Atazanavir
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Atazanavir was a welcome addition to the armamentarium of antiretroviral drugs for the treatment of HIV-1-infected adults in 2003 and in 2008 for the treatment of HIV-1-infected children. At the time of licensing, it had many advantages over other, older protease inhibitors not the least of which is potency (at least in the treatment-naive setting), a more favorable lipid profile than many other protease inhibitors (even when co-administered with ritonavir), low pill burden, and once-daily dosing. However, more recent data from properly conducted clinical trials have shown a more favorable toxicity profile of ritonavir-boosted darunavir or raltegravir leading to the demotion of atazanavir to an “alternative” drug, at least for naive patients. It still remains an important drug globally, both in the adult and pediatric setting, most especially now that the powder formulation is approved for use in infants aged 6 months or older. Further refinement of genetic testing to predict who is at the greatest risk of atazanavir-related hyperbilirubinemia will inform the extent to which switching away from boosted atazanavir could have been avoided, which has had a direct impact on the drug being used less, particularly in resource-rich settings.
How Artificial Intelligence and IoT Aid in Fighting COVID-19
Fadi Al-Turjman in AI-Powered IoT for COVID-19, 2020
Different systems are being tried in China, including drug repurposing. A pre-trained deep learning-based drug-target interaction model, termed Molecule Transformer-Drug Target Interaction (MT-DTI), was utilized to distinguish industrially accessible medications that could follow up on viral proteins of SARS-CoV-2. Atazanavir, an antiretroviral prescription used to treat and forestall the human immunodeficiency infection (HIV), was analyzed as the best substance (Luo et al., 2020).
Antimicrobials during Pregnancy
“Bert” Bertis Britt Little in Drugs and Pregnancy, 2022
This agent (atazanavir) is a protease inhibitor used to treat HIV. 1309 women used Atazanavir during the first trimester, and the frequency of birth defects was not increased (http://pregnancyregistry.gsk.com). The drug was not teratogenic in rabbits and rats given the usual therapeutic dose during pregnancy.
UGT1A1 and UGT1A3 activity and inhibition in human liver and intestinal microsomes and a recombinant UGT system under similar assay conditions using selective substrates and inhibitors
Published in Xenobiotica, 2021
T. V. Radhakrishna Mullapudi, Punna Rao Ravi, Ganapathi Thipparapu
Bilirubin can be an excellent substrate for conducting in vitro enzyme kinetic studies with UGT1A1. However, bilirubin is reported to have high membrane/protein binding, and its glucuronide metabolites are chemically unstable (Korprasertthaworn et al. 2019). β-estradiol is the substrate of choice for UGT1A1 since it is highly conjugated to form estradiol-3-glucuronide by UGT1A1 in the liver. Also, estradiol-3-glucuronidation shows a high correlation with the bilirubin glucuronidation in HLM, further supporting the use of β-estradiol-3-glucuronidation as a surrogate for bilirubin glucuronidation (Zhou et al. 2011). Atazanavir is an anti-retroviral protease inhibitor that causes hyperbilirubinemia with jaundice by preventing the glucuronidation and elimination of bilirubin via inhibition of UGT1A1. The selective UGT1A1 inhibition potential of atazanavir was further confirmed by the rapid reversible hyperbilirubinemia conditions associated with it (Zhang et al. 2005). Clinical Pharmacogenetics Implementation Consortium (CPIC) had recommended guidelines for atazanavir prescription in the context of UGT1A1 genotype (Gammal et al. 2016). Hepatic impairment is the major problem that occurs when toxic bile acids (end products of cholesterol metabolism) accumulate in hepatocytes in disease conditions like cholestasis (Li and Apte 2015). CDCA is an important bile acid that is exclusively metabolised by UGT1A3 to acyl-CDCA-24-glucuronide. Lithocholic acid, also a secondary bile acid, was reported to be a potent and selective inhibitor of UGT1A3 (Chen et al. 2018).
Managing antiretroviral therapy in the elderly HIV patient
Published in Expert Review of Clinical Pharmacology, 2018
Giovanni Guaraldi, Ines Pintassilgo, Jovana Milic, Cristina Mussini
Parsons et al. compared lopinavir trough concentrations in two age-differentiated cohorts of treatment-naïve PLWH [37]. A significant positive correlation existed between age and lopinavir trough concentration after adjusting for sex at 24 weeks, but not at 36 or 96 weeks. Other study including 44 OALWH showed that older age was associated with higher lopinavir concentration [38]. However, other reports have not confirmed any age-related differences in the pharmacokinetics of lopinavir/ritonavir [39,40]. In a prospective pharmacokinetic study, no clinically significant effect of age or gender on single-dose atazanavir in 60 healthy volunteers was reported [41]. On the contrary, a study including 51 OALWH receiving darunavir showed decreased clearance of 14% with every 10 years increase in age [42]. So far, we cannot ascertain that boosted PI plasma concentrations are higher in OALWH.
Emerging drugs for the treatment of HIV/AIDS: a review of 2019/2020 phase II and III trials
Published in Expert Opinion on Emerging Drugs, 2021
Marco Piscaglia, Maria Vittoria Cossu, Matteo Passerini, Francesco Petri, Martina Gerbi, Chiara Fusetti, Amedeo Capetti, Giuliano Rizzardini
Protease inhibitors (PIs) are often administered with a nucleoside backbone or as part of an NRTI-sparing regimen. They act by inhibiting the cleavage of the gag-pol polyprotein, resulting in the production of immature virions. They are active on both HIV-1 and HIV-2. They can be used in naive patients though they are now preferred in patients who have experienced treatment failures. PIs have, in fact, a high genetic barrier: they rarely select for RAMs even in patients with sub-optimal adherence [22]. They are therefore a valid option in patients with adherence problems. However, PIs have numerous side effects that make them less tolerable than other classes. In particular, insulin-resistance, diabetes, and hyperlipidemia are observed [23]. They also require a boosting agent for adequate efficacy. The most commonly used PIs are atazanavir and darunavir, boosted with ritonavir (RTV) or cobicistat (COBI), though darunavir appears to be the most potent, with the highest genetic barrier [24]. Atazanavir exhibits good gastrointestinal tolerability. Its limits are the need for fed intake and avoidance of proton pump inhibitors for optimal absorption, as well as the occurrence of hyperbilirubinemia, jaundice, nephrolithiasis, and renal toxicity [25,26].