Tenofovir disoproxil

Tenofovir in its prodrug form tenofovir, disoproxil fumarate (TDF), is indicated in the treatment of HIV infections (AIDS). It is administered as a single oral dose of 300 mg per day. When combined with emtricitabine and efavirenz, TDF has proven to be more efhcacious than the standard combination therapy of combivir (azidothymidine plus lamivudine) and efavirenz (Gallant et al. 2006) and less prone to cause adverse side effects (Pozniak et al. 2006 De Clercq 2007b). 

In addition to the NRTI lamivudine (3TC) and the NtRTI adefovir dipivoxU and tenofovir disoproxil fumarate (which has been recently licensed for the treatment of chronic hepatitis B), two other nucleoside analogues, that is, entecavir and L-dT (tel-bivudine) (Fig.4aa), have been licensed for the treatment of HBV infections. Two other compounds 3 -Val-L-dC (valtorcitabine) and L-FMAU (clevudine) (Fig. 4aa) are in clinical development for the treatment of HBV infections, and yet two other compounds, that is, racivir and elvucitabine (Fig. 3), yield potential for the treatment of both HBV and HIV infections. 

Tenofovir disoproxil 300 mg tab 300 mg qday CrCI None Asthenia, headache, Renal excretion... 

APV, amprenavir ATV, atazanavir CNS, central nervous system CVD, cardiovascular disease D/C, discontinue ddC, zalcitabine ddl, didanosine DEXA, dual-energy x-ray absorptiometry d4T, stavudine EFV, efavirenz HDL, high-density lipoprotein HIV, human immunodeficiency virus HTN, hypertension IDV, indinavir LDL, low-density lipoprotein LPV/r, lopinavir+ ritonavir MRI, magnetic resonance imaging NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor NVP, nevirapine PI, protease inhibitor RTV, ritonavir SQV, saquinavir TDF, tenofovir disoproxil fumarate TG, triglyceride TPV/r, tipranivir + ritonavir ZDV, zidovudine. 

Drugs may also undergo hydrolysis by intestinal esterases (hydrolases), more specifically carboxylesterases (EC 3.1.1.1) in the intestinal lumen and at the brush border membrane [58, 59]. It has been shown that intestinal hydrolase activity in humans was closer to that of the rat than the dog or Caco-2 cells [60]. In these studies, six propranolol ester prodrugs and p-nitrophenylacetate were used as substrates, and the hydrolase activity found was ranked in the order human > rat Caco-2 cells > dog for intestinal microsomes. The rank order in hydrolase activity for the intestinal cytosolic fraction was rat > Caco-2 cells = human > dog. The hydrolase activity towards p-nitrophenylacetate and tenofovir disoproxil has also been reported in various intestinal segments from rats, pigs and humans. The enzyme activity in intestinal homogenates was found to be both site-specific (duodenum > jejunum > ileum > colon) and species-dependent (rat > man > Pig)-... 

Mallants R, Van Oosterwyck K, Van Vaeck L, Mols R, De Clercq E, Augustijns P (2005) Multidrug resistance-associated protein 2 (MRP2) affects hepatobiliary elimination but not the intestinal disposition of tenofovir disoproxil fumarate and its metabolites. Xenobiotica 35 1055-1066. 

Further studies seem to have focused mainly on various prodrugs of a higher homologue of PMEA, namely 9-[2-(phosphonomethoxy)propyl] adenine (PMPA, tenofovir, 9.57, R = H). Tenofovir disoproxil (9.57, R = i-Pr0-C0-0-CH2) proved of particular interest and has been selected for further studies [ 127] [ 128]. 

Chapman TM, McGavin JK, Noble S. Tenofovir disoproxil fumarate. Drugs 2003 63 1597-608. 

Tenofovir disoproxil fumarate - It is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). Atazanavir without ritonavir should not be coadministered with tenofovir. 

Pharmacology Tenofovir disoproxil, an acyclic nucleoside phosphonate diester analog of adenosine monophosphate, inhibits the activity of HIV reverse transcriptase. 

Administration of tenofovir disoproxil following a high-fat meal increases the... 

Tablets 200 mg emtricitabine/300 mg tenofovir disoproxil fumarate (equivalent to 245 mg tenofovir disoproxil) (Rx)...

Consult the complete prescribing information for each agent prior to administration of emtricitabine/tenofovir disoproxil fumarate combination tablets. 

Emtricitabine/tenofovir disoproxil fumarate is not indicated for the treatment of chronic hepatitis B virus (HBV) infection safety and efficacy have not been established in patients coinfected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued emtricitabine or tenofovir disoproxil fumarate. Closely monitor hepatic function with clinical and laboratory follow-up for at least several months in patients who discontinue emtricitabine/tenofovir disoproxil fumarate and are coinfected with HIV and HBV. If appropriate, initiation of antihepatitis B therapy may be warranted (see Warnings). 

In treatment-naive patients, consider emtricitabine/tenofovir disoproxil fumarate as an alternative to the combination of tenofovir disoproxil fumarate plus lamivudine (3TC) for those patients who might benefit from a once-daily regimen. In treatment-experienced patients, guide the use of emtricitabine/tenofovir disoproxil fumarate by laboratory testing and treatment history. 

The dose of emtricitabine/tenofovir disoproxil fumarate is 1 tablet taken orally once daily with or without food. 

Renal function impairment Significantly increased drug exposures occurred when emtricitabine or tenofovir disoproxil fumarate were administered to patients with moderate to severe renal impairment. Because the safety and efficacy of the dosing... 

Pharmacokinetics One emtricitabine/tenofovir disoproxil fumarate tablet was bioequivalent to 1 emthcitabine capsule (200 mg) plus 1 tenofovir disoproxil fumarate tablet (300 mg) following single-dose administration to fasting healthy subjects. 

Fixed dose combination This combination contains fixed doses of 2 nucleoside analogs emtricitabine and tenofovir disoproxil fumarate. Do not administer concomitantly with emtricitabine or tenofovir disoproxil fumarate. 

Renal function impairment Emtricitabine and tenofovir disoproxil fumarate are principally eliminated by the kidney. Dosing interval adjustment is recommended in all patients with Ccr 30 to 49 mL/min do not administer the combination to patients with Ccr less than 30 mL/min or patients requiring hemodialysis. 

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of tenofovir disoproxil fumarate. 

Avoid emtricitabine/tenofovir disoproxil fumarate with concurrent or recent use of a nephrotoxic agent. Carefully monitor patients at risk for or with a history of renal dysfunction and those receiving concomitant nephrotoxic agents for changes in serum creatinine and phosphorus. 

The present NRTIs available for the treatment of HIV are zidovudine (azidothymidine, AZT), stavu-dine (d4T), didanosine (ddl), lamivudine (3TC), dideoxycytidine (ddC, zalcitabine) and abacavir, emtricitabine and tenofovir disoproxil. Combination formulations are abcavir combined with zidovudine and lamivudine and the abacavir-lamivudine combination. 

Tenofovir disoproxil fumarate (Viread) is a prodrug of tenofovir, a phosphorylated adenosine nucleoside analogue, and is the only available agent of its class. It is converted by cellular enzymes to tenofovir diphosphate, which competes with deoxyadenosine triphosphate (dATP) for access to reverse transcriptase and causes chain termination following its incorporation. Tenofovir was approved as part of a combination therapy for HIV in adults who failed treatment with other regimens it appears to be effective against HIV strains that are resistant to NRTIs. The pharmacokinetic properties of tenofovir are provided in Table 51.2. 

---