Renal dysfunction adefovir

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. 

In patients at risk of or having renal dysfunction, chronic administration of adefovir may result in nephrotoxicity. Closely monitor for renal function and adjust dose as required. 

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 is associated with a dose-dependent nephrotoxicity. The risk is low for treatment durations of up to 1 year at its recommended dosage for HBV but may rise in patients with preexisting renal dysfunction or in those treated for longer durations. Also, as with the antiretroviral nucleoside analogs (see Nucleoside Reverse Transcriptase Inhibitors), lactic acidosis and severe hepatomegaly with steatosis may occur. When coadministered with ibuprofen, the AUC of adefovir is increased by about 23%, apparently due to higher oral bioavailabilty. 

Urinary tract In 290 patients with chronic hepatitis B, of whom 145 had taken adefovir 10 mg/day, and 145 patients matched for age, sex, and baseline estimated glomerular filtration rate (eGFR), adefovir was a significant predictor of renal dysfunction (HR = 3.94) [7. ... 

Ha NB, Ha NB, Garcia RT, Trinh HN, Vu AA, Nguyen HA, Nguyen KK, Levitt BS, Nguyen MH. Renal dysfunction in chronic hepatitis B patients treated with adefovir dipivoxiL Hepatology 2009 50(3) 727-34. 

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 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. 

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). 

Combination studies One prospective study observed that six patients out of 51 treated with combination 3TC and adefovir for durations ranging from 2.1 to 8.4 years developed hypophosphataemia on serum blood testing with at least two other criteria for renal tubular dysfunction. This study monitored for serum biochemical abnormalities and significant deviations resulted in drug substitutions prior to the development of clinical symptoms [57 ]. 

Gara N, Zhao X, Collins MT, Chong WH, Kleiner DE, Jake Laing T, et al. Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. Aliment Pharmacol Ther 2012 35(ll) 1317-25. 

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