Dolutegravir

Usage

Dolutegravir is an antiretroviral medication, specifically an integrase strand transfer inhibitor (INSTI), prescribed in combination with other antiretroviral therapies (ART) for the treatment of HIV-1 infection in adults and children. It is used both in treatment-naive individuals and those with prior treatment experience. It is also used as part of a two-drug regimen with rilpivirine or lamivudine in specific patient populations.

Alternate Names

Dolutegravir sodium is the chemical name. Brand names for dolutegravir include Tivicay and Tivicay PD. Dolutegravir is also available as a component in fixed-dose combination tablets including Dovato (with lamivudine), Juluca (with rilpivirine), and Triumeq (with abacavir and lamivudine).

How It Works

Pharmacodynamics: Dolutegravir inhibits HIV integrase, an enzyme essential for viral replication. By blocking this enzyme, dolutegravir prevents the integration of viral DNA into the host cell’s DNA, thereby disrupting the viral life cycle.

Pharmacokinetics:

• Absorption: Dolutegravir is readily absorbed orally, with or without food (although some sources recommend against high-fat meals.) Tivicay and Tivicay PD are not interchangeable.
• Metabolism: Primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1, with minor contributions from CYP3A4.
• Elimination: Primarily through feces, with some renal excretion.

Mode of Action: Dolutegravir binds to the integrase active site and blocks the strand transfer step of viral DNA integration, which is essential for HIV replication. Specifically, it acts as an allosteric integrase inhibitor (INSTI), binding to the integrase enzyme and preventing it from acting on viral DNA. This prevents incorporation into host DNA, resulting in the inhibition of viral replication and decrease in viral load.

Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Dolutegravir’s primary mechanism is enzyme inhibition of HIV-1 integrase.

Elimination Pathways: Primarily hepatic metabolism via UGT1A1 glucuronidation, with some CYP3A contribution, followed by fecal excretion; some renal excretion.

Dosage

Standard Dosage

Adults:

• Treatment-naive or INSTI-naive: 50 mg orally once daily.
• INSTI-experienced with certain INSTI-associated resistance substitutions: 50 mg orally twice daily.
• With rilpivirine (Juluca) in virologically suppressed patients: 50 mg orally once daily.
• With lamivudine (Dovato) in treatment-naive or virologically suppressed patients: 50 mg dolutegravir/300 mg lamivudine once daily.

Children (Tivicay or Tivicay PD): Dose is based on body weight:

• ≥ 40 kg: 50 mg orally once daily
• 30 kg to < 40 kg: The Tivicay PD 10 mg dispersible tablets are more appropriate than the 50 mg dose in this weight band. Dosing for patients on Tivicay tablets would be adjusted for weight.
• 20 kg to < 30 kg: Tivicay PD 25 mg (five 5 mg tablets) or other strengths depending on regimen once a day.
• 14 kg to < 20 kg: Tivicay PD 20 mg (four 5 mg tablets) or other strengths depending on regimen once a day.
• 10 kg to < 14 kg: Tivicay PD 20 mg (four 5 mg tablets) or other strengths depending on regimen once a day.
• 6 kg to < 10 kg: Tivicay PD 15 mg (three 5 mg tablets) once a day.
• 3 kg to < 6 kg: Tivicay PD 5 mg (one 5 mg tablet) once a day.
• < 3 kg or <4 weeks old: Use and dose must be determined by your doctor.

Special Cases:

• Elderly Patients: No dose adjustment is generally recommended unless significant renal or hepatic impairment is present.
• Patients with Renal Impairment: No dose adjustment required.
• Patients with Hepatic Dysfunction: No dose adjustment needed for mild to moderate impairment. Not recommended in severe hepatic impairment.
• Patients with Comorbid Conditions: Caution is advised with certain medications; adjustments may be needed based on drug interactions.

Clinical Use Cases Dolutegravir is not typically adjusted for specific medical settings like intubation, surgical procedures, mechanical ventilation, or ICU use. Dose adjustments primarily depend on drug interactions and renal/hepatic function.

Dosage Adjustments

Dose adjustment to 50 mg twice daily is needed when co-administered with potent UGT1A and/or CYP3A inducers (e.g., rifampin, carbamazepine, efavirenz).

Side Effects

Common Side Effects:

• Headache
• Insomnia
• Diarrhea
• Nausea
• Fatigue
• Vomiting
• Dizziness

Rare but Serious Side Effects:

• Hypersensitivity reactions (rash, fever, muscle/joint aches, facial swelling, breathing difficulty)
• Liver toxicity (hepatitis, jaundice)
• Immune reconstitution inflammatory syndrome (IRIS)
• Depression
• Suicidal ideation

Long-Term Effects: May include changes in lipid levels and weight gain.

Adverse Drug Reactions (ADR): Hypersensitivity reactions, hepatotoxicity, and IRIS require immediate discontinuation of the drug and medical intervention.

Contraindications

• Hypersensitivity to dolutegravir
• Co-administration with dofetilide or fampridine

Drug Interactions

Dolutegravir has clinically significant interactions with:

• UGT1A/CYP3A inducers: Rifampin, carbamazepine, efavirenz (require dose adjustment of dolutegravir)
• Cation-containing antacids: Separate administration by several hours
• Metformin: Monitor renal function and metformin levels
• Other drugs: Several other drug interactions exist; refer to a comprehensive drug interaction resource before co-prescribing.

Pregnancy and Breastfeeding

Data suggest a potential increased risk of neural tube defects with dolutegravir use at the time of conception. While not absolutely contraindicated, alternative regimens may be considered during early pregnancy, especially before neural tube closure. Breastfeeding is generally considered safe with dolutegravir when viral load is suppressed.

Drug Profile Summary

• Mechanism of Action: Integrase strand transfer inhibitor
• Side Effects: Headache, insomnia, diarrhea, nausea, hypersensitivity reaction, hepatotoxicity
• Contraindications: Hypersensitivity, co-administration with dofetilide, fampridine
• Drug Interactions: Rifampin, carbamazepine, efavirenz, cation-containing antacids, metformin
• Pregnancy & Breastfeeding: Possible risk of neural tube defects at conception; breastfeeding generally safe with suppressed viral load
• Dosage: 50 mg once daily (adults), weight-based dosing (children); adjust with inducers.
• Monitoring Parameters: HIV-1 RNA, CD4 count, liver function tests, renal function, lipid profile, blood glucose.

Popular Combinations

• Dolutegravir + lamivudine (Dovato)
• Dolutegravir + rilpivirine (Juluca)
• Dolutegravir + abacavir + lamivudine (Triumeq)
• Dolutegravir + tenofovir disoproxil fumarate + lamivudine or emtricitabine

These combinations offer simplified regimens and improve adherence.

Precautions

• General Precautions: Assess for hypersensitivity, hepatic and renal function before starting.
• Specific Populations: Pregnancy—consider alternative regimens in early pregnancy. Monitor infants exposed during breastfeeding. No dosage adjustments for elderly or children, unless there is co-existing renal or hepatic impairment.
• Lifestyle Considerations: Alcohol, diet and smoking may affect drug metabolism; counsel patients accordingly.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Dolutegravir?

A: 50 mg once daily for adults. Pediatric dosing is weight-based. See detailed pediatric dosing above.

Q2: What is the mechanism of action of dolutegravir?

A: It inhibits HIV integrase, preventing integration of viral DNA into host cell DNA.

Q3: What are the common side effects of dolutegravir?

A: Headache, insomnia, diarrhea, nausea, and fatigue.

Q4: What are the serious side effects to watch out for with dolutegravir?

A: Hypersensitivity reactions, liver toxicity, and immune reconstitution inflammatory syndrome.

Q5: What are the contraindications to using dolutegravir?

A: Hypersensitivity to dolutegravir and co-administration with dofetilide or fampridine.

Q6: Does dolutegravir interact with other medications?

A: Yes, it interacts with several drugs, including rifampin, carbamazepine, efavirenz, cation-containing antacids, and metformin. Consult resources for detailed information on drug interactions.

Q7: Can dolutegravir be used in pregnant or breastfeeding women?

A: There is a potential risk of neural tube defects with use at conception; alternatives may be considered in early pregnancy. Breastfeeding is generally safe with a suppressed viral load.

Q8: What monitoring is recommended for patients on dolutegravir?

A: Monitor HIV-1 RNA, CD4 count, liver function tests, creatinine, lipids, and blood glucose.

Q9: Are there any dietary restrictions while taking dolutegravir?

A: It can be taken with or without food.

Q10: What should be done if a dose of dolutegravir is missed?

A: Take the missed dose as soon as possible, unless the next dose is due within 4 hours. If within 4 hours, skip the missed dose and resume the regular schedule.