Adefovir dipivoxil

Molecular formula C20H32N5O8P Molecular weight 501.47 CAS Registry No 142340-99-6 Merck Index 13,151 

Sample preparation 100 plasma vith 200 xL 0.1 tnduoroacetic acid in 

Evaporate the supernatant to dryness under reduced pressure at room temperature. Reconstitute with 0.34% chloroacetaldehyde in 100 mM pH 4.5 sodium acetate, vortex, centrifuge. Heat the supernatant at 95° for 40 min, evaporate to dr5Uiess, reconstitute with 100 xL 25 mM pH 6.0 potassium phosphate buffer containing 5 mM tetrabutylammonium hydrogen phosphate, inject a 50 p,L aliquot. 

Mobile phase Gradient. A was MeCN 25 mM pH 6.0 potassium phosphate buffer containing 5 mM tetrabutylammonium hydrogen phosphate 2 98. B was MeCN 25 mM pH 6.0 potassium phosphate buffer containing 5 mM tetrabutylammonium hydrogen phosphate 65 35. A B 100 0 for 2 min, to 0 100 over 13 min, re-equilibrate at initial conditions for 10 min. (Only adefovir is detected in blood. However, the method is reported to distinguish between adefovir and adefovir dipivoxil.) 

Marshbum, J. Nakamura, C. Lee, W.A. Shaw, J.P. Oral formulations of adefovir dipivoxil In vitro dissolution and in vivo bioavailabiUty in dogs, J.Pharm.Sci., 1997, 86, 1334-1338. 

---

Adefovir in its prodrug form, adefovir dipivoxil, is indicated in the treatment of chronic HBV infections (chronic hepatitis B), where, if administered orally as a single dose of lOmg per day, HBV DNA load is reduced significantly (>31ogio) over a 1- or 2-year period (Hadziyannis et al. 2005). 

Borroto-Esoda K, Miller MD, Arterburn S (2007) Pooled analysis of amino acid changes in the HBV polymerase in patients from four major adefovir dipivoxil chnical trials, J Hepatol 47 492 98... 

Persons with confirmed chronic hepatitis B should be evaluated for treatment, which may include interferon, pegylated interferon, lamivudine, adefovir dipivoxil, or entecavir. The drug of choice for chronic hepatitis B depends on the patient s past medical history, aminotransferase level, HBV DNA level, and most importantly, HBeAg status. 

Patients infected with HBeAg-negative chronic hepatitis B have a significant response while on adefovir dipivoxil, but the response is not sustained after treatment discontinuation. Serum ALT levels normalized in 72% of patients treated for 48 weeks compared to 29% who received placebo. Additionally, 51% had undetectable HBV DNA levels with adefovir dipivoxil, whereas none achieved this in the placebo arm.20,27,32... 

Resistance rates to adefovir dipivoxil are lower than with lamivudine, potentially allowing for prolonged treatment duration. At present, the longest trial with adefovir dipivoxil is 5 years with a resistance rate of 29%,35 compared to 5 years of lamivudine therapy with a resistance rate of 70%. 

The dose of adefovir dipivoxil is 10 mg once daily. The most common side effects include asthenia, abdominal pain, diarrhea, dyspepsia, headaches, nausea, and flatulence. Lactic acidosis, pancreatitis, and hepatomegaly have been reported rarely. Unlike lamivudine, adefovir dipivoxil is associated with dose-related nephrotoxicity, which was most commonly seen in HIV patients receiving doses larger than 60 mg. Therefore, the dose of adefovir dipivoxil must be adjusted in patients with renal insufficiency (CrCl less than 50 mL/minute). 

The side-effect profile for entecavir is similar to lamivudine and adefovir dipivoxil and comparable to placebo. Patients treated with entecavir should be monitored for signs and symptoms associated with lactic acidosis and severe hepatomegaly with steatosis, because some cases have been fatal. Dosage adjustments are required in patients with renal dysfunction. 

Annaert P, Tukker JJ, Van Gelder J, Naesens L, de Clercq E, Van den Mooter G, Kinget R, Augustijns P (2000) In vitro, ex vivo, and in situ intestinal absorption characteristics of the antiviral ester prodrug adefovir dipivoxil. J Pharm Sci 89 1054-1062. 

Drugs eliminated by the kidneys Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase serum concentrations of tenofovir and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. Drugs that decrease renal function also may increase serum concentrations of tenofovir. 

Adefovir dipivoxil, more recently introduced, is an option in those who have unsuccessful therapy with relapse after use of interferon alpha, and/or have become lamivudine resistant. 

National Institute for Health and Clinical Excellence. Hepatitis B (chronic) - adefovir dipivoxil and peginter-feron alpha-2a. Technology appraisal TA096. [2006], Available from URL www.nice.org.uk National Institute for Health and Clinical Excellence. Hepatitis C peginterferon and ribavirin. Technology appraisal TA106. [2006]. Available from URL WWW. nice. org. uk... 

Several anti-HBV agents have anti-HIV activity as well, including lamivudine, adefovir dipivoxil, and tenofovir. Emtricitabine, an antiretroviral NRTI, is under clinical evaluation for HBV treatment. Because NRTI agents may be used in patients co-infected with HBV and HIV, it is important to note that acute exacerbation of hepatitis may occur upon discontinuation or interruption of these agents. 

Although initially and abortively developed for treatment of HIV infection, adefovir dipivoxil gained approval, at lower and less toxic doses, for treatment of HBV infection. Adefovir dipivoxil is the diester prodrug of adefovir, an acyclic phosphonated adenine nucleotide analog (Rgure 49-2). It is phosphorylated by cellular kinases to the active diphosphate metabolite and then competitively inhibits HBV DNA polymerase to result in chain termination after incorporation into the viral DNA. Adefovir is active in vitro... 

Oral bioavailability of adefovir dipivoxil is about 59% and is unaffected by meals it is rapidly and completely hydrolyzed to the parent compound by intestinal and blood esterases. Protein binding is low (< 5%). The intracellular half-life of the diphosphate is prolonged, ranging from 5 to 18 hours in various cells this makes once-daily dosing feasible. Adefovir is excreted by a combination of glomerular filtration and active tubular secretion and reguires dose adjustment for renal dysfunction however, it may be administered to patients with decompensated liver disease. 

Adefovir dipivoxil is well tolerated. A dose-dependent nephrotoxicity has been observed in clinical trials, manifested by increased serum creatinine with decreased serum phosphorous and more common in patients with baseline renal insufficiency and those receiving high doses (60 mg/d). Other potential adverse effects are headache, diarrhea, asthenia, and abdominal pain. As with other NRTI agents, lactic acidosis and hepatic steatosis are considered a risk owing to mitochondrial dysfunction. No clinically important drug-drug interactions have been recognized to date. Pivalic acid, a by-product of adefovir dipivoxil metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not felt necessary to administer carnitine supplementation with the low doses used to treat patients with HBV (10 mg/d). 

Adefovir dipivoxil Drug analogue/Prodrug Adefovir 2002... 

NICE (National Institute for Health and Clinical Excellence) (2006) Guidance on the use of adefovir dipivoxil and pegylated interferon alpha-2b for the treatment of chronic hepatitis B. Available at http //www.nice.org.uk/guidance/TA96 [Accessed 2 July 2008],... 

Interferon alfa should typically be used in combination with antiviral agents such as lamivudine or adefovir dipivoxil (refer to BNF), the first-line treatment... 

---