Abacavir + Lamivudine + Zidovudine

Pharmacogenomics:

Abacavir

Human leucocyte antigen B (HLA-B) plays a critical role in the normal immune recognition of pathogens. HLA-B*57:01, a variant allele, is associated with an increased risk of hypersensitivity reactions to abacavir. Patients carrying HLA-B*57:01 allele have a higher risk of developing hypersensitivity reactions as compared to noncarriers during abacavir therapy. The frequency of HLA-B*57:01 allele is found to be the highest in Southwest Asian populations, where up to 20% of the population are carriers, and it is relatively common in European populations, with a frequency of 6-7%. On the other hand, the HLA-B*57:01 allele has the lowest frequency in African and Asian populations and was not detected in some African populations as well as in Japanese populations. Genetic testing for HLA-B*57:01 is required before treatment initiation.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of April 2012:

Genotype	Implications	Recommendations
Noncarrier of HLA-B*57:01	Low or decreased risk of abacavir hypersensitivity.	Use abacavir based on the standard dosing guidelines.
Carrier of HLA-B*57:01	Significantly increased risk of abacavir hypersensitivity.	Use of abacavir is not recommended.

Additionally, the annotation of US Food and Drug Administration (FDA) label for abacavir recommends that abacavir is contraindicated in patients carrying HLA-B*57:01 allele due to the risk for hypersensitivity reactions.

Moderate to severe: Contraindicated.

May be taken with or without food.

Hypersensitivity. Abnormally low neutrophil counts or low Hb levels. HLA-B*57:01-positive patients. Moderate to severe hepatic impairment. Lactation.

Patient with bone marrow depression; risk for coronary heart disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus), chronic HBV or HCV infection, hepatomegaly, hepatitis, hepatic steatosis. Obese women. Renal and mild hepatic impairment. Pregnancy.

Significant: Immune reconstitution syndrome, autoimmune disorders (e.g. Graves disease, polymyositis, Guillain-Barre syndrome), opportunistic infection; emergence of lamivudine-resistant HBV (in patients with HBV co-infection); increased risk of MI; lipoatrophy, symptomatic myopathy and myositis, osteonecrosis, pancreatitis; haematological toxicity (including anaemia, leucopenia, neutropenia); increased weight, serum lipids or blood glucose.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain.
General disorders and administration site conditions: Fatigue, malaise, fever, lethargy, asthenia.
Investigations: Increased amylase, serum triglycerides, serum ALT, AST, creatine phosphokinase or bilirubin.
Metabolism and nutrition disorders: Anorexia.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, muscle disorders, myopathy.
Nervous system disorders: Headache, dizziness.
Psychiatric disorders: Insomnia.
Respiratory, thoracic and mediastinal disorders: Cough, nasal symptoms.
Skin and subcutaneous tissue disorders: Rash, pruritus, alopecia.
Potentially Fatal: Serious hypersensitivity reactions; lactic acidosis and severe hepatomegaly with steatosis; exacerbation of hepatitis B.

PO: C

Screen for the presence of HLA-B*57:01 before treatment initiation. Monitor blood glucose, CBC with differential, serum creatine kinase, CD4 count, HIV RNA serum levels, bilirubin, serum transaminases, triglycerides and serum amylase. Assess for signs and symptoms of hypersensitivity reactions, pancreatitis and opportunistic infection.

Abacavir: May decrease the plasma concentrations of methadone. May increase the plasma concentrations of riociguat.
Lamivudine: May decrease the therapeutic effect of cladribine.
Zidovudine: May reduce the therapeutic effect of stavudine. Increased exposure with atovaquone and fluconazole. Decreased exposure with clarithromycin. May increase serum concentration with trimethoprim, methadone and probenecid. Decreased plasma concentration with rifampicin. May enhance the adverse effects with interferons. May alter the plasma concentrations of phenytoin.

Description:
Mechanism of Action: Abacavir, lamivudine and zidovudine are nucleoside reverse transcriptase inhibitors. They act synergistically to inhibit reverse transcriptase through incorporation of the triphosphate form in the viral deoxyribonucleic acid (DNA) chain which results in DNA chain termination.
Pharmacokinetics:
Absorption: Rapidly and well absorbed from the gastrointestinal tract.
Abacavir: Bioavailability: 83%. Time to peak plasma concentration: 0.7-1.7 hours.
Lamivudine: Bioavailability: 80-87%. Time to peak plasma concentration: 3.2 hours (fed); 0.9 hours (fasted).
Zidovudine: Bioavailability: 60-70%. Time to peak plasma concentration: 30-90 minutes.
Distribution: Crosses the placenta and blood-brain barrier; enters breast milk.
Abacavir: Volume of distribution: 0.86 ± 0.15 L/kg. Plasma protein binding: 50%.
Lamivudine: Distributed into extravascular spaces. Volume of distribution: 1.3 ± 0.4 L/kg. Plasma protein binding: <36%.
Zidovudine: Volume of distribution: 1-2.2 L/kg. Plasma protein binding: 25-38%.
Metabolism: Abacavir: Metabolised in the liver by alcohol dehydrogenase and glucuronyl transferase into inactive carboxylate and glucuronide metabolites. Undergoes intracellular metabolism into carbovir triphosphate (active metabolite).
Lamivudine: Metabolised intracellulary into active antiviral metabolite.
Zidovudine: Metabolised in the liver mainly into the inactive glucuronide; undergoes intracellular metabolism into the antiviral triphosphate and extensive first-pass metabolism.
Excretion: Abacavir: Via urine (approx 83%; 1.2% as unchanged drug, 30% as 5'-carboxylic acid metabolite, 36% as the glucuronide, 15% as other metabolites); faeces (16% total dose). Elimination half-life: 1.54 ± 0.63 hours.
Lamivudine: Mainly via urine (primarily as unchanged drug). Elimination half-life: 5-7 hours.
Zidovudine: Via urine (72-74% as metabolites, 14-18% as unchanged drug). Terminal elimination half-life: 0.5-3 hours.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 441300, Abacavir. https://pubchem.ncbi.nlm.nih.gov/compound/Abacavir. Accessed Nov. 26, 2024.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 60825, Lamivudine. https://pubchem.ncbi.nlm.nih.gov/compound/Lamivudine. Accessed Nov. 26, 2024.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 35370, Zidovudine. https://pubchem.ncbi.nlm.nih.gov/compound/Zidovudine. Accessed Nov. 26, 2024.

Store below 30°C.

Antivirals

J05AR04 - zidovudine, lamivudine and abacavir ; Belongs to the class of antivirals for treatment of HIV infections, combinations.

Martin MA, Klein TE, Dong BJ et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing. Clinical Pharmacology and Therapeutics. 2012 Apr;91(4):734-738. doi: 10.1038/clpt.2011.355. Accessed 09/07/2024

Abacavir, Lamivudine and Zidovudine Tablet (Lupin Pharmaceuticals, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 09/07/2024.

Abacavir, Lamivudine, and Zidovudine. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 09/07/2024.

Abacavir. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 09/07/2024.

Abacavir; Lamivudine, 3TC; Zidovudine, ZDV. Gold Standard Drug Database in ClinicalKey [online]. Elsevier Inc. https://www.clinicalkey.com. Accessed 09/07/2024.

Annotation of EMA Label for Abacavir and HLA-B. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 09/07/2024.

Annotation of FDA Label for Abacavir and HLA-B. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 09/07/2024.

Annotation of Swissmedic Label for Abacavir and HLA-B. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 09/07/2024.

Brayfield A, Cadart C (eds). Abacavir. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/07/2024.

Brayfield A, Cadart C (eds). Lamivudine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/07/2024.

Brayfield A, Cadart C (eds). Zidovudine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/07/2024.

Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 09/07/2024.

HLA-B - Abacavir. UpToDate Lexidrug, Pharmacogenomics Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 09/07/2024.

Joint Formulary Committee. Abacavir with Lamivudine and Zidovudine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 09/07/2024.

Lamivudine. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 09/07/2024.

Trizivir 300 mg/150 mg/300 mg Film-coated Tablets (ViiV Healthcare UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 09/07/2024.

Zidovudine. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 09/07/2024.