RESUMO
BACKGROUND: The clinical candidate alpibectir augments the activity of, and overcomes resistance to, the anti-TB drug ethionamide in vitro and in vivo. OBJECTIVES: A Phase 1, double-blind, randomized, placebo-controlled study to investigate the safety, tolerability, pharmacokinetics (PK) and food effect of alpibectir administered as single and multiple oral doses in healthy volunteers (NCT04654143). METHODS: Eighty participants were randomized. In single ascending dose (SAD), a total of six dose levels of alpibectir (0.5 to 40â mg) were tested under fasted and fed (10â mg) conditions as single daily doses in sequential cohorts. In multiple ascending dose (MAD), repeat doses (5 to 30â mg) were administered once daily for 7â days in three sequential cohorts. RESULTS: No serious adverse event was reported. Thirteen participants across groups experienced a total of 13 mild or moderate treatment-emergent adverse events. Alpibectir showed rapid absorption after single dose (mean Tmax range of 0.88 to 1.53â h). Food affected the PK of alpibectir, characterized by a slower absorption (mean Tmax 3.87â h), a lower Cmax (-17.7%) and increased AUC0-t (+19.6%) compared with the fasted condition. Following repeat dosing, dose proportionality was shown for both Cmax and AUC0-tau. Accumulation of alpibectir was observed across all doses, with a more profound effect on AUC during a dosing interval (AUC0-tau) compared with Cmax (1.8- and 1.3-fold on average), respectively. Steady state was considered to have been achieved by Day 7 of dosing. CONCLUSIONS: Alpibectir was generally well tolerated, and no clinically relevant safety findings were identified in the participants treated during SAD or MAD. The PK is dose-proportional and affected by food.
Assuntos
Antituberculosos , Voluntários Saudáveis , Humanos , Adulto , Masculino , Feminino , Método Duplo-Cego , Adulto Jovem , Pessoa de Meia-Idade , Antituberculosos/farmacocinética , Antituberculosos/administração & dosagem , Antituberculosos/efeitos adversos , Interações Alimento-Droga , Administração Oral , Adolescente , Placebos/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a MedicamentosRESUMO
New tuberculosis treatments are needed to address drug resistance, lengthy treatment duration and adverse reactions of available agents. GSK3036656 (ganfeborole) is a first-in-class benzoxaborole inhibiting the Mycobacterium tuberculosis leucyl-tRNA synthetase. Here, in this phase 2a, single-center, open-label, randomized trial, we assessed early bactericidal activity (primary objective) and safety and pharmacokinetics (secondary objectives) of ganfeborole in participants with untreated, rifampicin-susceptible pulmonary tuberculosis. Overall, 75 males were treated with ganfeborole (1/5/15/30 mg) or standard of care (Rifafour e-275 or generic alternative) once daily for 14 days. We observed numerical reductions in daily sputum-derived colony-forming units from baseline in participants receiving 5, 15 and 30 mg once daily but not those receiving 1 mg ganfeborole. Adverse event rates were comparable across groups; all events were grade 1 or 2. In a participant subset, post hoc exploratory computational analysis of 18F-fluorodeoxyglucose positron emission tomography/computed tomography findings showed measurable treatment responses across several lesion types in those receiving ganfeborole 30 mg at day 14. Analysis of whole-blood transcriptional treatment response to ganfeborole 30 mg at day 14 revealed a strong association with neutrophil-dominated transcriptional modules. The demonstrated bactericidal activity and acceptable safety profile suggest that ganfeborole is a potential candidate for combination treatment of pulmonary tuberculosis.ClinicalTrials.gov identifier: NCT03557281 .
Assuntos
Aminoacil-tRNA Sintetases , Tuberculose Pulmonar , Tuberculose , Masculino , Humanos , Rifampina/uso terapêutico , Antituberculosos/efeitos adversos , Tuberculose/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Aminoacil-tRNA Sintetases/uso terapêuticoRESUMO
Inhibition of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzymatic step in de novo pyrimidine synthesis, has broad immunosuppressive effects in vivo and shows promise as a therapeutic target for the treatment of malignancies, viral infections and auto-immune diseases. Whilst there are numerous DHODH inhibitors under development, leflunomide and teriflunomide are the only FDA approved compounds on the market, each of which have been issued with black-box warnings for hepatotoxicity. Mitochondrial dysfunction is a putative mechanism by which teriflunomide and leflunomide elicit their hepatotoxic effects, however it is as yet unclear whether this is shared by other nascent DHODH inhibitors. The present study aimed to evaluate the propensity for DHODH inhibitors to mediate mitochondrial dysfunction in two hepatic in vitro models. Initial comparisons of cytotoxicity and ATP content in HepaRG® cells primed for oxidative metabolism, in tandem with mechanistic evaluations by extracellular flux analysis identified multifactorial toxicity and moderate indications of respiratory chain dysfunction or uncoupling. Further investigations using HepG2 cells, a hepatic line with limited capability for phase I xenobiotic metabolism, identified leflunomide and brequinar as positive mitochondrial toxicants. Taken together, biotransformation of some DHODH inhibitor species may play a role in mediating or masking hepatic mitochondrial liabilities.
Assuntos
Antineoplásicos/toxicidade , Imunossupressores/toxicidade , Fígado/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Compostos de Bifenilo/toxicidade , Linhagem Celular , Respiração Celular/efeitos dos fármacos , Crotonatos/toxicidade , Ácidos Dicarboxílicos/toxicidade , Di-Hidro-Orotato Desidrogenase , Humanos , Hidroxibutiratos/toxicidade , Leflunomida/toxicidade , Fígado/metabolismo , Mitocôndrias/metabolismo , Modelos Biológicos , Nitrilas/toxicidade , Salicilanilidas/toxicidade , Toluidinas/toxicidade , Triazóis/toxicidadeRESUMO
Flucloxacillin is a ß-lactam antibiotic associated with a high incidence of drug-induced liver reactions. Although expression of HLA-B*57:01 increases susceptibility, little is known about the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the presentation of flucloxacillin-modified peptides by the risk allele. In this study, the binding of flucloxacillin to proteins of liver-like cells was characterized. Flucloxacillin was shown to bind to proteins localized in bile canaliculi regions, coinciding with the site of clinical disease. The localization of flucloxacillin was mediated primarily by the membrane transporter multidrug resistance-associated protein 2. Modification of multiple proteins by flucloxacillin in bile canaliculi regions may provide a potential local source of neo-antigens for HLA presentation in the liver.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Floxacilina/química , Humanos , Estrutura MolecularRESUMO
Intense efforts are underway to evaluate potential therapeutic agents for the treatment of COVID-19. In order to respond quickly to the crisis, the repurposing of existing drugs is the primary pharmacological strategy. Despite the urgent clinical need for these therapies, it is imperative to consider potential safety issues. This is important due to the harm-benefit ratios that may be encountered when treating COVID-19, which can depend on the stage of the disease, when therapy is administered and underlying clinical factors in individual patients. Treatments are currently being trialled for a range of scenarios from prophylaxis (where benefit must greatly exceed risk) to severe life-threatening disease (where a degree of potential risk may be tolerated if it is exceeded by the potential benefit). In this perspective, we have reviewed some of the most widely researched repurposed agents in order to identify potential safety considerations using existing information in the context of COVID-19.
Assuntos
Antivirais/efeitos adversos , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Reposicionamento de Medicamentos , Humanos , Pandemias , Medição de Risco , SegurançaRESUMO
During its clinical development fialuridine caused liver toxicity and the death of five patients. This case remains relevant due to the continued development of mechanistically-related compounds against a back-drop of simple in vitro models which remain limited for the preclinical detection of such delayed toxicity. Here, proteomic investigation of a differentiated, HepaRG, and proliferating, HepG2 cell model was utilised to confirm the presence of the hENT1 transporter, thymidine kinase-1 and -2 (TK1, TK2) and thymidylate kinase, all essential in order to reproduce the cellular activation and disposition of fialuridine in the clinic. Acute metabolic modification assays could only identify mitochondrial toxicity in HepaRG cells following extended dosing, 2 weeks. Toxic effects were observed around 10 µM, which is within a range of 10-15 X approximate Cmax. HepaRG cell death was accompanied by a significant decrease in mitochondrial DNA content, indicative of inhibition of mitochondrial replication, and a subsequent reduction in mitochondrial respiration and the activity of mitochondrial respiratory complexes, not replicated in HepG2 cells. The structural epimer of fialuridine, included as a pharmacological negative control, was shown to have no cytotoxic effects in HepaRG cells up to 4 weeks. Overall, these comparative studies demonstrate the HepaRG model has translational relevance for fialuridine toxicity and therefore may have potential in investigating the inhibition of mitochondrial replication over prolonged exposure for other toxicants.
Assuntos
Antivirais/farmacologia , Arabinofuranosiluracila/análogos & derivados , Hepatócitos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Arabinofuranosiluracila/farmacologia , Linhagem Celular Tumoral , Replicação do DNA/efeitos dos fármacos , DNA Mitocondrial/fisiologia , Relação Dose-Resposta a Droga , Humanos , Mitocôndrias/fisiologiaRESUMO
A structural motif that is found in two cancer drugs may be responsible for their ability to tackle cancers and for the side-effects caused by the drugs.
Assuntos
Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias , Complexo I de Transporte de Elétrons , Humanos , MitocôndriasRESUMO
The mitochondrion is an essential organelle responsible for generating cellular energy. Additionally, mitochondria are a source of inter-individual variation as they contain their own genome. Evidence has revealed that mitochondrial DNA (mtDNA) variation can confer differences in mitochondrial function and importantly, these differences may be a factor underlying the idiosyncrasies associated with unpredictable drug-induced toxicities. Thus far, preclinical and clinical data are limited but have revealed evidence in support of an association between mitochondrial haplogroup and susceptibility to specific adverse drug reactions. In particular, clinical studies have reported associations between mitochondrial haplogroup and antiretroviral therapy, chemotherapy and antibiotic-induced toxicity, although study limitations and conflicting findings mean that the importance of mtDNA variation to toxicity remains unclear. Several studies have used transmitochondrial cybrid cells as personalised models with which to study the impact of mitochondrial genetic variation. Cybrids allow the effects of mtDNA to be assessed against a stable nuclear background and thus the in vitro elucidation of the fundamental mechanistic basis of such differences. Overall, the current evidence supports the tenet that mitochondrial genetics represent an exciting area within the field of personalised medicine and drug toxicity. However, further research effort is required to confirm its importance. In particular, efforts should focus upon translational research to connect preclinical and clinical data that can inform whether mitochondrial genetics can be useful to identify at risk individuals or inform risk assessment during drug development.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Genótipo , Mitocôndrias/genética , Animais , Antibacterianos/toxicidade , Antirretrovirais/toxicidade , Antineoplásicos/toxicidade , Núcleo Celular , DNA Mitocondrial/genética , Desenvolvimento de Medicamentos , Variação Genética , Haplótipos , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Bile acids (BAs) are recognised as the causative agents of toxicity in drug-induced cholestasis (DIC). Research in isolated mitochondria and HepG2 cells have demonstrated BA-mediated mitochondrial dysfunction as a key mechanism of toxicity in DIC. However, HepG2 cells are of limited suitability for DIC studies as they do not express the necessary physiological characteristics. In this study, the mitotoxic potentials of BA mixtures were assessed in isolated mitochondria and a better-suited hepatic model, HepaRG cells. BAs induced structural alterations and a loss of mitochondrial membrane potential (MMP) in isolated mitochondria however, this toxicity did not translate to HepaRG cells. There were no changes in oxygen consumption rate, MMP or ATP levels in glucose and galactose media, indicating that there was no direct mitochondrial toxicity mediated via electron transport chain dysfunction in HepaRG cells. Assessment of key biliary transporters revealed that there was a time-dependent reduction in the expression and activity of multi-drug resistance protein 2 (MRP2), which was consistent with the induction of cytotoxicity in HepaRG cells. Overall, the findings from this study have demonstrated that mitochondrial dysfunction is not a mechanism of BA-induced toxicity in HepaRG cells.