Adefovir diphosphate functions as a DNA terminator in addition to targeting viral DNA polymerase. The first phosphorylation was found to be caused by adenylate oxidation, which was then followed by the oxidation of creatine and ADP to produce adefovir diphosphate [1].

Adefovir diaphragm has a 60% bioavailability and is not impacted by food. It has a 12-to 30-hour half-life. Adefovir has no discernible metabolites and is eliminated by the kidneys. In general, adefovir has no effect on cytochrome P450[3].

Absorption, Distribution and Excretion
Following oral administration of adefovir dipivoxil, approximate bioavailability of adefovir is 59%. A single 10-mg oral dose of adefovir dipivoxil in adults results in peak adefovir plasma concentration within 0.58-4 hours.
4% or less of adefovir is bound to plasma or serum proteins.
In vitro binding of adefovir to human plasma or human serum proteins is less than or equal to 4% over the adefovir concentration range of 0.1 to 25 ug/mL. The volume of distribution at steady-state following intravenous administration of 1.0 or 3.0 mg/kg/day is 392 +/- 75 and 352 +/- 9 mL/kg, respectively.
Food does not affect the area under the concentration-time curve (AUC) of adefovir.
For more Absorption, Distribution and Excretion (Complete) data for Adefovir (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
9-(2-Phosphonylmethoxyethyl)adenine (PMEA) was the only metabolite formed after oral administration of bis-POM PMEA. Three metabolites were detected after oral administration of either bis-(phenyl) PMEA or bis-(o-ethoxyphenyl) PMEA to rats: PMEA, the corresponding monoester, and 2-adenylacetic acid. The major metabolite of bis-(phenyl) PMEA was 2-adenylacetic acid following oral administration. 2-Adenylacetic acid appears to have been formed from the intact prodrugs by a P450 mediated oxidation of the ethyl side chain.
Following oral administration, adefovir dipivoxil is converted to the active adefovir.
PMEA is a known human metabolite of pradefovir.

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Biological Half-Life
Plasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 +/- 1.65 hours.
... Diphosphorylated ... PMEA has a relatively long intracellular half-life (16-18 hr) ...

Hepatotoxicity
Serum aminotransferase elevations are common during or after therapy of hepatitis B, but appear to be due to exacerbations of the underlying HBV infection rather than hepatotoxicity. Sudden withdrawal of adefovir therapy can lead to an acute flare of hepatitis as viral levels suddenly rise. These withdrawal flares are usually transient and self-limited, but in rare instances are symptomatic and severe and can lead to death or need for liver transplantation. Instances of moderate serum aminotransferase elevations early during treatment have been described in clinical trials, but these elevations are usually transient and asymptomatic and are found in up to 25% of persons who start nucleoside analogue therapy of hepatitis B. Finally, development of antiviral resistance can be followed by a flare of the underlying hepatitis B as HBV DNA levels rise. Antiviral resistance to adefovir is rare during the first 1 to 2 years of therapy, but increasing rates are found with long-term therapy.
Adefovir has not been associated with cases of lactic acidosis with hepatic steatosis and liver failure. Tenofovir, a nucleotide analogue similar to adefovir, has been associated with isolated cases of lactic acidosis, but only in combination with other antiretroviral agents that are more closely linked to this syndrome. Because adefovir is considered contraindicated in HIV infection (it has weak anti-HIV activity), it is not used in combination with typical antiretroviral drugs. There have been no convincing cases of lactic acidosis or of clinically apparent liver injury with symptoms or jaundice due to adefovir.
Likehood score: E (unlikely cause of clinically apparent, idiosyncratic liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Adefovir has not been studied in nursing mothers being treated for hepatitis B infection. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.
No differences exist in infection rates between breastfed and formula-fed infants born to hepatitis B-infected women, as long as the infant receives hepatitis B immune globulin and hepatitis B vaccine at birth. Mothers with hepatitis B are encouraged to breastfeed their infants after their infants receive these preventative measures.
◉ 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.

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Interactions
Potential increased risk of nephrotoxicity in patients receiving other nephrotoxic drugs (e.g., aminoglycosides, cyclosporine, tacrolimus, vancomycin, certain nonsteroidal anti-inflammatory agents [NSAIAs]); monitor closely.
Pharmacokinetic interaction (33% increase in peak plasma concentration and 23% increase in AUC of adefovirdipivoxil; no effect on pharmacokinetics of ibuprofen). Clinical importance unknown. May occur because of increased oral bioavailability of adefovir.
Tenofovir disoproxil fumarate and adefovir dipivoxil should not be used concomitantly for treatment of chronic HBV infection.
... Study GS-02-531 was an open-label, multicentre drug interaction trial to examine potential drug interactions between adefovir and tacrolimus in stable post-transplant recipients. Sixteen non-HBV-infected post-transplant recipients with median age 45.5 years (69% male, 44% Caucasian, 50% Hispanic and 6% Black) and stable hepatic and renal function on a stable daily dose of tacrolimus (2-10 mg total daily dose) were studied before (tacrolimus alone) and after co-administration of adefovir 10 mg daily for 14 days (Days 1-14). Pharmacokinetic (PK) analyses utilized non-compartmental methods. The median elimination half-life of tacrolimus was 14.47 and 12.59 h for Day 0 and Day 14 respectively. The geometric mean ratios for tacrolimus on Day 14 vs Day 0 were 105.2% [90% confidence interval (90% CI): 89.8-123%] for C(max) and 106.4% (90% CI: 92.9-122%) for AUC(tau). Both 90% CIs for the ratios were contained within the predefined lack of interaction bounds of 80 and 125% (i.e. within the bounds for the equivalence assessment), indicating that these PK parameters of tacrolimus are not significantly altered by co-administration of adefovir. Similarly, the observed adefovir PK parameters after 14 days of co-administration with tacrolimus were comparable to historical data in non-transplant patients receiving adefovir alone. Serum creatinine values were stable during the study period. There is no significant PK interaction between tacrolimus and adefovir co-administered to liver transplant recipients for 14 days.
Adefovir should not be used concurrently with VIREAD (tenofovir disoproxil fumarate) or tenofovir disoproxil fumarate-containing products including TRUVADA (emtricitabine/tenofovir disoproxil fumarate combination tablet), ATRIPLA (efavirenz/emtricitabine/tenofovir disoproxil fumarate combination tablet) and COMPLERA (emtricitabine/rilpivirine/tenofovir disoproxil fumarate).

[1]. 7.11 - Deoxyribonucleic Acid Viruses: Antivirals for Herpesviruses and Hepatitis B Virus. Comprehensive Medicinal Chemistry II. Volume 7, 2007, Pages 295-327.

[2]. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003 Feb 27;348(9):808-16.

[3]. 155 - Drugs to Treat Viral Hepatitis. Infectious Diseases. Volume 2, 2017, Pages 1327-1332.

Therapeutic Uses
Phosphonic Acids; Adenine/analogs & derivatives; Antiviral Agents; Reverse Transcriptase Inhibitors
Adefovir is indicated for the treatment of chronic hepatitis B in patients 12 years of age and older with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. This indication is based on histological, virological, biochemical, and serological responses in adult patients with HBeAg+ and HBeAg- chronic hepatitis B with compensated liver function, and with clinical evidence of lamivudine-resistant hepatitis B virus with either compensated or decompensated liver function. /Included in US product label/
For patients 12 to less than 18 years of age, the indication is based on virological and biochemical responses in patients with HBeAg+ chronic hepatitis B virus infection with compensated liver function. /Included in US product label/
This study investigated the efficacy, safety, and pharmacokinetics of adefovir dipivoxil (ADV) in children and adolescents with chronic hepatitis B (CHB). A total of 173 treatment-naive and treatment-experienced children with hepatitis B e antigen (HBeAg)+ CHB were randomized to ADV or placebo. Randomization was stratified by age (2 to <7 years; >7 to <12 years; >12 to <18 years) and prior treatment. Significantly more ADV-treated subjects aged 12 to <18 years achieved the primary efficacy endpoint (serum hepatitis B virus [HBV] DNA <1,000 copies/mL and normal alanine aminotransferase) compared to placebo-treated subjects (23% versus 0%; P = 0.007). In the younger groups, differences between ADV and placebo at the end of blinded treatment were not statistically significant. More ADV-treated subjects had HBeAg seroconversion: 18 of 113 (15.9%) versus three of 57 (5.3%) (but P = 0.051), and more met the combined endpoint of HBeAg seroconversion, HBV DNA <1,000 copies/mL and normal alanine aminotransferase (12/113 versus 0/57; P = 0.009). No subject developed an ADV-associated mutation that has been linked to HBV DNA rebound (that is, mutations rtN236T or rtA181V). ADV plasma concentrations were comparable across groups and within the target range. ADV treatment was well tolerated; no new safety issues were identified. Treatment-related adverse events were reported for 12% of ADV-treated and 10% of placebo-treated subjects. After 48 weeks of ADV treatment, antiviral efficacy in subjects ages 12 to <18 years with HBeAg+ CHB was similar to that observed in a study in adult treatment-naive subjects with HBeAg+ CHB. ADV was not different from placebo in subjects aged 2 to 11 years despite adequate plasma ADV exposure in all three age groups. CONCLUSION: ADV showed significant antiviral efficacy in subjects aged 12 to 17 years with HBeAg+ CHB, but was not different from placebo in subjects aged 2 to 11 years.

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Drug Warnings
/BOXED WARNING/ Severe acute exacerbations of hepatitis have been reported in patients who have discontinued anti-Hepatitis B therapy including adefovir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-Hepatitis B therapy. If appropriate, resumption of anti-Hepatitis B therapy may be warranted.
/BOXED WARNING/ In patients at risk of or having underlying renal dysfunction, chronic administration of adefovir may result in nephrotoxicity. These patients should be monitored closely for renal function and may require dose adjustment.
/BOXED WARNING/ HIV resistance may emerge in chronic hepatitis B patients with unrecognized or untreated Human Immunodeficiency Virus (HIV) infection treated with anti-hepatitis B therapies, such as therapy with adefovir, that may have activity against HIV.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals.
For more Drug Warnings (Complete) data for Adefovir (20 total), please visit the HSDB record page.

C8H12N5O4P

273.18

273.062

106941-25-7

Adefovir-d4;1190021-70-5

60172

White to off-white solid powder

1.9±0.1 g/cm3

632.5±65.0 °C at 760 mmHg

>260°C

336.3±34.3 °C

0.0±2.0 mmHg at 25°C

1.769

-2.06

3

8

5

18

327

0

SUPKOOSCJHTBAH-UHFFFAOYSA-N

InChI=1S/C8H12N5O4P/c9-7-6-8(11-3-10-7)13(4-12-6)1-2-17-5-18(14,15)16/h3-4H,1-2,5H2,(H2,9,10,11)(H2,14,15,16)

((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)phosphonic acid

GS-0393 GS-393 GS0393 GS393 GS 0393 GS 393 PMEA

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

0.1 M NaOH : ~10 mg/mL (~36.60 mM)
H2O : ~1 mg/mL (~3.66 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)