Pharmacological Aspects of Atazanavir
Peoples diagnosed with Human Immunodeficiency Virus (HIV) will undergo a specific therapy termed highly active antiretroviral therapy (HAART). HAART has significantly reduced the morbidity and mortality associated with HIV by 42% (Julio S.G. Montaner1, 2014). This regimen has the ability to reduce and even suppress plasma HIV RNA to levels that are undetectable. Atazanavir (ATV) is one of the drugs that compose the HAART regimen (Busti, Hall, & Margolis, 2004). ATV is a protease inhibitor (PI) that is typically boosted with ritonavir (another PI) or co-administered with an adenine analog reverse transcriptase inhibitor (i.e.tenofovir or efavirenz)(Busti et al., 2004). In this review, we will focus on the pharmacodynamics, bioanalytical approach, pharmacokinetic characteristics, and pharmacogenomics of ATV.
Pharmacodynamics characteristics of Atazanavir – the effects of the drug on the body
ATV is one of the first azapeptide PIs that can be taken once daily compared to other PIs taken multiple times daily(Bartlett, DeMasi, Quinn, Moxham, & Rousseau, 2001). An azapeptide is an amino residues that is replaced by a semicarbazide group(Piliero, 2002). ATV is known for being a protease inhibitor that specifically inhibits HIV-1 protease. HIV-1 protease is critical in the virus’s life cycle and is required for processing precursor polyproteins (i.e. major proteins encoded within retroviral genome: gag and gag-pol)(Piliero, 2002). HIV-1 protease cleaves the viral polyprotein precursors into individual proteins that are found in the active virus. This helps the virus process these proteins and divide(Piliero, 2002). ATV disrupts HIV’s life cycle by temporarily binding to HIV-1 protease’s active site. This binding inhibits cleavage formation and, ultimately, halts the formation of infectious mature viral proteins while promoting the formation of immature non-infectious viral structural proteins(Piliero, 2002; Robinson et al., 2000).
Despite the clear advantages associated with ATV administration, there are reported adverse health effects, which include but not limited to: opportunistic infections, nausea, vomiting, diarrhea, abdominal pain, headache, peripheral neuropathy, and rash(von Hentig, 2008). Patients taking ATV have an increased risk of asymptomatic hyperbilirubinemia also known as jaundice(Busti et al., 2004). This side effect is attributed to competitive inhibition of uridine diphosphate glucuronosyltransferase 1A1 which assists with the metabolism and the excretion of bilirubin(CompanyBristol-Myers, 2004). ATV is one of the few PIs in its category to have less abnormalities observed in plasma lipid profiles in patients that have used this drug compared to other PIs(Havlir & O’Marro, 2004). ATV’s potency in in vitro studies, infrequent metabolic issues, once a day dosing, and not being resistant to other PIs makes this a favorable component of the HAART regimen that will be discussed.
Bioanalytical approaches for Atazanavir
Atazanavir’s inhibitory activity, the effects of human serum proteins on its antiviral activity, and non–protein-bound (i.e. free concentration) for the protease inhibitor during dosing intervals have all been thoroughly analyzed. A fluorescence in vitro protease assay was used to assess ATV’s inhibitory activity when compared to other PIs [i.e. indinavir (IDV), nelfinavir (NFV), saquinavir (SQV), and ritonavir (RTV)](CompanyBristol-Myers, 2004). ATV inhibited the cleave activity of HIV-1 protease with a reported inhibitory constant (Ki) of 0.75 nM which fell in the range of the other PIs that ranged from 0.39 nM to 1.01 nM. In a panel of human cellular aspartyl proteases, the IC50 of ATV had a high specificity in inhibition that yielded 10,000-fold higher than observed for HIV-1 protease(CompanyBristol-Myers, 2004). The effect of human serum proteins on ATV’s antiviral activity was examined using a series of cell culture assays. 40% of human serum was added in the cell culture assay(type of assay was not disclosed by Bristol-Myers), the addition of the human serum had a 5-fold increase in the ATV EC50 from 1.5 nM to 7.8 nM(CompanyBristol-Myers, 2004). The cell culture assay they performed was indicative that in the presence of human serum, ATV was 3 to 19-fold more potent than the previously tested PIs(CompanyBristol-Myers, 2004). Finally, ATV was analyzed using hollow-fiber capillary perfusion experiments to determine non-protein-bound (i.e. free concentration) of the PI during dosing intervals(Katsumata et al., 2013). This assay is essential for evaluating the PI’s ability to provide the maximal level of suppression in viral replication. ATV’s EC50 increased more than 13.4 times and did provide maximal suppression of the virus’s ability to replicate in comparison to other PIs(Katsumata et al., 2013). Bioanalytical approaches done on ATV determined that this PI is overall one of the most potent PI with little interaction in the blood maximizing its efficacy.
ATV has been studied in 27 clinical studies to determine steady-state pharmacokinetics (PK) parameters. The dose used to determine PK parameter values (mean ± SD maximum concentration (C ) was 5358 ± 1371 max and 3152 ± 2231 ng/ml and area under the curve (AUC) was 29,303 ± 8263 and 22,262 ± 20,159 ng•hour/ml for healthy individuals and HIV- infected patients, respectively upon food consumption) was 400 mg(CompanyBristol-Myers, 2004). ATV’s bioavailability is 60-70% and increases with food intake while simultaneously reducing the PK variability. The Tmax, which is the max time to reach the maximum serum concentration (Cmax), was approximately 2.5 h(Artacho, Barreiro, & Fernandez-Montero, 2010). The AUC and Cmax values were calculated over a dose range of 200 – 800 mg. In patients that took ATV at 400 mg upon consuming a light meal had a Cmax of 3152 ng/ml and a mean AUC of 22,262 ng x h/ml(Artacho et al., 2010). This same study boosted ATV taken at 300 mg with a 100 mg of RTV and the Cmax did not show significance but AUC had a 4-fold increase(Achenbach, Darin, Murphy, & Katlama, 2011; Artacho et al., 2010). ATV was able to achieve steady state between the 4th and 8th day in both healthy individuals and HIV-infected subjects(von Hentig et al., 2008). Based upon these findings, ATV is to be taken with food to increase the oral bioavailability and taking a lower dosage of ATV with RTV did not increase serum concentration but did increase AUC, indicative of more ATV in plasma over time.
The distribution in the body for ATV was measured and quantified in cerebrospinal fluid (CSF) and ratios were taken for CSF/plasma as well as seminal fluid/plasma. The median concentration in CSF for 12 wks in patients that received ATV with a dose range of 400-600 mg was 132.3 ng/ml (range 7.2-249.8 ng/ml)(Best et al., 2009). The CSF/plasma ratio for ATV in infected subjects ranged between 0.0021 and 0.0226 with an n=4 subjects. The seminal fluid/plasma ratio in infected subjects ranged between 0.11 and 4.42 with an n=5 subjects. These CSF levels were above the EC50 (1 ng/ml) for treatment in subjects infected with the virus indicative that the brain can be a possible reservoir for the virus(Best et al., 2009). Studies have attributed the distribution of ATV in CSF to P-glycoprotein (P-gp) presence in the brain(Best et al., 2009; Kim et al., 1998). Literature has suggested that P-gp has the ability to limit the brain entry of PIs meaning that ATV at a dose above 400 mg has the potential as serving as a substrate for P-gp and possibly saturating the system leading to an increased concentration of ATV in the central nervous system (CNS)(Kim et al., 1998). The importance of the amount of ATV in the CSF can be indicative that the CNS can act as a reservoir for HIV replication. In the blood, ATV exhibited concentration independent protein binding to albumin and 1-acid glycoprotein of approximately 86%(van der Sandt et al., 2001). This independent protein binding suggests that there is a minimal potential for drug-drug interaction on protein bound drugs and for effects of fluctuation concentrations of plasma protein content due to any type of changes.
Metabolism was evaluated for ATV and it was found that CYP3A4 is the major isoform responsible for ATV metabolism, which is most abundant in the liver and intestines. ATV is a competitive inhibitor of CYP3A4 and UGT1A1. The Ki inhibition constant rate is 2.35 M for CYP3A4 and Ki for UGT1A1 was 1.9 M(Busti et al., 2004). ATV was not likely to inhibit CYP1A2 and CYP2C9 substrates at recommended dose ranges(CompanyBristol-Myers, 2004). ATV produced three minor metabolites, which were not indicative of CYP inhibition and did not produce greater effects than ATV(CompanyBristol-Myers, 2004). Fiber assays were done to assess effects such as Purkinje and there were no statistical significance or clinically important effects.
Routes of elimination were assessed for ATV. The kidneys were found to play a small role in the elimination of ATV and its metabolites. It was found that 13% of [14C]-labeled dose was excreted in the urine with 7% of the dose being the parent compound. Although important, kidneys were not the major route of elimination(CompanyBristol-Myers, 2004). Biliary elimination was the major pathway of elimination. Seventy-nine percent of the [14C]-labeled dose was found in feces with a fraction of the ATV dose unabsorbed(CompanyBristol-Myers, 2004).
Drug interaction considerations
Drug interactions are especially important because this drug is co-administered in the HAART regimen. Drug interactions were evaluated for nucleoside reverse transcriptase inhibitors (NRTIs), other PIs, UGT1A1 inhibition, and potential effects of cardiac conduction(Artacho et al., 2010). When ATV was co-administered with a variety of NRTIs, which could potentially be used for therapy, there were no significant interactions. Clarithromycin, an antibiotic commonly prescribed to HIV+ individuals, is a known CYP3A4 and P-gp inhibitor and increased ATV concentrations in plasma(Busti et al., 2004; CompanyBristol-Myers, 2004). The potential for ATV to inhibit UGT1A1 is associated with hyperbilirubinemia(CompanyBristol-Myers, 2004). The potential for drug-drug interactions via the UGT1A1 pathway is not clear due to different isoforms and their ability to conjugate with ATV. When co-administering ATV with RTV the formation of cardiac abnormalities was not significantly increased(Best et al., 2009; CompanyBristol-Myers, 2004). When ATV was administered with dilitiazem, which is a drug that treats high blood pressure and chest pain, there was a significant increase in PR interval duration relative to ATV alone but this interaction could be bypassed if 50% of the dilitiazem was administered with ATV(Best et al., 2009).
Although the manufacturer did not list pharmacogenomics considerations this was evaluated for ATV. A recent study in 118 Spanish HIV+ patients showed that the presence of at least one T allele at ABCB1 3435 C>T independently predicts lower ATV plasma concentrations possibly lessening the effect of the drug(Lakhman, Ma, & Morse, 2009). Individuals homozygous for ABCB1 2677T allele are capable of enhancing CYP34A expression in the liver and intestines(Lakhman et al., 2009). Individuals with this variation have a decreased plasma concentration which could alter the responsiveness to the drug. Individuals who also carry the variation of UGT1A1 allele *28 or *37 are shown to have a higher risk of hyperbilirubinemia when using ATV and are more likely to discontinue the usage(Lakhman et al., 2009). These variations of UGT1A1 prevent the glucuronidation and ultimately resulting in not being able to eliminate bilirubin(Lakhman et al., 2009).
Achenbach, C. J., Darin, K. M., Murphy, R. L., & Katlama, C. (2011). Atazanavir/ritonavir-based combination antiretroviral therapy for treatment of HIV-1 infection in adults. Future Virol, 6(2), 157-177. doi:10.2217/fvl.10.89
Artacho, M. A., Barreiro, P., & Fernandez-Montero, J. V. (2010). Long-term treatment of patients with HIV-1: the role of atazanavir. HIV AIDS (Auckl), 2, 157-166. doi:10.2147/HIV.S5069
Bartlett, J. A., DeMasi, R., Quinn, J., Moxham, C., & Rousseau, F. (2001). Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults. AIDS, 15(11), 1369-1377.
Best, B. M., Letendre, S. L., Brigid, E., Clifford, D. B., Collier, A. C., Gelman, B. B., . . . Group, C. (2009). Low atazanavir concentrations in cerebrospinal fluid. AIDS, 23(1), 83-87. doi:10.1097/QAD.0b013e328317a702
Busti, A. J., Hall, R. G., & Margolis, D. M. (2004). Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy, 24(12), 1732-1747. doi:10.1592/phco.24.17.1732.52347
CompanyBristol-Myers, B.-M. S. (2004). BMS-232632: atazanavir briefing document May 2003.http://www.fda/. gov/ohrms/dockets/ac/03/briefing/3950B1_01_BristolMyersSqui bb-Atazanavir.pdf.
Havlir, D. V., & O’Marro, S. D. (2004). Atazanavir: new option for treatment of HIV infection. Clin Infect Dis, 38(11), 1599-1604. doi:10.1086/420932
Julio S.G. Montaner1, Viviane D. Lima1,2, P. Richard Harrigan1,2, Lillian Lourenc ̧o1, Benita Yip1, Bohdan Nosyk1,3, Evan Wood1,2, Thomas Kerr1,2, Kate Shannon1,2, David Moore1,2, Robert S. Hogg1,3, Rolando Barrios1,5, Mark Gilbert4, Mel Krajden4, Reka Gustafson5, Patricia Daly5, Perry Kendall6. (2014). Expansion of HAART Coverage Is Associated with Sustained Decreases in HIV/AIDS Morbidity, Mortality and HIV Transmission: The ‘‘HIV Treatment as Prevention’’ Experience in a Canadian Setting. PLoS One, 9(2). doi:10.1371/
Katsumata, K., Chono, K., Kato, K., Ohtsu, Y., Takakura, S., Kontani, T., & Suzuki, H. (2013). Pharmacokinetics and pharmacodynamics of ASP2151, a helicase-primase inhibitor, in a murine model of herpes simplex virus infection. Antimicrob Agents Chemother, 57(3), 1339-1346. doi:10.1128/AAC.01803-12
Kim, R. B., Fromm, M. F., Wandel, C., Leake, B., Wood, A. J., Roden, D. M., & Wilkinson, G. R. (1998). The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest, 101(2), 289-294. doi:10.1172/JCI1269
Lakhman, S. S., Ma, Q., & Morse, G. D. (2009). Pharmacogenomics of CYP3A: considerations for HIV treatment. Pharmacogenomics, 10(8), 1323-1339. doi:10.2217/pgs.09.53
Piliero, P. J. (2002). Atazanavir: a novel HIV-1 protease inhibitor. Expert Opin Investig Drugs, 11(9), 1295-1301. doi:10.1517/13543722.214.171.1245
Robinson, B. S., Riccardi, K. A., Gong, Y. F., Guo, Q., Stock, D. A., Blair, W. S., . . . Lin, P. F. (2000). BMS-232632, a highly potent human immunodeficiency virus protease inhibitor that can be used in combination with other available antiretroviral agents. Antimicrob Agents Chemother, 44(8), 2093-2099.
van der Sandt, I. C., Vos, C. M., Nabulsi, L., Blom-Roosemalen, M. C., Voorwinden, H. H., de Boer, A. G., & Breimer, D. D. (2001). Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood–brain barrier. AIDS, 15(4), 483-491.
von Hentig, N. (2008). Atazanavir/ritonavir: a review of its use in HIV therapy. Drugs Today (Barc), 44(2), 103-132. doi:10.1358/dot.2008.44.2.1137107
von Hentig, N., Babacan, E., Lennemann, T., Knecht, G., Carlebach, A., Harder, S., . . . Haberl, A. (2008). The steady-state pharmacokinetics of atazanavir/ritonavir in HIV-1-infected adult outpatients is not affected by gender-related co-factors. J Antimicrob Chemother, 62(3), 579-582. doi:10.1093/jac/dkn204
Pharmacological Aspects of Atazanavir