely in the present study because an immediate-release tablet and an immediate-release suspension were administered orally, with similar results for each formulation. Flip-flop phenomena can occur in animals when gastric emptying and dissolution are delayed, but food had been withheld from the cats of the present study (ie, they had an empty stomach at the time of oral administration of voriconazole), and gastric emptying was expected to be rapid. The short Tmax of only 1.1 hours also supported a short gastric emptying time. It is possible that other unidentified components (eg, xantham gum) of the oral medications may have contributed to the long t1/2. Therefore, the cause of the unexpected long oral t1/2, in comparison with the IV t1/2, is unclear. It should be pointed out that the most accurate determination of oral t1/2 would require collection of samples for at least 3 t1/2 periods (which would have been 120 hours for this study). Samples were collected for a shorter period because we expected that the t1/2 would be shorter on the basis of the data after IV administration and our experiences with other species.
The long oral t1/2 of voriconazole may have been responsible for adverse events in the cats of the present study, which have been described in earlier case reports7–9 of voriconazole administration to cats at higher and more frequent doses. The long t1/2 of voriconazole in cats, compared with the t1/2 for other species, may permit less frequent dosing (potentially as infrequent as every 72 hours) with lower doses, which would be convenient given the challenges of medicating cats. Because the volume of distribution is similar among species (1.29 L/kg in cats, 1.35 L/kg in horses, 1.3 L/kg in dogs, and 2.1 L/kg in rats), and the biggest difference among species is CL, the long t1/2 is most likely related to lower CL in cats (1.37 mL/min/kg).12,13 Half-life is a hybrid parameter that depends on both CL and volume of distribution. Thus, if the volume of distribution is similar among animals, the only explanation for a longer t1/2 is slower CL. Clearance of voriconazole in other species is mainly dependent on metabolism by CYP enzymes, with the main enzyme in humans being CYP219.3 The CYP enzyme responsible for metabolism of voriconazole in cats is not known.26
The effects of repeated dosing with voriconazole have been evaluated in several species, including a study12 of humans, rats, mice, rabbits, guinea pigs, and dogs and another study13 of horses. Substantial differences among species are evident with regard to the effects of voriconazole on its own metabolism. In rats, mice, and, to a lesser extent, dogs, autoinduction of hepatic CYP metabolizing enzymes has been observed in repeat-dosing experiments.12 This results in a decrease in the AUC and Cmax with repeated doses over time. Because of the autoinduction of metabolizing enzymes in these species, regimens that involve progressive dose escalation are often required to maintain therapeutic drug concentrations. In 1 study12 of humans, rabbits, and guinea pigs, autoinduction was not seen, and steady-state concentrations were attained after approximately 5 days when the drug was administered twice daily. Contrary to observations in other animals, drug concentrations increased progressively over 14 days during administration every 48 hours to the cats in the study reported here, and a steady-state concentration was never reached. Additional studies are needed to determine whether it is possible to achieve steady-state concentrations in cats with less frequent administration (eg, every 72 hours).
In humans, large variability in voriconazole trough plasma concentrations has been observed during therapeutic drug monitoring.4 This in part is the result of genetic polymorphism in CYP219 activity.4 Exposure to voriconazole is increased 4-fold in humans who are poor metabolizers, compared with exposure for homozygous extensive metabolizers. There is also a 2-fold increase in exposure to voriconazole in heterozygous versus homozygous extensive metabolizers. These differences are clinically important because voriconazole concentrations are directly related to the likelihood of adverse effects.2,4,19,27 In addition, attainment of adequate plasma drug concentrations is essential for good clinical outcomes in humans.4,27,28 Considerable variability in pharmacokinetic parameters was evident in the cats of the present study. The recommended target voriconazole plasma concentration in humans is 1 to 5 μg/L.19,27,28 Routine use of therapeutic drug monitoring to optimize the drug dose is recommended in humans.19,27,28 Findings for the study reported here strongly supported the need for therapeutic drug monitoring in cats because of the apparent narrow therapeutic index of voriconazole in cats and the possibility of drug accumulation during long-term administration.
Adverse effects observed in cats of the present study differed from those previously reported in cats treated with voriconazole.7–10 In the study reported here, the primary adverse effect observed was miosis, the development of which appeared to be correlated with higher plasma voriconazole concentrations. In addition to miosis, 1 cat had apparent photophobia approximately 30 minutes after oral administration of the drug, which resolved within 1 hour. In contrast, mydriasis was reported in 2 cats following treatment with voriconazole at a dose of 10 to 13 mg/kg/d.9 Those cats had weak pupillary light responses and results for a retinal examination within anticipated limits.9 Other neurologic adverse effects were not observed in cats of the present study but have been described in other reports.7–10 Cats of those reports were treated with higher doses of voriconazole (5 to 13 mg/kg, PO, q 12 to 24 h), and adverse effects included ataxia, abnormal mentation, apparent blindness, pelvic limb paresis, nystagmus, and head tremors. Other reported abnormalities included biochemical evidence of kidney injury in 2 cats,7 hypokalemia in 1 cat,9 and an auscultable cardiac arrhythmia in another cat.9 Azotemia and hypokalemia were not detected in cats of the present study and have not been reported in humans or other animal species. The cause of the adverse effects in the other reported studies has remained undetermined, but 1 of the 2 azotemic cats had also been treated with a high dose of meloxicam.7 Cardiac arrhythmias have also been reported in humans.9,29 We did not identify cardiac arrhythmias in the cats of the present study, but ECG monitoring was performed for only a brief period. Endocrine effects of azole drugs are possible through their inhibition of CYP and efflux transporter proteins such as P-glycoproteins. Those effects can result in testosterone and cortisol synthesis and transient infertility in sexually intact animals. To our knowledge, those effects have not yet been studied in cats.30
The mechanism for miosis in the cats of the present study was not determined and requires further study. To our knowledge, neither miosis nor mydriasis has been described after voriconazole administration to humans or any other species. Approximately 23% to 35% of humans treated with voriconazole experience visual disturbances that include enhanced visual perception, blurred vision, color vision change, or photophobia. These visual disturbances are usually transient (30- to 60-minute duration), diminish with repeated doses, and rarely require discontinuation of treatment.31,32 Because of the effects of multiple doses of voriconazole on the vision of healthy human volunteers, it has been hypothesized that voriconazole has a pharmacological effect on rod and cone pathways, including a possible mechanism of disinhibition that places the retina in a more light-adapted state and leads to increased relative contrast sensitivity.32 Less commonly, use of voriconazole in humans has resulted in other reversible adverse effects, including hallucinations, peripheral sensory neuropathy, hepatopathy, rash, and photosensitivity.29,33–35 Routine monitoring of liver function tests is recommended before starting treatment, within the first 2 weeks after starting treatment, and every 2 to 4 weeks thereafter.29,31 Increases in liver enzyme activities or dermatologic adverse effects were not detected in the cats of the present study; however, the duration of treatment was short.
Hypersalivation was consistently observed after administration of the oral suspension to cats in the study reported here and resulted in failure of drug absorption in 1 cat. This was not evident after administration of the tablets. Excipients in the oral suspension may have contributed to ptyalism. Voriconazole suspension contained silicon dioxide, titanium dioxide, sodium citrate dehydrate, sodium benzoate, anhydrous citric acid, natural orange flavor, and sucrose. These are considered inactive excipients in humans, but effects of these components in cats are unknown, and it is possible that one of these ingredients contributed to ptyalism or mydriasis. In addition, the target dose could be obtained by splitting tablets; because the tablets were less expensive than the oral suspension, we chose to continue treatment with the tablet formulation. The various voriconazole formulations were administered to cats from which food had been withheld for 12 hours (ie, each cat had an empty stomach) because this has been found to enhance absorption of voriconazole in other species. It is possible that a slower rate of absorption that minimizes high plasma peak concentrations might result from administering voriconazole at the time of or shortly after feeding. This should be evaluated in another study.
The main limitation of the present study was the small number of cats and the relatively short duration of treatment, compared with the duration of treatment required for most fungal infections, which is typically months to years. On the basis of the data from the study reported here, we believe that an oral dosing regimen consisting of an induction dose of 25 mg/cat followed by 12.5 mg every 72 hours warrants investigation because it has the potential to result in optimal plasma drug concentrations while minimizing drug accumulation and the risk of adverse effects.
In the present study, voriconazole had a high bioavailability and an extremely long t1/2 after short-term oral administration to healthy cats. It appeared to have a narrow therapeutic index in cats because adverse effects were more prominent with higher plasma drug concentrations. Miosis was the main adverse effect when plasma drug concentrations were within the therapeutic range, but it was mild and did not appear to necessitate discontinuation of treatment. Further study of the optimal dose of this drug in cats should include use of a relatively low dose, compared with the dose for other species, with prolonged dosing intervals and therapeutic drug monitoring to ensure concentrations are maintained in the range of 1 to 3 μg/mL because miosis was observed at concentrations ranging from 2 to 3 μg/mL. Therapeutic drug monitoring is particularly important in cats because of the slow CL detected in this study.
Acknowledgments
Supported by the Center for Companion Animal Health at the University of California-Davis.
Presented in abstract form at the 17th Annual Congress of the American College of Veterinary Internal Medicine, Indianapolis, June 2015.
The authors thank Delta R. Dise for assistance with the HPLC and Taylor Calloway, Adam Schawel, Kristen Elliot, Cody Blumenshine, Arash Sarlati, Sarai Milliron, and Adriana Manrique for technical assistance.
ABBREVIATIONS
| AUC | Area under the time-concentration curve |
| CL | Systemic drug clearance |
| Cmax | Maximum concentration |
| CV | Coefficient of variation |
| CYP | Cytochrome P450 |
| F | Absolute fraction of the dose absorbed |
| HPLC | High-performance liquid chromatography |
| Tmax | Time to maximum concentration |
| t1/2 | Half-life |
Footnotes
Purina Adult Formula, Nestle Purina, Wilkes-Barre, Pa.
Arrow International Inc, Reading, Pa.
Vfend IV, Pfizer Ltd, Sandwich, Kent, England.
Vfend suspension, Pfizer Ltd, Sandwich, Kent, England.
Voriconazole tablets (generic Vfend), Mylan Inc, Canonsburg, Pa.
Cyano-bonded cartridges, Bond-Elut CN-E, 1 mL, Varian Inc, Harbor City, Calif.
Zorbax RX-C8 4.6 × 150-mm, Agilent Technologies, Wilmington, Del.
Pfizer Ltd, Global Research and Development, Sandwich, Kent, England.
Phoenix WinNonlin, version 6.1, Pharsight Corp, Cary, NC.
References
1. Middleton SM, Kubier A, Dirikolu L, et al. Alternate-day dosing of itraconazole in healthy adult cats. J Vet Pharmacol Ther 2016; 39: 27–31.
2. Mikulska M, Novelli A, Aversa F, et al. Voriconazole in clinical practice. J Chemother 2012; 24: 311–327.
3. Scott LJ, Simpson D. Voriconazole: a review of its use in the management of invasive fungal infections. Drugs 2007; 67: 269–298.
4. Owusu Obeng A, Egelund EF, Alsultan A, et al. CYP2C19 polymorphisms and therapeutic drug monitoring of voriconazole: are we ready for clinical implementation of pharmacogenomics? Pharmacotherapy 2014; 34: 703–718.
5. Okabayashi K, Imaji M, Osumi T, et al. Antifungal activity of itraconazole and voriconazole against clinical isolates obtained from animals with mycoses. Nihon Ishinkin Gakkai Zasshi 2009; 50: 91–94.
6. Lat A, Thompson GR III. Update on the optimal use of voriconazole for invasive fungal infections. Infect Drug Resist 2011; 4: 43–53.
7. Smith LN, Hoffman SB. A case series of unilateral orbital aspergillosis in three cats and treatment with voriconazole. Vet Ophthalmol 2010; 13: 190–203.
8. Barrs VR, Halliday C, Martin P, et al. Sinonasal and sino-orbital aspergillosis in 23 cats: aetiology, clinicopathological features and treatment outcomes. Vet J 2012; 191: 58–64.
9. Quimby JM, Hoffman SB, Duke J, et al. Adverse neurologic events associated with voriconazole use in 3 cats. J Vet Intern Med 2010; 24: 647–649.
10. Kano R, Kitagawat M, Oota S, et al. First case of feline systemic Cryptococcus albidus infection. Med Mycol 2008; 46: 75–77.
11. Goodwin ML, Drew RH. Antifungal serum concentration monitoring: an update. J Antimicrob Chemother 2008; 61: 17–25.
12. Roffey SJ, Cole S, Comby P, et al. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. Drug Metab Dispos 2003; 31: 731–741.
13. Davis JL, Salmon JH, Papich MG. Pharmacokinetics of voriconazole after oral and intravenous administration to horses. Am J Vet Res 2006; 67: 1070–1075.
14. Chan HM, Duran SH, Walz PH, et al. Pharmacokinetics of voriconazole after single dose intravenous and oral administration to alpacas. J Vet Pharmacol Ther 2009; 32: 235–240.
15. Sanchez-Migallon Guzman D, Flammer K, Papich MG, et al. Pharmacokinetics of voriconazole after oral administration of single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res 2010; 71: 460–467.
16. Hsu AJ, Dabb A, Arav-Boger R. Autoinduction of voriconazole metabolism in a child with invasive pulmonary aspergillosis. Pharmacotherapy 2015; 35: e20–e26.
17. Mulanovich V, Lewis RE, Raad II, et al. Random plasma concentrations of voriconazole decline over time. J Infect 2007; 55: e129–e130.
18. Moriyama B, Elinoff J, Danner RL, et al. Accelerated metabolism of voriconazole and its partial reversal by cimetidine. Antimicrob Agents Chemother 2009; 53: 1712–1714.
19. Ashbee HR, Barnes RA, Johnson EM, et al. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother 2014; 69: 1162–1176.
20. Lemetayer JD, Dowling PM, Taylor SM, et al. Pharmacokinetics and distribution of voriconazole in body fluids of dogs after repeated oral dosing. J Vet Pharmacol Ther 2015; 38: 451–456.
21. United States Pharmacopeia and National Formulary (USP 30-NF 25). Vol 2. Rockville, Md: United States Pharmacopeia Convention, 2007;1553–1554.
22. ICH. Validation of analytical procedures: text and methodology Q2 (R1), in Proceedings. International conference on harmonisation of technical requirements for registration of pharmaceutical for human use, 2005.
23. Yamaoka K, Nakagawa T, Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 1978; 6: 165–175.
24. Perrier D, Gibaldi M. General derivation of the equation for time to reach a certain fraction of steady state. J Pharm Sci 1982; 71: 474–475.
25. Yáñez JA, Remsberg CM, Sayre CL, et al. Flip-flop pharmacokinetics—delivering a reversal of disposition: challenges and opportunities during drug development. Ther Deliv 2011; 2: 643–672.
26. Court MH. Canine cytochrome P-450 pharmacogenetics. Vet Clin North Am Small Anim Pract 2013; 43: 1027–1038.
27. Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 2008; 46: 201–211.
28. Smith J, Safdar N, Knasinski V, et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 2006; 50: 1570–1572.
29. Eiden C, Peyrière H, Cociglio M, et al. Adverse effects of voriconazole: analysis of the French Pharmacovigilance Database. Ann Pharmacother 2007; 41: 755–763.
30. Taxvig C, Vinggaard AM, Hass U, et al. Endocrine-disrupting properties in vivo of widely used azole fungicides. Int J Androl 2008; 31: 170–177.
31. Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of voriconazole. Clin Pharmacokinet 2006; 45: 649–663.
32. Zrenner E, Tomaszewski K, Hamlin J, et al. Effects of multiple doses of voriconazole on the vision of healthy volunteers: a double-blind, placebo-controlled study. Ophthalmic Res 2014; 52: 43–52.
33. Aksoy F, Akdogan E, Aydin K, et al. Voriconazole-induced neuropathy. Chemotherapy 2008; 54: 224–227.
34. Tsiodras S, Zafiropoulou R, Kanta E, et al. Painful peripheral neuropathy associated with voriconazole use. Arch Neurol 2005; 62: 144–146.
35. Zonios DI, Gea-Banacloche J, Childs R, et al. Hallucinations during voriconazole therapy. Clin Infect Dis 2008; 47: e7–e10.
