RESUMO
The CNS disposition and metabolism of Fosdevirine (FDV), an HIV non-nucleoside reverse transcriptase inhibitor, was investigated in four patients who unexpectedly experienced seizures after at least 4 weeks of treatment in a Phase IIb, HIV-1 treatment experienced study. In addition, the CNS disposition and metabolism of FDV was examined in samples from rabbit, minipig, and monkey studies. LC-MS was used to characterize and estimate the concentrations of FDV and its metabolites in cerebral spinal fluid (seizure patients, rabbit, and monkey) and brain homogenate (rabbit, minipig, and monkey). The application of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) provided the spatial distribution of FDV and its metabolites in brain tissue (rabbit, minipig, and monkey). A cysteine conjugate metabolite resulting from an initial glutathione (GSH) Michael addition to the trans-phenyl acrylonitrile moiety of FDV was the predominant drug-related component in the samples from seizure patients, rabbits, and minipigs. This metabolite persisted in the CNS for an extended period of time after the last dose in both seizure patients and minipigs. Furthermore, the localization of this metabolite was found to be highly associated with the white matter in rabbit and minipig brain sections by MALDI IMS. In contrast, the predominant component in monkey CNS was FDV, which was shown to be highly associated with the gray matter. On the basis of these data, several hypothesizes are considered, which might provide insights into species differences in CNS toxicity/seizures observed after FDV dosing.
Assuntos
Sistema Nervoso Central/metabolismo , Indóis/metabolismo , Indóis/farmacocinética , Ácidos Fosfínicos/metabolismo , Ácidos Fosfínicos/farmacocinética , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Cromatografia Líquida/métodos , Feminino , Haplorrinos , Humanos , Indóis/toxicidade , Masculino , Ácidos Fosfínicos/toxicidade , Coelhos , Inibidores da Transcriptase Reversa/toxicidade , Suínos , Porco MiniaturaRESUMO
AIM: To evaluate potential drug interactions with antiretroviral therapies or supportive therapies for use in conjunction with the once daily, next generation non-nucleoside reverse transcriptase inhibitor GSK2248761 in patients with HIV-1 infection. METHODS: A series of phase I drug interaction studies was conducted. RESULTS: GSK2248761 was shown to be a weak CYP3A4 and CYP2D6 inhibitor in a clinical study with a probe cocktail. Mean plasma concentration-time profiles for atazanavir, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), darunavir (DRV, administered with ritonavir [RTV]), and drospirenone/ethinylestradiol were similar following co-administration of GSK2248761. Plasma raltegravir AUC(0,τ) and C(max) increased by 18% with no change in Cτ when raltegravir was co-administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), C(max) and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and C(max) increased following co-administration with GSK2248761, with the largest changes observed for simvastatin (3.7-fold and 4.3-fold). Changes in maximum and extent of GSK2248761 exposure were marginal after co-administration with atazanavir, TDF/FTC and raltegravir compared with GSK2248761 administered alone. Co-administration of GSK2248761 with DRV/RTV and LPV/RTV increased plasma GSK2248761 exposures by 1.25- to ≤2-fold compared with GSK2248761 administered alone, and increases in GSK2248761 exposure were higher following single dose co-administration of DRV/RTV or LPV/RTV compared with multiple doses. There were few drug-related AEs, and no treatment-related trends in blood chemistry, haematology, urinalysis, vital signs or ECG findings. CONCLUSIONS: These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated.
Assuntos
Fármacos Anti-HIV/farmacocinética , Indóis/farmacocinética , Ácidos Fosfínicos/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Adenina/administração & dosagem , Adenina/análogos & derivados , Adenina/farmacocinética , Androstenos/administração & dosagem , Androstenos/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Sulfato de Atazanavir , Atorvastatina , Anticoncepcionais Orais/administração & dosagem , Anticoncepcionais Orais/farmacocinética , Estudos Cross-Over , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Darunavir , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Método Duplo-Cego , Combinação de Medicamentos , Interações Medicamentosas , Emtricitabina , Etinilestradiol/administração & dosagem , Etinilestradiol/farmacocinética , Feminino , Fluorbenzenos/administração & dosagem , Fluorbenzenos/farmacocinética , Ácidos Heptanoicos/administração & dosagem , Ácidos Heptanoicos/farmacocinética , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Indóis/administração & dosagem , Análise dos Mínimos Quadrados , Modelos Lineares , Lopinavir/administração & dosagem , Lopinavir/farmacocinética , Masculino , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacocinética , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacocinética , Segurança do Paciente , Ácidos Fosfínicos/administração & dosagem , Piridinas/administração & dosagem , Piridinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirróis/administração & dosagemRESUMO
A model that predicts human metabolism and disposition of drug candidates would be of value in early drug development. In this study, a chimeric (uPA+/+)/SCID mouse model was evaluated with three structurally distinct compounds (GW695634, a benzophenone, SB-406725, a tetrahydroisoquinoline and GW823093, a fluoropyrrolidine) for which human metabolism and disposition was characterized. Human metabolite profiles in plasma and/or urine were compared to those of chimeric (uPA+/+)/SCID and control CD-1 or (uPA+/+)/SCID) mice. GW695634 and SB-406725 exhibited primarily hepatic metabolism and were chosen as probes to assess which human metabolites would likely circulate systemically. GW823093 exhibited a combination of hepatic and extrahepatic metabolism such that renal excretion of drug-related material was ~2-fold greater in humans than in mice, and thus chosen as a probe to assess if the chimeric (uPA+/+)/SCID mouse would predict the urinary excretion of human metabolites. We observed that human metabolism and disposition was well represented for GW695634, somewhat represented for GW823093 and minimally represented for SB-406725. Collectively, the results of this and other studies suggest that while limitations for prediction of human metabolism and disposition exist, humanized chimeric mouse models can potentially represent informative new tools in drug discovery and development.
Assuntos
Quimera/metabolismo , Fígado/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Animais , Benzofenonas/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos SCID , Fenilalanina/análogos & derivados , Fenilalanina/metabolismo , Pirrolidinas/metabolismo , Sulfonamidas/metabolismo , Tetra-Hidroisoquinolinas/metabolismoRESUMO
GW695634 is the prodrug of GW678248, a novel non-nucleoside reverse transcriptase inhibitor with potent antiviral activity against HIV/AIDS efavirenz- and nevirapine-resistant viruses. In mice, rats, and monkeys following oral administration of [(14)C]GW695634, the primary pathway of metabolic clearance was by amide hydrolysis and the main route of elimination (46%-75% of the dose) was in the feces. The primary metabolic pathway of clearance for GW695634 and GW678248 in the preclinical species was by amide hydrolysis. At least six metabolites were observed that were the products of GW695634 and GW678248 amide hydrolysis.
Assuntos
Benzofenonas/metabolismo , Inibidores da Transcriptase Reversa/metabolismo , Sulfonamidas/metabolismo , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Animais , Benzofenonas/análise , Benzofenonas/uso terapêutico , Bile/química , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Fezes/química , Feminino , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Sprague-Dawley , Inibidores da Transcriptase Reversa/análise , Inibidores da Transcriptase Reversa/uso terapêutico , Sulfonamidas/análise , Sulfonamidas/uso terapêuticoRESUMO
Morphological evaluation of humanized chimeric mouse livers from the PhoenixBio (uPA(+/+)/SCID) mouse model show robust replacement and expansion with human hepatocytes, however areas of human hepatocytes had prominent steatosis and a variable lack of sinusoids which was consistent with decreased hepatocellular perfusion and lacked bile canalicular formation between human and mouse hepatocytes.
Assuntos
Hepatócitos/transplante , Fígado/patologia , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Animais , Canalículos Biliares/patologia , Proliferação de Células , Pré-Escolar , Fígado Gorduroso/patologia , Hepatócitos/patologia , Humanos , Imuno-Histoquímica , Fígado/irrigação sanguínea , Fígado/ultraestrutura , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos SCID , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Microvasos/patologia , Quimeras de Transplante , Transplante Heterólogo , Ativador de Plasminogênio Tipo Uroquinase/genéticaRESUMO
Fresh hepatocytes have been the choice for interspecies comparative drug metabolism studies. Cryopreserved hepatocytes represent a readily available alternative when combined with acceptance limits based on the metabolic turnover of 7-ethoxycoumarin. Results for the ten NCEs examined show that the metabolites formed were strongly correlated in fresh and cryopreserved hepatocytes.