IC50: 2.7 nM (HIV-1 integrase)[1]

Dolutegravir (S/GSK1349572) has an EC50 of 0.51 nM against HIV-1 in PBMCs, 0.71 nM in MT-4 cells, and 2.2 nM in the pseudotyped self-inactivating virus (PHIV) assay. Dolutegravir's 50% cytotoxic concentrations (CC50) in proliferating IM-9, U-937, MT-4, and Molt-4 cells are, in order, 4.8, 7.0, 14, and 15 μM. The CC50 values in unstimulated and stimulated PBMCs are 189 μM and 52 μM, in that order. Dolutegravir's 0.51 nM EC50 against HIV-1 in PBMCs indicates that a cell-based therapeutic index of at least 9,400 is required[1].

In rats (0.23 mL/min/kg) and monkeys (2.12 mL/min/kg), the plasma clearance after a single intravenous (IV) dose of dolutegravir is low. Both the rat and monkey have half-lives of roughly six hours, and their steady-state volume of distribution (VSS) is small. When given orally as a solution to one male monkey and five fast-fasting rats, dolutegravir is highly bioavailable and quickly absorbed (75.6 and 87.0%, respectively). After oral administration of a suspension to non-fasted rats up to 250 mg/kg and non-fasted monkeys up to 50 mg/kg, dolutegravir exposure (Cmax and AUC) increased with increasing dose, albeit the increase is less than proportional[2].

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Dolutegravir is detectable in maternal milk in low amounts. It appears that elimination by newborn infants is prolonged and the drug has been detected in infant plasma during breastfeeding. Dolutegravir has been used safely in HIV-positive mothers during breastfeeding and is recommended as a first-line drug during breastfeeding. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
An HIV-positive mother took a combination tablet containing dolutegravir 50 mg, abacavir sulfate 600 mg and lamivudine 300 mg (Triumeq) once daily. Her infant was exclusively breastfed for about 30 weeks and partially breastfed for about 20 weeks more. No obvious side effects were noted.
In a study of African women with HIV infection received a dolutegravir-based regimen of 50 mg dolutegravir, 300 mg tenofovir disoproxil fumarate, and either 200 mg emtricitabine in South Africa or 300 mg lamivudine in Uganda during pregnancy and breastfeeding. This regimen was as safe for breastfed as an efavirenz-based regimen with the same other drugs.
An open-label, controlled, multicenter phase 3 trial women who were confirmed HIV-positive were randomized to receive one of 3 regimens: dolutegravir, emtricitabine, and tenofovir alafenamide (n = 208); dolutegravir, emtricitabine, and tenofovir disoproxil fumarate (n = 202); or efavirenz, emtricitabine, and tenofovir disoproxil fumarate (n = 207). The regimens were started at 14 to 28 weeks of pregnancy and continued postpartum. Of the 617 liveborn infants, 99% were breastfeeding at time of last infant HIV test, which was as late as 50 weeks of age. The mean infant duration on the study was 47.6 weeks of age. Infants who had any clinical or laboratory adverse event of grade 3 or higher ranged from 25 to 31%, but was not statistically significant between groups. Dolutegravir-containing regimens resulted in lower rates of virological failure, HIV drug resistance, and infant mortality up to 50 weeks postpartum compared with efavirenz, emtricitabine, and tenofovir disoproxil fumarate.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011 Feb;55(2):813-21.

[2]. The comparative disposition and metabolism of dolutegravir, a potent HIV-1 integrase inhibitor, in mice, rats, and monkeys. Xenobiotica. 2015 Jan;45(1):60-70.

[3]. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol Pharmacol. 2011 Oct;80(4):565-72.

Dolutegravir sodium is an organic sodium salt that is the monosodium salt of dolutegravir. Used for treatment of HIV-1. It has a role as a HIV-1 integrase inhibitor. It contains a dolutegravir(1-).
Dolutegravir (brand names: Tivicay and Tivicay PD) is a prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection in combination with:
Other HIV medicines in adults;
Other HIV medicines in children at least 4 weeks of age and older who weigh at least 6.6 lb (3 kg) and who meet specific requirements, as determined by a health care provider; or
Rilpivirine (brand name: Edurant) in adults to replace their current HIV medicines when their health care provider determines that they meet certain requirements.
Dolutegravir is always used in combination with other HIV medicines.
Dolutegravir Sodium is the sodium salt form of dolutegravir, an orally bioavailable integrase strand-transfer inhibitor (INSTI), with activity against human immunodeficiency virus type 1 (HIV-1) infection. Upon oral administration, dolutegravir binds to the active site of integrase, an HIV enzyme that catalyzes the transfer of viral genetic material into human chromosomes. This prevents integrase from binding to retroviral deoxyribonucleic acid (DNA), and blocks the strand transfer step, which is essential for the HIV replication cycle. This prevents HIV-1 replication.
See also: Dolutegravir (has active moiety); Dolutegravir sodium; lamivudine (component of); Dolutegravir sodium; rilpivirine hydrochloride (component of).

---

Drug Indication
Tivicay is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults, adolescents and children of at least 6 years of age or older and weighing at least 14 kg. Tivicay is indicated in combination with other anti-retroviral medicinal products for the treatment of Human Immunodeficiency Virus (HIV) infected adults, adolescents and children of at least 4 weeks of age or older and weighing at least 3 kg.

C20H18F2N3NAO5

441.36

441.111

1051375-19-9

Dolutegravir;1051375-16-6

46216142

Off-white to yellow solid powder

2.303

1

8

3

31

836

2

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+]

UGWJRRXTMKRYNK-VSLILLSYSA-M

InChI=1S/C20H19F2N3O5.Na/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);/q;+1/p-1/t10-,15+;/m1./s1

sodium;(3S,7R)-13-[(2,4-difluorophenyl)methylcarbamoyl]-7-methyl-9,12-dioxo-4-oxa-1,8-diazatricyclo[8.4.0.03,8]tetradeca-10,13-dien-11-olate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 4.5 mg/mL (10.20 mM)
H2O : < 0.1 mg/mL

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)