Dolutegravir | HIV-1 Integrase Strand Transfer Inhibitor I Treatment for HIV-1 | INSTI Inhibitor | Antiretroviral Agents

Dolutegravir [(4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide] is an orally available HIV-1 integrase strand transfer inhibitor (INSTI) developed as an unboosted once-daily therapy for use in combination with other antiretroviral agents. It is meant for the treatment of both treatment-naive and treatment-experienced patients with HIV-1 infection.

Like other drugs belonging in the INSTI class of antiretroviral agents, dolutegravir binds to the integrase site of HIV-1 and blocks the strand transfer integration step, thereby preventing the replication of HIV-1. The drug has advantages over prior INSTIs in that it can be given once daily without boosting and can overcome some prior INSTI failures [1].

Dolutegravir: 2D and 3D Structure

Integrase Strand Inhibitors (INSTIs) for HIV-1 Treatment

HIV-1 integrase (IN) is a virally encoded enzyme that catalyzes two biochemical reactions and is essential for replication. First, it catalyzes the removal of the terminal two nucleotides on the respective 3' ends of the viral DNA (termed 3' processing). Second, IN facilitates the nicking of host chromosomal DNA by the newly exposed 3' hydroxyl moieties, resulting in strand transfer of the viral dsDNA.

Antiretroviral regimens currently recommended for adults and adolescents with HIV-1 infection include two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in combination with a nonnucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI) or an INSTI.

The integrase strand inhibitors (INSTIs) are a relatively new class of antiretroviral drugs used in the treatment of HIV-1 infection. Drugs in this class block the strand transfer step of DNA integration of the HIV genome in the infected host cell, thereby preventing viral replication.

Two currently marketed INSTIs are Raltegravir (approved 2007) and Elvitegravir (approved 2012).  Raltegravir (RAL) was approved by the Food and Drug Administration (FDA) after studies showed it to be efficacious in both ART naive and experienced participants when dosed 400 mg twice daily.  The next INSTI, Elvitegravir (EVG), was approved in 2012 as part of a fixed-dose daily tablet containing tenofovir (TDF), emtricitabine (FTC), and the cytochrome P450 isoenzyme 3A (CYP3A) inhibitor cobicistat.  However, EVG is not manufactured as a stand-alone agent and requires pharmacologic boosting to be given once daily.  In addition, significant cross-resistance between RAL and EVG prevents sequential therapy with these two drugs. Certain mutations, such as Q148H/R, N155H and Y143R confer cross-resistance between Raltegravir and Elvitegravir, and further necessitate the development of second generation INSTIs.

Limitations relating to the use of both of these first-generation INSTIs have led to the development of Dolutegravir, a new-generation INSTI, administered once-daily, with a high genetic barrier to resistance. Dolutegravir fits loosely into the intasome binding pocket and retains its binding ability despite conformational changes in the pocket structure. The ability to readjust its binding position is believed to enhance the genetic barrier to ARV resistance, consequently classifying Dolutegravir as a second-generation INSTI.

Dolutegravir as INSTI Inhibitor:

Dolutegravir is a potent in vitro inhibitor of HIV integrase. It inhibits the integrase catalyzed viral DNA strand transfer with IC₅₀ values in the nanomolar range (1.7 nM) [2].

Dolutegravir is active against various HIV-1 clinical isolates (group M (clade A, B, C, D, E, F and G) and group O) and HIV-2 clinical isolates, with IC₅₀ values in the low nanomolar range (0.14 and 0.29 nM for HIV-2) [3, 4].

Dolutegravir showed anti-HIV activity similar to that seen against wild-type HIV-1 virus against 219 of 220 HIV integrase mutants containing single mutations and 189 of 211 mutants containing 2 or more mutations.

Using crystal structures of wild-type and mutant prototype foamy virus intasomes, an integrase tetramer assembled on a pair of viral DNA ends have shown that Dolutegravir enter farther into the pocket vacated by the displaced DNA base and thus makes contacts more intimate with viral DNA compared with those made by Raltegravir and Elvitegravir, suggesting that Dolutegravir has the ability to readjust its position and conformation in response to structural changes in the active sites of Raltegravir-resistant INIs [5].

Dolutegravir exhibits in vitro a potentially higher genetic barrier to resistance. In the passage of wild-type HIV-1 in the presence of Dolutegravir for up to 112 days, a maximum of 4.1-fold resistance and no highly resistant mutants were observed [6].

Dosages and Approvals:

Dolutegravir (Tradename: Tivicay) received its first approval on 12^th of August 2013 for the treatment of HIV-1 infection in the USA. It is approved as an oral pill taken daily in combination with other antiretroviral drugs. Tivicay is approved for use in a broad population of HIV-infected patients. It can be used to treat HIV-infected adults who have never taken HIV therapy (treatment-naive) and HIV-infected adults who have previously taken HIV therapy (treatment-experienced), including those who have been treated with other integrase strand transfer inhibitors. Tivicay is also approved for children ages 12 years and older weighing at least 40 kilograms (kg) who are treatment-naive or treatment-experienced but have not previously taken other integrase strand transfer inhibitors.

On November 4, 2013, Dolutegravir was approved by Health Canada. On January 16, 2014, Tivicay was approved by the European Commission for use throughout the European Union.

The approved dosage of Dolutegravir for treatment naive and treatment experienced patients is 50 mg daily. In cases when co-administered with certain UGT1A or CYP3A inducers or clinically suspected INSTI resistance the dosage should be 50 mg two times in a day. Same principal applies for pediatric patients also.

An analysis of the relationship between Dolutegravir and food intake concluded that there were no clinically significant correlations between the two and there was no change in Dolutegravir concentrations with or without a meal.

Summary

Common name: 572; 1349572; ‘572; GSK-1349572; GSK1349572; S-349572; S/GSK 1349572; S/GSK1349572; DGT

Trademarks: Tivicay

Molecular Formula: C20H19F2N3O5

CAS Registry Number: 1051375-16-6

CAS Name: (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide

Molecular Weight: 419.38

SMILES:C[C@@H]1CCO[C@@H]2N1C(=O)c3c(c(=O)c(cn3C2)C(=O)NCc4ccc(cc4F)F)O

InChI Key: RHWKPHLQXYSBKR-BMIGLBTASA-N

InChI: InChI=1S/C20H19F2N3O5/c1-10-4-5-30-15-9-24-8-13(17(26)18(27)16(24)20(29)25(10)15)19(28)23-7-11-2-3-12(21)6-14(11)22/h2-3,6,8,10,15,27H,4-5,7,9H2,1H3,(H,23,28)/t10-,15+/m1/s1

Mechanism of Action: HIV-1 Integrase Strand Transfer Inhibitor

Activity: Treatment of HIV-1; Antivirals

Status: Launched 2013 (US, Canada); 2014 (EU)

Chemical Class:  Small-molecules; 3-ring heterocyclics; Flourine containing; Hydroxyl containing; Amide linkage

Originator: ViiV Healthcare/GlaxoSmithKline

Dolutegravir Synthesis

Identifications:

1H NMR (Estimated) for Dolutegravir

Experimental: ¹H NMR (CDCl₃) δ  12.45 (s, 1H), 10.38 (br s, 1H), 8.30 (s, 1H), 7.40-7.30 (m, 1H), 6.85-6.75 (m, 2H), 5.26 (d, J = 5.8, 4.1 Hz, 2H), 5.05-4.95 (m, 1H), 4.64 (d, J = 5.9 Hz, 2H), 4.27 (dd, J = 13.4, 4.2 Hz, 1H), 4.12 (dd, J = 13.6, 6.0 Hz, 1H), 4.05 (t, J = 2.3 Hz, 1H), 4.02 (d, J = 2.2 Hz, 1H), 2.30-2.19 (m, 1H), 1.56 (dd, J = 14.0, 2.0 Hz, 1H), 1.42 (d, J = 7.0 Hz, 3H).

Sideeffects:

The most common adverse reactions (AEs) of moderate to severe intensity of treatment were insomnia and headache in treatment naive patients (including INSTI treatment naive). Less common adverse events included nausea and diarrhea (less than 1%).

The most commonly reported adverse events for treatment-experienced recipients of Dolutegravir or Raltegravir included diarrhoea (20 and 18 %, respectively) and upper respiratory tract infections (11 and 8 %).

In treatment-naive patients, cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels (fasted values) increased during 48 weeks of treatment with 2 NRTIs plus Dolutegravir or Raltegravir in the SPRING-2 trial. Hypersensitivity reactions have been reported in recipients of Dolutegravir and were characterized by rash, and constitutional findings, and sometimes organ dysfunction, including liver injury. Elevated ALT and/or AST levels were reported less than 3 % of patients treated with Dolutegravir [1].

References:

1. Ballantyne, A. D.; et. al. Dolutegravir: first global approval. Drugs 2013, 73(14), 1627-1637.

2. Johns, B. A.; et. al. Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744). J Med Chem 2013, 56(14), 5901-5916.

3. Katlama, C.; et. al. Dolutegravir for the treatment of HIV. Expert Opin Investig Drugs 2012, 21(4), 523-530.

4. Underwood, M.; et. al. S/GSK1265744: a next generation integrase inhibitor (INI) with activity against raltegravir-resistant clinical isolates. XVIII International AIDS Conference; 18-23 July 2010; Vienna, Austria.

5. Hare, S.; et. al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol 2011, 80(4), 565-572.

6. Kobayashi, M.; et. al. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother 2011, 55(2), 813-821.