 Chemical Structure.png)
Famciclovir (also known as BRL 42810) is a guanine class of antiviral drug used for the treatment of various herpesvirus infections, such as herpes zoster (shingles). It is also indicated for treatment of recurrent episodes of herpes simplex in HIV patients. It is a prodrug form of penciclovir with improved oral bioavailability.
Physicochemical Properties
| Molecular Formula | C14H19N5O4 |
| Molecular Weight | 321.33176 |
| Exact Mass | 321.143 |
| Elemental Analysis | C, 52.33; H, 5.96; N, 21.79; O, 19.92 |
| CAS # | 104227-87-4 |
| Related CAS # | Famciclovir-d4;1020719-42-9 |
| PubChem CID | 3324 |
| Appearance | White to off-white solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 550.2±60.0 °C at 760 mmHg |
| Melting Point | 102-104°C |
| Flash Point | 286.6±32.9 °C |
| Vapour Pressure | 0.0±1.5 mmHg at 25°C |
| Index of Refraction | 1.628 |
| LogP | -0.67 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 9 |
| Heavy Atom Count | 23 |
| Complexity | 404 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | NC1=NC=C2N=CN(CCC(COC(C)=O)COC(C)=O)C2=N1 |
| InChi Key | GGXKWVWZWMLJEH-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C14H19N5O4/c1-9(20)22-6-11(7-23-10(2)21)3-4-19-8-17-12-5-16-14(15)18-13(12)19/h5,8,11H,3-4,6-7H2,1-2H3,(H2,15,16,18) |
| Chemical Name | [2-(acetyloxymethyl)-4-(2-aminopurin-9-yl)butyl] acetate |
| Synonyms | Famvir, BRL-42810; BRL42810; BRL 42810 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vitro | By deacetylation, famciclovir metabolizes into BRL 42359, which oxidizes to penciclovir[3]. |
| ln Vivo | Necrotic hepatitis mice can be effectively cured by famciclovir (50–400 mg/kg; p.o. three times per day for a total of 10 doses)[1]. |
| Animal Protocol |
Animal Model: Four- to five-week-old Balb/c mice with HSV-1 infection[1] Dosage: 50, 100, 200 and 400 mg/kg Administration: Oral gavage; 50-400 mg/kg per day divided into three doses given every 8 h; for total 10 doses Result: significantly decreased the daily incidence of hepatitis when administered at a dose of 50 mg/kg; however, the treatment group receiving doses of 50 and 100 mg/kg was unable to isolate the infectious virus. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion 77 % Active tubular secretion contributes to the renal elimination of penciclovir. 1.08±0.17 L/kg [healthy male subjects following a single intravenous dose of penciclovir at 400 mg administered as a 1-hour intravenous infusion] 36.6 +/- 6.3 L/hr [healthy male] 0.48 +/- 0.09 L/hr/kg [healthy male] Following oral administration of famciclovir to lactating rats, penciclovir was distributed into breast milk at concentrations higher than those observed in plasma. Not known whether penciclovir crosses the placenta or is distributed into human milk. Following oral single-dose administration of 500 mg famciclovir to seven patients with herpes zoster, the AUC (mean + or - SD), Cmax, and tmax were 12.1+ or - 1.7 ug hr/mL, 4.0 + or - 0.7 ug/mL, and 0.7 + or - 0.2 hours, respectively. The AUC of penciclovir was approximately 35% greater in patients with herpes zoster as compared to healthy volunteers. Some of this difference may be due to differences in renal function between the two groups. Renal clearance of penciclovir following the oral administration of a single 500 mg dose of famciclovir to 109 healthy male volunteers was 27.7+ or - 7.6 L/hr. Active tubular secretion contributes to the renal elimination of penciclovir. For more Absorption, Distribution and Excretion (Complete) data for Famciclovir (11 total), please visit the HSDB record page. Metabolism / Metabolites Hepatic Famciclovir is deacetylated and oxidized to penciclovir. Penciclovir is phosphorylated to penciclovir triphosphate (the active metabolite) in cells infected with HSV-1, HSV-2, or VZV. The inactive metabolite 6-deoxy penciclovir is converted to penciclovir by aldehyde oxidase. Famciclovir not metabolized by CYP enzymes. Following oral administration, famciclovir is deacetylated and oxidized to form penciclovir. Metabolites that are inactive include 6-deoxy penciclovir, monoacetylated penciclovir, and 6-deoxy monoacetylated penciclovir (5%, <0.5% and <0.5% of the dose in the urine, respectively). Little or no famciclovir is detected in plasma or urine. An in vitro study using human liver microsomes demonstrated that cytochrome P450 does not play an important role in famciclovir metabolism. The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Biological Half-Life 10 hours Elimination half-life of penciclovir after oral administration of famciclovir 1.6-3 hours. Intracellular half-life of penciclovir triphosphate in cells infected with herpes simplex virus (HSV)-1 or HSV-2 is 10 and 20 hours, respectively; intracellular half-life in varicella zoster virus (VZV)-infected cells is 7-14 hours. The plasma elimination half-life of penciclovir was 2.0 + or - 0.3 hours after intravenous administration of penciclovir to 48 healthy male volunteers and 2.3 + or - 0.4 hours after oral administration of 500 mg famciclovir to 124 healthy male volunteers. The half-life in 17 patients with herpes zoster was 2.8 + or - 1.0 hours and 2.7 + or - 1.0 hours after single and repeated doses, respectively. |
| Toxicity/Toxicokinetics |
Hepatotoxicity Famciclovir has been associated with a low rate of serum aminotransferase elevations during oral therapy. In pooled analyses of patients on long term suppressive therapy, 3.2% of famciclovir vs 1.5% of placebo recipients had ALT elevations above twice normal. The elevations were transient and asymptomatic and resolved even without dose modification. Since approval, cases of cholestatic jaundice have been reported to the sponsor, but there have been no published cases. Thus, clinically apparent liver disease due to famciclovir must be rare if it occurs at all. Likelihood score: E (unlikely cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Because there is no published experience with famciclovir during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding 20-25% Interactions The conversion of 6-deoxy penciclovir to penciclovir is catalyzed by aldehyde oxidase. Interactions with other drugs metabolized by this enzyme and/or inhibiting this enzyme could potentially occur. Clinical interaction studies of famciclovir with cimetidine and promethazine, in vitro inhibitors of aldehyde oxidase, did not show relevant effects on the formation of penciclovir. Raloxifene, a potent aldehyde oxidase inhibitor in vitro, could decrease the formation of penciclovir. However, a clinical drug-drug interaction study to determine the magnitude of interaction between penciclovir and raloxifene has not been conducted. Potential pharmacokinetic interaction with other drugs metabolized by aldehyde oxidase. Potential increased plasma penciclovir concentrations when used concomitantly with other drugs eliminated by active renal tubular secretion (e.g., probenecid). |
| References |
[1]. Wutzler P, Ulbricht A, Färber I. Antiviral efficacies of famciclovir, valaciclovir, and brivudin in disseminated herpes simplex virus type 1 infection in mice. Intervirology. 1997;40(1):15-21. [2]. administration are replication defective. Hepatology. 1998 Feb;27(2):628-33. [3]. Evidence that famciclovir (BRL 42810) and its associated metabolites do not inhibit the 6 beta-hydroxylation of testosterone in human liver microsomes. Drug Metab Dispos. 1993 Jan-Feb;21(1):18-23. [4]. Drugs. 1995 Aug;50(2):396-415. |
| Additional Infomation |
Therapeutic Uses Antiviral Agents Oral famciclovir is used for the treatment of acute, localized herpes zoster (shingles, zoster). /Included in US product label/ Oral famciclovir is used for the treatment of recurrent mucocutaneous herpes simplex virus (HSV) infections (HSV-1 and HSV-2) in HIV-infected adults. /Included in US product label/ Famciclovir has been used for the management of chronic hepatitis B virus (HBV) infection in a limited number of patients. /NOT included in US product label/ For more Therapeutic Uses (Complete) data for Famciclovir (12 total), please visit the HSDB record page. Drug Warnings /These/ adverse events have been reported during post-approval use of Famvir. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Blood and lymphatic system disorders: Thrombocytopenia. Hepatobiliary disorders: Abnormal liver function tests, cholestatic jaundice. Nervous system disorders: Dizziness, somnolence. Psychiatric disorders: Confusion (including delirium, disorientation, and confusional state occurring predominantly in the elderly), hallucinations. Skin and subcutaneous tissue disorders: Urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema (e.g. face, eyelid, periorbital, and pharyngeal edema). The manufacturer recommends that the dosage interval of famciclovir be adjusted carefully in patients with impaired renal function to prevent drug accumulation while maintaining adequate plasma concentrations of penciclovir, the active metabolite of famciclovir. Increased serum concentrations of ALT (SGPT) occurred in 1.4-2.4% of patients receiving famciclovir in clinical trials for herpes zoster or genital herpes. Increased serum concentrations of alkaline phosphatase, total bilirubin, and albumin each occurred rarely in patients receiving the drug in clinical trials for herpes zoster or genital herpes. The most frequent adverse GI effect of famciclovir is nausea which occurred in approximately 13% of patients receiving the drug (versus in 11.6% in placebo recipients) in a large, controlled clinical trial for herpes zoster. Nausea resulted in discontinuance of famciclovir in less than 1% of patients in clinical trials for herpes zoster or genital herpes. Diarrhea was reported in approximately 8% of patients (5% of placebo recipients) and vomiting in approximately 5% of patients (3.4% of placebo recipients) in a large, controlled clinical trial for herpes zoster. Vomiting only rarely resulted in discontinuance of famciclovir in clinical trials for herpes zoster or genital herpes. Constipation, anorexia, abdominal pain, flatulence, and dyspepsia have occurred in patients receiving famciclovir in clinical trials for herpes zoster. Acute necroticohemorrhagic pancreatitis resulting in death has been reported following famciclovir administration for severe hepatitis B virus infection in a kidney graft recipient who was receiving cyclosporine concomitantly; a causal relationship to famciclovir was not established. Nausea, diarrhea, vomiting, or abdominal pain has been reported in 11, 7, 5, or 3%, respectively, of HIV-infected patients receiving famciclovir in clinical studies. For more Drug Warnings (Complete) data for Famciclovir (12 total), please visit the HSDB record page. Pharmacodynamics Famciclovir is a prodrug that undergoes rapid biotransformation to the active antiviral compound penciclovir. Penciclovir is an anti-viral drug which has inhibitory activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella zoster virus (VZV). Therefore, herpes viral DNA synthesis and replication are selectively inhibited. |
Solubility Data
| Solubility (In Vitro) |
DMSO : 64~100 mg/mL ( 199.16~311.21 mM ) Water : 64 mg/mL Ethanol : ~48 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.78 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.78 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (7.78 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 120 mg/mL (373.45 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1121 mL | 15.5603 mL | 31.1207 mL | |
| 5 mM | 0.6224 mL | 3.1121 mL | 6.2241 mL | |
| 10 mM | 0.3112 mL | 1.5560 mL | 3.1121 mL |