Dolutegravir Sodium

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Cat Number

API1051375199

CAS Number

1051375-19-9

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CAS Number

1051375-19-9

EINECS

944-454-6

Storage

Store at room temperature

Synonyms

Dolutegravir sodium salt; 1Q1V9V5WYQ; GSK-1349572A; CHEBI:76007

Molecular Formula

C20H18F2N3NaO5

Molecular Weight

441.36

Smiles

C[C@@H]1CCO[C@@H]2N1C(=O)C3=C(C(=O)C(=CN3C2)C(=O)NCC4=C(C=C(C=C4)F)F)[O-].[Na+]

Appearance

Off-white to yellow powder

Melting Point

>300°C

Boiling Point

669.0±55.0°C at 760 mmHg (Predicted)

General Description

Dolutegravir sodium is a second‑generation integrase strand transfer inhibitor (INSTI) with a metal‑chelating carbamoyl pyridone core. The molecule contains a difluorobenzyl group and a fused tricyclic ring system that allows high affinity for the integrase‑DNA complex. The sodium salt improves aqueous solubility.

Mechanism of Action

Dolutegravir binds to the active site of HIV‑1 integrase, specifically coordinating two magnesium ions in the catalytic core. It prevents the strand transfer step of integration, in which viral DNA is covalently inserted into the host genome. The drug does not inhibit the earlier 3′‑processing step. The resultant unintegrated viral DNA cannot direct productive infection.

Application

Dolutegravir is indicated for the treatment of HIV‑1 infection in adults and children, both as an initial regimen and for treatment‑experienced patients with resistance to other integrase inhibitors. It is also used with rilpivirine for virologically suppressed patients. The drug has a favorable tolerability profile. It elevates serum creatinine via inhibition of renal tubular secretion, without affecting actual glomerular filtration.

Dolutegravir (DTG), a second‑generation integrase strand transfer inhibitor, has a high barrier to resistance and limited cross‑resistance with first‑generation agents. In treatment‑naïve patients, DTG 50 mg daily was superior to darunavir/ritonavir and non‑inferior (and superior in some analyses) to efavirenz. In INSTI‑naïve treatment‑experienced patients, DTG was superior to raltegravir. Twice‑daily DTG was more efficacious than daily dosing in patients with prior INSTI exposure. The Q148 mutation with ≥2 additional mutations reduces DTG potency. A long‑acting formulation (GSK1265744LA) is in development.

Fig. 1 INSTI pathways of HIV-1 resistance with associated dissociative t 1/2 and fold change in EC50 compared to wild-type virus. (Dow DE, Bartlett JA, 2014)

References

Dow DE, Bartlett JA. Dolutegravir, the Second-Generation of Integrase Strand Transfer Inhibitors (INSTIs) for the Treatment of HIV. Infect Dis Ther. 2014;3(2):83-102.

An 18‑carbon chain modified ester prodrug nanocrystal of dolutegravir (NM2DTG) was developed as an ultra‑long‑acting integrase strand transfer inhibitor. Following a single parenteral injection, the formulation slowly releases drug from tissue macrophage depots at the injection site and adjacent lymphoid tissues, maintaining significant plasma drug levels for up to one year. Prodrug hydrolysis depends on nanocrystal dissolution, depot volume, perfusion, and pH. This formulation could improve adherence, tolerability, and access for HIV‑1 treatment and prevention.

Fig. 2 DTG PK studies in Balb/cJ mice and Sprague Dawley rats. (Deodhar S, et al., 2022)

References

Deodhar S, et al. Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation. Nat Commun. 2022;13(1):3226.

Does Dolutegravir Sodium require protection from moisture during storage?

Yes, it is hygroscopic. Moisture absorption can lead to hydrate formation and potential degradation of the pyridine ring. Store in tightly sealed containers with desiccant.

What is the recommended storage temperature for Dolutegravir Sodium?

Store at controlled room temperature (15-25°C). Avoid excessive heat above 30°C, which accelerates oxidative degradation.

Is Dolutegravir Sodium stable in tablet formulations with standard excipients?

Yes, when formulated with moisture-protective packaging (e.g., HDPE bottles with desiccant).

How is the impurity dolutegravir N-oxide (an oxidative degradation product) monitored?

This degradation product is quantified using a stability-indicating HPLC method, ensuring it remains within ICH limits.