What Is Famciclovir?

Famciclovir is a diethyl acyl ester of the 6-deoxy derivative of penciclovir. Its molecular formula is C14H19N5O4. It is well absorbed orally and has high bioavailability, so it replaces penciclovir.

Famciclovir is a second-generation ring-opening nucleoside antiviral drug, mainly used for herpes virus infections, especially shingles. Famciclovir is a prodrug of penciclovir, which is converted to penciclovir by enzymes in the intestinal wall and liver.

Chinese name: Famciclovir
English name: FAMCICLOVIR

CAS No.: 104227-87-4
Molecular formula: C14H19N5O4

Famciclovir Basic Information

Chinese name: Famciclovir

Chinese alias: Faciclovir; Faciclovir;

English name: famciclovir English alias: FaMcivir; 2- [2- (2-Amino-9H-purin-9-yl) ethyl] -1,3-propanediol Diacetate; Famciclovir; FaMciclovir API; Famvir;

CAS number: 104227-87-4

Molecular formula: C ₁₄ H ₁₉ N ₅ O ₄

Molecular weight: 321.33200

Exact mass: 321.14400

PSA: 122.22000

LogP: 1.12220

Physical and Chemical Properties of Famciclovir

Appearance and properties: off-white powder

Density: 1.4g / cm ³

Melting point: 102-104 ° C

Boiling point: 550.2ºC at 760 mmHg

Flash point: 286.6ºC

Refractive index: 1.628

Water solubility: insoluble

Storage conditions: Store in original container in a cool dark place.

Vapor pressure: 3.73E-12mmHg at 25 ° C ^[1]

Famciclovir molecular structure data

1. Molar refractive index: 82.66

2. Molar volume (cm ³ / mol): 239.8

3. Isotonic specific volume (90.2K): 639.3

4. Surface tension (dyne / cm): 50.4

5. Polarizability (10-24cm ³ ): 32.77

Famciclovir Computational Chemistry Data

1. Hydrophobic parameter calculation reference value (XlogP): None

2.Number of hydrogen-bonded donors: 1

3.Number of hydrogen bond acceptors: 8

4.Number of rotatable chemical bonds: 9

5.Number of tautomers: 3

6. Topological molecular polar surface area 122

7.Number of heavy atoms: 23

8.Surface charge: 0

9.Complexity: 404

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 0

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

15. Number of covalent bond units: 1 ^[2]

Famciclovir production method

Method 1: 0.5 mol of 2-amino-6-chloropurine was dissolved in 500 ml of water containing 50 g of sodium hydroxide and hydrogenated at 0.7 MPa hydrogen pressure and 50 ° C. for 3 h in the presence of 10 g of palladium-carbon to obtain 83% yield of 2 -Aminopurine. 2-aminopurine, 2- (2-iodoethyl) propanediol diethyl ester, and potassium carbonate were stirred in dimethylformamide at room temperature for 18 h to obtain famciclovir in a 58% yield. Method 2: 2- (2-iodoethyl) propanediol diacetate, 2-amino-6-iodopurine and potassium carbonate in dimethylformamide, and stirred for 18 hours to obtain compound (I) in a yield of 79.4% Then, under the palladium-carbon catalyst, famciclovir is obtained by hydrogenation reduction in ethanol.

Method 3: 22.5g of guanine, 88g of triethylmethylammonium chloride and sulfoxide, slowly stirred at 50-70 ° C for 0.5h, and then maintained at 70 ° C for 0.5h to obtain 28.5g of 8-chlorobird Purine, which contains 14.1% water. 8-Chloroguanine is converted to the hydrochloride salt and dried in the presence of phosphorus pentachloride. A solution of 6.6 g of triethylmethylammonium chloride in 1 ml of acetonitrile was added to the hydrochloride (2.04 g), 5.6 ml of phosphorus oxychloride was added, and the mixture was heated at 60 ° C for 1 h to obtain 1.78 g of 2-amino-6. , 8-dichloropurine. 5.8 g of 2-amino-6,8-dichloropurine, 9.4 g of 2- (2-iodoethyl) propanediol diacetate and 5.9 g of potassium carbonate in 100 ml of dimethylformamide, and stirred at room temperature overnight, 4.7 g of compound (II) was obtained. 3.9 g of compound (II) was hydrogenated and reduced under a hydrogen pressure of 0.35 MPa in the presence of 5% palladium-carbon to obtain 2.4 g of famciclovir. ^[3]

Famciclovir adverse reactions

Common adverse reactions are headache and nausea.

1. Nervous system: dizziness, insomnia, drowsiness, paresthesia, etc .;

2. Digestive system: diarrhea, abdominal pain, indigestion, anorexia, vomiting, constipation, flatulence, etc .;

3. Systemic reactions: fatigue, pain, fever, chills, etc .;

4. Other reactions: rash, pruritus, sinusitis, pharyngitis, etc .;

Famciclovir Pharmacokinetics

Famciclovir is quickly absorbed orally, with a bioavailability of 77%, and is quickly transferred to penciclovir in the body. T1 / 2 is about 2 hours, and about 60-65% is excreted by the kidney. There is a long half-life (9-10 hours) in varicella-zoster virus-infected cells, and the intracellular half-life of herpes simplex virus type 1 and type 2 infection is 10 hours and 20 hours, respectively.

Mechanism of Famciclovir

After entering the human body, it quickly turns into penciclovir. Penciclovir can be phosphorylated by the virus-encoded thymidine kinase to OCV monophosphate, and then phosphorylated by the host to penciclovir triphosphate. The triphosphate is in the virus. Infected cells are rapidly formed, slowly metabolized, resulting in prolonged half-life, participate in guanosine triphosphate (Pgtp) competition of HBV DNA-p, and enter the DNA, acting on the initiation and extension steps of DNA synthesis, inhibiting DNA synthesis. Varicella-zoster virus, herpes simplex virus types 1 and 2 and HBV have strong inhibitory effects.

Famciclovir Drug Analysis

Method name: Famciclovir API-Famciclovir-High Performance Liquid Chromatography

Scope of application: This method uses high performance liquid chromatography to determine the content of famciclovir in famciclovir API.

This method is applicable to the famciclovir drug substance.

Principle of the method: The test product was dissolved in the mobile phase and quantitatively diluted, and then entered into a high-performance liquid chromatography for chromatographic separation. The peak area of famciclovir was detected at a wavelength of 305 nm using an ultraviolet absorption detector, and the content was calculated.

Reagent: 1. Acetonitrile

2. Potassium dihydrogen phosphate (0.02mol / L)

Equipment: 1. Instrument

1.1 HPLC

1.2 Column

Octadecylsilane-bonded silica gel is used as a filler, and the number of theoretical plates calculated based on the famciclovir peak should not be less than 2500.

1.3 UV absorption detector

Chromatographic conditions

2.1 Mobile phase: acetonitrile 0.02mol / L potassium dihydrogen phosphate = 20 80

2.2 Detection wavelength: 305nm

2.3 Column temperature: room temperature

Sample preparation: 1. Preparation of reference solution

Accurately weigh the appropriate amount of famciclovir reference, diluted with mobile phase

2. Preparation of test solution

Accurately weigh the appropriate amount of the test sample, and dilute it with mobile phase to make a solution containing 50 & microg per 1 mL, which is the test solution.

Note: "Precision weighing" means that the weighed weight should be accurate to one thousandth of the weighed weight. "Precision measurement" means that the accuracy of measuring the volume should meet the accuracy requirements of the volume pipette in national standards.

Operating steps: Precisely pipette 20 mL of each of the reference solution and the test solution, and inject them into a high-performance liquid chromatograph. Measure the peak area of famciclovir (C14H19N5O4) with a UV absorption detector at a wavelength of 305 nm and calculate its content.

References: Pharmacopoeia of the People's Republic of China, compiled by the National Pharmacopoeia Committee, Chemical Industry Press, 2005 Edition, Part Two, p.274.

Research Process of Famciclovir

Optimal therapeutic dose

Studies on the treatment of hepatitis B: The results of a randomized study of double tadpoles showed that oral FCV decreased serum HBV-DNA by up to 90%, but increased after stopping the drug. The current report to prevent and treat HBV infection in liver transplantation can make patients significantly reduce HBV infection and prolong the survival time of patients without famciclovir. The therapeutic dose is 125-500mg / day. Trepo et al. [149] were treated with 125 mg, 250 mg, 500 mg tid or placebo for 16 weeks and followed for 8 months. Another 16 weeks of open-label treatment. Results: It was shown that the inhibitory effect of famciclovir on HBV increased with increasing dose. Comparing the efficacy of the three groups, the effect of the 500 mg tid group was the best. It is recommended as a conventional treatment dose.

Nucleoside antiviral efficacy

Tsiquaye et al. [150] have demonstrated the effect of oral famciclovir on duck HBV replication in duck embryo liver tissue and non-hepatic tissue cells. In the same year, Boker and others used prostaglandin E plus famciclovir for the first time to treat a patient with severe hepatitis B after liver transplantation. After treatment, the patient's liver function recovered, virus replication was inhibited, HBV DNA and HBeAg were both negative, only HBsAg was positive, and liver histological inflammation changed, and the patient resumed normal work. Main et al. [151] treated famciclovir with eleven patients with chronic hepatitis B for the first time in a double-blind placebo-controlled study. Ten days after oral famciclovir, HBV DNA was reduced by more than 90% in 6 patients. Haller et al. [152] reported that he treated 18 patients with hepatitis B reinfection after liver transplantation with oral famciclovir between 1993 and 1995. The first 15 patients started treatment after clinical manifestations of hepatitis, and the next 3 patients started treatment immediately after detection of HBV DNA. All patients were well tolerated by famciclovir. Results Eight patients had negative HBV DNA, 7 patients had improved clinical symptoms, 5 patients had no change, and 6 patients had deteriorated and died. Patients who started treatment earlier had better results than those who started treatment late. Kruger et al. [153] made a preliminary observation on the efficacy of famciclovir in the treatment of recurrent hepatitis B after liver transplantation. Twelve patients were treated with famciclovir at 500 mg tid for at least 3 months (one patient had a dose of 750 mg tid within 2 weeks of starting treatment). Nine patients (75%) had a decrease in serum HBV DNA levels shortly after treatment. After 3 months, the average HBV DNA levels were 80% below baseline, 90% after 6 months, and> 95% after 12 months of treatment. . Continuing treatment, 5 patients had negative HBV DNA conversion by dot blot hybridization, and 1 patient had negative HBV DNA by PCR. Three patients discontinued due to ineffectiveness. Six of the 12 patients had an average 80% reduction in ALT compared to before treatment, and 4 patients returned to normal. One patient died of peritonitis at the 13th week of treatment. The cause of death was not related to famciclovir. All patients were well tolerated by famciclovir, and no significant adverse reactions occurred during treatment. Retransplantation of livers due to recurrent hepatitis B is rarely successful. Almost all patients will undergo reinfection of the transplanted liver, and liver failure will occur more rapidly in the second transplant than in the first transplant. . McCaughan et al. [1541] reported that only 20 patients with two liver transplants survived more than 6 months. The reason for survival was that this patient was treated with ganciclovir / famciclovir after liver transplantation and HBV DNA was negative. Famciclovir has been treated for 26 months. Three years after the liver transplant, the patient is still normal. The authors believe that long-term use of nucleoside antiviral drugs after liver transplantation can improve the prognosis of patients with liver transplantation.

Combination therapy with other antiviral drugs

Combined use with other antiviral drugs to treat HBV infection has also been reported. Kruger [155] reported that a 56-year-old male patient with hepatitis B-associated nodular polyarteritis was successfully treated with famciclovir and -2b interferon, with success. Piqueras et al. [156] reported the successful treatment of liver failure in a patient with chronic hepatitis B with famciclovir plus interferon. Marques et al. [157] treated famciclovir plus alpha interferon for five weeks in adults with chronic HBV infection who had previously failed interferon therapy. The treatment method is: first treat famciclovir for 4 weeks, then add interferon alpha for 12 weeks, and finally stop interferon, and continue to use famciclovir for 4 weeks. Results Two patients had negative HBV DNA conversion and improved liver function and liver histology. Hou Jinlin et al. [120] also confirmed in the study of HBV dynamic changes during lamivudine and lamivudine + famciclovir treatment, the combination treatment can improve the antiviral efficacy of lamivudine.

Although the study of famciclovir predates lamivudine, reports of its use in the treatment of hepatitis B in recent years are much lower than lamivudine. The main reason is that its anti-HBV effect is lower than lamivudine, and it can also induce YMDD drug resistance mutation of HBV polymerase, and the treatment cost is higher than lamivudine.

Seehofer et al. [72] retrospectively analyzed the treatment of 179 cases of recurrent HBV infection after liver transplantation from 1988 to 1998, comparing the use of famciclovir or lamivudine + hepatitis B immunoglobulin in the treatment of liver transplantation. For the efficacy of recurrent HBV infection, famciclovir is found to be less effective than lamivudine, and lamivudine treatment remains effective in patients who develop resistance after famciclovir treatment. Rayes et al. [10] conducted a comparative study of long-term application of famciclovir and lamivudine (20 cases) in the treatment of hepatitis B after liver transplantation. Thirty-two patients were treated with famciclovir, 20 patients were treated with lamivudine, and 7 patients were treated with lamivudine after famciclovir failed. Results HBV DNA was negative in 19 patients treated with famciclovir and 76% of patients treated with lamivudine; HBsAg was negative in 24% of patients treated with lamivudine, while none in patients treated with famciclovir One patient had HBsAg negative conversion. Lamivudine treatment is also effective in patients who fail famciclovir treatment. The authors believe that the antiviral effect of lamivudine is stronger than famciclovir.

Poor treatment with famciclovir alone

Recently, Berenguer et al. [158] reported that six patients with HBV infection (HBsAg-positive, HBV DNA-positive, 4 of which were HBeAg-positive) after liver transplantation were treated with famciclovir 500mg tid for at least 12 months. Results None of the patients were completely effective. Three patients had near-normal ALT, and none had anti-HBs or anti-HBe seroconversion. The HBV DNA was negative in 2 patients, and decreased in 1 patient. The remaining 3 patients even had higher DNA levels than before treatment. Histology of the liver improved in only 1 patient after treatment. Therefore, the authors believe that famciclovir alone is not effective in treating HBV infection after liver transplantation.

In phase III clinical trials of famciclovir, famciclovir was confirmed to be a powerful anti-HBV drug, but it was also found that long-term use could also cause YMDD motif variation of HBV polymerase. Animal test results also confirm that HBV is cross-resistant to lamivudine and famciclovir. Mutimer [43] confirmed that in two variants resistant to lamivudine, M550V-L526M was cross-resistant to famciclovir, while M550I was not related to famciclovir. According to Rayes et al. [10], the resistance rate of lamivudine in long-term patients was 55%, while famciclovir was 80%.

Amendments to Famciclovir

2010 Chinese Pharmacopoeia revised and updated content

Famciclovir

Fanxiluowei

Famciclovir

Page number: 2005 edition two-274

[Revised]

[Properties] This product is white or almost white crystalline powder; odorless, bitter.

This product is soluble in water, methanol, ethanol or dichloromethane, slightly soluble in ethyl acetate, and almost insoluble in ether.

[Inspection] Take this product and add the mobile phase to make a test solution containing 0.2mg per 1ml. Precisely measure 1ml and place it in a 100ml volumetric flask. Add the mobile phase to the mark and use it as a control solution. Except for the detection wavelength. Adjust the chromatographic conditions under other photometric determination items outside 221nm, take the reference solution 20 & micro; l, inject it into the liquid chromatograph, and adjust the detection sensitivity so that the peak height of the main component chromatographic peak is 20% to 25% of full scale; Precisely measure 20 & micro each of the test solution and the control solution, and inject them into the liquid chromatograph respectively, and record the chromatogram to 2.5 times the main peak retention time. The area of each single impurity peak in the chromatogram of the test solution must not be larger than 1/2 of the area of the main peak of the control solution, and the sum of the areas of the peaks of each impurity must not be greater than the area of the main peak of the control solution.