Tenofovir (PMPA) is an acyclic nucleotide analog with demonstrated activity against HIV types 1 and 2 in vitro. Tenofovir contains a single phosphate group which permits efficient phosphorylation to its active form (tenofovir diphosphate) by constitutively active kinases in resting and activated T cells, monocytes, and macrophages. Since tenofovir is not orally bioavailable, a pro-drug was developed, tenofovir disoproxil fumarate (tenofovir DF), which is rapidly converted to tenofovir following absorption. Tenofovir DF is administered as one tablet once daily. Tenofovir DF has been evaluated in antiretroviral treatment-naïve and experienced patients and
has been studied in various combinations within all licensed antiretroviral agents. Early clinical studies determined the optimal dose of tenofovir DF to be 300 mg once daily. This dose has demonstrated statistically significant and durable activity in two placebo-controlled studies (Studies 902 and 907) as measured by time-weighted decreases from baseline in log10 plasma HIV-1 RNA levels and, in Study 907, by a higher proportion of patients treated with tenofovir DF as compared to placebo achieving plasma HIV-1 RNA levels below the limit of quantification. Tenofovir DF is currently in phase 3 development. An MAA and an NDA for tenofovir DF was submitted in May 2001. Tenofovir has a favorable resistance profile, as it is active against wild type
and most drug-resistant viruses. Experiments using HIV molecular clones show that tenofovir has activity against drug-resistant strains exhibiting zidovudine resistance (D67N+K70R+T215Y), lamivudine resistance (M184V), didanosine resistance (L74V), zalcitabine resistance (T69D), as well as multi-nucleoside resistance (Q151M). Reduced activity has been observed with the K65R RT mutation and with the T69S insertion mutants but the occurrence of these mutations appears to be uncommon in vivo. Clinical studies have shown that tenofovir has activity against all common nucleoside-resistant, non-nucleoside-resistant, and protease inhibitor-resistant strains of HIV-1. Studies have also shown a low incidence of genotypic ( 3%) or phenotypic
resistance to tenofovir arising during 48 weeks of tenofovir DF therapy. Consequently, tenofovir DF has been shown to have durable antiretroviral activity through 24 and 48 weeks in HIV-infected patients with either immunologic or virologic progression despite extensive prior therapy. Antiretroviral benefit was observed independent of race, gender, age, baseline plasma HIV RNA or CD4 cell count. Administration of tenofovir DF with food results in enhanced bioavailability. In addition, the terminal elimination half-life of tenofovir DF in serum supports a one tablet, once daily dosing schedule – a convenient alternative to traditional antiretroviral therapies for HIV infection that often have complex dosing restrictions and/or high pill
burdens, which can negatively affect both quality of life and adherence. No clinically significant drug interactions have been observed. No differences in pharmacokinetics have been observed based upon age, gender or body weight. Treatment with tenofovir DF is well tolerated. Clinical adverse events, laboratory abnormalities, and rates of study drug discontinuation were similar in tenofovir DF and placebo treated patients. A slightly higher incidence of mild to moderate gastrointestinal adverse events were reported in tenofovir DF treated patients. In vitro studies evaluating tenofovir binding to DNA polymerase gamma, ratio of mitochondrial / cellular DNA, and production of lactic acid have shown a low potential for the development of
mitochondrial toxicity for tenofovir. In the long term management of HIV infection, new antiretroviral agents that can be easily administered and are capable of providing sustained activity with little or no selection of drug resistance are needed to ensure durable viral suppression and to preserve future treatment options. Tenofovir DF will be a valuable new addition to current therapies and should provide benefit to both treatment naïve and treatment experienced patients.
|
