ritonavir and Chemical-and-Drug-Induced-Liver-Injury

We report the first published case of a drug induced liver injury (DILI) presumed secondary to a drug-drug interaction between ritonavir and levonorgestrel progestogen-only emergency contraception (POEC). Our patient is a 25-year-old female living with human immunodeficiency virus (HIV), taking antiretroviral therapy (ART) containing tenofovir alafenamide/emtricitabine and darunavir/ritonavir. She was found to have elevated transaminases at a routine clinic appointment consistent with hepatocellular DILI. Further investigation found the most likely cause of this was a drug-drug interaction (DDI) between the ritonavir component of her ART and recent use of levonorgestrel POEC 3 days earlier. Evidence suggests that ritonavir increases levonorgestrel exposure, yet our patient received double the usual dose as per dispensing guidance at the time. We review the pharmacokinetics of ritonavir-levonorgestrel DDIs and highlight the need for consistent guidelines on this topic.

Topics: Adult; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Darunavir; Female; HIV Infections; Humans; Levonorgestrel; Ritonavir; Tenofovir

Adverse drug reactions (ADRs) are a common cause of attrition in drug discovery and development and drug-induced liver injury (DILI) is a leading cause of preclinical and clinical drug terminations. This perspective outlines many of the known DILI mechanisms and assessment methods used to evaluate and mitigate DILI risk. Literature assessments and retrospective analyses using verified DILI-associated drugs from the Liver Tox Knowledge Base (LTKB) have been used to derive the predictive value of each end point, along with combination approaches of multiple methods. In vitro assays to assess inhibition of the bile salt export pump (BSEP), mitotoxicity, reactive metabolite (RM) formation, and hepatocyte cytolethality, along with physicochemical properties and clinical dose provide useful DILI predictivity. This Perspective also highlights some of the strategies used by medicinal chemists to reduce DILI risk during the optimization of drug candidates.

Topics: Animals; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Drug Discovery; Drug Evaluation, Preclinical; Hepatocytes; Humans; Liver; Mitochondria, Liver; Pharmaceutical Preparations; Risk Assessment; Tissue Distribution

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Drug Labeling; Humans; Pharmaceutical Preparations; Risk

Ritonavir-boosted lopinavir (LPV/r) is a protease inhibitor used for the treatment of human immunodeficiency virus (HIV) infection in both normal patients and in certain situations. In patients with renal failure, LPV/r does not require dosage adjustment because it is metabolized in the liver. Cohort studies have shown that the incidence of varying degrees of renal disease and/or crystalluria related to combination antiretroviral therapy with tenofovir and some protease inhibitors (PI) does not appear with LPV/r or that the incidence is much lower with this combination. Neurocognitive impairments are described in a high proportion of patients with HIV infection and viral replication or related inflammatory activity in the subarachnoid space. In these patients, LPV/r is one of the therapeutic options. A score has been published that rates antiretroviral drugs according to the concentration attained in the cerebrospinal fluid (CSF). LPV/r levels reached in CSF exceed the IC50 of wild-type HIV and has a valuable score (score 3) of the drugs currently used. The most important comorbid condition is chronic hepatitis, due to its frequency and because the biotransformation of LPV/r occurs in the liver. In these circumstances, it is important to evaluate the influence of liver failure on blood drug levels and how these values may cause liver toxicity. LPV/r dose modification has not been established in the presence of liver failure. LPV/r-induced liver toxicity has only been reported with a certain frequency when liver enzymes were elevated at baseline or in patients with chronic hepatitis C, although most cases of liver toxicity were mild.

Topics: AIDS Dementia Complex; Chemical and Drug Induced Liver Injury; Drug Combinations; Hepatitis, Viral, Human; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; HIV-2; Humans; Lopinavir; Renal Insufficiency; Reverse Transcriptase Inhibitors; Ritonavir; Subarachnoid Space

Darunavir, previously known as TMC-114, is a new protease inhibitor (PI) with a high affinity for the HIV-1 protease and strong ability to inhibit its action, even in mutated forms. Consequently, this drug is considered to have great intrinsic potency and a high genetic barrier. At the time of writing, data on the tolerability and safety of darunavir come mainly from studies of late rescue therapy (POWER, DUET), which have included more than 1,600 patients. Recent data, relating to shorter time periods, are also available from studies in early treatment-experienced patients (TITAN) and in treatment-naïve patients (ARTEMIS), increasing experience to a further 600 patients. Lastly, more than 4,000 patients who have received darunavir through the Expanded Access Program have allowed the drug's generally good safety and tolerability profile to be defined. In the studies performed to date, darunavir has been well tolerated, with a better profile than that of the PIs used in control groups in terms of adverse effects such as diarrhea, gastrointestinal tolerability and lipid alterations. Moreover, to date, no unexpected severe adverse effects have been reported.

Topics: Adult; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase III as Topic; Darunavir; Drug Therapy, Combination; Dyslipidemias; Female; Gastrointestinal Diseases; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Lopinavir; Male; Multicenter Studies as Topic; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Salvage Therapy; Sulfonamides

Ritonavir-boosted tipranavir (TPV/r) was evaluated as initial therapy in treatment-naïve HIV-1-infected patients because of its potency, unique resistance profile, and high genetic barrier. Trial 1182.33, an open-label, randomized trial, compared two TPV/r dose combinations versus ritonavir-boosted lopinavir (LPV/r). Eligible adults, who had no prior antiretroviral therapy were randomized to twice daily (BID) 500/100 mg TPV/r, 500/200 mg TPV/r, or 400/100 mg LPV/r. Each treatment group also received Tenofovir 300 mg + Lamivudine 300 mg QD. The primary endpoint was a confirmed viral load (VL) <50 copies/mL at week 48 without prior antiretroviral regimen changes. Primary analyses examined CD4-adjusted response rates for non-inferiority, using a 15% non-inferiority margin. At week 48, VL<50 copies/mL was 68.4%, 69.9%, and 72.4% in TPV/r100, TPV/r200, and LPV/r groups, respectively, and TPV/r groups showed non-inferiority to LPV/r. Discontinuation due to adverse events was higher in TPV/r100 (10.3%) and TPV/r200 (15.3%) recipients versus LPV/r (3.2%) recipients. The frequency of grade ≥3 transaminase elevations was higher in the TPV/r200 group than the other groups, leading to closure of this group. However, upon continued treatment or following re-introduction after treatment interruption, transaminase elevations returned to grade ≤2 in >65% of patients receiving either TPV/r200 or TPV/r100. The trial was subsequently discontinued; primary objectives were achieved and continuing TPV/r100 was less tolerable than standard of care for initial highly active antiretroviral therapy. All treatment groups had similar 48-week treatment responses. TPV/r100 and TPV/r200 regimens resulted in sustained treatment responses, which were non-inferior to LPV/r at 48 weeks. When compared with the LPV/r regimen and examined in the light of more current regimens, these TPV/r regimens do not appear to be the best options for treatment-naïve patients based on their safety profiles.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Disease Progression; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; Gastrointestinal Diseases; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Proportional Hazards Models; Pyridines; Pyrones; Ritonavir; Sulfonamides; Tenofovir; Young Adult

Rifampicin and protease inhibitors are difficult to use concomitantly in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there is concern that the current recommended dose is suboptimal. The principal aim of this study was to compare bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in patients with HIV-associated tuberculosis who initiated lopinavir/ritonavir-based antiretroviral therapy in Vietnam. Concentrations of lopinavir/ritonavir were also measured.. This was a randomized, open-label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis in Ho Chi Minh City (Clinical trial registry number NCT00651066). Rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir -based antiretroviral therapy using patient randomization lists. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after 2 weeks of rifabutin 300 mg daily, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir.. Sixteen and seventeen patients were respectively randomized to the two arms, and pharmacokinetic analysis carried out in 12 and 13 respectively. Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2 - 5 fold increases of the 25-O-desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations.. Based on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis.. ClinicalTrials.gov NCT00651066.

Topics: Adult; Antibiotics, Antitubercular; Area Under Curve; Asian People; Biological Availability; Chemical and Drug Induced Liver Injury; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Rifabutin; Ritonavir; Treatment Outcome; Tuberculosis; Vietnam

The authors had for aim to describe the effectiveness and the safety of a saquinavir/ritonavir (SQV/r) regimen, 1000/100mg twice daily, in HIV-infected pregnant patients.. We made a prospective and observational study of HIV positive female patients beginning or going on SQV/r antiretroviral treatment (ART) during pregnancy.. Sixty-two patients were enrolled from July 2007 to June 2009 in 10 infectious diseases units in France. Thirty-six women (group 1) were ART naive on inclusion, 20 (group 2) had been previously treated and then switched to SQV/r, six (group 3) were treated with SQV/r before pregnancy. 58 patients delivered while on SQV/r regimen after a median pregnancy duration of 39 WA. Eighty percent had a viral load below 50 copies/mL and 93% below 400 copies/mL: respectively 77% and 93.5% in group 1, 83% and 89% in group 2, 83% and 100% in group 3. The median SQV minimum concentrations (C(min)) measured at the third trimester and at delivery were adequate, respectively 0.91 mg/L and 0.86 mg/L. Most women (52%) had a vaginal delivery; 12 (21%) had an elective caesarean section, for obstetrics factors in eight cases. None of the newborns were HIV-infected at 6 months of age (n = 59, one death at day 3). Only one severe adverse event occurred due to saquinavir (maternal grade 3 hepatotoxicity).. SQV/r 1000/100mg twice daily seems to be effective and safe in HIV-infected pregnant women with adequate saquinavir C(min).

Topics: Adult; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Cohort Studies; Delivery, Obstetric; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-2; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Prospective Studies; Ritonavir; Saquinavir; Treatment Outcome; Viral Load; Viremia; Young Adult; Zidovudine

Abstract Our objective was to evaluate the liver toxicity of antiretroviral regimens including fosamprenavir plus ritonavir (FPV/r) 1400/100 mg once daily (QD) in HIV/hepatitis C virus (HCV)-coinfected patients. This was a prospective cohort study that included 117 HIV/HCV-coinfected patients who started FPV/r 1400/100 mg QD-based antiretroviral therapy (ART) and who neither had received a previous antiretroviral regimen containing FPV nor had a past history of virologic failure while receiving protease inhibitors (PI). The primary end point of the study was the occurrence of grade 3-4 liver enzymes elevations (LEE) within 1 year after starting FPV/r QD. Factors potentially associated with grade 3-4 LEE, including baseline liver fibrosis, were analyzed. Eleven (9%) patients had a grade 3-4 LEE during the follow-up, resulting in an incidence of severe liver toxicity of 9% (95% confidence interval 4.1-14.6%). None of these cases led to FPV/r discontinuation. Baseline liver fibrosis could be assessed in 97 (83%) patients. Six of 71 patients (8%) with significant fibrosis had a grade 3-4 LEE versus 2 of 26 (8%) without significant fibrosis (p=1.0). Twenty (21%) patients had cirrhosis at baseline. There were no cases of LEE among cirrhotics. In conclusion, the incidence of severe liver toxicity after 1 year of therapy with FPV/r QD-based ART in HIV/HCV-coinfected patients is similar to what has been reported with other boosted PIs. In addition, the presence of significant fibrosis or cirrhosis was not associated with the emergence of liver toxicity. Thus, ART regimens containing FPV/r QD may be considered safe in HIV/HCV-coinfected patients, including those with cirrhosis.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Cohort Studies; Drug Therapy, Combination; Female; Furans; Hepacivirus; Hepatitis C; HIV Infections; Humans; Liver Cirrhosis; Male; Middle Aged; Organophosphates; Ritonavir; RNA, Viral; Sulfonamides

Lopinavir/ritonavir (LPV/r) has been the gold standard in first line rescue treatment for many years. No other boosted protease inhibitor (PI/r) has managed to demonstrate that it is superior to LPV/r. In this regard, the TITAN study compared the efficacy and safety of darunavir (DRV/r) in 595 patients, at a dose of 600/100 mg two times a day against the normal LPV/r dose, combined with at least 2 other optimised antiretroviral drugs. The efficacy of the treatment at 48 weeks (VL<400 copies/mL) was significantly higher in the DRV/r goup compared to the LPV/r group, both in the analysis by protocol (77% vs. 68%), the non-inferiority of DRV/r being demonstrated (estimated difference +9%, 95% CI 2-16), and by intention to treat (77% vs. 67%), the superiority of DRV/r being demonstrated (estimated difference 10%, 95% CI 2-17%). The incidence of diarrhoea and increase in triglycerides was higher in the LPV/r group. The differences in efficacy of both treatments in favour of DRV/r started to be seen from a basal primary mutation in the protease, with these differences increasing as the number of these mutations increased. In patients with virological failure, DRV/r protected the protease and reverse transcriptase against mutations, thus preserving future therapeutic options. We have some theoretical and clinical data available that enables us to consider the possibility of administering DRV/r once a day in some patients with a few mutations in the protease and in those where this dosing regime is considered important. With the results of the TITAN study, DRV/r must be considered the new gold standard in first line rescue, at least in those patients with a primary mutation in the protease.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Darunavir; Diarrhea; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Lopinavir; Male; Prognosis; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Salvage Therapy; Sulfonamides

To assess the efficacy and safety of a once-daily regimen with didanosine, lamivudine, saquinavir, and low-dose ritonavir in antiretroviral (ARV)-naive patients with tuberculosis treated with rifampin and the influence of rifampin on plasma trough concentration (Ctrough) of saquinavir.. Single-arm, prospective, multicenter, open-label pilot study, including 32 adult ARV-naive subjects with HIV infection and tuberculosis under standard treatment that included rifampin (600 mg q.d.) and isoniazid (300 mg q.d.). After 2 months of tuberculosis treatment, patients were started on once-daily ARV therapy, consisting of didanosine, lamivudine, ritonavir (200 mg), and saquinavir soft gel capsules (1600 mg). HIV RNA level, CD4 cell count, clinical and laboratory toxicity, and saquinavir Ctrough during and after antituberculosis therapy were analyzed.. After 48 weeks of follow-up, 20 of 32 patients (62.5%; 95% CI: 45.8% to 79.2%) in the intent-to-treat population and 20 of 28 (71.4%; 95% CI: 54.4% to 88.4%) in the on-treatment population had an HIV RNA level <50 copies/mL. Treatment tolerance was acceptable in all patients except for 2 with biologic hepatic toxicity leading to discontinuation. Seven patients had virologic failure. In 10 patients (36%), saquinavir Ctrough was <0.05 microg/mL during tuberculosis therapy and 5 of them had virologic failure. The median saquinavir Ctrough was 44% lower (interquartile range: 19% to 71%) with coadministration of rifampin than without.. The combination of didanosine, lamivudine, saquinavir, and ritonavir may be a useful treatment regimen for patients with tuberculosis in whom a once-daily protease inhibitor-containing regimen is considered indicated. Nevertheless, on the basis of pharmacokinetic profile the dose of 1600/200 mg of saquinavir/ritonavir cannot be recommended. Further studies with higher doses of saquinavir (2000 mg) boosted with ritonavir are warranted.

Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; Humans; Lamivudine; Male; Pilot Projects; Ritonavir; Saquinavir; Spain; Treatment Outcome; Tuberculosis

Topics: Antiviral Agents; Chemical and Drug Induced Liver Injury; Humans; Hydroxylamines; Ritonavir

Topics: Antiviral Agents; Chemical and Drug Induced Liver Injury; COVID-19; COVID-19 Drug Treatment; Humans; Ritonavir

Favipiravir is an antiviral drug that is expected to have a therapeutic effect on SARS-CoV2 infection. Teratogenicity and hyperuricemia are known as the main side effects of favipiravir, but little is known about other side effects. This report describes a case of cholestatic liver injury induced by favipiravir. A 73-year-old Japanese with a history of alcoholic hepatitis was infected with SARS-CoV2. Drug therapy was instituted with lopinavir/ritonavir combined with interferon β-1b. However, his condition worsened despite additional support with continuous hemodiafiltration and veno-venous extracorporeal membrane oxygenation. We suspected complications of bacterial pneumonia and started favipiravir in addition to antimicrobial therapy. Favipiravir was administered at 6000 mg/day on the first day and 2400 mg/day for the second and subsequent days for 14 days. After the initiation of antibiotics, transaminase and total bilirubin were elevated, suggesting a transient cholestasic liver dysfunction. The liver dysfunction in this case may have been triggered by antibacterial treatment, and high dose of favipiravir may have promoted the deterioration of liver function. Monitoring of liver function is vital and close attention should be paid when using favipiravir at high doses or in patients with impaired liver function.

Topics: Aged; Amides; Antiviral Agents; Chemical and Drug Induced Liver Injury; Cholestasis; COVID-19; COVID-19 Drug Treatment; Drug Therapy, Combination; Extracorporeal Membrane Oxygenation; Humans; Lopinavir; Male; Pyrazines; Ritonavir; SARS-CoV-2

Background Liver injury has been documented independently in novel coronavirus disease 2019 (COVID-19) patients and patients treated with lopinavir-ritonavir. Objective to investigate the drug-induced liver injury associated with lopinavir-ritonavir among the patients with COVID-19. Methods We conducted a disproportionality analysis of US Food and Drug Administration Adverse Event Reporting System (FAERS) between 2020Q1 and 2021Q1 to evaluate the association between lopinavir-ritonavir and risk of drug-induced liver injury (or severe drug-induced liver injury) and calculated their reporting odds ratios (RORs) with 95% confidence intervals (CIs). Results A total of 3,425 cases of drug-induced liver injury were reported in 19,782 patients with COVID-19. The ROR for drug-induced liver injury was 2.99 (2.59-3.46), 3.16 (2.68-3.73), and 5.39 (4.63-6.26) when comparing lopinavir-ritonavir with all other drugs, hydroxychloroquine/chloroquine only, and remdesivir, respectively. For severe drug-induced liver injury, RORs for lopinavir-ritonavir provided evidence of an association compared with all other drugs (3.98; 3.15-5.05), compared with hydroxychloroquine/chloroquine only (5.33; 4.09-6.94), and compared with remdesivir (3.85; 3.03-4.89). Conclusions In the FAERS, we observed a disproportional signal for drug-induced liver injury associated with lopinavir-ritonavir in patients with COVID-19.

Topics: Adverse Drug Reaction Reporting Systems; Aged; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; COVID-19; Drug Combinations; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Ritonavir; United States; United States Food and Drug Administration

At present, there is no definitive antiviral treatment for coronavirus disease 2019 (COVID-19). We describe our early experience with remdesivir in four critically ill COVID-19 patients. Patients received a 200 mg loading dose, followed by 100 mg daily intravenously for up to 10 days. All patients had been previously treated with other antivirals before remdesivir initiation. One patient experienced a torsade de pointes requiring cardiac resuscitation and one died due to multiple organ failure. Three patients showed biochemical signs of liver injury. Lymphocyte count increased in all patients soon after remdesivir initiation. Nasal swab SARS-CoV-2 RNA became negative in three of four patients after 3 days of therapy. We observed an in vivo virological effect of remdesivir in four critically ill, COVID-19 patients, coupled with a significant burden of adverse events. Although limited by the low number of subjects studied, our preliminary experience may be relevant for clinicians treating COVID-19.

Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; Betacoronavirus; Chemical and Drug Induced Liver Injury; Convalescence; Coronavirus Infections; COVID-19; Critical Illness; Darunavir; Drug Administration Schedule; Drug Combinations; Fatal Outcome; Humans; Hydroxychloroquine; Lopinavir; Multiple Organ Failure; Pandemics; Pneumonia, Viral; Ritonavir; RNA, Viral; SARS-CoV-2; Torsades de Pointes

Topics: Amides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Antiviral Agents; Betacoronavirus; Chemical and Drug Induced Liver Injury; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cytochrome P-450 Enzyme System; Drug Combinations; Drug Interactions; Histone Deacetylase Inhibitors; Humans; Hydroxychloroquine; Immunosuppression Therapy; Kidney Diseases; Long QT Syndrome; Lopinavir; Neoplasms; Pandemics; Pneumonia, Viral; Poly(ADP-ribose) Polymerase Inhibitors; Proteasome Inhibitors; Protein Kinase Inhibitors; Pyrazines; Ritonavir; SARS-CoV-2

Topics: Alanine Transaminase; Antiviral Agents; Aspartate Aminotransferases; Betacoronavirus; Chemical and Drug Induced Liver Injury; Chloroquine; Clinical Laboratory Techniques; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; COVID-19 Testing; Diagnosis, Differential; Drug Combinations; Hepatitis, Viral, Human; Humans; Liver; Liver Function Tests; Lopinavir; Male; Middle Aged; Pandemics; Pneumonia, Viral; Ritonavir; SARS-CoV-2

In late 2019, a new coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-was discovered in Wuhan, China, and the World Health Organization later declared coronavirus disease 2019 (COVID-19) a pandemic. Numerous drugs have been repurposed and investigated for therapeutic effectiveness in the disease, including those from "Solidarity," an international clinical trial (azithromycin, chloroquine, hydroxychloroquine, the fixed combination lopinavir/ritonavir, and remdesivir).. Our objective was to evaluate adverse drug reaction (ADR) reporting for drugs when used in the treatment of COVID-19 compared with use for other indications, specifically focussing on sex differences.. We extracted reports on COVID-19-specific treatments from the global ADR database, VigiBase, using an algorithm developed to identify reports that listed COVID-19 as the indication. The Solidarity trial drugs were included, as were any drugs reported ≥ 100 times. We performed a descriptive comparison of reports for the same drugs used in non-COVID-19 indications. The data lock point date was 7 June 2020.. In total, 2573 reports were identified for drugs used in the treatment of COVID-19. In order of frequency, the most reported ADRs were electrocardiogram QT-prolonged, diarrhoea, nausea, hepatitis, and vomiting in males and diarrhoea, electrocardiogram QT-prolonged, nausea, vomiting, and upper abdominal pain in females. Other hepatic and kidney-related events were included in the top ten ADRs in males, whereas no hepatic or renal terms were reported for females. COVID-19-related reporting patterns differed from non-pandemic reporting for these drugs.. Review of a global database of suspected ADR reports revealed sex differences in the reporting patterns for drugs used in the treatment of COVID-19. Patterns of ADR sex differences need further elucidation.

Topics: Abdominal Pain; Adenosine Monophosphate; Alanine; Antibodies, Monoclonal, Humanized; Antiviral Agents; Azithromycin; Chemical and Drug Induced Liver Injury; Chloroquine; COVID-19 Drug Treatment; Databases, Pharmaceutical; Diarrhea; Drug Combinations; Drug Eruptions; Drug Repositioning; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hydroxychloroquine; Long QT Syndrome; Lopinavir; Male; Nausea; Oseltamivir; Ritonavir; Sex Distribution; Sex Factors; Vomiting

Topics: Adolescent; Adult; Betacoronavirus; Chemical and Drug Induced Liver Injury; Child; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cytokines; Female; Humans; Inflammation; Male; Middle Aged; Pandemics; Pneumonia, Viral; Ritonavir; SARS-CoV-2; T-Lymphocyte Subsets; Young Adult

Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Carbamates; Chemical and Drug Induced Liver Injury; Creatinine; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Liver Function Tests; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Sodium; Sulfonamides; Uracil; Valine

Ritonavir (RTV) is on the World Health Organization's List of Essential Medicines for antiretroviral therapy, but can cause hepatotoxicity by unknown mechanisms. Multiple clinical studies found that hepatotoxicity occurred in 100% of participants who were pretreated with rifampicin or efavirenz followed by RTV-containing regimens. Both rifampicin and efavirenz are activators of the pregnane X receptor (PXR), a transcription factor with significant inter-species differences in ligand-dependent activation. Using PXR-humanized mouse models, we recapitulated the RTV hepatotoxicity observed in the clinic. PXR was found to modulate RTV hepatotoxicity through CYP3A4-dependent pathways involved in RTV bioactivation, oxidative stress, and endoplasmic reticulum stress. In summary, the current work demonstrated the essential roles of human PXR and CYP3A4 in RTV hepatotoxicity, which can be applied to guide the safe use of RTV-containing regimens in the clinic.

Topics: Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP3A; Disease Models, Animal; Endoplasmic Reticulum Stress; Humans; Mice; Oxidative Stress; Pregnane X Receptor; Ritonavir

Ritonavir (RIT) is a human immune deficiency virus (HIV) protease inhibitor (PI) active against HIV-1 and HIV-2. Among various adverse effects of PIs, hepatotoxicity is a very common adverse reaction of RIT which is concentration dependent. Red clover isoflavones are found to possess anti-inflammatory, antioxidant and anti-apoptosis activity. Furthermore, recent studies have demonstrated that these isoflavones can be used to alleviate the side-effects of drugs. Hence, the present study was inquested to ascertain the effect of Formononetin (FMN) and Biochanin A (BCA) on RIT induced hepatotoxicity.. Five groups of animals were subjected to treatment as control, toxic control (RIT), third group (RIT + FMN), fourth group (RIT + BCA), the fifth group (RIT + FMN + BCA) and sixth group (FMN + BCA) for 14 days. The animals were evaluated for estimation of liver toxicity markers, inflammatory biomarkers, in-vivo biochemical antioxidant parameters. The liver tissues were further evaluated histopathologically and western blotting examination for localization of apoptotic gene expression that plays a pivotal role in hepatotoxicity.. FMN and BCA ameliorated the increased levels of biochemical markers of liver, attenuated the RIT induced Bax, caspase-3, NFκB and eNOS activation and persuaded the Bcl. FMN and BCA exerts hepatoprotective effect through modulating the oxidative stress, inflammation, apoptosis and reversing the tissue degeneration suggesting its therapeutic role in hepatotoxicity and other hepatocellular diseases.

Topics: Animals; Antioxidants; Apoptosis; Chemical and Drug Induced Liver Injury; Genistein; Isoflavones; Liver; Liver Diseases; Male; NF-kappa B; Oxidative Stress; Protective Agents; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Ritonavir

Drug induced liver injury (DILI), a major cause of pre- and post-approval failure, is challenging to predict pre-clinically due to varied underlying direct and indirect mechanisms. Nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and Ritonavir, a protease inhibitor, are antiviral drugs that cause clinical DILI with different phenotypes via different mechanisms. Assessing DILI in vitro in hepatocyte cultures typically requires drug exposures significantly higher than clinical plasma Cmax concentrations, making clinical interpretations of mechanistic pathway changes challenging. We previously described a system that uses liver-derived hemodynamic blood flow and transport parameters to restore primary human hepatocyte biology, and drug responses at concentrations relevant to in vivo or clinical exposure levels. Using this system, primary hepatocytes from 5 human donors were exposed to concentrations approximating clinical therapeutic and supra-therapeutic levels of Nevirapine (11.3 and 175.0 μM) and Ritonavir (3.5 and 62.4 μM) for 48 h. Whole genome transcriptomics was performed by RNAseq along with functional assays for metabolic activity and function. We observed effects at both doses, but a greater number of genes were differentially expressed with higher probability at the toxic concentrations. At the toxic doses, both drugs showed direct cholestatic potential with Nevirapine increasing bile synthesis and Ritonavir inhibiting bile acid transport. Clear differences in antigen presentation were noted, with marked activation of MHC Class I by Nevirapine and suppression by Ritonavir. This suggests CD8+ T cell involvement for Nevirapine and possibly NK Killer cells for Ritonavir. Both compounds induced several drug metabolizing genes (including CYP2B6, CYP3A4 and UGT1A1), mediated by CAR activation in Nevirapine and PXR in Ritonavir. Unlike Ritonavir, Nevirapine did not increase fatty acid synthesis or activate the respiratory electron chain with simultaneous mitochondrial uncoupling supporting clinical reports of a lower propensity for steatosis. This in vitro study offers insights into the disparate direct and immune-mediated toxicity mechanisms underlying Nevirapine and Ritonavir toxicity in the clinic.

Topics: Anti-HIV Agents; Cell Culture Techniques; Cells, Cultured; Chemical and Drug Induced Liver Injury; Drug Evaluation, Preclinical; Hepatocytes; Humans; Liver; Nevirapine; Ritonavir; Transcriptome

Ritonavir is an antiretroviral drug to treat HIV AIDS and inhibits cytochrome P450 3A4. To treat diabetes mellitus in HIV, repaglinide is coadministered with ritonavir in the clinic. Multiple cytochrome P450 (CYP) isoforms are involved in the metabolism of repaglinide like CYP2C8 and CYP 3A4. In order to predict and understand drug-drug interactions of these two drugs, the pharmacokinetics and pharmacodynamics (PK/PD) of repaglinide and ritonavir were studied in normal, diabetic and hepatic impaired rats. The purpose of the study was to assess the influence of ritonavir on the PK/PD of repaglinide in rats with normal, diabetic and impaired hepatic function.. Human oral therapeutic doses of ritonavir and repaglinide were extrapolated to rats based on the body surface area. Ritonavir (20 mg/kg, p.o.), alone and along with repaglinide (0.5 mg/kg, p.o.), was given to normal, diabetic and hepatic impaired rats, and the PK/PD were studied.. The pharmacokinetic parameters like peak plasma concentration (Cmax), area under the plasma concentration time profile (AUC) and elimination half life of repaglinide were significantly (p<0.0001) increased when compared to repaglinide control rats. The repaglinide clearance (CL) was significantly (p<0.0001) decreased in the presence of ritonavir treatment. In the presence of ritonavir, repaglinide hypoglycemic activity was increased significantly (p<0.0005) when compared with repaglinide control group.. The significant difference in the PK/PD changes have been due to the increased plasma exposure and decreased total body clearance of repaglinide, which may be due to the inhibition of the CYP P450 metabolic system and organic anion-transporting polypeptide transporter by ritonavir.

Topics: Alloxan; Animals; Blood Glucose; Carbamates; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Experimental; Drug Synergism; Male; Piperidines; Rats; Ritonavir

Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin is one of the current recommended therapies for HCV genotype 1b monoinfected patients in compensated (Child-Pugh A) cirrhosis. Whether it is known that the worsening of liver function is a rare but possible complication of Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir therapy, to our knowledge no description of treatment-related acute liver failure is available in the literature.. An 84-year-old Caucasian man with chronic compensated HCV genotype 1b cirrhosis received Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin therapy. After 13 days he developed grade 4 hyperbilirubinaemia and ascites. Even though treatment was promptly stopped, patient's clinical condition worsened, and he underwent hospitalization, several paracentheses, and developed sub-acute kidney injury. The bilirubinemia returned under three times the upper normal limit only after five months. Notably, he achieved sustained virological response despite the very short duration of therapy.. Hepatic decompensation and acute liver failure are rare but severe complications of Ritonavir-boosted Paritaprevir, Ombitasvir and Dasabuvir plus Ribavirin therapy in patients with compensated cirrhosis. Close monitoring for signs or symptoms of worsening of liver disease is mandatory, and further research for stratifying risk factors are required.

Topics: 2-Naphthylamine; Aged, 80 and over; Anilides; Antiviral Agents; Ascites; Carbamates; Chemical and Drug Induced Liver Injury; Cyclopropanes; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Hyperbilirubinemia; Lactams, Macrocyclic; Liver Cirrhosis; Liver Failure, Acute; Liver Function Tests; Macrocyclic Compounds; Male; Proline; Ritonavir; Sulfonamides; Sustained Virologic Response; Time Factors; Treatment Outcome; Uracil; Valine

Drug-induced liver injury (DILI) accounts for 20-40% of all instances of clinical hepatic failure and is a common reason for withdrawal of an approved drug or discontinuation of a potentially new drug from clinical/nonclinical development. Numerous individual risk factors contribute to the susceptibility to human DILI and its severity that are either compound- and/or patient-specific. Compound-specific primary mechanisms linked to DILI include: cytotoxicity, reactive metabolite formation, inhibition of bile salt export pump (BSEP), and mitochondrial dysfunction. Since BSEP is an energy-dependent protein responsible for the efflux of bile acids from hepatocytes, it was hypothesized that humans exposed to drugs that impair both mitochondrial energetics and BSEP functional activity are more sensitive to more severe manifestations of DILI than drugs that only have a single liability factor. As annotated in the United States National Center for Toxicological Research Liver Toxicity Knowledge Base (NCTR-LTKB), the inhibitory properties of 24 Most-DILI-, 28 Less-DILI-, and 20 No-DILI-concern drugs were investigated. Drug potency for inhibiting BSEP or mitochondrial activity was generally correlated across human DILI concern categories. However, drugs with dual potency as mitochondrial and BSEP inhibitors were highly associated with more severe human DILI, more restrictive product safety labeling related to liver injury, and appear more sensitive to the drug exposure (Cmax) where more restrictive labeling occurs.. These data affirm that severe manifestations of human DILI are multifactorial, highly associated with combinations of drug potency specifically related to known mechanisms of DILI (like mitochondrial and BSEP inhibition), and, along with patient-specific factors, lead to differences in the severity and exposure thresholds associated with clinical DILI.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Chemical and Drug Induced Liver Injury; Humans; Male; Mitochondria, Liver; Rats; Rats, Sprague-Dawley; Severity of Illness Index

Drugs like statins may induce rhabdomyolysis. Simvastatin and lovastatin have a high hepatic metabolism and their potential toxicity could be increased by interactions with other drugs that reduce their metabolism.. A case-report is presented of an HIV-infected patient treated with antiretroviral drugs who developed a rhabdomyolysis-induced renal failure and liver toxicity when simvastatin was substituted for atorvastatin. A literature review is also presented.. The patient required hospital admission and showed a favorable response after hydration and urine alkalinization. There were 4 additional cases published of which there was one death.. Drug-drug interactions can increase the risk of statin induced rhabdomyolysis. In order to evaluate them properly, physicians at all levels of clinical care should be aware of all drugs prescribed to their patients and the contraindicated combinations.

Topics: Antiretroviral Therapy, Highly Active; Atorvastatin; Chemical and Drug Induced Liver Injury; Comorbidity; Contraindications; Cost-Benefit Analysis; Cytochrome P-450 CYP3A Inhibitors; Drug Substitution; Drug Synergism; Dyslipidemias; Female; HIV Infections; HIV Protease Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Tubular Necrosis, Acute; Middle Aged; Rhabdomyolysis; Ritonavir; Simvastatin

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Liver enzyme elevations (LEE) were investigated in 2717 episodes of initiation of antiretroviral therapy since January 2010 in 1982 HIV patients. Serum hepatitis C virus (HCV)-RNA was positive in 24%. Any grade of LEE was recognized in 9% of episodes, being 6% in HCV-negative and 17% in HCV-positive patients (P < 0.001). Grades 3-4 LEE only occurred in 0.4% of patients. Overall, LEE were more frequent with ritonavir-boosted darunavir and atazanavir than with raltegravir and etravirine.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Coinfection; Cyclopropanes; Darunavir; Female; Follow-Up Studies; Hepatitis C; HIV Infections; Humans; Liver; Male; Nevirapine; Oligopeptides; Pyridines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

Drug-induced liver injury is a major issue of concern and has led to the withdrawal of a significant number of marketed drugs. An understanding of structure-activity relationships (SARs) of chemicals can make a significant contribution to the identification of potential toxic effects early in the drug development process and aid in avoiding such problems. This process can be supported by the use of existing toxicity data and mechanistic understanding of the biological processes for related compounds. In the published literature, this information is often spread across diverse sources and can be varied and unstructured in quality and content. The current work has explored whether it is feasible to collect and use such data for the development of new SARs for the hepatotoxicity endpoint and expand upon the limited information currently available in this area. Reviews of hepatotoxicity data were used to build a structure-searchable database, which was analyzed to identify chemical classes associated with an adverse effect on the liver. Searches of the published literature were then undertaken to identify additional supporting evidence, and the resulting information was incorporated into the database. This collated information was evaluated and used to determine the scope of the SARs for each class identified. Data for over 1266 chemicals were collected, and SARs for 38 classes were developed. The SARs have been implemented as structural alerts using Derek for Windows (DfW), a knowledge-based expert system, to allow clearly supported and transparent predictions. An evaluation exercise performed using a customized DfW version 10 knowledge base demonstrated an overall concordance of 56% and specificity and sensitivity values of 73% and 46%, respectively. The approach taken demonstrates that SARs for complex endpoints can be derived from the published data for use in the in silico toxicity assessment of new compounds.

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Humans; Structure-Activity Relationship; Tetracyclines; Thiophenes

The bile salt export pump (BSEP) is an efflux transporter, driving the elimination of endobiotic and xenobiotic substrates from hepatocytes into the bile. More specifically, it is responsible for the elimination of monovalent, conjugated bile salts, with little or no assistance from other apical transporters. Disruption of BSEP activity through genetic disorders is known to manifest in clinical liver injury such as progressive familial intrahepatic cholestasis type 2. Drug-induced disruption of BSEP is hypothesized to play a role in the development of liver injury for several marketed or withdrawn therapeutics. Unfortunately, preclinical animal models have been poor predictors of the liver injury associated with BSEP interference observed for humans, possibly because of interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation or constitutive expression, as well as other mechanisms. Thus, a BSEP-mediated liver liability may go undetected until the later stages of drug development, such as during clinical trials or even postlicensing. In the absence of a relevant preclinical test system for BSEP-mediated liver injury, the toxicological relevance of available in vitro models to human health rely on the use of benchmark compounds with known clinical outcomes, such as marketed or withdrawn drugs. In this study, membrane vesicles harvested from BSEP-transfected insect cells were used to assess the activity of more than 200 benchmark compounds to thoroughly investigate the relationship between interference with BSEP function and liver injury. The data suggest a relatively strong association between the pharmacological interference with BSEP function and human hepatotoxicity. Although the most accurate translation of risk would incorporate pharmacological potency, pharmacokinetics, clearance mechanisms, tissue distribution, physicochemical properties, indication, and other drug attributes, the additional understanding of a compound's potency for BSEP interference should help to limit or avoid BSEP-related liver liabilities in humans that are not often detected by standard preclinical animal models.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Assay; Biological Transport; Cell Line; Cell Membrane; Chemical and Drug Induced Liver Injury; Cytoplasmic Vesicles; Drug Evaluation, Preclinical; Humans; Liver; Rats; Reproducibility of Results; Spodoptera; Transfection; Xenobiotics

Drug-induced liver injury (DILI) is one of the most important reasons for drug development failure at both preapproval and postapproval stages. There has been increased interest in developing predictive in vivo, in vitro, and in silico models to identify compounds that cause idiosyncratic hepatotoxicity. In the current study, we applied machine learning, a Bayesian modeling method with extended connectivity fingerprints and other interpretable descriptors. The model that was developed and internally validated (using a training set of 295 compounds) was then applied to a large test set relative to the training set (237 compounds) for external validation. The resulting concordance of 60%, sensitivity of 56%, and specificity of 67% were comparable to results for internal validation. The Bayesian model with extended connectivity functional class fingerprints of maximum diameter 6 (ECFC_6) and interpretable descriptors suggested several substructures that are chemically reactive and may also be important for DILI-causing compounds, e.g., ketones, diols, and α-methyl styrene type structures. Using Smiles Arbitrary Target Specification (SMARTS) filters published by several pharmaceutical companies, we evaluated whether such reactive substructures could be readily detected by any of the published filters. It was apparent that the most stringent filters used in this study, such as the Abbott alerts, which captures thiol traps and other compounds, may be of use in identifying DILI-causing compounds (sensitivity 67%). A significant outcome of the present study is that we provide predictions for many compounds that cause DILI by using the knowledge we have available from previous studies. These computational models may represent cost-effective selection criteria before in vitro or in vivo experimental studies.

Topics: Bayes Theorem; Chemical and Drug Induced Liver Injury; Humans; Ligands

In RESIST, enfuvirtide co-administered with ritonavir-boosted tipranavir was associated with higher plasma tipranavir concentrations, which seldom rose above those associated with an increased risk of grade 3/4 transaminase elevations. Transaminase elevation rates (6.5%) and clinical hepatic event rates (5.9 events/100 person exposure years) were lower in the tipranavir/ritonavir with enfuvirtide group than in the tipranavir/ritonavir without enfuvirtide group. Observed increases in plasma tipranavir concentrations thus had no apparent effect on the risk of hepatotoxicity.

Topics: Alanine Transaminase; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Liver Diseases; Lopinavir; Peptide Fragments; Pyridines; Pyrimidinones; Pyrones; Randomized Controlled Trials as Topic; Ritonavir; Saquinavir; Sulfonamides; Treatment Outcome; Viral Load

Topics: Chemical and Drug Induced Liver Injury; Drug Industry; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Rifampin; Ritonavir; Saquinavir; United States

We describe the hepatotoxicity encountered in a cohort of HIV-positive patients treated with lopinavir/ritonavir. We used the database from the SCOLTA project, an on-line pharmacovigilance programme involving 25 Italian infectious disease centres. A total of 755 patients were followed, over a mean observation period of 16 months. The incidence of severe events was low despite the high prevalence of patients co-infected with hepatitis virus at enrollment.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Italy; Liver Diseases; Lopinavir; Male; Middle Aged; Product Surveillance, Postmarketing; Pyrimidinones; Ritonavir

Topics: Chemical and Drug Induced Liver Injury; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Liver; Lopinavir; Pyrimidinones; Ritonavir

Hepatotoxicity has been demonstrated to be associated with antiretroviral therapy. Previous studies have included small numbers of patients and, thus, were unable to produce adequate statistical comparisons. I review data analyses from the Amsterdam, CHORUS, ICONA and Target studies (5133 patients), which were conducted by a number of investigators. There were differences between the cohorts with respect to the incidence of viral hepatitis and definitions of hepatotoxicity used. However, in all cohorts, hepatotoxicity in human immunodeficiency virus type 1-infected patients was significantly associated with coinfection with viral hepatitis. In 3 cohorts, elevated baseline alanine aminotransferase levels predicted subsequent hepatotoxicity. Overall, there was a low incidence of long-term hepatotoxicity in these cohorts and no consistent association between a particular drug or drug class. Nevirapine use within the first 12 weeks after initiation of therapy with this drug and ritonavir use are associated with increased risk of antiretroviral-associated hepatotoxicity.

Topics: Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Cohort Studies; Humans; Multivariate Analysis; Nevirapine; Ritonavir

Topics: Acute Disease; Adult; Alanine Transaminase; Anti-Inflammatory Agents; Anus Neoplasms; Aryl Hydrocarbon Hydroxylases; Budesonide; Carcinoma, Squamous Cell; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Middle Aged; Oxidoreductases, N-Demethylating; Ritonavir

This retrospective cohort study investigated whether particular antiretroviral agents are associated with a higher risk for developing grade 4 liver enzyme elevations (LEEs) in patients with human immunodeficiency virus (HIV) type 1 infection who are starting to receive highly active antiretroviral therapy (HAART). Grade 4 LEE was defined as aminotransferase levels >10 times the upper limit of normal and >200 U above baseline levels. A multivariate Cox model was used to identify risk factors. The incidence of LEE was 6.3%. No patients died of LEE consequences. Risk factors were higher baseline alanine aminotransferase levels, chronic hepatitis B or C virus infection, antiretroviral therapy-naive patients undergoing their first HAART regimen, recent start of a regimen of nevirapine or high-dose ritonavir, and female sex. In hepatitis B virus (HBV)-coinfected patients, discontinuing lamivudine (3TC) use was a risk factor. In 97% of cases, >or=1 risk factor was present. In HBV-coinfected patients using 3TC, continued use of 3TC should be considered, even if 3TC-resistant HIV strains develop.

Topics: Adult; Alanine Transaminase; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Chemical and Drug Induced Liver Injury; Cohort Studies; Female; Hepatitis B; Hepatitis C; HIV Infections; HIV-1; Humans; Incidence; Lamivudine; Liver Function Tests; Male; Nevirapine; Proportional Hazards Models; Retrospective Studies; Reverse Transcriptase Inhibitors; Risk Factors; Ritonavir; Sex Factors; Transaminases

Ritonavir (RTV), a protease inhibitor, and carbamazepine (CBZ), an anticonvulsant, were administered concurrently to a patient who had human immunodeficiency virus infection and epilepsy. The combination resulted in elevated serum concentrations of CBZ, with accompanying vomiting, vertigo, and transient liver dysfunction. After discontinuing RTV and reducing the dosage of CBZ, the serum concentration of CBZ returned to the optimal range, symptoms subsided, and liver function returned to baseline. Carbamazepine is metabolized in the liver to a large extent by the cytochrome P450 (CYP) system, especially CYP3A4, 2C8, and 1A2, whereas RTV is metabolized primarily by CYP3A and is a potent inhibitor of this enzyme. Careful clinical monitoring may help prevent adverse drug interactions when these drugs are administered concurrently.

Topics: Adult; Anti-HIV Agents; Anticonvulsants; Carbamazepine; Chemical and Drug Induced Liver Injury; Drug Interactions; Humans; Male; Ritonavir; Vertigo; Vomiting

Acute hepatitis led to abnormal coagulopathy, bleeding, and death in a nonhemophiliac infant infected with the human immunodeficiency virus, possibly due to zidovudine or ritonavir or both. Acute hepatitis during ritonavir treatment and episodes of spontaneous bleeding have been reported in patients with hemophilia. Zidovudine is associated with elevated liver enzymes, elevated bilirubin, and hepatomegaly leading to abnormal coagulopathy, bleeding, and death in adults. A temporal relationship between the start of combination antiretroviral therapy and onset of hepatosplenomegaly and rise in liver enzymes suggests that zidovudine or ritonavir, or both, are the likely cause of this adverse event. Ritonavir is believed to cause direct hepatotoxicity, probably by inducing acute mitochondrial toxicity, and may hasten reverse transcriptase inhibitor-induced liver toxicity. Liver function of patients receiving a combination of nucleoside reverse transcriptase inhibitor and protease inhibitors should be closely monitored.

Topics: Acute Disease; Anti-HIV Agents; Chemical and Drug Induced Liver Injury; Fatal Outcome; Hemorrhage; HIV Infections; Humans; Infant; Male; Ritonavir; Zidovudine

Topics: Acquired Immunodeficiency Syndrome; Acute Kidney Injury; Adult; Alcoholism; Chemical and Drug Induced Liver Injury; Hepatitis C, Chronic; HIV Protease Inhibitors; Humans; Indinavir; Male; Rhabdomyolysis; Ritonavir

Some reports have suggested that drug-induced hepatotoxicity can be associated with antiretroviral therapy in HIV-positive people coinfected with chronic hepatitis C virus (HCV). Several presentations at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) examined this possible interaction. The impact of highly active antiretroviral therapy (HAART) on persons coinfected with HCV was described. There is increasing clinical recognition that HCV can lead to significant liver-related morbidity and mortality among HIV-infected persons.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Ritonavir; RNA, Viral

Topics: Adult; Biological Availability; Chemical and Drug Induced Liver Injury; Child; Clinical Trials as Topic; Drug Interactions; Gastrointestinal Diseases; HIV Infections; HIV Protease Inhibitors; Humans; Ritonavir