Darunavir

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.

Darunavir is also used to associated treatment for these conditions: Human Immunodeficiency Virus Type 1 (HIV-1) Infection

How Darunavir 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.

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.

Food Interaction

• Take with food. Food increases absorption.

[Moderate] ADJUST DOSING INTERVAL: Food enhances the absorption and oral bioavailability of darunavir administered in combination with low-dose ritonavir.

The mechanism is unknown.

When administered with food, the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of darunavir were approximately 30% higher than when administered in the fasting state.

Darunavir exposure was similar for the range of meals studied.

The total caloric content of the various meals evaluated ranged from 240 Kcal (12 grams fat) to 928 Kcal (56 grams fat).

MANAGEMENT: To ensure maximal oral absorption, darunavir coadministered with ritonavir should be taken with food.

The type of food is not important.

Darunavir Drug Interaction

Moderate: emtricitabine / tenofovir, emtricitabine / tenofovirMinor: etravirine, etravirineUnknown: amoxicillin / clavulanate, amoxicillin / clavulanate, diphenhydramine, diphenhydramine, glucose, glucose, raltegravir, raltegravir, metoprolol, metoprolol, ritonavir, ritonavir, acetaminophen, acetaminophen, cholecalciferol, cholecalciferol

Darunavir Disease Interaction

Major: hepatotoxicity, hemophiliaModerate: hyperglycemia

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.

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.

Half Life

The terminal elimination half-life of darunavir is approximately 15 hours when it is combined with ritonavir.

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.

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.

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