• COVID-19
• antivirals
• chronic kidney disease
• clinical trials
• monoclonal antibodies
• pharmacodynamics
• pharmacokinetics

• Deutsche Forschungsgemeinschaft

• Evotaz
• HIV-1
• antiviral
• cytochrome P450
• pharmacology
• protease

• Child
• Humans
• Anti-HIV Agents/pharmacology
• Anti-Infective Agents
• Antiviral Agents/pharmacology
• Atazanavir Sulfate/pharmacology
• Cobicistat
• Cytochrome P-450 Enzyme System
• Drug Interactions
• HIV Infections/drug therapy
• HIV Infections/metabolism
• HIV Protease Inhibitors/pharmacology
• HIV-1
• Protease Inhibitors/pharmacology
• United States

• COVID-19
• Clinical trials
• Molnupiravir
• Personalized medicine
• Pharmacogenomics

• Humans
• Pharmacogenetics
• Precision Medicine
• Pandemics
• COVID-19 Drug Treatment

• COVID-19
• pharmacogenetics
• treatment

• COVID-19
• antivirals
• broad spectrum
• drug repurposing
• emerging virus

The outbreak of Coronavirus disease 2019 (COVID-19) has evolved into an emergent global pandemic. Many drugs without established efficacy are being used to treat COVID-19 patients either as an offlabel/compassionate use or as a clinical trial. Although drug repurposing is an attractive approach with reduced time and cost, there is a need to make predictions on success before the start of therapy. For the optimum use of these repurposed drugs, many factors should be considered such as drug–gene or dug–drug interactions, drug toxicity, and patient co-morbidity. There is limited data on the pharmacogenomics of these agents and this may constitute an obstacle for successful COVID-19 therapy. This article reviewed the available human genome interactions with some promising repurposed drugs for COVID-19 management. These drugs include chloroquine (CQ), hydroxychloroquine (HCQ), azithromycin, lopinavir/ritonavir (LPV/r), atazanavir (ATV), favipiravir (FVP), nevirapine (NVP), efavirenz (EFV), oseltamivir, remdesivir, anakinra, tocilizumab (TCZ), eculizumab, heme oxygenase 1 (HO-1) regulators, renin–angiotensin–aldosterone system (RAAS) inhibitors, ivermectin, and nitazoxanide. Drug-gene variant pairs that may alter the therapeutic outcomes in COVID-19 patients are presented. The major drug variant pairs that associated with variations in clinical efficacy include CQ/HCQ (CYP2C8, CYP2D6, ACE2, and HO-1); azithromycin (ABCB1); LPV/r (SLCO1B1, ABCB1, ABCC2 and CYP3A); NVP (ABCC10); oseltamivir (CES1 and ABCB1); remdesivir (CYP2C8, CYP2D6, CYP3A4, and OATP1B1); anakinra (IL-1a); and TCZ (IL6R and FCGR3A). The major drug variant pairs that associated with variations in adverse effects include CQ/HCQ (G6PD; hemolysis and ABCA4; retinopathy), ATV (MDR1 and UGT1A1*28; hyperbilirubinemia; and APOA5; dyslipidemia), NVP (HLA-DRB1*01, HLA-B*3505 and CYP2B6; skin rash and MDR1; hepatotoxicity), and EFV (CYP2B6; depression and suicidal tendencies).

• Antiretroviral
• HIV infection
• antihypertensive treatment
• cardiovascular disease.
• hypertension
• interactions

• Anti-Retroviral Agents/therapeutic use
• Antihypertensive Agents/pharmacology
• Antihypertensive Agents/therapeutic use
• Calcium Channel Blockers/therapeutic use
• HIV Infections/drug therapy
• HIV Infections/epidemiology
• Humans
• Hypertension

• Antiviral
• COVID-19
• Coronavirus
• Repurposed drugs
• SARS-CoV-2

• Antiviral Agents/chemistry
• Antiviral Agents/therapeutic use
• COVID-19/immunology
• COVID-19/therapy
• COVID-19 Vaccines/immunology
• Drug Repositioning
• Humans
• SARS-CoV-2/drug effects
• SARS-CoV-2/immunology

• BCG Vaccine/therapeutic use
• Betacoronavirus
• COVID-19
• Coronavirus Infections/diagnosis
• Coronavirus Infections/drug therapy
• Coronavirus Infections/epidemiology
• Coronavirus Infections/immunology
• Epidemics
• HIV Infections/diagnosis
• HIV Infections/drug therapy
• HIV Infections/epidemiology
• HIV Infections/immunology
• Humans
• Influenza A Virus, H1N1 Subtype
• Influenza, Human/diagnosis
• Influenza, Human/drug therapy
• Influenza, Human/epidemiology
• Influenza, Human/immunology
• Lung/immunology
• Middle East Respiratory Syndrome Coronavirus
• Pandemics
• Pneumonia, Viral/diagnosis
• Pneumonia, Viral/drug therapy
• Pneumonia, Viral/epidemiology
• Pneumonia, Viral/immunology
• Public Health
• Respiratory Tract Infections/diagnosis
• Respiratory Tract Infections/drug therapy
• Respiratory Tract Infections/epidemiology
• Respiratory Tract Infections/immunology
• SARS-CoV-2
• Severe Acute Respiratory Syndrome/diagnosis
• Severe Acute Respiratory Syndrome/drug therapy
• Severe Acute Respiratory Syndrome/epidemiology
• Severe Acute Respiratory Syndrome/immunology
• Tuberculosis/diagnosis
• Tuberculosis/epidemiology
• Tuberculosis/immunology
• Tuberculosis/prevention & control
• Virus Diseases/diagnosis
• Virus Diseases/drug therapy
• Virus Diseases/epidemiology
• Virus Diseases/immunology

• C-trough
• Cotrimoxazole
• adverse drug reactions
• antiretroviral drugs
• atazanavir
• hyperbilirubinemia
• prophylaxis.

• Androgen blockers
• antiretrovirals
• direct acting antivirals
• drug interactions
• estradiol
• gender-affirming therapy
• hepatitis C
• hiv
• testosterone
• transgender care

Plasma concentrations of antiretrovirals (ARVs) regimens have considerably varied in individuals of human immunodeficiency virus (HIV) because of variations in the expression of drug‐metabolizing and transporter genes. Transporter genes play an important role in the disposition of drugs. Polymorphism in transporter gene (ABCC3) affects the MRP3 expression and varies the treatment outcome.

We examined the polymorphism of ABCC3‐1767G/A gene in a total of 165 HIV patients (out of 165 HIV patients, 34 were with and 131 were without hepatotoxicity) and 156 healthy individuals using the polymerase chain reaction–restriction fragment length polymorphism method.

In univariate analysis, we found a decreased prevalence of ABCC3 1767GA, 1767GA+AA genotypes, and 1767A allele in patients with hepatotoxicity as compared to patients without hepatotoxicity (23.5% vs. 28.2% and 23.5% vs. 30.53%; 11.76% vs. 16.41%), while a higher prevalence of 1767AA genotype was observed in HIV patients in comparison with healthy controls (2.3% vs. 1.3%, odds ratio [OR] = 1.71, 95% confidence interval [CI]: 0.23–15.03, p = .89). The frequency of ABCC3‐1767AA genotype was dispersed higher in individuals with early and advanced HIV disease stage in comparison with healthy controls (5.3% vs. 1.3%, OR = 4.73, p = .70; 8.9% vs. 1.3%, OR = 1.89, p = .91). A higher occurrence of ABCC3‐1767AA genotype was found in tobacco using HIV patients without hepatotoxicity compared with nonusers (4.7% vs. 1.1%, OR = 4.28, p = .52). The distribution of ABCC3‐1767GA genotype was higher in nevirapine receiving HIV patients irrespective of their hepatotoxicity status as compared to nonusers (30.4% vs. 9.1%, OR = 3.34, p = .22; 29.4% vs. 16.7%, OR = 1.69, p = .77). In multivariate analysis, HIV patients receiving nevirapine and with hepatotoxicity was found to have a significant risk for severity of hepatotoxicity (OR = 4.56, 95% CI: 1.60–12.99, p = .004).

ABCC3 1767G/A polymorphism was not significantly associated with susceptibility to ARV‐associated hepatotoxicity, although ABCC3 1767AA genotype designated a risk for acquisition of hepatotoxicity and advancement of the disease. Nevirapine usage emerged as an independent risk factor for hepatotoxicity severity.

• ABCC3
• ARV-associated hepatotoxicity
• HIV patients
• genetic polymorphism
• multidrug-resistant protein

Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose-limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences. Genetic variants in the DNA of these enzymes and transporters could predict a part of the drug-related toxicity and efficacy of treatment, which has been shown in retrospective and prospective trials and meta-analyses. Patient characteristics, lifestyle and comedication also influence irinotecan pharmacokinetics. Other factors, including dietary restriction, are currently being studied. Meanwhile, a more tailored approach to prevent excessive toxicity and optimize efficacy is warranted. This review provides an updated overview on today’s literature on irinotecan pharmacokinetics, pharmacodynamics, and pharmacogenetics.

• cell-free
• genetic prototyping
• in vitro transcription/translation

• Cell-Free System
• Genetic Engineering/methods
• HIV/enzymology
• HIV Protease/genetics
• HIV Protease/metabolism
• Luminescent Proteins/genetics
• Luminescent Proteins/metabolism
• Plant Proteins/genetics
• Plant Proteins/metabolism
• Protein Biosynthesis
• RNA, Messenger/metabolism
• Recombinant Proteins/biosynthesis
• Recombinant Proteins/chemistry
• Recombinant Proteins/genetics
• Spectrometry, Fluorescence
• Spinacia oleracea/genetics
• Transcription, Genetic
• Ubiquitin/genetics
• Ubiquitin/metabolism

• P50 GM098792 NIGMS NIH HHS

• Antiretroviral therapy
• CYP inhibitors
• HIV
• drug–drug interactions
• nanoparticles
• pharmacodynamics

• atazanavir
• hyperbilirubinemia
• pharmacogenomics

• HIV/AIDS
• Treatment-experienced
• antiretroviral resistance
• antiretroviral therapy
• atazanavir
• elvitegravir/cobicistat/emtricitabine/tenofovir

Everolimus, a mammalian target of rapamycin inhibitor, is an emerging drug, which is being increasingly applied in oncology and solid organ transplantation. Oral ulcers are a frequent side effect associated with this immunosupressor. We report the case of a renal transplant recipient who developed disfiguring oral and perianal ulcers secondary to everolimus's toxicity. This is probably the first report of perianal involvement. Dermatologists need to be aware of the potential mucocutaneous adverse effects related to these new drugs that are becoming evermore common in our clinical practice.

Viruses are major pathogenic agents causing a variety of serious diseases in humans, other animals, and plants.

Drugs that combat viral infections are called antiviral drugs. There are no effective antiviral drugs for many viral infections. However, there are several drugs for influenza, a couple of drugs for herpesviruses, and some new antiviral drugs for treatment of HIV and hepatitis C infections.

The arsenal of antivirals is complex. As of March 2014, it consists of approximately 50 drugs approved by the FDA, approximately half of which are directed against HIV. Antiviral drug creation strategies are focused on two different approaches: targeting the viruses themselves or targeting host cell factors.

Direct virus-targeting antiviral drugs include attachment inhibitors, entry inhibitors, uncoating inhibitors, protease inhibitors, polymerase inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, nonnucleoside reverse-transcriptase inhibitors, and integrase inhibitors.

Protease inhibitors (darunavir, atazanavir, and ritonavir), viral DNA polymerase inhibitors (acyclovir, valacyclovir, valganciclovir, and tenofovir), and an integrase inhibitor (raltegravir) are included in the list of Top 200 Drugs by sales for the 2010s.

• attachment inhibitors
• entry inhibitors
• integrase inhibitors
• nonnucleoside reverse-transcriptase inhibitors
• nucleoside and nucleotide reverse-transcriptase inhibitors
• polymerase inhibitors
• protease inhibitors
• uncoating inhibitors

Highly active antiretroviral therapy (HAART) has substantially changed human immunodeficiency virus (HIV) infection from an inexorably fatal condition into a chronic disease with a longer life expectancy. This means that HIV patients should receive antiretroviral drugs lifelong, and the problems concerning with a chronic treatment (tolerability, side effects, adherence to treatment) have now become dominant. In this context, strategies for the treatment personalization have taken a central role in optimizing the therapeutic response and prevention of adverse drug reactions. In this setting, the study of pharmacogenetics features could be a very useful tool in clinical practice; moreover, nowadays the study of genetic profiles allows optimizations in the therapeutic management of People Living With HIV (PLWH) through the use of test introduced into clinical practice and approved by international guidelines for the adverse effects prevention such as the genetic test HLA-B*5701 to detect hypersensitivity to Abacavir. For other tests further studies are needed: CYP2B6 516 G > T testing may be able to identify patients at higher risk of Central Nervous System side effects following standard dosing of Efavirenz, UGT1A1*28 testing before initiation of antiretroviral therapy containing Atazanavir may aid in identifying individuals at risk of hyperbilirubinaemia. Pharmacogenetics represents a ​​research area with great growth potential which may be useful to guide the rational use of antiretrovirals.

• Pharmacogenetics
• Pharmacogenomics
• Single nucleotide polymorphism
• Pharmacokinetics
• Highly active antiretroviral therapy
• Polymorphism
• Phenotype
• Pharmacodynamic

• HIV
• atazanavir
• bilirubin
• drug interaction
• pharmacodynamic model
• pharmacokinetic model

The aim of this work was to analyze the atazanavir–bilirubin relationship, using a new mathematical approach to pharmacokinetic–pharmacodynamic models, for competitive drug interactions based on Michaelis–Menten equations.

Because atazanavir induces an increase of plasma bilirubin levels, in a concentration-dependent manner, we developed a mathematical model, based on increments of atazanavir and bilirubin concentrations at steady state, in HIV infected (HIV⁺) patients, and plotted the corresponding nomogram for detecting suboptimal atazanavir exposure.

By applying the obtained model, the results indicate that an absolute value or an increment of bilirubin at steady state below 3.8 μmol/L, are predictive of suboptimal atazanavir exposure and therapeutic failure.

We have successfully implemented a new mathematical approach to pharmacokinetic–pharmacodynamic model for atazanavir–bilirubin interaction. As a result, we found that bilirubin plasma levels constitute a good marker of exposure to atazanavir and of viral suppression.

• HIV/AIDS
• atazanavir
• bilirubin
• pharmacodynamics
• pharmacokinetics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors
• ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters/antagonists & inhibitors
• ATP-Binding Cassette Transporters/metabolism
• Animals
• CHO Cells
• Cricetinae
• Cricetulus
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System/genetics
• Cytochrome P-450 Enzyme System/metabolism
• Dogs
• Drug Interactions
• Enzyme Induction
• Female
• Glucuronosyltransferase/antagonists & inhibitors
• Glucuronosyltransferase/genetics
• Glucuronosyltransferase/metabolism
• HIV Integrase Inhibitors/metabolism
• HIV Integrase Inhibitors/pharmacology
• Hepatocytes/drug effects
• Hepatocytes/enzymology
• Heterocyclic Compounds, 3-Ring/metabolism
• Heterocyclic Compounds, 3-Ring/pharmacology
• Humans
• Isoenzymes
• Madin Darby Canine Kidney Cells
• Male
• Membrane Transport Proteins/drug effects
• Membrane Transport Proteins/genetics
• Membrane Transport Proteins/metabolism
• Microsomes, Liver/drug effects
• Microsomes, Liver/enzymology
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins/antagonists & inhibitors
• Multidrug Resistance-Associated Proteins/metabolism
• Neoplasm Proteins/antagonists & inhibitors
• Neoplasm Proteins/metabolism
• Organic Anion Transporters/antagonists & inhibitors
• Organic Anion Transporters/metabolism
• Oxazines
• Piperazines
• Pyridones
• Transfection

• Anti-HIV Agents/administration & dosage
• Anti-HIV Agents/adverse effects
• Anti-HIV Agents/pharmacokinetics
• Anti-HIV Agents/therapeutic use
• Antiretroviral Therapy, Highly Active
• Drug Interactions
• Drug Resistance, Viral/genetics
• HIV Infections/drug therapy
• HIV Infections/genetics
• HIV-1/genetics
• Humans
• Mutation
• Pharmacogenetics
• Polymorphism, Genetic
• Tissue Distribution

To establish in vitro and in silico models that predict clinical drug–drug interactions (DDIs) with the OATP1B1 (SLCO1B1) transporter.

The inhibitory effect of 146 drugs and drug-like compounds on OATP1B1-mediated transport was studied in HEK293 cells. A computational model was developed to predict OATP1B1 inhibition. Concentration-dependent effects were investigated for six compounds; clinical DDIs were predicted by calculating change in exposure (i.e. R-values) in eight different ways.

Sixty-five compounds were identified as OATP1B1 inhibitors at 20 μM. The computational model predicted the test set with 80% accuracy for inhibitors and 91% for non-inhibitors. In vitro–in vivo comparisons underscored the importance of using drugs with known clinical effects as references. Thus, reference drugs, cyclosporin A, gemfibrozil, and fenofibrate, provided an inhibition interval to which three antiviral drugs, atazanavir, lopinavir, and amprenavir, could be compared and their clinical DDIs with OATP1B1 classified.

Twenty-two new OATP1B1 inhibitors were identified, a predictive OATP1B1 inhibition in silico model was developed, and successful predictions of clinical DDIs were obtained with OATP1B1.

• Atorvastatin
• Computer Simulation
• Drug Interactions
• Estradiol/analogs & derivatives
• Estradiol/pharmacology
• Gene Expression
• HEK293 Cells
• Heptanoic Acids/pharmacology
• Humans
• Liver-Specific Organic Anion Transporter 1
• Models, Biological
• Organic Anion Transporters/antagonists & inhibitors
• Organic Anion Transporters/metabolism
• Pyrroles/pharmacology

• Atazanavir
• Rash

• Aldehydes/analysis
• Aldehydes/chemistry
• Aldehydes/metabolism
• Aldehydes/urine
• Animals
• Atazanavir Sulfate
• Biotransformation
• Chromatography, High Pressure Liquid
• Cytochrome P-450 CYP3A/genetics
• Cytochrome P-450 CYP3A/metabolism
• Cytochrome P-450 CYP3A Inhibitors
• Enzyme Inhibitors/pharmacology
• Feces/chemistry
• HIV Protease Inhibitors/analysis
• HIV Protease Inhibitors/chemistry
• HIV Protease Inhibitors/pharmacokinetics
• HIV Protease Inhibitors/urine
• Humans
• Hydrazines/analysis
• Hydrazines/chemistry
• Hydrazines/metabolism
• Hydrazines/urine
• Ketoconazole/pharmacology
• Metabolomics/methods
• Mice
• Microsomes, Liver/drug effects
• Microsomes, Liver/metabolism
• Oligopeptides/analysis
• Oligopeptides/chemistry
• Oligopeptides/pharmacokinetics
• Oligopeptides/urine
• Pyridines/analysis
• Pyridines/chemistry
• Pyridines/pharmacokinetics
• Pyridines/urine
• Recombinant Proteins/metabolism
• Spectrometry, Mass, Electrospray Ionization
• Tandem Mass Spectrometry

• P20 RR021940 NCRR NIH HHS
• 5P20-RR021940 NCRR NIH HHS