Atazanavir

Description

Atazanavir is an inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, an enzyme that is essential for the processing of Gag and Gag-Pol polyproteins into structural and enzymatic proteins required for viral replication. It has a similar pharmacophore motif to the other six widely marketed HIV protease inhibitors, most of which are based upon a hydroxyethylamine template. Uniquely, it possesses an aza-peptide motif but maintains many similar pharmacophore elements including lipophilic moieties that presumably bind to S₂, S₁, S′₁ , and S′₂ positions. Atazanavir is pseudo-symmetric about the central template, incorporating D-tert-Leucine at both termini. This compound is synthesized in about seven steps, with a key coupling of the chiral epoxide (derived from phenylalanine and imparting one chiral center) and N-tert-boc-N′-(4-[2-pyridyl]benzyl)hydrazine. Removal of both tert-Boc groups and double acylation with methoxycarbonyl-tert-Leucine provides the product. Another synthesis of atazanavir entails ten steps and utilizes α-(tert-bocamino) phenylpropanal as a chiral intermediate. It is a potent inhibitor of indinavir-resistant and saquinavir-resistant strains of HIV-1 (IC₅₀=0.03–0.1 and 0.04–0.1 μM, respectively). In 300 patients who had failed previous treatment, atazanavir (400 mg once daily) was compared to lopinavir (400 mg twice daily) and ritonavir (100 mg); both arms additionally receiving two non-reverse transcriptase inhibitors. After 24 weeks, HIV RNA levels of ＜400 copies/mL were noted in 61% of patients receiving atazanavir and 81% of those taking lopinavir/ritonavir. After 96 weeks of therapy with atazanavir, HIV RNA copy levels were found to be ＜400 and ＜50 in 80 and 58% of patients, respectively. A study of the cross-resistance profile relative to other protease inhibitors using a panel of 551 clinical isolates (without prior atazanavir exposure but with cross-resistance to one or two other protease inhibitors; the majority had resistance to nelfinavir) showed that greater than 80% retained susceptibility to atazanavir. All of the resistant isolates from patients taking atazanavir had an I50 L substitution. The recommended dosage of atazanavir is 400 mg once daily. It has a mean half-life range of 7.9–6.5 h with about 60% bioavailability and moderate plasma protein binding (86% albumin and 89% alpha-1- acid glycoprotein (AAG)). Atazanavir was well tolerated in clinical studies and it displayed minimal lipid modulation when tested in combination with two non-reverse transcriptase inhibitors. Atazanavir had no effect on total cholesterol, low-density lipoprotein, and triglyceride levels when compared with other protease inhibitors that caused sustained elevations in these lipid levels.

Chemical Properties

Crystalline Solid

Originator

Novartis (US)

Uses

enzyme inhibitor

Uses

Atazanavir is an inhibitor of HIV-1 protease (EC50 = 2.6 nM). In isolated cells, it has additive to moderately synergistic antiviral effects when combined with other antiretroviral drugs. As a result, it is commonly used in vivo in combination therapy for HIV-1 infection. Atazanavir competitively inhibits UDP-gluronosyltransferase, which conjugates bilirubin for clearance, leading to hyperbilirubinemia in a significant portion of those receiving atazanavir therapy.

Uses

Atazanavir is a novel azapeptide protease inhibitor (PI)

Uses

Atazanavir is a novel azapeptide HIV protease inhibitor (PI). Antiviral.

Definition

ChEBI: A heavily substituted carbohydrazide that is an antiretroviral drug of the protease inhibitor (PI) class used to treat infection of human immunodeficiency virus (HIV).

brand name

Reyataz (Bristol-Myers Squibb).

Acquired resistance

Mutations at positions 50 (I50L), 84 (I84V) and 88 (N88S) of the protease gene are associated with resistance.

General Description

Atazanavir is an antiretroviral agent that has been approvedby the FDA for use in combination with other anti-RTagents for the treatment of HIV infections. The drug is alwaysused in combination with RT inhibitors.

Pharmaceutical Applications

An azapeptide formulated as the sulfate for oral use.

Biochem/physiol Actions

Atazanavir is an antiviral HIV protease inhibitor.

Mechanism of action

Atazanavir is dosed orally once daily, thus reducing "pill burden," and it appears to have minimal impact on lipid parameters but does increase total bilirubin. The drug is well absorbed when administered orally with food (bioavailability, ~68%). The drug is highly bound to plasma protein (86%) and is metabolized by CYP3A isoenzyme. Atazanavir is a moderate inhibitor of CYP3A, and potential drug–drug interactions are possible with CYP3A inhibitors and inducers.

Pharmacokinetics

Oral absorption: c. 68%
C_max 400 mg once daily: c. 3.15 μg/L
300 mg + ritonavir 100 mg once daily: c. 4.47 μg/L
C_min 400 mg once daily: c. 0.27 μg/L
300 mg + ritonavir 100 mg once daily: c. 0.65 μg/L
Plasma half-life: c. 8.6 h (300 mg+ ritonavir 100 mg)
Volume of distribution: c. Not known/available
Plasma protein binding: c. 86%
Absorption
Administration with food enhances bioavailability and reduces pharmacokinetic variability. Absorption is dependent on gastric pH. It should be given separately from proton-pump inhibitors or H2-receptor antagonists. Buffered or entericcoated formulations should be given (with food) 2 h before or 1 h after co-administration of didanosine.
Distribution
It penetrates moderately well into the CNS. The semen:plasma ratio is 0.11–4.42. It is distributed into breast milk.
Metabolism
It is extensively metabolized by CYP3A4. Administration with ritonavir prevents metabolization and enhances the pharmacokinetic profile.
Excretion
Following a single 400 mg dose, 79% and 13% of the dose was recovered in the feces and urine, respectively. It should be used with caution in the presence of mild hepatic impairment and should not be used in patients with more severe hepatic impairment.

Clinical Use

Treatment of HIV infection (in combination with other antiretroviral drugs)

Side effects

The most common adverse reactions (≥2%) are nausea, jaundice/ scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurological symptoms, dizziness, myalgia, diarrhea, depression and fever.

target

HIV

Drug interactions

Potentially hazardous interactions with other drugs
Anti-arrhythmics: possibly increased levels of amiodarone and lidocaine.
Antibacterials: concentration of both drugs increased when given with clarithromycin; rifabutin concentration increased - reduce dose of rifabutin; rifampicin reduces atazanavir concentration - avoid; avoid with telithromycin in severe renal and hepatic impairment.
Anticoagulants: avoid with apixaban and rivaroxaban.
Antidepressants: concentration reduced by St John’s wort - avoid.
Antifungals: concentration increased by posaconazole; concentration of voriconazole increased or decreased, concentration of atazanavir also reduced.
Antimalarials: avoid with artemether/lumefantrine; may increase quinine concentration.
Antipsychotics: possibly inhibits metabolism of aripiprazole - reduce dose of aripiprazole; possibly increased concentration of pimozide and quetiapine - avoid.
Antivirals: concentration reduced by boceprevir; concentration of daclatasvir increased, reduce dose of daclatasvir; absorption reduced by didanosine tablets; concentration reduced by efavirenz - avoid; concentration of elvitegravir increased when atazanavir boosted with ritonavir - reduce elvitegravir dose; concentration possibly reduced by nevirapine - avoid; concentration of paritaprevir increased; increased risk of ventricular arrhythmias with saquinavir - avoid; concentration reduced by tenofovir and tenofovir concentration possibly increased; avoid with indinavir; concentration of maraviroc increased, consider reducing dose of maraviroc; possibly reduces telaprevir concentration, also concentration of atazanavir increased; concentration of tipranavir increased, also concentration of atazanavir reduced; avoid with elbasvir/grazoprevir, increased grazoprevir concentration.
Anxiolytics and hypnotics: possibly increases concentration of midazolam - avoid with oral midazolam.
Calcium-channel blockers: concentration of diltiazem increased - reduce dose of diltiazem; possibly increased verapamil concentration.
Ciclosporin: possibly increased concentration of ciclosporin.
Colchicine: possibly increases risk of colchicine toxicity, avoid in hepatic or renal impairment.
Cytotoxics: possibly increases concentration of axitinib, reduce dose of axitinib; possibly increases concentration of bosutinib, avoid or reduce dose; possibly increases concentration of crizotinib and everolimus - avoid; avoid with cabazitaxel and pazopanib; concentration of ibrutinib possibly increased, reduce dose of ibrutinib; possibly inhibits metabolism of irinotecan - increased risk of toxicity.
Dapoxetine: avoid concomitant use, increased risk of toxicity.
Ergot alkaloids: possibly increased concentration of ergot alkaloids - avoid.
Orlistat: absorption possibly reduced by orlistat.
Ranolazine: possibly increases ranolazine concentration - avoid.
Sildenafil: possibly increased side effects of sildenafil.
Sirolimus: possibly increased concentration of sirolimus.
Statins: avoid with simvastatin - increased risk of myopathy; possibly increased risk of myopathy with atorvastatin, pravastatin and rosuvastatin - reduce rosuvastatin dose.
Tacrolimus: possibly increased concentration of tacrolimus.
Ticagrelor: possibly increases concentration of ticagrelor - avoid.
Ulcer-healing drugs: concentration significantly reduced by omeprazole and esomeprazole and possibly other proton pump inhibitors - avoid; concentration possibly reduced by histamine H2 antagonists.

Metabolism

Atazanavir is principally metabolised by CYP3A4 isozyme to oxygenated metabolites. Metabolites are then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolic pathways consist of N-dealkylation and hydrolysis. Two minor metabolites of atazanavir in plasma have been characterised. Neither metabolite demonstrated in vitro antiviral activity.
Following a single 400 mg dose of [14C]-atazanavir, 79% and 13% of the total radioactivity was recovered in the faeces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the faeces and urine, respectively.