Tenofovir dosing

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). 

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. 

Renal function impairment Ad usi the dosing interval of tenofovir in patients with baseline creatinine clearance (Ccr) less than 50 mL/min using the recommendations in the following table. The safety and effectiveness of these dosing interval recommendations have not been clinically evaluated closely monitor clinical response to treatment and renal function in these patients. 

The pharmacokinetics of tenofovir have not been evaluated in nonhemodialysis patients with Ccr less than 10 mL/min therefore, no dosing recommendation is available for these patients. 

Metabolism/Excretion - Following a single oral dose of tenofovir, the terminal elimination half-life is approximately 17 hours. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. 

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. 

Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in... 

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. 

Didanosine (ddl) NRTT1 Tablets, 400 mg daily,3 adjusted for weight. 30 min before or 2 h after meals. Separate dosing from fluoroquinolones and tetracyclines by 2 h Peripheral neuropathy, pancreatitis, diarrhea, nausea, hyperuricemia. Possible increase in myocardial infarction Avoid concurrent neuropathic drugs (eg, stavudine, zalcitabine, isoniazid), ribavirin, and alcohol. Do not administer with tenofovir... 

Tenofovir disopoxilfumarate is a water-soluble prodrug of active tenofovir. The oral bioavailability in fasted patients is approximately 25% and increases to 39% after a high-fat meal. The prolonged serum (12-17 hours) and intracellular half-lives allow once-daily dosing. Elimination occurs by both glomerular filtration and active tubular secretion. 

Allopurinol increases didanosine plasma concentrations and their coadministration is not recommended. Ganciclovir, tenofovir and disoproxil also increase didanosine plasma concentrations, and dose reduction is recommended. Conversely, methadone decreases didanosine plasma concentrations, and appropriate doses for the combination have not been established. Didanosine should not be administered with drugs that cause pancreatic or neurotoxicity. Ribavirin increases its risk of toxicity and should not be coadministered. 

Tenofovir is indicated for use in combination with other antiretroviral agents. Initial studies demonstrated potent HIV-1 suppression in treatment-experienced adults with evidence of viral replication despite ongoing antiretroviral therapy similar benefit in antiretroviral-naive patients has yet to be demonstrated. The once-daily dosing regimen of tenofovir lends added convenience. 

Although initially and abortively developed for treatment of HIV infection, adefovir has been recently approved, at lower and less toxic doses, for treatment of HBV infection. Like tenofovir (see Antiretroviral Agents), adefovir is a nucleotide analog. As an analog of adenosine monophosphate, adefovir is phosphorylated by cellular kinases to the active disphosphate metabolite it then competitively inhibits HBV DNA polymerase and results in chain termination after incorporation into the viral DNA. 

In 2001, tenofovir disoproxil fumarate 61, a prodrug of tenofovir was approved for treatment of HIV, subsequently being preregistered in the USA for treatment of hepatitis B. Emtricitabine 62, a reverse transcriptase inhibitor, was approved in 2003 for HIV. What is of import is that these compounds are now part of fixed dose combination therapies for treatment of HIV, either two drug (tenofovir disoproxil fumarate/emtricitabine) or three drug Atripla (tenofovir disoproxil fumarate/emtricitabine/efavirenz) formulations. Thus, even 50 + years after Bergmann s discovery of bioactive arabinose nucleosides, small molecules synthesised as result of his discoveries are still in clinical use and others are in clinical trials for treatment of viral diseases. 

AMPHOTERICIN NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS - TENOFOVIR, ZIDOVUDINE Possibly T adverse effects with tenofovir and zidovudine Additive toxicity Avoid if possible otherwise monitor FBC and renal function (weekly). 1 doses as necessary... 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS GANCICLOVIRAfALGANCIC LOVIR 1. T adverse effects with tenofovir, zidovudine and possibly didanosine, lamivudine and zalcitabine 2. Possibly 1 efficacy of ganciclovir 1. Uncertain possibly additive toxicity. Lamivudine may compete for active tubular secretion in the kidneys 2. Uncertain L bioavailability 1. Avoid if possible otherwise monitor FBC and renal function weekly. It has been suggested that the dose of zidovudine should be halved from 600 mg to 300 mg daily. Monitor for peripheral neuropathy, particularly with zalcitabine 2. Uncertain clinical significance if in doubt, consider alternative cytomegalovirus prophylaxis... 

DIDANOSINE TENOFOVIR Possibly t adverse effects, including pancreatitis, lactic acidosis and neuropathy t plasma levels of didanosine additive effects Co-administration not recommended. Monitor closely for antiviral efficacy and side-effects (pancreatitis, neuropathy, lactic acidosis, renal failure). Not recommended in patients with a high viral load and low CD4 count (enteric-coated and buffered tablets), i dose of didanosine to 250 mg has been tried. Do not use in combination as triple therapy with lamivudine as there is a high level of treatment failure... 

Tenofovir is not metabolized to a significant extent by CYPs and is not known to inhibit or induce these enzymes. However, tenofovir has been associated with a few potentially important pharmacokinetic drug interactions. A 300-mg dose of tenofovir increased the didanosine AUC by 44 to 60% probably as a consequence of inhibition of the enzyme purine nucleoside phosphorylase by both tenofovir and tenofovir monophosphate. These two drugs probably should not be used together, or if this is essential, the dose of didanosine should be reduced from 400 to 250 mg/day. 

Although tenofovir is not known to induce CYPs, it has been reported to reduce the atazanavir AUC by approximately 26%. In addition, low-dose ritonavir (100 mg twice daily) increases the tenofovir AUC by 34%, and atazanavir increases the tenofovir AUC by 25%. The mechanism of these interactions is unknown. 

---