Toxicogenetics of Lopinavir/Ritonavir in Hiv-Infected European Patients

Aspiroz, Elena López; Figueroa, Salvador Enrique Cabrera; Cruz, Raquel; Hurtado, Gloria Liliana Porras; Martín, Ana Cristina López; Hurlé, Alfonso Domínguez-Gil; Carracedo, Ángel

doi:10.2217/pme.14.7

Cited by 7 publications

(9 citation statements)

References 51 publications

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“… Increased uric acid Ribavirin 2 −/− ITPA (2B: Hemolysis, thrombocytopenia) 1) SLC28A2, SLC28A3, SLC2A1 (PK) 69 Intestinal uptake via CNTs (encoded by SLC ). Hemolytic anemia Lopinavir/ritonavir 34 −/− ABCB1, ABCC1 (3: Efficacy in HIV); ABCC2, SLCO1B (4: PK) 1) CYP3A4, CYP3A5, SLCO1B1, ABCC2, DRD3, MDR1 (PK) 39 , 70 , 71 2) CETP, MCP1, ABCC2, LEP, SLCO 1B3, IL6 (Toxicity) 40 Inactivation via CYP3A4 QT prolongation, CV events, dyslipidemia, liver injury, GI disturbances Darunavir/cobicistat 1 −/− SLCO3A1 (N/A d : PK) – Inactivation via CYP3A4 Liver injury, dyslipidemia, sulfonamide allergy Interferon beta-1b 4 −/− IRF6 (3: Liver injury), Various SNPs (3: Efficacy in multiple sclerosis) 1) HLA-DRB1*04, HLA-DRB1*15, rs9272105, rs4961252 (Neutralizing antibody) 42 , 72 Limited data on metabolism/transporter pathways Liver injury, depression, heart failure, leukopenia, flu-like symptoms, and etc. Tocilizumab 33 −/− IL6R, CD69, FCGR3A, GALNT18 (3: Efficacy in rheumatoid arthritis) – Limited data on metabolism/transporter pathways Thrombocytopenia, liver injury, neutropenia, rash, hypertension, infection Ruxolitinib 13 −/− – – Inactivation mainly via CYP3A4 and partly via CYP2C9 Cytopenia, dyslipidemia, infection, liver injury Baricitinib 11 −/− – – Efflux transport mainly via OAT3 and partly via BCRP and p-glycoprotein.…”

Section: Methodsmentioning

confidence: 99%

“…Clearance of lopinavir in a population PK model was higher in individuals with SLCO1B1*4/*4 and lower in individuals with two or more variant alleles of SLCO1B1*5, ABCC2 or a CYP3A tag compared to the reference group (12.6 vs. 3.9 vs. 5.4 l/h, respectively, p < 0.01) 39 . Another genetic association study explored 290 variants for their effects on lopinavir/ritonavir related toxicity among 104 Caucasian patients with HIV; variants in the CETP, MCP-1, ABCC2, LEP, and SLCO1B3 genes were associated with dyslipidemia and hyperbilirubinemia, and a variant in IL-6 was associated with diarrhea (all p < 0.01) 40 .…”

Section: Azithromycinmentioning

confidence: 99%

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Pharmacogenomics of COVID-19 therapies

et al. 2020

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A new global pandemic of coronavirus disease 2019 (COVID-19) has resulted in high mortality and morbidity. Currently numerous drugs are under expedited investigations without well-established safety or efficacy data. Pharmacogenomics may allow individualization of these drugs thereby improving efficacy and safety. In this review, we summarized the pharmacogenomic literature available for COVID-19 drug therapies including hydroxychloroquine, chloroquine, azithromycin, remdesivir, favipiravir, ribavirin, lopinavir/ritonavir, darunavir/cobicistat, interferon beta-1b, tocilizumab, ruxolitinib, baricitinib, and corticosteroids. We searched PubMed, reviewed the Pharmacogenomics Knowledgebase (PharmGKB ®) website, Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the U.S. Food and Drug Administration (FDA) pharmacogenomics information in the product labeling, and the FDA pharmacogenomics association table. We found several drug-gene variant pairs that may alter the pharmacokinetics of hydroxychloroquine/chloroquine (CYP2C8, CYP2D6, SLCO1A2, and SLCO1B1); azithromycin (ABCB1); ribavirin (SLC29A1, SLC28A2, and SLC28A3); and lopinavir/ritonavir (SLCO1B1, ABCC2, CYP3A). We also identified other variants, that are associated with adverse effects, most notable in hydroxychloroquine/chloroquine (G6PD; hemolysis), ribavirin (ITPA; hemolysis), and interferon β-1b (IRF6; liver toxicity). We also describe the complexity of the risk for QT prolongation in this setting because of additive effects of combining more than one QT-prolonging drug (i.e., hydroxychloroquine/chloroquine and azithromycin), increased concentrations of the drugs due to genetic variants, along with the risk of also combining therapy with potent inhibitors. In conclusion, although direct evidence in COVID-19 patients is lacking, we identified potential actionable genetic markers in COVID-19 therapies. Clinical studies in COVID-19 patients are deemed warranted to assess potential roles of these markers.

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Section: Methodsmentioning

confidence: 99%

Section: Azithromycinmentioning

confidence: 99%

Pharmacogenomics of COVID-19 therapies

et al. 2020

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“…A latency period of 1 month or longer is common, which may make this a less relevant feature in the treatment of SARS-CoV-2.. There are genetic variations (polymorphisms) across patients, such as a loss-of-function of CYP3A4 [80], that can make patients more susceptible to metabolic toxicities [81]. Screening for these susceptibilities is not practical in the setting of short duration treatment for SARS-CoV-2.…”

Section: Lopinavir-ritonavirmentioning

confidence: 99%

COVID-19: Therapeutics and Their Toxicities

et al. 2020

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SARS-CoV-2 is a novel coronavirus that emerged in 2019 and is causing the COVID-19 pandemic. There is no current standard of care. Clinicians need to be mindful of the toxicity of a wide variety of possibly unfamiliar substances being tested or repurposed to treat COVID-19. The United States Food and Drug Administration (FDA) has provided emergency authorization for the use of chloroquine and hydroxychloroquine. These two medications may precipitate ventricular dysrhythmias, necessitating cardiac and electrolyte monitoring, and in severe cases, treatment with epinephrine and high-doses of diazepam. Recombinant protein therapeutics may cause serum sickness or immune complex deposition. Nucleic acid vaccines may introduce mutations into the human genome. ACE inhibitors and ibuprofen have been suggested to exacerbate the pathogenesis of COVID-19. Here, we review the use, mechanism of action, and toxicity of proposed COVID-19 therapeutics.

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“…GWAS after analyzing 290 variants with the toxicity of LPV/RTV among 104 Caucasian patients with HIV revealed that dyslipidemia and hyperbilirubinemia were significantly associated with some genetic variants of the CETP, MCP-1, ABCC2, LEP, and SLCO1B3 genes. Also, a genetic variant of the IL-6 gene was significantly associated with resulting in diarrhea (all p < 0.01) (Aspiroz et al, 2014;Takahashi et al, 2020).…”

Section: Lopinavir/ritonavirmentioning

confidence: 95%

Pharmacogenetics and Precision Medicine Approaches for the Improvement of COVID-19 Therapies

et al. 2022

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Many drugs are being administered to tackle coronavirus disease 2019 (COVID-19) pandemic situations without establishing clinical effectiveness or tailoring safety. A repurposing strategy might be more effective and successful if pharmacogenetic interventions are being considered in future clinical studies/trials. Although it is very unlikely that there are almost no pharmacogenetic data for COVID-19 drugs, however, from inferring the pharmacokinetic (PK)/pharmacodynamic(PD) properties and some pharmacogenetic evidence in other diseases/clinical conditions, it is highly likely that pharmacogenetic associations are also feasible in at least some COVID-19 drugs. We strongly mandate to undertake a pharmacogenetic assessment for at least these drug–gene pairs (atazanavir–UGT1A1, ABCB1, SLCO1B1, APOA5; efavirenz–CYP2B6; nevirapine–HLA, CYP2B6, ABCB1; lopinavir–SLCO1B3, ABCC2; ribavirin–SLC28A2; tocilizumab–FCGR3A; ivermectin–ABCB1; oseltamivir–CES1, ABCB1; clopidogrel–CYP2C19, ABCB1, warfarin–CYP2C9, VKORC1; non-steroidal anti-inflammatory drugs (NSAIDs)–CYP2C9) in COVID-19 patients for advancing precision medicine. Molecular docking and computational studies are promising to achieve new therapeutics against SARS-CoV-2 infection. The current situation in the discovery of anti-SARS-CoV-2 agents at four important targets from in silico studies has been described and summarized in this review. Although natural occurring compounds from different herbs against SARS-CoV-2 infection are favorable, however, accurate experimental investigation of these compounds is warranted to provide insightful information. Moreover, clinical considerations of drug–drug interactions (DDIs) and drug–herb interactions (DHIs) of the existing repurposed drugs along with pharmacogenetic (e.g., efavirenz and CYP2B6) and herbogenetic (e.g., andrographolide and CYP2C9) interventions, collectively called multifactorial drug–gene interactions (DGIs), may further accelerate the development of precision COVID-19 therapies in the real-world clinical settings.

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Toxicogenetics of Lopinavir/Ritonavir in Hiv-Infected European Patients

Abstract: Replication analysis should confirm the novel results obtained in this study prior to its application in the clinical practice to achieve a safer LPV/r-based combined antiretroviral therapy.

Cited by 7 publications

References 51 publications

Pharmacogenomics of COVID-19 therapies

Pharmacogenomics of COVID-19 therapies

COVID-19: Therapeutics and Their Toxicities

Pharmacogenetics and Precision Medicine Approaches for the Improvement of COVID-19 Therapies

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