• View in gallery

    Mean ± SD plasma penciclovir concentrations at various times after a single oral administration of 62.5 mg (9 to 18 mg/kg) of famciclovir to 8 cats (A) and after the last oral administration of 62.5 mg of famciclovir following administration every 12 hours (black triangles) to 4 cats (16 to 18 mg/kg) or every 8 hours (white triangles) to 4 cats (9 to 16 mg/kg) for 3 days (B).

  • View in gallery

    Mean ± SD plasma penciclovir concentration at various times after the final oral dose of famciclovir (62.5 mg) administered every 8 or 12 hours for 3 days to the same cats as in Figure 1. The slopes of trough plasma penciclovir concentrations-versus-time plots (dashed and dotted lines) were not significantly (P < 0.05) different from zero for either administration interval.

  • View in gallery

    Dose-normalized AUC for penciclovir versus famciclovir dose in 8 cats following single and multiple doses of famciclovir administered every 8 or 12 hours. Linear regression analysis of the dosenormalized AUC versus dose following a single famciclovir administration (solid line) revealed a strong inverse correlation (r 2 = 0.92).

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Pharmacokinetics and safety of penciclovir following oral administration of famciclovir to cats

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  • 1 K.L. Maddy Equine Analytical Chemistry Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95616.
  • | 2 Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.
  • | 3 Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616.
  • | 4 K.L. Maddy Equine Analytical Chemistry Laboratory, School of Veterinary Medicine, University of California, Davis, CA 95616.

Abstract

Objective—To investigate penciclovir pharmacokinetics following single and multiple oral administrations of famciclovir to cats.

Animals—8 adult cats.

Procedures—A balanced crossover design was used. Phase I consisted of a single administration (62.5 mg, PO) of famciclovir. Phase II consisted of multiple doses of famciclovir (62.5 mg, PO) given every 8 or 12 hours for 3 days. Plasma penciclovir concentrations were assayed via liquid chromatography—mass spectrometry at fixed time points after famciclovir administration.

Results—Following a single dose of famciclovir, the dose-normalized (15 mg/kg) maximum concentration (Cmax) of penciclovir (350 ± 180 ng/mL) occurred at 4.6 ± 1.8 hours and mean ± SD apparent elimination half-life was 3.1 ± 0.9 hours. However, the dose-normalized area under the plasma penciclovir concentration-time curve extrapolated to infinity (AUC0→∞) during phase I decreased with increasing dose, suggesting either nonlinear pharmacokinetics or interindividual variability among cats. Accumulation occurred following multiple doses of famciclovir administered every 8 hours as indicated by a significantly increased dose-normalized AUC, compared with AUC0→∞ from phase 1. Dose-normalized penciclovir Cmaxfollowing administration of famciclovir every 12 or 8 hours (290 ± 150 ng/mL or 780 ± 250 ng/mL, respectively) was notably less than the in vitro concentration (3,500 ng/mL) required for activity against feline herpesvirus-1.

Conclusions and Clinical Relevance—Penciclovir pharmacokinetics following oral famciclovir administration in cats appeared complex within the dosage range studied. Famciclovir dosages of 15 mg/kg administered every 8 hours to cats are unlikely to result in plasma penciclovir concentrations with activity against feline herpesvirus-1.

Abstract

Objective—To investigate penciclovir pharmacokinetics following single and multiple oral administrations of famciclovir to cats.

Animals—8 adult cats.

Procedures—A balanced crossover design was used. Phase I consisted of a single administration (62.5 mg, PO) of famciclovir. Phase II consisted of multiple doses of famciclovir (62.5 mg, PO) given every 8 or 12 hours for 3 days. Plasma penciclovir concentrations were assayed via liquid chromatography—mass spectrometry at fixed time points after famciclovir administration.

Results—Following a single dose of famciclovir, the dose-normalized (15 mg/kg) maximum concentration (Cmax) of penciclovir (350 ± 180 ng/mL) occurred at 4.6 ± 1.8 hours and mean ± SD apparent elimination half-life was 3.1 ± 0.9 hours. However, the dose-normalized area under the plasma penciclovir concentration-time curve extrapolated to infinity (AUC0→∞) during phase I decreased with increasing dose, suggesting either nonlinear pharmacokinetics or interindividual variability among cats. Accumulation occurred following multiple doses of famciclovir administered every 8 hours as indicated by a significantly increased dose-normalized AUC, compared with AUC0→∞ from phase 1. Dose-normalized penciclovir Cmaxfollowing administration of famciclovir every 12 or 8 hours (290 ± 150 ng/mL or 780 ± 250 ng/mL, respectively) was notably less than the in vitro concentration (3,500 ng/mL) required for activity against feline herpesvirus-1.

Conclusions and Clinical Relevance—Penciclovir pharmacokinetics following oral famciclovir administration in cats appeared complex within the dosage range studied. Famciclovir dosages of 15 mg/kg administered every 8 hours to cats are unlikely to result in plasma penciclovir concentrations with activity against feline herpesvirus-1.

Feline herpesvirus-1 is a major cause of respiratory and ocular disease in cats, with an estimated seroprevalence in feline populations of 50% to 97%.1-3 Infection of susceptible kittens with FHV-1 typically causes moderate to severe upper respiratory tract and ocular disease with approximately 100% morbidity.4 Illness may be fatal, especially in young kittens. Following primary exposure, FHV-1 establishes lifelong neural latency in at least 80% of cats, and periods of viral reactivation occur throughout life in many of these cats.5 Herpetic infection may be associated with conjunctivitis,6 rhinosinusitis,7 keratitis,8 corneal sequestration,9 eosinophilic keratitis,9 anterior uveitis,10 or dermatitis.11,12 As such, primary and recrudescent herpetic disease in cats represents a diverse array of common and often frustrating clinical syndromes worldwide.

Presently, in the United States, there are no antiviral drugs approved for treatment of cats infected with FHV-1. However, several antiviral agents developed for treatment of humans infected with herpesviruses have been used in cats.13,14 Unfortunately, many of the agents developed for humans infected with herpesviruses have low efficacy against FHV-1,15,16 are poorly bioavailable in cats,17 or are toxic when systemically administered to cats.17,18 Toxicity is of less concern when antiviral agents developed for the treatment of herpesviruses in humans are applied topically to cats' eyes; however, concerns regarding their efficacy against FHV-1 remain.15,16 Therefore, development or discovery of a safe and effective antiviral agent for treating cats infected with FHV-1 is an important goal.

Anecdotal reports of the use of famciclovir at approximately 6 to 10 mg/kg every 24 or 12 hours to treat cats with herpetic disease have recently emerged. Famciclovir is a prodrug of the antiviral drug penciclovir. Penciclovir is a nucleoside deoxyguanosine analogue with a similar mechanism of action as acyclovir and potent antiviral activity for the human herpesviruses varicella zoster virus and herpes simplex virus types 1 and 2.19 Recently, we examined the antiviral efficacy of penciclovir and other antiviral drugs against FHV-1 cultured in vitro.16 The median penciclovir concentration at which FHV-1 plaque numbers were reduced by 50% relative to control wells (13.9μM [3,500 ng/mL]) was similar to other drugs that have had some clinical effect as topical treatments for cats infected with FHV-1 and was superior to that reported for acyclovir, the only drug sometimes recommended for systemic administration to FHV-1–infected cats.15,16 However, to the authors' knowledge, the pharmacokinetics and safety of penciclovir following oral administration of famciclovir to cats have not been determined. Therefore, the purpose of the study reported here was to investigate the pharmacokinetics and safety of penciclovir following single and multiple oral doses of famciclovir in healthy cats.

Materials and Methods

Cats—Eight sexually intact specific-pathogenfree female domestic shorthair cats (mean ± SD body weight, 4.3 ± 1.1 kg; age, 2.5 ± 1.5 years) were used in this study. Cats were determined to be healthy via physical examination and results of serum biochemical analyses, CBC, and urinalysis prior to beginning the study. Room temperature (21° ± 2°C) and light-todark cycle (14:10 hours) of the cat housing area at the University of California Feline Nutrition and Pet Care Center were controlled. All cats had free access to fresh water and a commercially prepared, dry expanded diet.a The proximate dry-matter composition of this dieta was 33.4% crude protein, 16.3% crude fat, 7.2% ash, and 1.3% crude fiber. The study was approved by the Institutional Animal Care and Use Committee of the University of California, Davis (protocol 11914).

Experimental design—A balanced crossover design was used with 8 cats randomly assigned to enter phase I or II. Phase I consisted of a single oral administration of 62.5 mg of famciclovirb to each cat (9 to 18 mg/kg). Phase II consisted of a multiple dose trial of 62.5 mg of famciclovir given orally every 8 hours (n = 4 cats; 9 to 16 mg/kg) or 12 hours (4 cats; 16 to 18 mg/kg) for 3 days. Famciclovir tablets (125 mg) were carefully cut in half with a pill cutter, but were not compared by weight prior to administration. Each dose of famciclovir in phases I and II was administered concurrently with approximately 5 g of a commercial wet dietc (120 kcal/100 g; 36.4% protein, 59.4% fat, and 4.2% carbohydrate). At least 10 days were allowed to elapse between phases I and II.

Catheter placement and sample collection—To facilitate collection of multiple blood samples, percutaneous placement into the jugular vein of a 5.5-F, 13-cm triple-lumen catheterd was performed during anesthesia in all cats prior to commencement of the study. Briefly, food was withheld from all cats for 12 hours before induction of anesthesia via IV administration of ketamine (5 mg/kg) and diazepam (0.2 mg/kg). Anesthesia was maintained with isoflurane in oxygen delivered via an endotracheal tube until catheter placement was complete. Catheters were maintained for the duration of the study except in 3 cats that dislodged their catheters between study phases. These 3 cats were anesthetized with the same protocol as described, and an identical catheter was placed in the opposite jugular vein.

In phase I, blood samples (3 to 4 mL/sample) were obtained immediately prior to famciclovir administration and 15, 30, 45, 60, and 90 minutes and 2, 3, 4, 6, 9, and 12 hours following oral administration of famciclovir. In phase II, trough plasma penciclovir concentrations were assessed in blood samples obtained immediately prior to each famciclovir administration on each of the 3 study days. Following administration of the last dose of famciclovir in phase II, blood samples were collected at the same posttreatment time points described for phase I. During both phases, each blood sample volume was replaced with an equal volume of lactated Ringer's solution. Blood samples were centrifuged for 10 minutes at 2,000 × g, and the resulting plasma was collected and stored at −20°C for penciclovir determination. Although stability of penciclovir at −20°C was not specifically assessed, quality-control samples (50 and 500 ng/mL) were subjected to identical storage, solidphase extraction, and chromatographic procedures as the test samples.

Liquid chromatography–mass spectrometry assay—Penciclovire and acyclovirf were commercially obtained. The reference, calibration, and test samples were transferred into autosampler vials and vortexed for 5 to 10 seconds. A mixture containing 9 parts acetonitrile to 1 part 1M acetic acid and acyclovir (500 ng/mL; internal standard) was added to each sample vial. Following addition of the internal standard, the contents of each vial were again mixed for 1 minute on a multipulse rack vortexerg (speed, 60 to 70; pulse, 60) and all samples were refrigerated at 4°C for 30 minutes. The samples were vortexed for approximately 20 seconds and centrifuged at 1,580 × g for 15 minutes at 4°C. The vials then were transferred to an autosampler rack, and 10 μL of supernatant was injected for analysis.

Quantitative analyses were conducted with a linear ion-trap mass spectrometerh equipped with a high-performance liquid chromatography system.i Separation of the penciclovir and internal standard was performed on a phenyl columnj (3 × 150 mm; particle size, 3 μm). The mobile phase was composed of a solvent mixture of acetonitrile with 0.2% formic acid as solvent A and water with 0.2% formic acid as solvent B. The liquid chromatography pump provided a gradient of solvent A from 1.0% to 90% during 4.5 minutes at a flow rate of 0.5 mL/min.

The concentration of penciclovir in each sample was determined by use of the internal standard method via the peak area ratio and linear regression analysis. The response for penciclovir was linear and gave correlation coefficients (ie, r2) of ≥ 0.99. The technique was optimized to provide a minimum limit of quantitation of 10 ng/mL. The percentage recovery for penciclovir at 50 ng/mL was 92% of the standard. Intraday accuracy (percentage of nominal concentration) was 96% and 99% for 50 and 500 ng/mL, respectively. Interday accuracy (percentage of nominal concentration) was 94% and 98% for 50 and 500 ng/mL, respectively. Intraday precision (percentage of relative SD) was 3.9% and 3.3% for 50 and 500 ng/mL, respectively. Interday precision (percentage of relative SD) was 3.7% and 5.2% for 50 and 500 ng/mL, respectively.

Data analysis—Analysis of pharmacokinetic data was performed with a commercial software program,k and plasma penciclovir concentration-time data were assessed via noncompartmental analysis.20 The Cmax and Tmax were estimated from the data. Linear trapezoidal areas were used in calculating the AUC, and other pharmacokinetic parameters were determined by use of standard noncompartmental equations. Specifically, the kel was calculated as the slope of the terminal phase of the plasma-concentration curve that included a minimum of 3 points, and t1/2(λz) was calculated as t1/2(λz) = 0.693/kel. To assess whether dosing interval had a significant effect on penciclovir pharmacokinetic variables, a Mann-Whitney nonparametric test with a Hochberg correction for multiple tests was used to compare Cmax, Tmax, Cp(avg), Css(min), fluctuationss, AUC0→τ, and t1/2(λz). The Cp(avg) was calculated as Cp(avg) = AUC0→τ/τ. The fluctuationss was calculated as fluctuationss (%) = 100 × (Cmax – Css(min))/Cp(avg). To accommodate differences in the administered doses (mg/kg) of famciclovir, the Cmax, Cp(avg), Css(min), and AUC were normalized to reflect values expected if all cats received a 15 mg/kg oral dose, for example, dose-normalized Cmax = (Cmax/dose) × 15.

To determine whether penciclovir accumulated with multiple orally administered doses of famciclovir, least squares linear regression of the plasma troughs following orally administered doses of famciclovir was performed with a commercial software program.l In addition, the accumulation index was calculated as R = 1/(1 – e[–kel × τ]). To assess whether penciclovir metabolism was induced or inhibited by prolonged famciclovir administration, the dose-normalized AUC0→τ from phase I and dose-normalized AUC0→τ from phase II were compared by use of a paired difference t test. The Cmax, Tmax, and t1/2(λz) determined from single and multiple dose administration were also compared with a paired difference t test. Least squares linear regression was used to evaluate the relationship between dose-normalized AUC and dose. Significance was set at P < 0.05 for all analyses. All data are presented as mean ± SD.

Safety of oral famciclovir administration—Physical examinations were performed on each cat prior to beginning each phase and twice daily during phase II. The examination included assessment of rectal temperature, heart and respiratory rates, capillary refill time, mucous membrane color, behavior, PCV, and plasma total protein concentration, as well as auscultation of the lungs and heart. A CBC, serum biochemical analyses, and analysis of urine obtained via cystocentesis or free catch were performed prior to beginning the study and 6 to 8 hours after the last administration of famciclovir in each cat. To determine whether chronic famciclovir administration affected hematologic or biochemical values, data obtained before and after dose administration were compared by use of a paired difference t test with a Bonferroni correction for multiple t tests. Significance was set at P < 0.05 for all analyses.

Results

Pharmacokinetics of penciclovir—Following a single orally administered dose of 9 to 18 mg of famciclovir/kg, plasma penciclovir concentration typically increased gradually, with a dose-normalized (15 mg/kg) Cmax of 350 ± 180 ng/mL at 4.6 ± 1.8 hours following drug administration (Figure 1; Table 1). Mean plasma penciclovir concentration 12 hours after dose administration was 60 ± 24 ng/mL, which corresponded with a t1/2(λz) of 3.1 ± 0.9 hours.

Table 1—

Mean ± SD values for pharmacokinetic parameters of penciclovir determined via noncompartmental analysis following a single orally administered dose (9 to 18 mg/kg to 8 cats) or multiple orally administered doses (16 to 18 mg/kg, q 12 h, to 4 cats; or 9 to 16 mg/kg, q 8 h, to 4 cats) of famciclovir.

Table 1—
Figure 1—
Figure 1—

Mean ± SD plasma penciclovir concentrations at various times after a single oral administration of 62.5 mg (9 to 18 mg/kg) of famciclovir to 8 cats (A) and after the last oral administration of 62.5 mg of famciclovir following administration every 12 hours (black triangles) to 4 cats (16 to 18 mg/kg) or every 8 hours (white triangles) to 4 cats (9 to 16 mg/kg) for 3 days (B).

Citation: American Journal of Veterinary Research 68, 11; 10.2460/ajvr.68.11.1252

The plasma penciclovir concentration-versus-time profile that resulted from multiple oral famciclovir administrations every 12 hours was similar to that obtained following administration of a single dose (Figure 1). However, greater accumulation occurred when famciclovir was administered every 8 hours. Although the Tmax and dose-normalized Cmax values obtained after multiple oral administrations of famciclovir (every 8 or 12 hours) were not significantly different from those obtained after a single dose, the mean dose-normalized Cmax value following administration every 8 hours (780 ng/mL) was more than double that associated with single-dose administration (350 ng/mL; Table 1). The dosenormalized Cp(avg) and Css(min) values were significantly greater when the administration interval was 8 versus 12 hours, suggesting that accumulation occurred with the every-8-hours regimen. By contrast, the t1/2z) obtained after a single dose (3.1 ± 0.9) was not significantly different from that obtained after oral administration of multiple doses of famciclovir every 12 hours (3.6 ± 0.1; P = 0.26) or that obtained after administration every 8 hours (4.2 ± 2.2; P = 0.11). Regardless of whether famciclovir was administered every 8 or 12 hours, the slope of the trough penciclovir plasma concentrationversus-time plot was not significantly different from 0 (Figure 2). The dose-normalized AUCs following a single orally administered dose (2,100 ± 200 ng·h·mL−1) and multiple orally administered doses of famciclovir every 12 hours (2,400 ± 1,300 ng·h·mL−1) were not significantly (P = 0.75) different. However, the dosenormalized AUC0→τ at steady state following multiple orally administered doses every 8 hours (5,500 ± 1,000 ng·h·mL−1) was significantly (P = 0.04) greater than the dose-normalized AUC0md following a single oral administration (3,100 ± 700 ng·h·mL−1). In contrast to the increase in plasma penciclovir concentration detected at steady state with the every-8-hour dosing regimen, the dose-normalized AUC0→τ following a single dose of famciclovir decreased with increasing dose, suggesting nonlinear pharmacokinetics (Figure 3).

Figure 2—
Figure 2—

Mean ± SD plasma penciclovir concentration at various times after the final oral dose of famciclovir (62.5 mg) administered every 8 or 12 hours for 3 days to the same cats as in Figure 1. The slopes of trough plasma penciclovir concentrations-versus-time plots (dashed and dotted lines) were not significantly (P < 0.05) different from zero for either administration interval.

Citation: American Journal of Veterinary Research 68, 11; 10.2460/ajvr.68.11.1252

Figure 3—
Figure 3—

Dose-normalized AUC for penciclovir versus famciclovir dose in 8 cats following single and multiple doses of famciclovir administered every 8 or 12 hours. Linear regression analysis of the dosenormalized AUC versus dose following a single famciclovir administration (solid line) revealed a strong inverse correlation (r 2 = 0.92).

Citation: American Journal of Veterinary Research 68, 11; 10.2460/ajvr.68.11.1252

Safety of orally administered famciclovir—Famciclovir administration every 8 or 12 hours did not have a clinically important effect on rectal temperature (range, 37° to 39°C), heart rate (range, 144 to 298 beats/min), or respiratory rate (range, 42 to 90 breaths/min). No adverse effects associated with famciclovir administration were observed in any of the cats during the study period. Following administration of multiple doses of famciclovir and coincident frequent blood sampling, PCV significantly (P = 0.01) decreased from a baseline value of 34 ± 4% to 25 ± 3% 12 hours after the last dose of famciclovir was administered. A concurrent significant (P = 0.01) decrease in total protein from a baseline value of 6.7 ± 0.6 g/dL to 6.0 ± 0.6 g/dL 12 hours after the last administration of famciclovir also was detected. Hemoglobin concentration 12 hours after the last administration of famciclovir (8.9 ± 1.2 g/dL) was also significantly (P = 0.01) decreased from a baseline value of 11.7 ± 2.5g/dL. In addition, WBC concentration significantly (P = 0.01) increased from 7,800 ± 2,700 cells/μL at baseline to 12,000 ± 3,000 cells/μL 6 to 8 hours after the last administration. This change was secondary to a significant increase in neutrophils (4,500 ± 1,200 cells/μL to 6,700 ± 1,400 cells/μL; P = 0.01) and monocytes (130 ± 80 cells/μL to 350 ± 120 cells/μL; P = 0.01) following multiple doses of famciclovir. Hemoglobin concentration and PCV after famciclovir administration were less than reference ranges,m but total protein and WBC concentrations remained within reference ranges. No other significant hematologic or serum biochemical changes were detected after famciclovir administration.

Discussion

The mean (range) famciclovir dose of 15 mg/kg (9 to 18 mg/kg) administered in the present study was similar to that reported for other species, including humans.21 However, with the exception of the similar t1/2(λz) of approximately 2 to 3 hours in cats, dogs, and humans, the pharmacokinetics of penciclovir following a single dose of famciclovir administered orally to cats differed, compared with other species.19,21 For example, in humans administered 10 mg of famciclovir/kg, a plasma penciclovir Cmax of 5,000 ng/mL was evident within 0.75 hours,21 whereas in the cats in the present study, 4.6 hours was required to attain a plasma penciclovir Cmax of only 350 ng/mL. Dogs and rats had similar maximum plasma penciclovir concentrations to humans when administered moderately higher doses of 25 and 40 mg/kg, respectively.19 The lower penciclovir Cmax and delayed Tmax reported for cats in the present study suggest that absorption of famciclovir, metabolism to penciclovir, or a combination of those factors is reduced in cats relative to humans, rats, and dogs. Furthermore, the dose-normalized AUC for penciclovir had an inverse relationship to the famciclovir dose administered to cats in the present study. This would be consistent with nonlinear famciclovir absorption, metabolism, or a combination of those factors. Finally, the greater-than-expected accumulation detected when famciclovir was administered every 8 hours suggests that nonlinear elimination of penciclovir may occur. Taken together, these data suggest that at least 2 potentially opposing and saturable events may be affecting the complex pharmacokinetic profile of this compound in this species.

Because our data were generated with a relatively narrow dose range administered to only 8 cats, interpretation of the kinetics of this compound may be confounded by interindividual variation among cats. In addition, dosage comparisons were performed among cats following a single famciclovir dose only, and no comparisons of dose were performed on any individual cats. Finally, plasma penciclovir concentrations were highly variable among cats. Although this could be explained by nonlinear pharmacokinetics, it may also reflect differences in dosage, absorption, and interindividual variability. For example, tablet preparation likely provided a minor source of variability among and within cats during the multiple-dose phase of the study. Tablets were cut in half with a pill cutter, but were not compared by weight prior to administration. Diurnal variability was also detected in trough plasma penciclovir concentrations following multiple doses of famciclovir, particularly when administered every 8 hours. Trough plasma penciclovir concentrations were typically lowest at 6 AM and highest at either 2 or 10 PM. Diurnal differences in food consumption or hepatic blood flow may have contributed to this variability.

Because of the potential complexity of the kinetics of famciclovir and penciclovir in this species and the inherent variability among cats, there are several ways in which data generated in the present study can be interpreted. Ultimately, studies that use penciclovir administered IV and wider dose ranges of orally administered famciclovir will be required to answer some of the questions raised by the present study. However, if the kinetics of famciclovir and penciclovir in cats are indeed nonlinear, there are at least 3 potential mechanisms by which this might occur. First, absorption of famciclovir may not increase proportionally with increasing dose. Second, it is possible that the metabolism of famciclovir to penciclovir is less than dose proportional, perhaps because of enzyme saturation. With increasing famciclovir dose, both of these mechanisms would result in less-than-expected increases in plasma penciclovir concentration (as suggested in the present study), but would not influence the drug's half-life. Third, nonlinear kinetics would be detected if the mechanism by which penciclovir is eliminated is saturable. In that case, an increase in famciclovir dose would lead to greater-than-predicted increases in penciclovir concentration, along with an increase in half-life because of decreased metabolite clearance. Because any or all of these mechanisms may occur in any combination, the relative role of these potentially opposing mechanisms cannot be determined with data generated in the present study.

Evidence exists in other species and in cats to support the less than dose-proportional metabolism of famciclovir to penciclovir detected in cats from the present study. In humans, famciclovir is metabolized by di-deacetylation, predominantly in the blood, to BRL 42359 and subsequent 6-oxidation of BRL 42359 to penciclovir by aldehyde oxidase in the liver.19,22 Because saturation of hepatic aldehyde oxidase is possible and because hepatic aldehyde oxidase activity is nearly absent in cats,23 conversion of BRL 42359 to penciclovir would be expected to be slow or incomplete in cats. This is also supported by evidence of nonlinear kinetics in dogs and rats administered famciclovir, albeit at much greater doses (250 and 4,000 mg/kg, respectively).19 Although humans and rats have good and moderate hepatic aldehyde oxidase activities, respectively, dogs and cats have minimal hepatic aldehyde oxidase activity.23 These data suggest that metabolism of famciclovir alone may not completely account for the differences in Cmax and Tmax observed between cats and dogs and that variation in absorption may also play a role.

When considering the absorption of famciclovir in the present study, it is possible that concurrent administration of even the small amount of food provided to cats, along with free access to food before and after administration of famciclovir, may have slowed drug absorption or metabolic conversion of famciclovir to penciclovir. Administration of famciclovir to humans 0.5 hours after ingestion of food significantly reduced plasma penciclovir Cmax by 53% and delayed Tmax by 2.5 hours.24 Additionally, although famciclovir is initially freely soluble (> 25% wt/vol) in water at 25°C, it rapidly precipitates to the sparingly soluble (2% to 3% wt/vol) monohydrate.25 If such precipitation occurred in vivo, it could result in dissolution-limited oral bioavailability of famciclovir. This mechanism appears unlikely because it would be expected that a decrease in relative versus absolute absorption would occur. In addition, it is unknown why precipitation would occur in vivo in cats but not in other mammals such as rats, dogs, and humans.

Assuming that penciclovir pharmacokinetics follow a 1-compartment body model, the accumulation index, which reflects the ratio of concentrations at steady state to those following a single dose, was 1.1 and 1.4 for the 12- and 8-hour dosing intervals, respectively. In contrast, for the group receiving famciclovir every 8 hours, the ratio of dose-normalized penciclovir Cmax after multiple administrations was 2.2 times as great as that detected following a single dose. Although AUC0mT at steady state should equal AUC0→τ following a single dose, it was > 2 times as high in cats that received famciclovir every 8 hours. These data suggest nonlinear elimination of penciclovir, but similar findings were not detected in cats that received famciclovir every 12 hours. Likewise, if Css(min) values followed linear predictions, a 30% higher value would be expected for 8-hour versus 12-hour administration. Instead, a 4-times and significant increase in Css(min) values was detected for the 8-hour group. Thus, despite the small and nonsignificant change in t1/2 (3.6 and 4.2 hours for the 12- and 8-hour administration regimens, respectively) under steady-state conditions, these results suggested that at least some cats had a decrease in penciclovir clearance when administered famciclovir every 8 hours. Although this presumed change in renal clearance of penciclovir could be caused by renal toxicosis, no significant differences in circulating creatinine and BUN concentrations or urine specific gravity were detected, and these values remained within reference ranges for all cats after receiving multiple doses of famciclovir.

Famciclovir administered orally at 9 to 18 mg/kg every 8 or 12 hours appeared to be tolerated well by cats in the present study. No clinical signs of adverse effects were detected at any time point throughout either phase of the study. The only CBC or serum biochemical values that changed significantly were PCV and hemoglobin concentration, which were decreased at the end of the study. Although both changes could have resulted from drug administration, they would also be expected as a result of the frequent blood sampling required to accurately determine plasma penciclovir concentration and drug disposition. The volume of blood collected from cats receiving famciclovir every 8 or 12 hours was 117 ± 3 mL or 105 ± 3 mL, respectively, over a 2.5-week period. The concurrent decrease in total protein concentration was also a likely result of sampling techniques. Although this change was significant, total protein concentration did not decrease to below the reference range. The significant increase in leukocyte concentration likely represented generalized bone marrow stimulation associated with erythropoiesis secondary to frequent blood sampling. By contrast, administration of the pharmacologically related antiviral agent valacyclovir to cats infected with FHV-1 was associated with neutropenia and bone marrow suppression in addition to electrolyte abnormalities and crystalluria.18 None of these changes was detected in any cats in the present study. However, it is important to note that the hematologic and biochemical changes detected in FHV-1–infected cats that received valacyclovir began after 5 days of drug administration,18 whereas cats in the present study were healthy and received famciclovir for only 3 days.

Although orally administered famciclovir appeared to be tolerated well by cats, further studies are required to investigate the efficacy of famciclovir administration for herpetic disease in cats. The dose-normalized penciclovir Cmax obtained in the present study after administration of multiple doses of famciclovir every 12 or 8 hours was a fifth to a tenth of the target penciclovir concentration for FHV-1 suggested by results of an in vitro study16 (13.9μM [3,500 ng/mL]). Because of the apparently complex pharmacokinetics of famciclovir and penciclovir in cats, higher famciclovir dose or increased administration frequency may not completely correct this.

ABBREVIATIONS

FHV-1

Feline herpesvirus-1

Cmax

Maximum detected plasma penciclovir concentration

Tmax

Time after oral administration at which Cmax was detected

kel

Elimination rate constant

AUC

Area under the plasma penciclovir concentration-time curve

t1/2(λz)

Apparent elimination half-life

Cp(avg)

Mean plasma penciclovir concentration during the dosing interval at steady state

Css(min)

Minimum detected plasma penciclovir concentration during the dosing interval at steady state

Fluctuationss

Steady-state fluctuation

AUC0→τ

Area under the plasma penciclovir concentration-time curve during the dosing interval

τ

Administration interval

AUC00→∞

Area under the plasma penciclovir concentration-time curve extrapolated to infinity

a.

Whiskas Dry Kitten Food, Waltham USA Inc, Vernon, Calif.

b.

Famvir (125-mg, round, film-coated biconvex tablet with beveled edges), Novartis Pharmaceuticals Corp, East Hanover, NJ.

c.

Waltham Coat Care Tuna Formula, Waltham USA Inc, Vernon, Calif.

d.

Arrow International Inc, Reading, Pa.

e.

Calbiochem, La Jolla, Calif.

f.

Sigma Aldrich, St Louis, Mo.

g.

Glas-Col Apparatus Co, Terre Haute, Ind.

h.

LTQ, Thermo Electron Corp, San Jose, Calif.

i.

Model 1100, Agilent Technologies, Palo Alto, Calif.

j.

Zorbax XDB-phenyl 3-μm × 150-mm column, MacMod Analytical Inc, Chads Ford, Pa.

k.

WinNonlin, version 5.0.1, Pharsight Corp, Palo Alto, Calif.

l.

SigmaPlot, version 9.01, Systat Software Inc, Point Richmond, Calif.

m.

IDEXX Reference Laboratories, West Sacramento, Calif.

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Contributor Notes

Presented in part at the annual forum of the American College of Veterinary Internal Medicine, Louisville, May–June 2006.

Supported by the Center for Companion Animal Health, School of Veterinary Medicine, University of California, Davis, Calif.

The authors thank Debbie Bee for technical assistance.

Address correspondance to Dr. Maggs.