Other Names

BMS 232632, Reyataz®.  

Combination formulation:  Atazanavir 300 mg/cobicistat 150 mg (Evotaz®)

Atazanavir is an azapeptide HIV–1 protease inhibitor. The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV–1 infected cells, thus preventing formation of mature virions.

Activity

Atazanavir exhibits anti-HIV–1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2-5 nM against a variety of laboratory and clinical HIV–1 isolates.  Atazanavir has additive in vitro antiviral activity with the protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and NRTIs (didanosine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine) without enhanced cytotoxicity.

Atazanavir:  

• Oral powder, 50 g per packet.  50 mg in 1.5 g of powder packet (contains aspartame, sucrose, and orange-vanilla flavour)- for ˃ 3 months and between 10 to < 25 kg (available in US or via Special Access Program (SAP) Canada, ph: 613-941-2108)

• 100 mg capsules (blue/white) available in US

• 150 mg capsules (blue/powder blue); DIN 02248610

• 200 mg capsules (blue/blue); DIN 02248611

• 300 mg capsules (blue/red); DIN 02294176

Combination formulation:  300 mg atazanavir/150 mg cobicistat tablet (Evotaz®); DIN 02446731 

Reyataz® (atazanavir):

Powder: 50 mg/1.5 g dispersible oral powder packet. Mix with food such as applesauce or yogurt (1 TBSP minimum). Mixing with a beverage (milk, formula, water- 30 mL + additional 15 mL after to consume residual drug) can be used if infant is able to drink from a cup. For younger infants who cannot eat solid food, mix with infant formula (10 mL + additional 10 mL after to consume residual drug) and administer via oral syringe. Stable for 1 hour at room temperature once mixed in food or beverage (Refer to Reyataz® US Product Monograph for additional information on mixing/administration).²⁸⁸⁸

Capsules: May be opened and the contents mixed with applesauce for immediate ingestion with a light meal.  In-house study showed that the bioavailability of the contents of two 200-mg atazanavir capsules mixed with applesauce was 91.7% relative to atazanavir capsules taken intact. In addition, administration of the contents of two 200-mg capsules was well tolerated (Bristol Myers Squibb, Personal Communication, October 22, 2008).

Capsules: In an open label, multicentre study of atazanavir and atazanavir/ritonavir in children 91 days-21 years, the pharmacokinetics of atazanavir capsules and atazanavir orange-vanilla flavoured powder were studied.  Day 7 atazanavir kinetics were compared in children of similar age receiving powder vs. capsules; the powder was found to be 40% less bioavailable at the same BSA-based dose.  Therefore, suggest converting from powder to capsule by multiplying the powder dose by 0.6 and rounding up to the nearest 50 mg.²⁸⁹¹

Evotaz® (atazanavir/cobicistat): The manufacturer recommends to swallow the tablet whole; do not crush or chew tablets.²⁵⁶⁶

The use of proton pump inhibitor is common after sleeve gastrectomy. Use with caution and follow manufacturer recommendations with regards to coadministration of acid-reducing agents and atazanavir. 

In a case series, three patients on atazanavir/ritonavir underwent sleeve gastrectomy. All three patients maintained virologic suppression after gastrectomy. In one patient, pre and post atazanavir and ritonavir levels were performed. Atazanavir and ritonavir C12h pre and post gastrectomy were 0.97 mg/L and 0.64 mg/L and 0.25 mg/L and traces respectively. ³³⁹⁴

A 56-year-old male, virally suppressed on TFD/FTC and atazanavir/ritonavir 300/100 mg once daily, was diagnosed with gastric adenocarcinoma and underwent total gastrectomy followed by an oesophagojejunostomy with a Roux-en-Y reconstruction and chemotherapy with IV oxaliplatin and fluorouracil x12 cycles. Prior to the surgery, TDF and atazanavir trough concentrations were measured periodically (at least once per year) and were within 90-120 ng/mL and 600-700 ng/mL, respectively. At 1 and 3 months after chemotherapy, TDF trough concentrations remained similar (89 and 119 ng/mL, respectively), while atazanavir trough concentrations were significantly reduced (178 and 150 ng/mL, respectively). No drug-drug interaction was noted with atazanavir. HIV RNA remained undetectable 18 months after the surgery.³⁶²⁰

In a case series of 17 patients who underwent sleeve gastrectomy, most of the antiretrovirals, including lamivudine, abacavir, darunavir, tenofovir and emtricitabine exhibited adequate plasma concentrations both at baseline and during follow-up at 3- and 6-month post-surgery.³⁶²⁵ However, raltegravir in 4 patients showed a large inter-individual variability of C_max and AUC at baseline and at 6-month post-surgery. In one patient, the AUC of raltegravir at baseline (4753 μg / h l) and at 6-month post-surgery (5274 μg / h l) were both below literature standards (14,000-26,460 μg / h l). Atazanavir C_max and AUC in 3 patients were also under the literature standard values and worsened post-surgery (n = 2). Ritonavir C_max and AUC were within normal range post-surgery (n =3). Among the 17 patients, 12 (70%) maintained undetectable viral load during follow-up. Those patients were on lamivudine, abacavir, tenofovir, and emtricitabine among other antiretrovirals that were not assayed. Four patients on raltegravir or atazanavir had viral rebound after surgery, requiring treatment modification which led to undetectable viral load. 

In a retrospective cohort study of 24 patients, three patients did not maintain virologic suppression following sleeve gastrectomy. Two of them were on ritonavir boosted atazanavir with tenofovir disoproxil fumrate/emtricitabine. Regimens were modified with improvement in viral loads. The authors suggested that the increase in viral loads may be due to a decrease in acid production and concomitant use of acid-suppressive therapy.³⁶⁵⁰

In a case series of 7 patients undergoing bariatic surgery, all had virologic suppression except for one patient (atazanavir/ritonavir, TDF, emtricitabine) after gastric banding.³⁶²⁹ Patient had undetectable viral load after switching to dolutegravir, rilpivirine, and lamivudine. 

Avoid concomitant administration with antacids, proton-pump inhibitors, or H2-blockers, as atazanavir absorption is significantly compromised.

Atazanavir is an inhibitor of CYP3A and UGT1A1.  Atazanavir is a weak inhibitor of CYP2C8. With boosted atazanavir, ritonavir appears to induce CYP2C8 and offset inhibition by ATV.¹⁴⁶³

Oral Bioavailability:

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir if antacids, buffered medications, H2-receptor antagonists, and proton-pump inhibitors are administrated with atazanavir.  Avoid concomitant use (kinetic study showed significantly reduced atazanavir exposure when coadministered with omeprazole; atazanavir absorption did not improve when given either boosted with ritonavir or with 8 oz cola).

Protein Binding:

Atazanavir: 86%, binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively).

Cobicistat: Cobicistat is 97-98% bound to human plasma proteins.

Tmax:

Atazanavir, Atazanavir/ritonavir: 2-2.5 hours

Atazanavir/cobicistat: 

  Atazanavir: 3.5 hours

  Cobcicstat: 3 hours

Serum T½:

Atazanavir: 7 hours

Atazanavir/ritonavir: 12 hours

Atazanavir/cobicistat: 7.5 hours

Metabolism:

Extensively metabolized by CYP3A4.  Atazanavir inhibits CYP3A and UGT1A1 at clinically relevant concentrations. Atazanavir is a weak inhibitor of CYP2C8. Caution when unboosted atazanavir is coadministered with drugs that are 2C8 substrates with narrow therapeutic indices (e.g., paclitaxel, repaglinide); clinically significant interactions with 2C8 substrates are not expected when atazanavir is boosted with ritonavir.

Atazanavir does not inhibit CYP2C19 or CYP2E1 at clinically relevant concentrations.

Excretion:

Approximately 7% excreted unchanged in the urine.  

47 HIV-positive patients treated with ATV containing regimens were tested to determine if ABCB1 and CYP3A5 polymorphisms are associated with ATV concentrations and/or immunological responses.  

• ABCB1 haplotype (3435CT-2677GT) was significantly associated with faster ATV oral clearance than 3435CC-2677GG (mean 12.79 VS 7.3L/hr, p=0.018).  Trend for ↑ clearance observed in C3435T and G2677T variant carriers
• Mean CD4 counts were 375 for ABCB1 2677GG and 547 for 2677GT (p=0.036)  
• No relationships were identified with CYP 3A5

Authors state these pilot data provide rationale for the development of individualized ATV regimens.²⁹¹³

Atazanavir/cobicistat: 8.2% of cobicistat was recovered in urine.²⁸⁹⁰

Note: For more complete information and the most current safety data on antiretrovirals in pregnancy refer to the current US DHHS Perinatal Guidelines. 

Teratogenicity/adverse pregnancy outcomes

• Prospective reports in the Antiretroviral Pregnancy Registry (data through Jan 2020): birth defects reported in 31/1403 (2.2%, 95% CI 1.5-3.1%) infants with first-trimester ATV exposure.(APR Jan 2020)
• The SMARTT study evaluated the association of in utero ARV exposures with congenital anomalies in n=2580 HIV-exposed uninfected (HEU) children. The reported prevalence of congenital anomalies was 6.78% (95% CI, 5.85-7.82%). In adjusted analysis, there was an association between first trimester ATV exposure (26 of 222 infants) and congenital anomalies (adjusted OR 1.95, 95% CI, 1.24-3.05). The specific anomaly associated with ATV exposure was musculoskeletal (aOR 2.57, 95% CI 1.30-5.08) and skin anomalies (aOR 6.01, 95% CI 1.43-25.33).³⁴⁶³
  

Other Safety Data

• Effect of in utero ATV exposure on infant unconjugated bilirubin unclear. Nonpathalogic elevations in infant unconjugated bilirubin reported in some, but not all, clinical trials. 

Pharmacokinetics

• Pharmacokinetic studies evaluating the pharmacokinetic profile of ATV/r 300 mg/100 mg during pregnancy have reported a lower ATV AUC during pregnancy compared to ATV AUC in non pregnant women with HIV. An observational study in n=25 pregnant women receiving ATV/r plus either TDF/FTC or ABC/3TC reported no difference in ATV intracellular concentrations and intracellular/plasma ratios during the first, second or third trimesters.³⁴⁷⁵
• Pharmacokinetics studies evaulating the pharmacokinetic profile of ATV/r 300 mg/100mg when taken during pregnancy with concomitant TDF have reported ATV AUC 30% lower than the ATV AUC of women not taking TDF.^2907,2908 Other studies have not reported a decrease in ATV AUC or target ATV trough concentrations of <0.15 mg/L in the third trimester when taken with TDF.^{3476, 3477}
• A pharmacokinetic study has reported data on the effect of an increased ATV/r 400 mg/100 mg in the third trimester in pregnant women with (n=35) or without (n=37) concomitant TDF. With the increased dose of ATV/r 400 mg/100 mg in the third trimester, median ATV AUC was similar to that seen in nonpregnant historical controls taking the standard dose ATV /r 300 mg/100 mg. Non-significant differences in reduced ATV exposure with TDF use was reported in the second and third trimester.³⁴⁷⁸ 
• IMPAACT P1026s reported pharmacokinetic data in the second trimester, third trimester and post-partum for pregnant women who received ATV 300 mg with COBI 150 mg. ATV trough concentrations were 80% (second trimester) and 85% (third trimester) that historical ATV trough concentrations in non pregnant adults with HIV.³⁴⁷⁹
  

Dosing recommendations

• ATV concentrations are reduced in pregnancy and are further reduced with ATV is given concomitantly with TDF or an H2RA. 
  • Use of unboosted ATV is not recommended
  • Use of ATV is not recommended for ARV experienced pregnant women who are taking TDF and an H2RA
  • Use of an increased dose ATV/r 400 mg/100 mg during the second and third trimesters results in ATV concentrations similar to nonpregnant adults receiving standard doses. May consider increase ATV/r dosing in all women in second and third trimester; US product monograph recommends increase ATV/r dosing only for ARV-experience pregnant women in second and third trimester if also receiving TDF or an H2RA
• ATV/cobi is not recommended during pregnancy; ATV trough concentrations are 80-85% lower than concentrations in non-pregnant adults
  

Lactation

Atazanavir exceeded the IC50 for wild type in plasma, breast milk and vaginal secretions.  Median percentage of plasma concentrations was 7.3% (day 5 breast milk), 7.9% (day 14 breast milk) and 4.8% (vaginal secretions).²⁹¹¹

Skin rash (21%), < 1% severe rash; asymptomatic indirect hyperbilirubinemia (30%), jaundice (10%), headache, fever, arthralgias, depression, insomnia, dizziness, nausea/vomiting/diarrhea, paresthesias, prolongation of PR interval of EKG. 

Protease class effects include: hyperlipidemia & hypertriglyceridemia (except atazanavir), hyperglycemia, fat maldistribution, weight gain, increase in LFTs, hepatitis, increased bleeding in hemophiliacs, osteonecrosis. 

Kidney Stones (uncommon)

• American Reports: 30 cases ATV associated nephrolithiasis recorded between Dec 2002 to Jan 2007 in the US FDA Adverse Event Reporting System Database (Voluntary reporting)
• French Case Series: 11/1134 patients developed ATV nephrolithiasis (Mar 2004 – Feb 2007).  4 pts had history of kidney stones before ATV exposure. Mean onset for ADR ~ 23 months. 1/6 patients that were kept on ATV developed recurrent kidney stones despite instructions to drink more fluids, including acidic beverages such as cola.
• Reports suggest kidney stones composed of 60-100% ATV crystals   
• Exact mechanism for ADR is unknown. 
• 7% of the ATV dose is excreted unchanged in the urine. Like IDV, the solubility of ATV is increased in acid fluids

Risk Factors: not drinking enough fluid, having urine that is not acidic, having a history of kidney stones.

A case report of a 37 year old HIV/HCV coinfected male (60 kg) who ingested 8700 mg atazanavir without ritonavir; last ritonavir 100 mg dose was taken ~24 hours prior to overdose.  Transient elevation in total bilirubin and Scr and asymptomatic increases in PR and QTc intervals were observed at 24-48 hours post-overdose; values returned to baseline at one-month follow-up.  Atazanavir plasma concentrations were 5400 ng/mL and 594 ng/mL at 22 and 62 hours post-overdose.²⁹⁰¹

Baseline Assessment

Assess risk factors for diabetes, coronary artery disease (less with ATV), osteonecrosis (i.e. steroids, ETOH, diabetes, hyperlipidemia), and  hepatic dysfunction (i.e. HBV/HCV, ETOH use). CBC/diff, LFTs, glucose, fasting cholesterol profile. 

Routine Labs

CBC/diff, LFTs, glucose q 3 mos. Fasting lipids (8-12 hr level) q 3-6 months post-therapy, then annually. If TG > 2.3 mmol/L at baseline, repeat after 1-2 months.

Store at room temperature.

Bristol-Myers Squibb Canada