Dolutegravir

Oral
HIV-1 infection

Patient (without integrase inhibitor resistance) concomitantly taking carbamazepine, rifampicin, efavirenz, nevirapine, tipranavir/ritonavir, fosamprenavir/ritonavir, etravirine (without boosted protease inhibitors), oxcarbazepine, phenytoin, phenobarbital, St. John’s wort: In combination with other antiretroviral agents:
Adult: 50 mg bid.
Child: 6-<12 years 15-<20 kg: 20 mg bid; 20-<30 kg: 25 mg bid; 30-<40 kg: 35 mg bid; ≥40 kg: 50 mg bid. 12-<18 years ≥40 kg: 50 mg bid.

Pharmacogenomics:

Dolutegravir is mainly metabolised via glucuronidation by UGT1A1 enzyme and to a lesser extent by CYP3A enzyme component. UGT1A1 polymorphism may affect the pharmacokinetic response of dolutegravir in certain patients. Individuals with UGT1A1 genotypes that confer poor dolutegravir metabolism are known as poor metabolisers while those with UGT1A1 genotype that confer normal dolutegravir metabolism are known as normal metabolisers.

EMA and FDA-approved drug labels for dolutegravir cited that results from a meta-analysis using pharmacogenomics samples collected in healthy subjects in clinical studies indicate that UGT1A1 poor metabolisers had a 32% lower dolutegravir clearance and a 46% higher dolutegravir exposure as compared with UGT1A1 normal metabolisers. Studies in individuals with HIV infection having UGT1A1 gene polymorphism also showed significant increase in dolutegravir trough concentrations compared to patients with normal allele. However, there is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. Therefore, dosage adjustments are not necessary based on UGT1A1 polymorphisms.

Pharmacogenetic testing prior to initiating dolutegravir treatment has not been addressed by currently available references.

May be taken with or without food.

Hypersensitivity to dolutegravir. Lactation. Concomitant use with dofetilide.

Patient with hepatitis B or C co-infection; integrase inhibitor resistance Q148 mutation with ≥2 secondary mutations including, but not limited to G140A/C/S, E138A/K/T, or L74I; history of depression or psychiatric illness. Severe renal and hepatic impairment. Children. Pregnancy. UGT1A1 poor metabolisers. Avoid concomitant use with metabolic inducers such as etravirine (without boosted protease inhibitors), efavirenz, nevirapine, tipranavir/ritonavir, fosamprenavir/ritonavir, rifampicin, carbamazepine, and St. John’s wort in patient with integrase inhibitor resistance.

Significant: Hepatotoxicity (e.g. elevated serum liver biochemistry, hepatitis, acute liver failure), immune reconstitution syndrome including autoimmune disorders (e.g. Graves’ disease, polymyositis, Guillain-Barré syndrome), opportunistic infections, osteonecrosis. Rarely, neural tube defects (during early pregnancy).
Gastrointestinal disorders: Diarrhoea, nausea, vomiting, flatulence, abdominal pain and discomfort.
General disorders and administration site conditions: Fatigue.
Investigations: Increased creatine phosphokinase, serum lipase, total bilirubin.
Metabolism and nutrition disorders: Hyperglycaemia.
Nervous system disorders: Headache, dizziness.
Psychiatric disorders: Insomnia, anxiety, depression, abnormal dreams; suicidal ideation or attempt.
Skin and subcutaneous tissue disorders: Rash, pruritus.
Potentially Fatal: Hypersensitivity reactions (e.g. rash, organ dysfunction including liver injury, constitutional findings).

PO: B

This drug may cause dizziness, if affected, do not drive or operate machinery. Women of childbearing potential (WOCBP) must use effective contraception throughout treatment.

Perform pregnancy testing in WOCBP prior to initiation of treatment. Assess the risks and benefits of continuing dolutegravir versus switching to another antiretroviral and consider switching to an alternative regimen for WOCBP seeking to become pregnant or with confirmed pregnancy (within the 1st trimester) during treatment. Monitor viral load, CD4 count, lipid profile; LFTs at baseline and periodically during treatment; signs and symptoms of hypersensitivity.

Decreased plasma concentrations with etravirine (without boosted protease inhibitors), efavirenz, nevirapine, tipranavir/ritonavir, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, rifampicin. Increased plasma levels of metformin and fampridine. May reduce the absorption of dolutegravir with concomitant use of Mg- or Al-containing antacids, Fe or Ca supplements, including multivitamins; sucralfate. Elevated plasma concentrations with atazanavir.
Potentially Fatal: May increase the plasma concentration of dofetilide thus increasing the risk of serious adverse effects.

Slowed rate and increased extent of absorption with high-fat meals. May decrease plasma levels of dolutegravir with St. John’s wort.

Description:
Mechanism of Action: Dolutegravir is an inhibitor of HIV integrase that binds to integrase active site and blocks the strand transfer step of retroviral DNA integration, thereby preventing the HIV replication cycle.
Pharmacokinetics:
Absorption: Rapidly absorbed from the gastrointestinal tract. Slowed rate and increased extent of absorption with food, particularly high-fat meals. Time to peak plasma concentration: 2-3 hours.
Distribution: Present in male and female genital tract, and CSF. Crosses the placenta and enters breast milk. Volume of distribution: Approx 17.4 L. Plasma protein binding: ≥98.9%.
Metabolism: Metabolised in the liver via glucuronidation primarily by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), and to a lesser extent by CYP3A isoenzyme.
Excretion: Mainly via faeces (53% as unchanged drug); urine (31% as metabolites, <1% as unchanged drug). Elimination half-life: Approx 14 hours.

Source: National Center for Biotechnology Information. PubChem Database. Dolutegravir, CID=54726191, https://pubchem.ncbi.nlm.nih.gov/compound/Dolutegravir (accessed on Jan. 21, 2020)

Store between 15-30°C. Protect from moisture.

Antivirals

J05AJ03 - dolutegravir ; Belongs to the class of integrase inhibitors. Used as direct acting antiviral in the systemic treatment of viral infections.

Annotation of EMA Label for Dolutegravir and UGT1A1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 17/07/2019.

Annotation of FDA Label for Dolutegravir and UGT1A1. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 17/07/2019.

Anon. Dolutegravir. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 02/04/2020.

Anon. Dolutegravir. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 02/04/2020.

Buckingham R (ed). Dolutegravir. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 02/04/2020.

Dolutegravir and the Possible Risk of Neural Tube Defects When Taken Early in Pregnancy. Medsafe. http://www.medsafe.govt.nz/. Accessed 02/04/2020.

GlaxoSmithKline (NZ) Ltd. Tivicay 50 mg Film-Coated Tablets data sheet 29 October 2019. Medsafe. http://www.medsafe.govt.nz/. Accessed 02/04/2020.

Joint Formulary Committee. Dolutegravir. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 24/04/2020.

Juluca, Tivicay, Triumeq (Dolutegravir): FDA to Evaluate- Potential Risk of Neural Tube Birth Defects. U.S. FDA. https://www.fda.gov/. Accessed 12/07/2018.

Tivicay Film-Coated Tablets (GlaxoSmithKline Pharmaceutical Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my/. Accessed 02/04/2020.

Tivicay Film-Coated Tablets (ViiV Healthcare BV). European Medicines Agency [online]. Accessed 02/04/2020.

Tivicay Tablet, Film Coated (ViiV Healthcare Company). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 02/04/2020.