Denavir
In vitro antiviral activity of penciclovir, a novel purine nucleoside, against duck hepatitis B virus.

Shaw T, Amor P, Civitico G, Boyd M, Locarnini S.

Macfarlane Burnet Centre for Medical Research, Fairfield Hospital, Victoria, Australia.

The in vitro antihepadnavirus activities of the purine nucleoside analogs ganciclovir (9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine) and penciclovir [9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine; BRL 39123] were compared in primary duck hepatocyte cultures congenitally infected with the duck hepatitis B virus (DHBV). Both compounds inhibited DHBV DNA replication to a comparable extent during continuous short-term treatment of the cultures. However penciclovir was more active both during longer-term continuous treatment (50% inhibitory concentrations: penciclovir, 0.7 +/- 0.1 microM; ganciclovir, 4.0 +/- 0.2 microM) and in washout experiments (50% inhibitory concentrations: penciclovir, 3.0 +/- 0.4 microM; ganciclovir, 46 +/- 1.5 microM) designed to compare the persistence of inhibitory activity after removal of the extracellular compound. The effects on viral protein synthesis were similar to the effects on viral DNA replication. These data suggest that penciclovir or its oral form, famciclovir, may have clinical utility in the treatment of chronic hepatitis B virus infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8031035&dopt=Abstract penciclovir Denavir



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Metabolic and pharmacokinetic studies following oral administration of 14C-famciclovir to healthy subjects.

Filer CW, Allen GD, Brown TA, Fowles SE, Hollis FJ, Mort EE, Prince WT, Ramji JV.

Drug Metabolism and Pharmacokinetics Department, SmithKline Beecham Pharmaceuticals, Welwyn, Herts, UK.

1. Following oral administration of 14C-famciclovir (500 mg) to three healthy male subjects, drug-related material was rapidly absorbed as judged by peak plasma concentrations of radioactive material being achieved by 0.75 h (6.7 +/- 0.9 microgram equiv./ml (mean +/- SD). 2. Famciclovir underwent extensive first-pass metabolism and was only detected in the plasma of one subject at low concentrations (0.5 microgram/ml). Famciclovir was rapidly and extensively metabolized to the active antiviral compound penciclovir, which reached peak concentrations in the plasma of 3.6 +/- 0.7 microgram/ml (0.75 h). The plasma elimination half-life value for penciclovir was 2.1 +/- 0.1 h. The 6-deoxy precursor of penciclovir, BRL 42359, was the only other relatively major metabolite detected in plasma. Peak plasma concentrations of BRL 42359 (1.0 +/- 0.1 microgram/ml) were achieved at 0.5 h. 3. After 3 days, 73.0 +/- 6.1% of the radioactive dose was excreted in urine, showing that good absorption of drug-related material occurred. Renal excretion was rapid since 60.2 +/- 4.2 and 72.3 +/- 5.7% of the dose was recovered in the urine samples collected up to 6 and 24 h, respectively. A good recovery of the administered radioactive dose was obtained since a further 26.6 +/- 5.1% of the dose was excreted in the faeces over a 72-h period. 4. Penciclovir and BRL 42359 were the major metabolites detected in urine and faeces. Penciclovir accounted for 59.2 +/- 4.9 and 4.2 +/- 1.4% of the dose in 0-24 h urine and 0-48 h faeces, respectively. Corresponding values for BRL 42359 were 5.0 +/- 0.5 and 17.0 +/- 6.2%, respectively. These metabolites were identified in the biological samples using hplc-ms and ms-ms with thermospray ionization.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8059539&dopt=Abstract penciclovir Denavir



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Evidence that famciclovir (BRL 42810) and its associated metabolites do not inhibit the 6 beta-hydroxylation of testosterone in human liver microsomes.

Harrell AW, Wheeler SM, Pennick M, Clarke SE, Chenery RJ.

Department of Drug Metabolism and Pharmacokinetics, SmithKline Beecham, Welwyn, Herts, UK.

Famciclovir is the diacetyl 6-deoxy analog of the active antiviral compound penciclovir with potential use in the treatment of infections caused by the herpes family of viruses. The major pathway of metabolism of famciclovir is deacetylation to BRL 42359 followed by oxidation to penciclovir. It is possible that famciclovir may be coadministered with cyclosporin A to combat viral infections induced by immunosuppression in organ transplant and bone marrow transplant patients. As a result, information is required on possible interactions between the cytochrome P-450 3A substrate cyclosporin A and famciclovir and its metabolites in humans. In order to probe cytochrome P-450 3A activity, testosterone 6 beta-hydroxylation in two human liver microsomal preparations was measured. Nicardipine and ketoconazole, two drugs with known inhibitory interactions with cyclosporin A, were used as positive controls. Profiles of 6 beta-hydroxytestosterone production showed no inhibition effected by famciclovir, penciclovir, or BRL 42359 when marked inhibition was observed in incubations containing nicardipine, nifedipine, or ketoconazole. Further incubations of [14C]BRL 42359 with human liver cytosol and microsomes indicated that BRL 42359 is oxidized to penciclovir in cytosol but not in microsomes and that this reaction was not dependent on the presence of NADPH. Because P-450 resides mainly in the microsomal fraction and is dependent on the presence of cofactors for catalytic activity, it seems that this oxidation is not catalyzed by cytochrome P-450.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8095215&dopt=Abstract penciclovir Denavir



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

Boike SC, Pue MA, Freed MI, Audet PR, Fairless A, Ilson BE, Zariffa N, Jorkasky DK.

Department of Clinical Pharmacology, SmithKline Beecham Pharmaceuticals, Philadelphia, PA.

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).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8162668&dopt=Abstract penciclovir Denavir



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In vitro activity of penciclovir against clinical isolates of acyclovir-resistant and foscarnet-resistant herpes simplex virus.

Safrin S, Phan L.

Department of Medicine, University of California-San Francisco.

We tested 23 clinical isolates of acyclovir-susceptible, acyclovir-resistant, and foscarnet-resistant herpes simplex virus for susceptibility to penciclovir. Isolates showed cross-resistance to penciclovir and acyclovir, but penciclovir retained a relative activity against foscarnet-resistant isolates. Its clinical utility for the treatment of resistant herpes simplex virus infections remains to be studied.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8257152&dopt=Abstract penciclovir Denavir