Abacavir/dolutegravir/lamivudine

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Abacavir/dolutegravir/lamivudine
Abacavir, dolutegravir and lamivudine.svg
Combination of
Abacavirnucleoside analog reverse transcriptase inhibitor
Dolutegravirintegrase inhibitor
Lamivudinenucleoside analog reverse transcriptase inhibitor
Clinical data
Trade namesTriumeq, Triumeq PD
AHFS/Drugs.comMonograph
MedlinePlusa617015
License data
Pregnancy
category
  • AU: B3
Routes of
administration
By mouth
ATC code
Legal status
Legal status
  • US: ℞-only [1]
  • EU: Rx-only [2]
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
ChemSpider
  • none
KEGG

Abacavir/dolutegravir/lamivudine, sold under the brand name Triumeq among others, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS.[1] It is a combination of three medications with different and complementary mechanisms of action: abacavir (reverse transcriptase inhibitor), dolutegravir (integrase inhibitor) and lamivudine (nucleoside analog reverse transcriptase inhibitor).[1]

The medication was developed by ViiV Healthcare and was approved for use in the United States and in the European Union in 2014.[2][3][4]

Abacavir is a nucleotide reverse transcriptase inhibitor.[1] Specifically, abacavir is a guanosine analogue that interferes with HIV viral RNA-dependent DNA polymerase, ultimately resulting in inhibition of replication of HIV. Dolutegravir inhibits the HIV replication cycle by binding to the integrase active site and inhibiting the strand transfer step of HIV-1 DNA integration. Lamivudine is a cytosine analogue that inhibits HIV reverse transcription by terminating the viral DNA chain.[5]

Medical uses

Abacavir/dolutegravir/lamivudine is indicated for the treatment of HIV/AIDS in adults and adolescents aged 12 years of age and older who weigh at least 40 kilograms (88 lb).[1][2]

Adverse effects

The following adverse reactions were reported in <2% of patients:[1][5]

See individual agents as well as other combination products for additional information.

Pregnancy

Abacavir/dolutegravir/lamivudine should only be used in pregnancy if the potential benefits outweigh the risks.[1][6]

Breastfeeding

The US Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers do not breastfeed their infants to avoid risking postnatal transmission of HIV.[7][8] This recommendation is coupled with the potential for serious adverse reactions in nursing infants.[medical citation needed] Dolutegravir and abacavir were shown to be excreted in the milk of lactating rats.[medical citation needed] Lamivudine was shown to be excreted in human breast milk.[9]

History

Approval

The patent was filed on April 28, 2006,[10] and expires on October 5, 2027.[11] It was approved for use in the United States and in the European Union in 2014.[3][2]

Major label changes

In August 2015, the Food and Drug Administration (FDA) sent a bulletin regarding label updates for dolutegravir and Triumeq regarding drug-drug information.[9]

Drug interactions was updated to include a statement that in vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.[9] Furthermore, information regarding drug interactions with carbamazepine and metformin.[9]

Additionally, less common adverse reactions observed in clinical trials was updated to include suicidal ideation, attempt, behavior, or completion in order to be consistent with dolutegravir label.[12]

In September 2015, the FDA added a boxed warning of hypersensitivity reactions, lactic acidosis, and severe hepatomegaly in abacavir-containing products regarding HLA-B*507 allele.[13]

Boxed warning (9/2015)

  • Hypersensitivity reactions
  • Lactic acidosis and severe hepatomegaly with steatosis
  • Exacerbations of hepatitis B

Dosage and administration

  • Dosage recommendation with certain concomitant medications (8/2015)
  • Not recommended due to lack of dosage adjustment (9/2015)

Contraindications (9/2015)

Warnings and precautions, hypersensitivity reactions (9/2015)

Society and culture

Economics

A year supply of abacavir/dolutegravir/lamivudine costs around US$33,000 as it is under patent and not available as a generic.[5]

In July 2015, ViiV Healthcare struck a deal with Shanghai-based Desano Pharmaceuticals for a cheaper supply of dolutegravir (Tivicay) with the goal of cutting the cost in China and other developing countries. After approval of dolutegravir (Tivicay) in 2014, it came with a retail cost of $14,000 per year in the United States.[14]

Research

Clinical trials

Efficacy of abacavir/dolutegravir/lamivudine was demonstrated in antiretroviral treatment-naive participants by SINGLE (ING114467), the randomized, controlled trial and other trials in treatment-naive subjects (see dolutegravir).[citation needed]

In the SINGLE trial, 414 participants received dolutegravir + abacavir/lamivudine once daily and 419 participants received efavirenz/emtricitabine/tenofovir once daily. dolutegravir + abacavir/lamivudine compared to efavirenz/emtricitabine/tenofovir showed a reduction in viral load of HIV-1 RNA <50 copies/mL in 80% of participants compared to 72% of participants, respectively. Furthermore, in participants with baseline plasma viral load of <100,000 and >100,000 copies/mL, dolutegravir + abacavir/lamivudine compared to efavirenz/emtricitabine/tenofovir showed a reduction to <50 copies/mL in 85% and 71% compared to 73% and 72%, respectively.[15]

Post-marketing experience

In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been reported voluntarily from a population of unknown size. As such, it is not always possible to estimate frequency or establish a causal relationship to drug exposure.[9]

Abacavir and/or Lamivudine

Amyotrophic lateral sclerosis

The safety and tolerability of Triumeq was evaluated for amyotrophic lateral sclerosis (ALS) patients as part of the Lighthouse trial, an open-label, phase 2a study, conducted in Australia beginning in late 2016 over 24 weeks.[16][17] The study premise was human endogenous retroviruses, specifically human endogenous retrovirus K (HERV-K) may be a trigger or cause of ALS. Research has linked HERV-K to ALS based on increased nonspecific reverse transcriptase activity in the cerebrospinal fluid and blood of ALS patients, as well as HERV-K being found in the motor neurons of ALS patients. Triumeq was chosen as all three component drugs have good penetration of the central nervous system, particularly dolutegravir, which has high clearance rates for CNS HIV. The study found a significant decrease in HERV-K DNA in serum among study participants and showed a decrease in the slope of clinical progression based on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) of roughly 30%.[17] The trial has since progressed to Phase 3.

References

  1. ^ a b c d e f g "Triumeq- abacavir sulfate, dolutegravir sodium, lamivudine tablet, film coated". DailyMed. March 23, 2021. Retrieved April 1, 2022.
  2. ^ a b c d "Triumeq EPAR". European Medicines Agency (EMA). Retrieved April 7, 2020.
  3. ^ a b "Triumeq (abacavir sulfate, dolutegravir, and lamivudine), Fixed-Dose Combination Tablets". U.S. Food and Drug Administration (FDA). August 11, 2015. Retrieved April 7, 2020.
  4. ^ "FDA Approves Triumeq". drugs.com. August 22, 2014.
  5. ^ a b c "Login". Lexicomp. Retrieved December 10, 2015.
  6. ^ "FDA: Potential Risk of Neural Tube Birth Defects". Food and Drug Administration. Archived from the original on July 24, 2018. Retrieved May 19, 2018.
  7. ^ "Human immunodeficiency virus (HIV)". U.S. Centers for Disease Control and Prevention (CDC). March 2, 2022. Retrieved April 1, 2022.
  8. ^ "HIV and Pregnant Women, Infants, and Children". U.S. Centers for Disease Control and Prevention (CDC). March 7, 2022. Retrieved April 1, 2022.
  9. ^ a b c d e "Triumeq". ViiV Healthcare. Archived from the original on December 22, 2015. Retrieved December 15, 2015.
  10. ^ US 8129385, Johns BA, Kawasuji T, Taishi T, Taoda Y, "Substituted 5-hydroxy-3,4,6,9,9a, 10-hexanhydro-2h-1-oxa04a,8a-diaza-anthracene-6,10-dioness", issued 6 March 2012, assigned to Shionogi & Co., Ltd. (Osaka, JP) and GlaxoSmithKline LLC (Philadelphia, PA) 
  11. ^ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". U.S. Food and Drug Administration (FDA). Retrieved December 10, 2015.
  12. ^ "Tivicay (dolutegravir) and Triumeq (abacavir/dolutegravir/lamivudine) product labeling was updated". U.S. Food & Drug Administration (FDA). Archived from the original on December 22, 2015. Retrieved December 15, 2015.
  13. ^ "Safety Information - Ziagen (abacavir sulfate) Tablets and Oral Solution". www.fda.gov. Archived from the original on December 22, 2015. Retrieved December 15, 2015.
  14. ^ Palmer E (July 2, 2015). "GSK's ViiV turns to Chinese company for cheap supply of Tivicay API". Fierce Pharma. Retrieved December 15, 2015.
  15. ^ Clinical trial number NCT01263015 for "A Trial Comparing GSK1349572 50mg Plus Abacavir/Lamivudine Once Daily to Atripla (Also Called The SINGLE Trial" at ClinicalTrials.gov
  16. ^ Gold J, Rowe DB, Kiernan MC, Vucic S, Mathers S, van Eijk RP, et al. (November 2019). "Safety and tolerability of Triumeq in amyotrophic lateral sclerosis: the Lighthouse trial". Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration. 20 (7–8): 595–604. doi:10.1080/21678421.2019.1632899. PMID 31284774. S2CID 195843560.
  17. ^ a b Pridmore W (February 19, 2021). "Updates from the fray: rational off-label and over-the-counter prescribing in amyotrophic lateral sclerosis". RRNMF Neuromuscular Journal. 2 (1). doi:10.17161/rrnmf.v2i1.14789. ISSN 2692-3092. S2CID 234923415.

External links