Dolutegravir
Dolutegravir Uses, Dosage, Side Effects, Food Interaction and all others data.
Dolutegravir is a HIV-1 intergrase inhibitor that blocks the strand transfer step of the integration of the viral genome into the host cell (INSTI). The effect of this drug has no homology in human host cells which gives it an excellent tolerability and minimal toxicity. Dolutegravir was developed by ViiV Healthcare and FDA approved on August 12, 2013. On November 21, 2017, dolutegravir, in combination with rilpivirine, was approved as part of the first complete treatment regimen with only two drugs for the treatment of adults with HIV-1 named Juluca.
HIV-1 infected subjects on dolutegravir monotherapy demonstrated rapid and dose-dependent reduction of antiviral activity with declines of HIV-1 RNA copies per ml. The antiviral response was maintained for 3 to 4 days after the last dose. The sustained response obtained in clinical trials indicates that dolutegravir has a tight binding and longer dissociative half-life providing it a high barrier to resistance.[A31343] The combination therapy (ripivirine and dolutegravir) presented the same viral suppression found in previous three-drug therapies without integrase strand transfer inhibitor mutations or rilpivirine resistance.[L1033]
| Trade Name | Dolutegravir |
| Availability | Prescription only |
| Generic | Dolutegravir |
| Dolutegravir Other Names | Dolutegravir |
| Related Drugs | Biktarvy, Truvada, tenofovir, ritonavir, Complera, Atripla, Stribild |
| Weight | 10mg, 25mg, 50mg, 5mg, 600mg + 50mg + 300mg |
| Type | Oral Tablet, Dispersible, Tablet |
| Formula | C20H19F2N3O5 |
| Weight | Average: 419.3788 Monoisotopic: 419.129277143 |
| Protein binding | Dolutegravir is highly protein bound to human plasma proteins reaching a percentage 98.9% of the administered dose. |
| Groups | Approved |
| Therapeutic Class | |
| Manufacturer | Sun Pharmaceutical Industries Limited, Hetero Labs Limited, Aurobindo Pharma Ltd, Mylan Laboratories Limited |
| Available Country | United States, India, Nigeria |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Dolutegravir is an antiviral agent used for the treatment of HIV-1 infections in combination with other antiretroviral agents.
Dolutegravir is indicated in combination with other antiretroviral agents for the treatment of patients with HIV-1 infection that comply with the characteristics of being adults or children aged 12 years and older and present at least a weight of 40 kg. The FDA combination therapy approval of dolutegravir and rilpivirine is indicated for adults with HIV-1 infections whose virus is currently suppressed (< 50 copies/ml) on a stable regimen for at least six months, without history of treatment failure and no known substitutions associated to resistance to any of the two components of the therapy.
Dolutegravir is also used to associated treatment for these conditions: Human Immunodeficiency Virus Type 1 (HIV-1) Infection
How Dolutegravir works
Dolutegravir is an HIV-1 antiviral agent. It inhibits HIV integrase by binding to the active site and blocking the strand transfer step of retroviral DNA integration in the host cell. The strand transfer step is essential in the HIV replication cycle and results in the inhibition of viral activity. Dolutegravir has a mean EC50 value of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells.
Toxicity
There was no significant increases in drug-related neoplasms or in genotoxic effects or in mating or fertility effects.
Food Interaction
- Avoid multivalent ions. Cations should be separated from dolutegravir administration by 2 hours before and 6 hours after cation administration. Cations can be administered with dolutegravir if given with food.
- Avoid St. John's Wort.
- Take with or without food. Food, particularly high-fat meals, may increase the AUC, Cmax, and Tmax of dolutegravir.
[Minor] Food increases the extent of absorption and slows the rate of absorption of dolutegravir.
When administered with a low-, moderate- or high-fat meal, dolutegravir peak plasma concentration (Cmax) increased by 46%, 52% and 67%, systemic exposure (AUC) increased by 33%, 41% and 66%, and time to reach Cmax (Tmax) increased from 2 hours to 3, 4 and 5 hours, respectively, compared to administration under fasted conditions.
Dolutegravir may be taken with or without food.
Dolutegravir multivitamins interaction
[Major] ADJUST DOSING INTERVAL: Coadministration with medications containing polyvalent cations such as aluminum, calcium, iron, or magnesium may decrease the oral bioavailability of dolutegravir.
The mechanism of interaction has not been established.
In 16 study subjects, administration of a single 50 mg dose of dolutegravir simultaneously with an antacid (Maalox) decreased dolutegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin; 24 hours post-dose) by 72%, 74% and 74%, respectively, compared to administration without the antacid.
When the antacid was administered 2 hours after dolutegravir, the Cmax, AUC and Cmin of dolutegravir decreased by just 18%, 26% and 30%, respectively.
Administration of single-dose dolutegravir simultaneously with a multivitamin (One-A-Day) decreased the Cmax, AUC and Cmin of dolutegravir by 35%, 33% and 32%, respectively.
Dolutegravir should be administered 2 hours before or 6 hours after medications containing polyvalent cations such as antacids, laxatives, or mineral supplements.
Dolutegravir Drug Interaction
Minor: diltiazem, ritonavirUnknown: testosterone, lorazepam, bictegravir / emtricitabine / tenofovir alafenamide, ubiquinone, sulfamethoxazole / trimethoprim, emtricitabine / tenofovir alafenamide, glucose, lithium, pregabalin, metoprolol, metoprolol, acetaminophen, abacavir / dolutegravir / lamivudine, emtricitabine / tenofovir, sildenafil, cyanocobalamin, ascorbic acid, cholecalciferol
Dolutegravir Disease Interaction
Volume of Distribution
The administration of a dose of 50 mg of dolutegravir presents an apparent volume of distribution of 17.4 L. The median dolutegravir concentration in CSF was 18 ng/mL after 2 weeks of treatment.
Elimination Route
When 50 mg of dolutegravir once daily was orally administered to HIV-1 infected adults, the AUC, Cmax, and Cmin is 53.6 mcg h/mL, 3.67 mcg/mL, and 1.11 mcg/mL, respectively. The peak plasma concentration was observed 2 to 3 hours post-dose. Steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24h ranging from 1.2 to 1.5. When 50 mg once daily is given to pediatric patients (12 to < 18 years and weighing ≥40 kg) the Cmax, AUC, and C24 is 3.49 mcg/mL, 46 mcg.h/mL, and 0.90 mcg/mL respectively.
Half Life
The half-life of dolutegravir is 14 hours.
Clearance
The apparent clearance rate of dultegravir is 1.0 L/h.
Elimination Route
When a single oral dose of dolutegravir is given, nearly all complete dose is recovered in a proportion of 53% excreted unchanged in the feces and 31% excreted in urine. The renal eliminated recovered dose consists of ether glucuronide of dolutegravir (18.9%), a metabolite formed by oxidation at the benzylic carbon (3.0%), a hydrolytic N-dealkylation product (3.6%) and unchanged drug (< 1%).
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