Pharmacokinetic modeling of penciclovir and BRL42359 in the plasma and tears of healthy cats to optimize dosage recommendations for oral administration of famciclovir.

OBJECTIVES To determine, following oral administration of famciclovir, pharmacokinetic (PK) parameters for 2 of its metabolites (penciclovir and BRL42359) in plasma and tears of healthy cats so that famciclovir dosage recommendations for the treatment of herpetic disease can be optimized. ANIMALS 7 male domestic shorthair cats. PROCEDURES In a crossover study, each of 3 doses of famciclovir (30, 40, or 90 mg/kg) was administered every 8 or 12 hours for 3 days. Six cats were randomly assigned to each dosage regimen. Plasma and tear samples were obtained at predetermined times after famciclovir administration. Pharmacokinetic parameters were determined for BRL42359 and penciclovir by compartmental and noncompartmental methods. Pharmacokinetic-pharmacodynamic (PK-PD) indices were determined for penciclovir and compared among all dosage regimens. RESULTS Compared with penciclovir concentrations, BRL42359 concentrations were 5- to 11-fold greater in plasma and 4- to 7-fold greater in tears. Pharmacokinetic parameters and PK-PD indices for the 90 mg/kg regimens were superior to those for the 30 and 40 mg/kg regimens, regardless of dosing frequency. Penciclovir concentrations in tears ranged from 18% to 25% of those in plasma. Administration of 30 or 40 mg/kg every 8 hours achieved penciclovir concentrations likely to be therapeutic in plasma but not in tears. Penciclovir concentrations likely to be therapeutic in tears were achieved only with the two 90 mg/kg regimens. CONCLUSIONS AND CLINICAL RELEVANCE In cats, famciclovir absorption is variable and its metabolism saturable. Conversion of BRL42359 to penciclovir is rate limiting. The recommended dosage of famciclovir is 90 mg/kg every 12 hours for cats infected with feline herpesvirus.

A novel uHPLC-MS/MS method for the quantitation of AZD7451 (AZ12607092) in human plasma.

Tropomyosin-related kinases (Trk) are tyrosine kinase receptors implicated in tumor proliferation, invasion, and survival signaling across a number of tumors, making them potentially attractive targets for the treatment of cancer. AZD7451 is a potent and selective inhibitor of Trk kinases currently undergoing a Phase I dose escalation in glioblastoma multiforme at the National Cancer Institute. A key part of early clinical testing for AZD7451 involves demonstrating that pharmacokinetic half-life and clinical exposures of AZD7451 are sufficient to inhibit Trk receptors in preclinical models. To address this need, an ultra sensitive analytical method was developed to measure the AZD7451 profile in human plasma. A liquid-liquid extraction recovered >80% of AZD7451 before quantitative analysis by ultra HPLC-MS/MS. A Varian Polaris(®) C18-A column and a mass transition of m/z 383.5→340.5 (m/z 389.6→342.0 for the internal standard [(2)H6]-AZD7451) was used, and a dynamic calibration range of 0.5-1000ng/mL was established, which provided a sensitive (<8.5% deviation), and precise (<6%) quantitative assay for AZD7451. AZD7451 demonstrated stability in human plasma at room temperature for 24h (<7% change) and after extraction at 4°C for 24h (<8% change), and was stable through 4 freeze/thaw cycles (<8% change). This method was used to measure AZD7451 plasma levels in clinical samples to confirm the sensitivity at several time points following AZD7451 treatment in subjects with glioblastoma.

Dissolution testing and potentiometric determination of famciclovir in pure, dosage forms and biological fluids.

The performance characteristics of two new plastic membrane ion selective electrodes (ISEs) used for the determination of famciclovir (Fcv) based on the ion associate of Fcv with phosphotungstic acid (PTA) or phosphomolybdic acid (PMA) are described. Different experimental conditions as type of plasticizer to be incorporated in the membrane, life span, effect of soaking, pH, temperature, and interferences were studied. Both electrodes showed similar performance under these conditions, exhibiting Nernstian slopes of S (Fcv-PTA)=58.60±0.84 mV/decade and S (Fcv-PMA)=58.77±0.68 mV/decade within a usable concentration range of 10⁻5-10⁻² [Fcv/M] at 298/K. Famciclovir was assayed potentiometrically in its pure solution, pharmaceutical preparations and biological fluids (urine and plasma) using proposed electrodes under batch and flow injection analysis (FIA) conditions with a recovery % ranging between 96.76% and 102.83% having RSD of 0.66%-1.81%. The electrodes were also successfully applied in the determination of the dissolution profile of Fcv tablets and the results came in agreement with the validated results of the HPLC method obtained from the quality control unit of the company producing the tablets.

Estimates of the pharmacokinetics of famciclovir and its active metabolite penciclovir in young Asian elephants (Elephas maximus).

OBJECTIVE: To determine plasma pharmacokinetics of penciclovir following oral and rectal administration of famciclovir to young Asian elephants (Elephas maximus). ANIMALS: 6 healthy Asian elephants (5 females and 1 male), 4.5 to 9 years old and weighing 1,646 to 2,438 kg. PROCEDURES: Famciclovir was administered orally or rectally in accordance with an incomplete crossover design. Three treatment groups, each comprising 4 elephants, received single doses of famciclovir (5 mg/kg, PO, or 5 or 15 mg/kg, rectally); there was a minimum 12-week washout period between subsequent famciclovir administrations. Serial blood samples were collected after each administration. Samples were analyzed for famciclovir and penciclovir with a validated liquid chromatography-mass spectroscopy assay. RESULTS: Famciclovir was tolerated well for both routes of administration and underwent complete biotransformation to the active metabolite, penciclovir. Mean maximum plasma concentration of penciclovir was 1.3 µg/mL at 1.1 hours after oral administration of 5 mg/kg. Similar results were detected after rectal administration of 5 mg/kg. Mean maximum plasma concentration was 3.6 µg/mL at 0.66 hours after rectal administration of 15 mg/kg; this concentration was similar to results reported for humans receiving 7 mg/kg orally. CONCLUSIONS AND CLINICAL RELEVANCE: Juvenile Asian elephants are susceptible to elephant endotheliotropic herpesvirus. Although most infections are fatal, case reports indicate administration of famciclovir has been associated with survival of 3 elephants. In Asian elephants, a dose of 8 to 15 mg of famciclovir/kg given orally or rectally at least every 8 hours may result in penciclovir concentrations that are considered therapeutic in humans.

Pharmacokinetics of penciclovir in healthy cats following oral administration of famciclovir or intravenous infusion of penciclovir.

OBJECTIVE: To investigate the pharmacokinetics of penciclovir in healthy cats following oral administration of famciclovir or IV infusion of penciclovir. ANIMALS: 6 cats. PROCEDURES: Cats received famciclovir (40 [n = 3] or 90 [3] mg/kg, PO, once) in a balanced crossover-design study; the alternate dose was administered after a ≥ 2-week washout period. After another washout period (≥ 4 weeks), cats received an IV infusion of penciclovir (10 mg/kg delivered over 1 hour). Plasma penciclovir concentrations were analyzed via liquid chromatography-mass spectrometry at fixed time points after drug administration. RESULTS: Mean ± SD maximum plasma concentration (C(max)) of penciclovir following oral administration of 40 and 90 mg of famciclovir/kg was 1.34 ± 0.33 µg/mL and 1.28 ± 0.42 µg/mL and occurred at 2.8 ± 1.8 hours and 3.0 ± 1.1 hours, respectively; penciclovir elimination half-life was 4.2 ± 0.6 hours and 4.8 ± 1.4 hours, respectively; and penciclovir bioavailability was 12.5 ± 3.0% and 7.0 ± 1.8%, respectively. Following IV infusion of penciclovir (10 mg/kg), mean ± SD penciclovir clearance, volume of distribution, and elimination half-life were 4.3 ± 0.8 mL/min/kg, 0.6 ± 0.1 L/kg, and 1.9 ± 0.4 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Penciclovir pharmacokinetics following oral administration of famciclovir were nonlinear within the dosage range studied, likely because of saturation of famciclovir metabolism. Oral administration of famciclovir at 40 or 90 mg/kg produced similar C(max) and time to C(max) values. Therefore, the lower dose may have similar antiviral efficacy to that proven for the higher dose.

Pharmacokinetics of penciclovir after oral administration of its prodrug famciclovir to horses.

We investigated the pharmacokinetics of penciclovir after oral administration of its prodrug famciclovir to horses. Following an oral dose of famciclovir at 20 mg/kg, maximum plasma concentrations of penciclovir occurred between 0.75 and 1.5 hr (mean 0.94 + or - 0.38 hr) after dosing and were in the range 2.22 to 3.56 microg/ml (mean 2.87 + or - 0.61 microg/ml). The concentrations of penciclovir declined in a biphasic manner after the peak concentration was attained. The mean half-life of the rapid elimination phase was 1.73 + or - 0.34 hr whereas that of the slow elimination phase was 34.34 + or - 13.93 hr. These pharmacokinetic profiles observed were similar to those of another antiherpesvirus drug, acyclovir, previously reported in horses following oral dosing of its prodrug valacyclovir.

Vitreous penetration of orally administered famciclovir.

PURPOSE: To determine the vitreous penetration of penciclovir (Denavir; GlaxoSmithKline, Philadelphia, Pennsylvania, USA) after oral administration of the prodrug famciclovir (Famvir; Novartis Pharmaceuticals Corp, East Hanover, New Jersey, USA). DESIGN: Prospective interventional case series. METHODS: Ten patients undergoing elective pars plana vitrectomy at a single institution were enrolled to take 3 oral doses of famciclovir 500 mg the day preceding surgery and a fourth dose on the morning of surgery. Blood and undiluted vitreous samples were acquired from each patient during surgery. High-performance liquid chromatography was used to determine the concentration of penciclovir in each sample. Exclusion criteria included prior vitrectomy, compromised blood-retina barrier, renal or hepatic disease, human immunodeficiency virus infection, bone marrow or renal transplantation, pregnancy or breastfeeding, history of adverse reaction or allergy to famciclovir or penciclovir, and antiviral, probenecid, or cimetidine use within 1 month of surgery. RESULTS: Ten eyes of 10 patients ranging in age from 26 to 82 were included. All patients had normal renal and hepatic function as determined by history and laboratory values. Mean serum penciclovir concentration +/- standard deviation was 4.45 +/- 1.31 microg/ml (range, 2.51 to 6.34 microg/ml). Mean vitreous penciclovir concentration was 1.21 +/- 0.38 microg/ml (range, 0.39 to 1.88 microg/ml). Mean vitreous-to-serum concentration ratio of penciclovir was 0.28 +/- 0.09 (range, 0.16 to 0.41). CONCLUSIONS: Oral administration of famciclovir results in vitreous concentrations of penciclovir within the inhibitory ranges for herpes simplex 1, herpes simplex 2, and varicella zoster virus. Oral famciclovir may be a reasonable alternative to intravenous acyclovir (Zovirax; GlaxoSmithKline) in the treatment of acute retinal necrosis, especially in cases of acyclovir resistance or patient inability to tolerate prolonged intravenous treatment.

Pharmacokinetic evaluation of emtricitabine in combination with other nucleoside antivirals in healthy volunteers.

Emtricitabine is a potent nucleoside reverse transcriptase inhibitor approved as a once-daily drug in combination with other antiretroviral agents for the treatment of HIV infection. Several phase I studies were conducted in healthy volunteers over the course of clinical development to evaluate whether pharmacokinetic drug-drug interactions exist between emtricitabine and other nucleoside antivirals that are extensively eliminated by renal excretion. Potential interactions with stavudine and famciclovir were evaluated in single-dose studies, whereas interactions with zidovudine and its major metabolite, zidovudine glucuronide, were evaluated in a multiple-dose study. Plasma pharmacokinetic profiles and, in some studies, urinary excretion data were evaluated when each drug was administered alone and in combination with emtricitabine. Safety and plasma pharmacokinetic profiles of each drug administered alone or with emtricitabine were consistent with historical data. Statistical analyses indicated that there were no significant interactions between emtricitabine and these 3 nucleoside antivirals.

Pharmacokinetics of famciclovir in subjects with varying degrees of renal impairment.

OBJECTIVE: To characterize the pharmacokinetics of a single 500 mg oral dose of famciclovir in subjects with varying degrees of renal impairment. METHODS: Twenty-seven subjects were enrolled in an open-label parallel-group study. Eighteen patients had renal impairment (average age [ +/- SD], 49 +/- 12 years), and nine subjects were healthy volunteers (average age, 28 +/- 7 years). Patients with renal impairment were stratified into groups based on estimated creatinine clearance (CLCR): mild impairment (CLCR, 60 to 80 ml/min/1.73 m2), moderate impairment (CLCR, 30 to 59 ml/min/1.73 m2) and severe impairment (CLCR, 5 to 29 ml/min/1.73 m2). Plasma and urine specimens were analyzed for concentrations of penciclovir, the antivirally active metabolite of famciclovir, by reverse-phase HPLC. Plasma data were analyzed with use of model-independent methods. RESULTS: In subjects with normal renal function (CLCR > 80), the mean maximum plasma concentrations of penciclovir was 2.83 micrograms/ml (range, 1.30 to 3.82 micrograms/ml) and the mean time to reach maximum concentration was 0.89 hours (range, 1/2 to 1 1/2 hours). The mean apparent terminal elimination half-life was 2.15 hours (range, 1.56 to 2.87 hours). A linear relationship was observed between the plasma elimination rate constant and CLCR and between renal clearance and CLCR. Mean area under the plasma concentration-time curve from zero to infinity was approximately tenfold higher and the plasma elimination rate constant was approximately fourfold lower in patients with severe renal impairment than in subjects with normal renal function. CONCLUSION: Consideration should be given to modification of the dosing schedule of famciclovir from the usual 8-hour interval to a 12-hour interval for patients with moderate renal impairment (CLCR 30 to 59 ml/min/1.73 m2) or a 24-hour interval for patients with severe renal impairment (CLCR < 30 ml/min/1.73 m2).