Health and Pills

Viread: Development and Pharmacology

Since the introduction of zidovudine (AZT, Retrovir) in 1987, a relatively large number of drugs have been developed for the treatment of HIV-induced AIDS. Currently available anti-retroviral drugs are sub-classified based on their chemical structure and site of action as nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine and abacavir), non-nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine and efavirenz), or protease inhibitors (PIs: saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and lopinavir). The use of these and all anti-retrovirals as monotherapy is limited largely by the rapid development of viral resistance. Thus, current Public Health Service HIV treatment guidelines recommend the use of drug combinations consisting of three or four anti-AIDS drugs. These combinations, now referred to as highly active anti-retroviral therapy (HAART), typically include a combination of two NRTIs with one or two PIs, or two NRTIs with an NNRTI. These HAART approaches have proven to be more effective than the use of single agents in providing prolonged reductions in HIV and have contributed significantly to the reduction of mortality associated with AIDS since 1995.

Tenofovir disoproxil fumarate is the most recent NRTI approved for inclusion in regimens for the treatment of HIV. This drug is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate, and expresses its antiviral action by a mechanism similar to other NRTIs. Tenofovir disoproxil fumarate (Viread) requires initial diester hydrolysis for conversion to tenofovir and subsequent, stepwise phosphorylation by cellular enzymes to form tenofovir diphosphate, like other NRTIs. Tenofovir diphosphate then inhibits the activity of HIV reverse transcriptase by two mechanisms: 1) Reversible inhibition via competition with the natural substrate deoxyadenosine 5′-triphosphate for binding at the active site of the enzyme and 2) Chain termination when incorporated into the growing viral DNA chain by the enzyme. Tenofovir diphosphate also is a weak inhibitor of mammalian DNA polymerases alpha, b, and mitochondrial DNA polymerase gamma. The in vitro antiviral activity of tenofovir against laboratory and clinical isolates of HIV has been assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The IC₅₀ (50% inhibitory concentrations) for tenofovir is in the range of 0.04 µM to 8.5 µM. In drug combination studies of tenofovir with another NRTI, or an NNRTI inhibitor of HIV reverse transcriptase and protease inhibitors, additive to synergistic effects are observed. However, most such drug combinations have not been studied in humans.

HIV strains with reduced susceptibility (i.e., resistance) to tenofovir have been isolated and characterized in vitro and from HIV patients. The resistant strains express a K65R mutation in reverse transcriptase and show a 3- to 4-fold reduction in susceptibility to tenofovir. HIV strains with the K65R mutation also have been isolated from a small proportion (3%) of patients treated with tenofovir in clinical trials. However, since these patients had been treated previously with other antiretrovirals, the rate and extent of tenofovir-associated resistance mutations in antiretroviral-naïve patients remains unknown. HIV strains with the K65R mutation also have been observed in HIV-infected patients treated with didanosine, zalcitabine, or abacavir. Furthermore, it has been demonstrated that HIV strains with multiple zidovudine-associated reverse transcriptase mutations other than K65R also are less susceptible to tenofovir (an average of a three-fold reduction in susceptibility) in vitro. Therefore at least some cross-resistance may occur in patients who develop the K65R and other reverse transcriptase mutations following treatment with these drugs.

Viread: Therapeutics

Tenofovir, in combination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection. This indication is based primarily on analyses of plasma HIV-1 RNA levels and CD4 cell counts in a controlled study of tenofovir of 24 weeks duration (Study 907), and in a controlled, dose-ranging study of tenofovir of 48 weeks duration (Study 902). Both studies were conducted with adults previously treated with other antiretroviral therapy and who had evidence of continued HIV-1 viral replication. Studies in antiretroviral-naïve patients are currently underway to assess the risk-benefit ratio for this population. In Study 907 tenofovir was added to a stable background regimen of antiretroviral agents in 550 treatment-experienced patients. At study onset patients had a mean baseline CD4 cell count of 426 cells/mm³ (range 23-1385), median baseline plasma HIV RNA of 2,340 copies/mL (range 50-75,900), and mean duration of prior HIV treatment of 5.4 years. The mean age of the patients was 42 years; 85% were male, 69% were Caucasian, 17% were African-American and 12% were Hispanic. Over the 24-week treatment period, 149 patients (40%) showed a reduction of plasma HIV RNA levels to below 400 copies/mL, and 71 of these patients (19% of total study group) had plasma HIV RNA levels below 50 copies/mL. Also, the mean change in absolute CD4 counts by week 24 of this study was +11 cells/mm³ for the tenofovir group and -5 cells/mm 3 for the placebo group.

In Study 902 tenofovir was evaluated at three dose levels (75 mg QD, 150 mg QD and 300 mg QD) when added to a stable background regimen of antiretroviral agents in 186 treatment-experienced patients. Placebo patients received tenofovir 300 mg QD at week 24 and all patients received open label tenofovir (300 mg QD) after week 48. The patients enrolled in this study had a mean baseline CD4 cell count of 374 cells/mm³ (range 9-1,240), median baseline plasma HIV RNA of 5,010 copies/mL (range 52-575,000), and mean duration of prior HIV treatment of 4.6 years. The mean age was 42 years, and 92% were male, 74% were Caucasian, 13% were African-American, and 11% were Hispanic. At week 24, the rate of drug discontinuation was 11% for the tenofovir group versus 25% for the placebo group. Through week 24 the proportion of patients achieving HIV RNA levels <400 copies/mL was 19% in the tenofovir-treated group and 7% in the placebo group. Over this time period, 11% of tenofovir-treated patients and 0% of patients receiving placebo achieved HIV RNA levels <50 copies/mL. The mean change in absolute CD4 counts by week 24 were -14 cells/mm³ for the tenofovir-treated group and +20 cells/mm³ for the placebo group. The mean change in CD4 count at week 48 was +11 cells/mm³ for the tenofovir-treated group.

The virologic response to tenofovir therapy in Studies 902 and 907 also was evaluated with respect to baseline viral genotype (222 patients). In these studies, 94% of the participants evaluated had baseline HIV isolates expressing at least one zidovudine- or lamivudine/abacavir-associated mutation, as well as other mutations. In addition, the majority of participants evaluated had mutations associated with either PI or NNRTI use. Virologic responses for patients in the genotype sub-study were similar to the overall results in Studies 902 and 907. Varying degrees of cross-resistance of tenofovir to pre-existing zidovudine-associated mutations were observed, and appeared to depend on the number of specific mutations. Tenofovir-treated patients whose HIV expressed three or more specific zidovudine-associated mutations (including either the M41L or L210W reverse transcriptase mutation) showed reduced responses to tenofovir therapy; however, these responses were still improved compared to placebo. The presence of the other known zidovudine mutations (i.e., D67N, K70R, T215Y/F or K219Q/E/N mutations), or the lamivudine/abacavir-associated mutation (M184V), did not appear to affect responses to tenofovir therapy. It should be noted, however, that the interpretation of genotypic mutations is complex, and conclusions regarding the clinical relevance of particular mutations or mutational patterns are subject to change pending additional data.

Viread: Adverse Reactions

More than 1,000 patients have been treated with tenofovir alone or in combination with other antiretroviral drugs in clinical trials to date. The most common adverse events that occurred in patients treated with regimens that included tenofovir were mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting and flatulence. Less than 1% of patients discontinued participation in the clinical studies due to adverse gastrointestinal events. Laboratory abnormalities observed in clinical studies occurred with similar frequency in the tenofovir and placebo treated groups. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals. A majority of these cases have been in women, and obesity and prolonged nucleoside exposure have been identified as risk factors. Particular caution should be exercised when administering nucleoside analogs, including tenofovir, to any patient with known risk factors for liver disease. Treatment with tenofovir should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis, even in the absence of marked transaminase elevations). Also, while not reported as significant with tenofovir, redistribution and accumulation of body fat including central obesity, dorsocervical fat enlargement (”buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving anti-retroviral therapy.

Viread: Drug interactions

At concentrations substantially higher (~ 300-fold) than those observed in vivo, tenofovir does not inhibit in vitro drug metabolism mediated by CYP450 isoforms, including CYP3A4, CYP2D6, CYP2C9 and CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrates has been observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450-mediated interactions involving tenofovir with other drugs is relatively low. Since tenofovir is primarily excreted renally by a combination of glomerular filtration and active tubular secretion, co-administration with drugs that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir or the co-administered drug by competition for this elimination pathway. Examples of such a potential interaction among the antiviral drugs include cidofovir, acyclovir, valacyclovir, ganciclovir and valganciclovir. Also, drugs that decrease renal function may increase serum concentrations of tenofovir. When administered with tenofovir, C_max and AUC of didanosine (buffered formulation) reportedly are increased by 28% and 44%, respectively. Thus, patients using tenofovir and didanosine concurrently should be monitored for long term didanosine-associated adverse events, even though an increased rate of didanosine-associated adverse events has not been observed with this combination to date.

Viread: Pharmacokinetics

The oral bioavailability of tenofovir from the parent drug formulation in patients who have fasted is approximately 25%. Following oral administration of a single 300 mg dose of tenofovir disoproxil fumarate (Viread) in the fasting state, maximum serum concentrations (C_max) are achieved in 1-1.5 hours. The C_max and AUC values are 296 ng/mL and 2,287 ng.h/mL, respectively. The pharmacokinetics of tenofovir are dose proportional over the therapeutic dose range (75-600 mg) and are not affected by repeated dosing. Administration of tenofovir following a high-fat meal (~700 to 1,000 kcal containing 40%-50% fat) increases the oral bioavailability, with an increase in tenofovir AUC of about 40% and an increase in C_max of approximately 14%. Thus, tenofovir should be taken with a meal to enhance the bioavailability. The plasma protein binding of tenofovir is very low (less than 10%) over the therapeutic concentration range (0.01-25 µg/mL). The volume of distribution of tenofovir at steady-state is about 1.3 L/kg following intravenous administration. In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP450 enzymes. Following IV administration of tenofovir disoproxil, approximately 70%-80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours. After multiple oral doses, approximately 30% of the administered dose is recovered in urine over 24 hours. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Thus, there may be competition for elimination with other compounds that are also renally eliminated by this mechanism.

The pharmacokinetics of tenofovir are similar in male and female patients. Adequate controlled studies have not been performed to determine if there are pharmacokinetic differences between children, the elderly, and different racial and ethnic groups. The pharmacokinetics of tenofovir have not been studied in patients with hepatic impairment or with renal impairment (creatinine clearance <60 mL/min). However, since tenofovir and tenofovir disoproxil are not metabolized by liver enzymes, hepatic impairment is not anticipated to significantly alter pharmacokinetics. Also, since tenofovir is primarily eliminated renally, tenofovir pharmacokinetics are likely to be affected by renal impairment.

Viread: Dosage and Administration

Tenofovir disoproxil fumarate is available as film-coated tablets. Each tablet contains 300 mg of tenofovir disoproxil fumarate (Viread), which is equivalent to 245 mg of tenofovir disoproxil. The recommended dose is 300 mg once daily taken orally with a meal. When administered with didanosine, tenofovir should be administered two hours before, or one hour after, administration of didanosine.