Phosphazide

Phosphazide (the trade name of the drug is Nikavir ^® ) is the original Russian anti-HIV drug that underwent the full scope of preclinical and clinical trials and was registered in the Russian Federation in 1999 ^[1] . During the application, the drug has established itself as an effective antiviral well-tolerated agent. The drug was awarded the State Prize of the Russian Federation in the field of science and technology for the 2000th year .

Drug Research

Pre-registration tests of phosphazide were carried out in 1997–1999. as a multicenter clinical trial coordinated by the Federal Scientific and Methodological Center for the Prevention and Control of AIDS. The Republican Clinical Infectious Disease Hospital (Leningrad Region), the Tver, Nizhny Novgorod and Tyumen Regional Centers for the Prevention and Control of AIDS and Infectious Diseases participated in the test as local centers.

• At the first stage of the study, phosphazide was used as monotherapy. The study included 103 patients (75 men and 28 women, average age 26 years). In accordance with the Russian clinical classification of HIV infection (Pokrovsky V.I., 1989), stages 2B or 2B were diagnosed in 69.9% of patients, STD in 23.3%, ST and 3B in 6.8%. The duration of therapy was 12 weeks. Patients received from 0.4 to 1.2 g of phosphazide per day. The effectiveness of treatment was evaluated according to clinical criteria - the progression of the disease or its absence; immunological - a change in the number of CD4 lymphocytes in 1 μl of blood; virological - a change in the level of HIV RNA in 1 ml of plasma. In the course of therapy, no patient showed progression of HIV infection. In all cases, an increase in platelet count and the disappearance of signs of toxicity were noted during treatment. During the study, there were no significant changes in the parameters of the biochemical analysis of blood. The study showed good efficacy and tolerability of phosphazide monotherapy and made it possible to recommend a dosage regimen of 0.4 g 2 times a day.
• At the next stage of the study, the possibility of replacing zidovudine with phosphazide was studied, due to the development of adverse events of the 2nd – 4th degree of toxicity. No patients observed the development of serious adverse events when taking phosphazide, and in no case was treatment discontinued. In addition, 36–48 weeks after replacing zidovudine with phosphazide, an increase in the number of CD4 lymphocytes by 70–100 cells / μl was detected.

Clinical application

In 1999, the clinical use of phosphazide was approved for chemotherapy of patients with HIV infection in the Russian Federation.

• The inclusion of phosphazide in HAART regimens allowed us to evaluate the efficacy and safety of the drug as part of combination antiretroviral therapy. The first study of a regimen that included phosphazide, and conducted in accordance with the rules of “good clinical practice” (GCP), was a combination of three HIV reverse transcriptase inhibitors. The aim of the study was to evaluate the safety and efficacy of a combination therapy regimen consisting of two nucleoside reverse transcriptase inhibitors (phosphazide and didanosine) and a non-nucleoside reverse transcriptase inhibitor (nevirapine) in patients with HIV infection who had not previously received antiretroviral therapy. Tolerance to combination antiretroviral therapy, including phosphazide, didanosine and nevirapine, was satisfactory.
• During 2001-2002 employees of the Federal Scientific-Methodological and Moscow Regional Centers for AIDS Prevention and Control conducted a study aimed at evaluating the effectiveness and safety of HAART, which included two nucleoside reverse transcriptase inhibitors (phosphazide and didanosine) and an enhanced protease inhibitor (saquinavir + ritonavir), HIV-infected patients who have not previously received antiretroviral therapy. Phosphazide combination therapy was safe. Most of the adverse events were from the gastrointestinal tract, had a mild severity and a transient character.
• In 2008-2009 On the basis of the Perm Regional Center for the Prevention and Control of AIDS and Infectious Diseases, the clinical efficacy of HAART using phosphazide was studied. The evaluation of the effectiveness of HAART regimens was evaluated by immunological parameters - the number of CD4 cells in 1 μl of blood, as well as by reducing the level of viral load before treatment and after 4, 12, 24, 36 and 48 weeks from its start. All patients were monitored by clinicians. HAART success assessment was determined by clinical, immunological and virological criteria. The results obtained in regimens including phosphazide showed higher efficacy in case of anemia, hepatitis, cirrhosis of the liver, tuberculosis, as well as in cases where a prompt virologic response is required.
• The safety of phosphazide is evidenced by the results obtained by employees of the Research Institute of Virology. DI. Ivanovsky, when studying the action of this drug in patients with acute viral hepatitis B. The phosphazide therapy of patients with acute hepatitis B provided a favorable clinical course of the disease and was accompanied by a significant reduction in the period of the icteric period, significantly faster rates of decrease in the activity of serum enzymes (AsAt, AlAt, alkaline phosphatase, GGTP) and earlier elimination of serum markers of acute hepatitis B (HBeAg, HBsAg, HBV DNA).
• One of the significant advantages of phosphazide is the safety of its use in patients with liver diseases of viral etiology, since most HIV-infected patients also suffer from chronic hepatitis B or C. On the basis of the Krasnoyarsk regional center for the prevention and control of AIDS, a study was conducted of the effectiveness and safety of HAART regimens including phosphazide. There, the frequency of hematological disorders was later evaluated and the possibility of obtaining a quick and early virological response (BVI and PRVO, respectively) to the treatment of chronic viral hepatitis C in patients with HIV infection receiving antiretroviral therapy (ART) was shown. Clinical studies have allowed us to expand the scope of phosphazide, and it is currently indicated for the treatment of viral hepatitis B in patients with mild and moderate (icteric) forms.
• On the basis of the St. Petersburg Center for the Prevention and Control of AIDS and Infectious Diseases and the specialized department for the treatment of tuberculosis in HIV-infected patients of the City Tuberculosis Hospital No. 2 of St. Petersburg, data were obtained on the use of phosphazide in patients with HIV infection and tuberculosis.

The active substance phosphazide belongs to the class of reverse transcriptase inhibitors (revertases) of retroviruses, being a modified analogue of the natural nucleoside thymidine. The competitive inhibitory activity of azidothymidine triphosphate with respect to HIV reverse transcriptase is approximately 100 times greater than that for human DNA polymerase, thus phosphazide does not affect the normal metabolism of the human body. Low toxicity and good tolerance of phosphazide makes it possible to use it in various HAART regimens ^[2] , in the treatment of HIV infection ^{[3] [4]} , in combination with the treatment of chronic viral hepatitis C ^[5] and tuberculosis ^[6] , to prevent transmission Mother-to-Child HIV Infection ^[7]

The drug phosphazide - Nikavir ^® (tablets 200 mg and 400 mg) is included in the list of vital and most important drugs, approved by order of the Government of the Russian Federation dated 07.12.2011 No. 2199-r.

Pharmacodynamics

Phosphazide, having penetrated into an infected cell, is phosphorylated twice to an active metabolite - azidothymidine triphosphate, which is inserted instead of thymidine triphosphate into the proviral DNA strand synthesized by revertase, which leads to inhibition of revertase, termination of the DNA strand and termination of the reproduction of viral particles. The therapeutic effect is based on this mechanism. drug to reduce the concentration of HIV in the patient’s blood.

The drug also inhibits the replication of some other mammalian viruses, for example, hepatitis B.

Pharmacokinetics

Phosphazide is well absorbed from the gastrointestinal tract. Full absorption time is 3-3.5 hours; elimination half-life - 3-4 hours; the maximum concentration of phosphazide in blood plasma - 19-22 μg / ml is achieved after 4-5 hours.

Oral bioavailability is 20%. The relative bioavailability of phosphazide is 83.7%. Phosphazide crosses the blood-brain barrier and is found in cerebrospinal fluid at a concentration of 15-64% of the initial dose. The active substance penetrates the placenta well, as a result of which its concentration in the blood of the umbilical cord is comparable to that in the mother's blood. Phosphazide metabolism occurs in the liver with the formation of glucuronide, which is excreted by the kidneys in the urine.

Indications for use

Adult HIV treatment in combination with other antiretroviral drugs.

Emergency HIV prevention in case of risk of infection through injections, cuts, contact with mucous membranes and skin damage. Treatment of acute hepatitis B in mild and moderate form (icteric period).

Contraindications

Hypersensitivity to phosphazide or to any of the excipients of the drug. Children under 18 years old.

Caution

Severe nausea, vomiting, anemia (hemoglobin concentration below 50 g / l), increased transaminase activity (more than 5 times relative to the upper limit of normal), hypercreatininemia, neuropenia, thrombocytopenia.

Pregnancy and lactation

HIV-infected pregnant women are not recommended to take the drug before the 14th week of pregnancy; if it is necessary to use the drug during lactation, it is necessary to decide on the termination of breastfeeding.

Dosage and administration

Take orally. The daily dose for HIV infection is 800-1200 mg in 2 or 3 doses. It is recommended to take the drug before meals and drink it with a glass of water. The drug is prescribed for a long, almost unlimited period. If necessary, the course can be interrupted, but its duration should be at least 12 weeks with a break between courses - no more than 12 weeks.

To prevent infection with the human immunodeficiency virus, it is recommended as soon as possible, but no later than 72 hours after a possible infection, to start taking 400 mg 3 times a day for 4 weeks.

In acute hepatitis, the drug is prescribed 400 mg 2 times a day for 20 days.

Side effect

In the first days of taking the drug - nausea, headache, heaviness in the epigastrium, diarrhea. From the hemopoietic organs: anemia, granulocytopenia.

Interaction with other drugs

The combined use of phosphazide with zidovudine, stavudine leads to a mutual decrease in activity against HIV.

The combined use with interferon alpha, didanosine, lamivudine, foscarnet leads to a mutual increase in activity against HIV.

The combined use with doxorubicin, interferon alfa, amphotericin-B, co-trimoxazole, vinblastine, vincristine, ganciclovinorm, dapsone, sulfadiazine and other sulfonamides can lead to a mutual enhancement of myelotoxicity, therefore additional control over the concentration of hemoglobin and granulocytes is required.

Special instructions

If some adverse events occur in the early stages of administration, it should not be canceled, it is recommended to continue therapy under the supervision of a doctor.

Violation of the drug treatment regimen can lead to the development of resistance of the retrovirus to it, which will entail a decrease in the effectiveness of the therapy and the need to replace the drug.

Therapy with the drug does not reduce the risk of transmitting HIV to other people through sexual contact or blood transfusion.

Phosphazide toxicity

Phosphazide is a low toxic substance. Its toxicity is 5-6 times lower than the toxicity of zidovudine . When assessing the tolerability of the drug, it should be borne in mind that these side effects and other symptoms and syndromes can be manifestations not only of therapy, but also of HIV infection itself and associated diseases.

Release Form

200 mg and 400 mg tablets.

Phosphazide Medications

• Antiretroviral Therapy Online
• Highly Active Antiretroviral Therapy