Abacavir

Abacavir

A sulfate salt form of abacavir, used in the treatment of HIV and AIDS.

Drug class

It is a nucleoside reverse transcriptase inhibitor analog of guanosine.

Mechanism of action

• This agent decreases HIV viral loads,
• Reduces or prevents the damage to the immune system, and
• It reduces the risk of developing AIDS.

Abacavir tablet

Brand names

ABC, Ziagen

Formulation

300 mg tablet (adult) 20 mg/mL pediatric oral solution (pediatric)

Dosage

• Child and Adolescent (Weighing ≥30 kg) and Adult Dose: One tablet twice daily
• Pediatric dose: the recommended dose for pediatric use was ABC 8 mg/kg twice daily, for a total of 16 mg/kg per day.

Hypersensitivity

• Hypersensitivity reactions (HSRs) can be fatal.
• These usually occur during the first few weeks of starting therapy.
• Symptoms may include fever, rash, nausea, vomiting, malaise or fatigue, loss of appetite, and respiratory symptoms (e.g., cough, shortness of breath).

HLA-B 5701 testing

• Test patients for the HLA-B*5701 allele before starting therapy to predict the risk of HSRs.
• Patients who test positive for the HLA-B*5701 allele should not be given ABC.
• Patients with no prior HLA-B*5701 testing who are tolerating ABC do not need to be tested.

Metabolism/Elimination

• ABC is systemically metabolized by alcohol dehydrogenase and glucuronyl transferase.
• The majority of ABC is excreted as metabolites in urine.
• ABC requires a dose adjustment in patients with hepatic insufficiency.

Contra-indications / caution

• Do not use FDC tablets such as Trizivir, Epzicom, and Triumeq (or the generic equivalents of these FDC tablets) in patients with impaired hepatic function, because the dose of ABC cannot be adjusted.
• Do not use Trizivir, Epzicom, and Triumeq (or the generic equivalents of these FDC tablets) in patients with creatinine clearance <50 mL/min and patients on dialysis, because the dose of 3TC cannot be adjusted.

Abacavir 3d structure

Drug Interactions

• Abacavir (ABC) does not inhibit, nor is it metabolized by, hepatic cytochrome P450 enzymes.
• Therefore, it does not cause significant changes in the clearance of agents that are metabolized through these pathways, such as protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors.
• ABC plasma concentrations can decrease when ABC is used concurrently with the boosted PIs atazanavir/ritonavir, lopinavir/ritonavir, and darunavir/ritonavir
• Alcohol exposure (0.7 g per kg ethanol, which is equivalent to five alcoholic drinks) has been shown to interfere with ABC metabolism by affecting the activity of alcohol dehydrogenase and glucuronyl transferase. This interference led to a 41% increase in ABC area under the curve plasma exposure in adult men with HIV who received ABC 600 mg daily.
• ABC oral solution contains sorbitol, which decreased the exposure of lamivudine (3TC) oral solution in adults when the drugs were administered concurrently.

Major Toxicities

• More common: Nausea, vomiting, fever, headache, diarrhea, rash, anorexia.
• Less common (more severe): Serious and sometimes fatal hypersensitivity reactions (HSRs) that have been observed in approximately 5% of adults and children (the rate varies by race/ethnicity) who were receiving ABC. The HSR to ABC is a multi-organ clinical syndrome that is usually characterized by rash or signs or symptoms in two or more of the following groups:
• Fever
• Constitutional symptoms, including malaise, fatigue, or achiness
• Gastrointestinal signs and symptoms, including nausea, vomiting, diarrhea, or abdominal pain
• Respiratory signs and symptoms, including dyspnea, cough, or pharyngitis
• Laboratory and radiologic abnormalities, including elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, lymphopenia, and pulmonary infiltrates. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have also been reported. Pancreatitis can occur. HSRs generally occur during the first 6 weeks of therapy, but they have also been reported after a single dose of ABC. If an HSR is suspected, ABC should be stopped immediately and not restarted—hypotension and death may occur upon rechallenge. The risk of an ABC HSR is associated with the presence of the HLA-B*5701 allele; the risk is greatly reduced by not using ABC in those who test positive for the HLA-B*5701 allele.

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

FDA Approval - Pediatric use

• ABC is approved by the Food and Drug Administration (FDA) for use in children with HIV aged ≥3 months as part of the nucleoside reverse transcriptase inhibitor (NRTI) component of antiretroviral therapy (ART).
• The World Health Organization (WHO), however, recommends using ABC as a component of the NRTI backbone for children weighing ≥3 kg, starting at 4 weeks of age (see Dosages of Antiretroviral Drugs from WHO).
• This recommendation is based on the general principle of using non-thymidine analogues in first-line regimens and thymidine analogues in second-line regimens.

Efficacy

Both the once-daily and twice-daily doses of ABC have demonstrated durable antiviral efficacy in pediatric clinical trials that is comparable to the efficacy observed for other NRTIs in children.

Pharmacokinetics in Children

• Pharmacokinetic (PK) studies of ABC in children aged <12 years have demonstrated that metabolic clearance of ABC in adolescents and young adults (aged 13–25 years) is slower than that observed in younger children and approximates clearance seen in older adults
• Once-daily dosing with either the tablet or the liquid formulation of ABC produces plasma exposures that are comparable to those seen with a twice-daily dosing schedule that uses the same total daily dose of ABC.

Toxicity

ABC has less of an effect on mitochondrial function than the NRTIs zidovudine, stavudine, or didanosine and less bone and renal toxicity than tenofovir disoproxil fumarate.

Brandname

Abacavir is marketed as Ziagen

Brand names of combination products

Epzicom® (containing Abacavir, Lamivudine) Triumeq® (containing Abacavir, Dolutegravir, Lamivudine) Trizivir® (containing Abacavir, Lamivudine, Zidovudine)

Cost

About 60 tablets or capsules abacavir (Ziagen) cost between $559–$670 in the United States.

Manufacturer

Glaxosmithkline (GSK)

Coupons

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