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Tenofovir: A New Antiretroviral Nucleotide Analog Drug

by Jeffrey Kwong, MS, MPH, ANP edited by Bill Valenti, MD, Richard S Ferri PhD, ANP, ACRN, FAAN

The newest antiretroviral agent to be approved for HIV disease is tenofovir disoproxil fumarate, the pro-drug formulation of tenofovir (Viread¨). Tenofovir is one of a new class of antiretrovirals known as nucleotide analogs; it is approved for use in the treatment of HIV in combination with other antiretrovirals. Nucleotide analogs function similarly to nucleoside reverse transcriptase inhibitors by interfering with reverse transcription. However, the nucleotides are active in their native form, whereas nucleosides only work in cells that have the machinery to activate the drug by a process called phosphorylation. This means that the nucleotide analogs may be active against HIV in a wider variety of infected cells.

Tenofovir serves as an analog of one of the naturally occurring nucleic acids (deoxyadenosine 5˘-triphosphate). During viral replication, tenofovir competes with the naturally occurring nucleic acid and incorporates into the DNA sequence, thereby terminating the genetic chain and halting reverse transcription.

Tenofovir is available as a 300 mg tablet that is readily absorbed following oral administration. It has an extended half-life that allows for once-daily dosing. Studies assessing the effects of food on tenofovir have shown that when tenofovir is administered with a high-fat meal (700 kcal to 1000 kcal, containing 40%-50% fat), there is an increase in bioavailability of 40%, with an increase in the maximum concentration of 14%.1 Due to this increase in drug concentration and improved absorption, it is recommended that tenofovir be taken with food.

Tenofovir is not a substrate of cytochrome P450 (CYP450), and therefore does not compete for the same metabolic pathway as most of the other HIV antiretrovirals. Pharmacokinetic studies have shown that approximately 32% ± 10% of orally administered tenofovir is recovered unchanged in the urine after 24 hours.1 It is believed that tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion in the kidneys.

During clinical investigations and drug development, the pharmacokinetic profile of tenofovir was not studied in children, in the elderly, or in patients with severe hepatic impairment.2 However, since tenofovir is not hepatically metabolized, it is thought that the impact on persons with severe liver disease should be minimal. There is a paucity of data on the effects of tenofovir on patients with severe renal impairment (creatinine clearance <60 mg/min). Since tenofovir is renally eliminated, it is postulated that tenofovir's pharmacokinetics would be affected in patients with altered renal clearance. Therefore, use of tenofovir in patients with impaired renal function is not recommended.2

Data from clinical trials with tenofovir have shown that the drug is well tolerated and has minimal side effects.3-5 The most common side effects associated with tenofovir are gastrointestinal symptoms, most notably nausea, vomiting, diarrhea, and flatulence. These symptoms resolve over time and less than 1% of patients in clinical trials discontinued participation in the trials due to gastrointestinal adverse events.3-5

Other adverse events associated with tenofovir have been demonstrated in animal studies. In several animal models, high concentrations of tenofovir (6 to 12 times the human exposure level) have shown bone toxicity in the form of osteomalacia and reduced bone mineral density.2 The etiology of bone toxicity is unclear, and studies in humans have yet to demonstrate these types of events.

In terms of serious adverse events, tenofovir, like other nucleoside analogs, may lead to lactic acidosis with severe hepatomegaly with steatosis.2 Patients on tenofovir should be monitored for signs or symptoms of lactic acidosis while on therapy.

Medications that are known to be excreted via renal filtration should be used cautiously in patients who are taking tenofovir. In  healthy volunteers, drug-interaction studies have been conducted using co-administration with other HIV antiretrovirals. The only significant drug-drug interaction noted was when tenofovir was co-administered with didanosine (Videx¨, Bristol-Myers Squibb).2

When didanosine and tenofovir are co-administered, didanosine concentrations increase by 28% and the area under the curve (AUC) increases by approximately 44%. Current recommendations stipulate that these two drugs be administered separately; tenofovir should be administered two hours before or one hour after didanosine. Investigators are examining the potential option of co-administering didanosine with tenofovir with meals.

Because of the potential boosting effect of tenofovir on didanosine levels, tenofovir may be able to increase levels of didanosine high enough to overcome the effects of food on didanosine absorption. This would allow co-administration of both drugs with meals, thereby improving some of the tolerability issues associated with didanosine on an empty stomach. Further information is needed before prescribing these medications together, however, and Food and Drug Administration (FDA) guidelines do not currently recommend combining these drugs.

References

     1.   BarditchCrovo P, Deeks, SG, Colier A, et al. Phase I/II trial of the pharmacokinetics, safety, and antiviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrobial Agents Chemother. 2001;45: .

     2.   Viread¨ (tenofovir DF) Prescribing Information. Gilead Sciences, Inc., October 2001.

     3.   Cheng A, Barriere S, Coakley DF, et al. Safety profile of tenofovir DF in antiretroviral-experienced patients from randomized, double-blind, placebo-controlled clinical trials. Presented at the 9th Conference on Retrovirus and Opportunistic Infections, Seattle, WA, February 24-28, 2002. [Abstract 416-W]

     4.   Follansbee S, Reynes J, Nelson M, et al. The Viread Expanded Access Program (EAP): Safety and efficacy of tenofovir disoproxil fumarate (TDF) in antiretroviral treatment (ART) experienced patients. Presented at the 9th Conference on Retrovirus and Opportunistic Infections, Seattle, WA, February 24-28, 2002. [Abstract; poster 415-W]

     5.   Schooley R, Ruane P, Myers R, et al. Tenofovir disoproxil fumarate (TDF) in the treatment of antiretroviral experienced patients: a 48 week analysis of a randomized, double blind, placebo-controlled study. Presented at the 5th International Congress on Drug Therapy in HIV infection, Glasgow, UK, October 22-26, 2000. [Abstract PL6.3]

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