Adefovir dipivoxil dosing

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). 

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). 

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). 

It is inhibitory in vitro against a range of DNA and RNA viruses, but its clinical use is limited to HBV infections. Inhibitory concentrations for HBV range from 0.2 to 1.2 xM in cell culture, and it is active against lamivudine-resistant HBV strains. Oral adefovir dipivoxil shows dose-dependent inhibition of hepad navirus replication in animal models. In vitro combinations of adefovir and lamivudine or other anti-HBV nucleosides show enhanced antihepad-navirus activity in vitro. 

Adefovir dipivoxil canses dose-related nephrotoxicity and tubular dysfunction, manifested by azotemia and hypophosphatemia, acidosis, glycosnria, and proteinuria that usually are reversible months after discontinuation. The lower dose (10 mg/day) nsed in chronic HBV infection patients has been associated with a few adverse events (e.g., headache, abdominal discomfort, diarrhea, and asthenia) and negligible renal toxicity compared with a threefold higher dose. 

Chnical use is limited to HBV infections, including lamivudine-resistant HBV strains. Oral adefovir dipivoxil shows dose-dependent inhibition of hepadnavirus replication. In vitro combinations of adefovir and lamivudine or other anti-HBV nucleosides show enhanced antihepadnavirus activity. 

Adefovir is renally excreted. After oral administration of adefovir dipivoxil, -30-45% of the dose is recovered unchanged in urine within 24 hours the elimination is 5-7.5 hours. Dose reductions are indicated for Cl values <50 mUmin. Adefovir is removed by hemodialysis. 

High doses in animals cause renal tubular dysfunction, hepatotoxicity, and toxicity to lymphoid tissues. Adefovir dipivoxil is not associated with reproductive toxicity (pregnancy category C). 

Adefovir dipivoxil (4) was initially developed as a treatment for HIV, but the FDA in 1999 rejected the drug due to concerns about the severity and frequency of kidney toxicity when dosed at 60 or 120 mg, respectively. However, 4 was effective at a much lower dose of 10 mg for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum alanine aminotransferases (primarily ALT) or histologically active disease. It works by blocking reverse transcriptase, an enzyme that is crucial for the HBV to reproduce in the body. Overall, the efficacy of 4 against wild-type and lamivudine (2)-resistant HBV and the delayed emergence of 4-resistance during monotherapy contribute to the durable safety and efficacy observed in a wide range of chronic hepatitis B patients. ... 

Wong T, Girgis CM, Ngu MC, Chen RC, Emmett L, Archer KA, Seibel MJ. Hypo-phosphatemic osteomalacia after low-dose adefovir dipivoxil therapy for hepatitis B. J Clin Endocrinol Metab 2010 95(2) 479-80. 

Wu C, Zhang H, Qian Y, Wang L, Gu X, Dai Z. Hypophosphatemic osteomalacia and renal Fanconi syndrome induced by low-dose adefovir dipivoxil a case report and literature review suggesting ethnic predisposition. J Clin Pharm Ther 2013 38(4) 321-6. 

Law ST, Li KK, Ho YY. Nephrotoxicity, including acquired Fanconi s s)mdrome, caused by adefovir dipivoxil - is there a safe dose J Clin... 

Adefovir (ADV) is a nucleoside analogue, which causes a break in the molecular chain through its competitive integration in the newly synthesized HBV DNA. ADV dipivoxil is a prodrug, which is converted into active ADV in the intestinal tract. Its half-life is 7-8 hours. Elimination is via the kidneys. Therefore, the dose must be adjusted in the case of renal insufficiency It should be noted... 

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