Durart R
Durart R Uses, Dosage, Side Effects, Food Interaction and all others data.
Darunavir is a protease inhibitor used with other HIV protease inhibitor drugs as well as ritonavir for the effective management of HIV-1 infection. As a second-generation protease inhibitor, darunavir is designed to combat resistance to standard HIV therapy. It was initially approved by the FDA in 2006.
Darunavir is being studied as a possible treatment for SARS-CoV-2, the coronavirus responsible for COVID-19, due to in vitro evidence supporting its ability to combat this infection. Clinical trials are underway and are expected to conclude in August 2020.
Darunavir is an inhibitor of the human immunodeficiency virus (HIV) protease, which prevents HIV viral replication. When administered with ritonavir in combination antiretroviral therapy, darunavir significantly decreases viral load and increases CD4 cell counts, decreasing the morbidity and mortality of HIV infection.
Ritonavir is an HIV protease inhibitor that interferes with the reproductive cycle of HIV. Although it was initially developed as an independent antiviral agent, it has been shown to possess advantageous properties in combination regimens with low-dose ritonavir and other protease inhibitors. It is now more commonly used as a booster of other protease inhibitors and is available in both liquid formulation and as capsules.
While ritonavir is not an active antiviral agent against hepatitis C virus (HCV) infection, it is added in combination therapies indicated for treatment of HCV infections as a booster. Ritonavir is a potent CYP3A inhibitor that increases peak and trough plasma drug concentrations of other protease inhibitors such as Paritaprevir and overall drug exposure. American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) guidelines recommend ritonavir-boosted combination therapies as a first-line therapy for HCV Genotype 1a/b and 4 treatment-naïve patients with or without cirrhosis.
Ritonavir is found in a fixed-dose combination product with Ombitasvir, Dasabuvir, and Paritaprevir as the FDA-approved product Viekira Pak. First approved in December 2014, Viekira Pak is indicated for the treatment of HCV genotype 1b without cirrhosis or with compensated cirrhosis, and when combined with Ribavirin for the treatment of HCV genotype 1a without cirrhosis or with compensated cirrhosis.
| Trade Name | Durart R |
| Generic | Darunavir + Ritonavir |
| Weight | 400mg |
| Type | Tablet |
| Therapeutic Class | |
| Manufacturer | Mylan Pharmaceuticals Pvt Ltd |
| Available Country | India |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Darunavir is a HIV protease inhibitor used in the treatment of human immunodeficiency virus (HIV) infection in patients with history of prior antiretroviral therapies.
Darunavir, co-administered with ritonavir, and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) in children age 3 or above and adults with HIV-1 infection.
Ritonavir is an HIV protease inhibitor used in combination with other antivirals in the treatment of HIV infection.
Indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Durart R is also used to associated treatment for these conditions: Human Immunodeficiency Virus Type 1 (HIV-1) InfectionHuman Immunodeficiency Virus (HIV) Infections
How Durart R works
The HIV-1 protease enzyme is necessary for viral precursor protein processing and viral maturation in preparation for infection, and is therefore a target for antiretroviral therapy for HIV. Protease inhibitors are used as a part of highly active antiretroviral therapy (HAART) in patients diagnosed with HIV infection. It has been shown to effectively suppress the virus, leading to significantly decreased morbidity and mortality rates.
Darunavir, a HIV protease inhibitor, prevents HIV replication through binding to the enzyme, stopping the dimerization and the catalytic activity of HIV-1 protease. In particular, it inhibits the cleavage of HIV encoded Gag-Pol proteins in cells that have been infected with the virus, halting the formation of mature virus particles, which spread the infection. The close contact that darunavir makes with the primary chains of the active site amino acids (Asp-29 and Asp-30) on the protease likely contributes to its potency and efficacy against resistant variants of HIV-1.
Darunavir is known to bind to different sites on the enzyme: the active site cavity and the surface of one of the flexible flaps in the protease dimer. Darunavir can adapt to changes in the shape of a protease enzyme due to its molecular flexibility.
Ritonavic inhibits the HIV viral proteinase enzyme that normally cleaves the structural and replicative proteins that arise from major HIV genes, such as gag and pol. Gag encodes proteins involved in the core and the nucleocapsid, while pol encodes the the HIV reverse transcriptase, ribonuclease H, integrase, and protease . The pol-encoded proteins are initially translated in the form of a larger precursoe polypeptide, gag-pol, and needs to be cleaved by HIV protease to form other complement proteins . Ritonavir prevents the cleavage of the gag-pol polyprotein, which results in noninfectious, immature viral particles. Ritonavir is a potent inhibitor of cytochrome P450 CYP3A4 isoenzyme present both in the intestinal tract and liver . It is a type II ligand that perfectly fits into the CYP3A4 active site cavity and irreversibly binds to the heme iron via the thiazole nitrogen, which decreases the redox potential of the protein and precludes its reduction with the redox partner, cytochrome P450 reductase . Ritonavir may also play a role in limiting cellular transport and efflux of other protease inhibitors via the P-glycoprotein and MRP efflux channels .
Toxicity
LD50 information for darunavir is not readily available in the literature. One-time doses of up to 3,200 mg of darunavir in an oral solution and up to 1,600 mg of the tablet formulation of darunavir with ritonavir have been given volunteers without significant symptoms.
Information about an overdose with darunavir with ritonavir is limited. No specific antidote exists for this drug. Treatment of In the case of an overdose, employ general supportive measures. Monitor vital signs and clinical status. It is unlikely that darunavir not amenable to removal by dialysis due to its high level of protein binding.
Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose. The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice. Oral LD value in rats is >2500 mg/kg. Adverse effects of ritonavir may arise from drug-drug interactions. Other effects include hepatotoxicity, pancreatitis, and allergic reactions/hypersensitivity.
Volume of Distribution
The volume of distribution of darunavir in one pharmacokinetic study in conjunction with ritonavir was 206.5 L (with a range of 161.0–264.9) in healthy young adult volunteers. Another pharmacokinetic study revealed a volume of distribution of 220 L.
The estimated volume of distribution of ritonavir is 0.41 ± 0.25 L/kg.
Elimination Route
The absolute oral bioavailability of one single 600 mg dose of darunavir alone and with 100 mg of ritonavir twice a day was 37% and 82%, respectively. Exposure to darunavir in boosted patients has been found to be 11 times higher than in unboosted patients. Tmax is achieved approximately 2.4 to 4 hours after oral administration.
When darunavir is taken with food, the Cmax and AUC of darunavir given with ritonavir increase by 30% when compared to the fasted state.
The absolute bioavailability of ritonavir has not been determined. Following oral administration, peak concentrations are reached after approximately 2 hours and 4 hours (Tmax) after dosing under fasting and non-fasting conditions, respectively. It should be noted that ritonavir capsules and tablets are not considered bioequivalent.
Half Life
The terminal elimination half-life of darunavir is approximately 15 hours when it is combined with ritonavir.
The approximate half-life of ritonavir is 3-5 hours.
Clearance
Darunavir has a low renal clearance. After intravenous administration, the clearance darunavir administered alone and with 100 mg ritonavir twice daily, was 32.8 L/h and 5.9 L/h, respectively.
The apparent oral clearance at steady-state is 8.8 ± 3.2 L/h. Renal clearance is minimal and estimated to be 7
Elimination Route
A mass balance study in healthy volunteers demonstrated that after single dose administration of 400 mg 14C-darunavir, given with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of radiolabeled darunavir was obtained in the feces and urine, respectively. Excretion of unchanged drug accounted for 8.0% of the darunavir dose in volunteers who were unboosted.
In boosted darunavir administration, unchanged darunavir made up 48.8% of the excreted dose in boosted subjects due to inhibition of darunavir metabolism by ritonavir. Unchanged drug in the urine made up 1.2% of the administered dose in volunteers who where unboosted, and 7.7% in boosted volunteers.
Ritonavir is primarily eliminated in the feces. Following oral administration of a single 600mg dose of radiolabeled ritonavir, approximately 11.3 ± 2.8% of the dose was excreted into the urine, of which 3.5 ± 1.8% was unchanged parent drug. The same study found that 86.4 ± 2.9% of the dose was excreted in the feces, of which 33.8 ± 10.8% was unchanged parent drug.
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