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1.
Proc Natl Acad Sci U S A ; 121(2): e2314101120, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38165935

RESUMO

Mycobacterium abscessus (Mab), a nontuberculous mycobacterial (NTM) species, is an emerging pathogen with high intrinsic drug resistance. Current standard-of-care therapy results in poor outcomes, demonstrating the urgent need to develop effective antimycobacterial regimens. Through synthetic modification of spectinomycin (SPC), we have identified a distinct structural subclass of N-ethylene linked aminomethyl SPCs (eAmSPCs) that are up to 64-fold more potent against Mab over the parent SPC. Mechanism of action and crystallography studies demonstrate that the eAmSPCs display a mode of ribosomal inhibition consistent with SPC. However, they exert their increased antimicrobial activity through enhanced accumulation, largely by circumventing efflux mechanisms. The N-ethylene linkage within this series plays a critical role in avoiding TetV-mediated efflux, as lead eAmSPC 2593 displays a mere fourfold susceptibility improvement against Mab ΔtetV, in contrast to the 64-fold increase for SPC. Even a minor shortening of the linkage by a single carbon, akin to 1st generation AmSPC 1950, results in a substantial increase in MICs and a 16-fold rise in susceptibility against Mab ΔtetV. These shifts suggest that longer linkages might modify the kinetics of drug expulsion by TetV, ultimately shifting the equilibrium towards heightened intracellular concentrations and enhanced antimicrobial efficacy. Furthermore, lead eAmSPCs were also shown to synergize with various classes of anti-Mab antibiotics and retain activity against clinical isolates and other mycobacterial strains. Encouraging pharmacokinetic profiles coupled with robust efficacy in Mab murine infection models suggest that eAmSPCs hold the potential to be developed into treatments for Mab and other NTM infections.


Assuntos
Anti-Infecciosos , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Humanos , Animais , Camundongos , Espectinomicina/farmacologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Antibacterianos/farmacologia , Micobactérias não Tuberculosas , Anti-Infecciosos/farmacologia , Etilenos/farmacologia , Testes de Sensibilidade Microbiana
2.
Clin Pharmacokinet ; 62(7): 943-953, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37326917

RESUMO

The US Food and Drug Administration's Animal Rule provides a pathway for approval of drugs and biologics aimed to treat serious or life-threatening conditions wherein traditional clinical trials are either not ethical or feasible. In such a scenario, determination of safety and efficacy are based on integration of data on drug disposition and drug action collected from in vitro models, infected animals, and healthy volunteer human studies. The demonstration of clinical efficacy and safety in humans based on robust, well-controlled animal studies is filled with challenges. This review elaborates on the challenges in the translation of data from in vitro and animal models to human dosing for antimicrobials. In this context, it discusses precedents of drugs approved under the Animal Rule, along with the approaches and guidance undertaken by sponsors.


Assuntos
Anti-Infecciosos , Aprovação de Drogas , Animais , Estados Unidos , Humanos , United States Food and Drug Administration , Preparações Farmacêuticas , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Fatores Biológicos
3.
Pharmaceutics ; 15(6)2023 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-37376207

RESUMO

Spectinamides 1599 and 1810 are lead spectinamide compounds currently under preclinical development to treat multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. These compounds have previously been tested at various combinations of dose level, dosing frequency, and route of administration in mouse models of Mycobacterium tuberculosis (Mtb) infection and in healthy animals. Physiologically based pharmacokinetic (PBPK) modeling allows the prediction of the pharmacokinetics of candidate drugs in organs/tissues of interest and extrapolation of their disposition across different species. Here, we have built, qualified, and refined a minimalistic PBPK model that can describe and predict the pharmacokinetics of spectinamides in various tissues, especially those relevant to Mtb infection. The model was expanded and qualified for multiple dose levels, dosing regimens, routes of administration, and various species. The model predictions in mice (healthy and infected) and rats were in reasonable agreement with experimental data, and all predicted AUCs in plasma and tissues met the two-fold acceptance criteria relative to observations. To further explore the distribution of spectinamide 1599 within granuloma substructures as encountered in tuberculosis, we utilized the Simcyp granuloma model combined with model predictions in our PBPK model. Simulation results suggest substantial exposure in all lesion substructures, with particularly high exposure in the rim area and macrophages. The developed model may be leveraged as an effective tool in identifying optimal dose levels and dosing regimens of spectinamides for further preclinical and clinical development.

4.
Sci Transl Med ; 15(691): eabl9344, 2023 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-37043558

RESUMO

Venezuelan and eastern equine encephalitis viruses (VEEV and EEEV, respectively) are mosquito-borne, neuroinvasive human pathogens for which no FDA-approved therapeutic exists. Besides the biothreat posed by these viruses when aerosolized, arthropod transmission presents serious health risks to humans, as demonstrated by the 2019 outbreak of EEE disease in the United States that resulted in 38 confirmed cases, 19 deaths, and neurological effects in survivors. Here, we describe the discovery of a 2-pyrrolidinoquinazolinone scaffold, efficiently synthesized in two to five steps, whose structural optimization resulted in profound antiviral activity. The lead quinazolinone, BDGR-49, potently reduced cellular VEEV and EEEV titers by >7 log at 1 µM and exhibited suitable intravenous and oral pharmacokinetic profiles in BALB/c mice to achieve excellent brain exposure. Outstanding in vivo efficacy was observed in several lethal, subcutaneous infection mouse models using an 8-day dosing regimen. Prophylactically administered BDGR-49 at 25 mg kg-1 per day fully protected against a 10× LD50 VEEV Trinidad donkey (TrD) challenge in BALB/c mice. Similarly, we observed 70% protection when 10× LD50 EEEV FL93-939-infected C57BL/6 mice were treated prophylactically with BDGR-49 at 50 mg kg-1 per day. Last, we observed 100% therapeutic efficacy when mice, challenged with 10× LD50 VEEV TrD, were dosed at 48 hours after infection with BDGR-49 at 25 mg kg-1 per day. Mouse brain viral titers at 96 hours after infection were reduced to values near the limit of detection. Collectively, these results underscore the substantial development potential of a well-tolerated, brain-penetrant lead compound that shows promise in preventing and treating encephalitic alphavirus disease.


Assuntos
Vírus da Encefalite Equina Venezuelana , Encefalomielite Equina do Leste , Humanos , Cavalos , Animais , Camundongos , Estados Unidos , Antivirais/farmacologia , Antivirais/uso terapêutico , Camundongos Endogâmicos C57BL , Encéfalo
5.
ACS Pharmacol Transl Sci ; 6(4): 587-599, 2023 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-37082746

RESUMO

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme of the cyclooxygenase (COX) cascade that generates prostaglandin E2 (PGE2) during inflammatory conditions. PGE2 is known to be a potent immune signaling molecule that mediates both peripheral and central inflammations. Inhibition of mPGES-1, rather than COX, may overcome the cardiovascular side effects associated with long-term COX inhibition by providing a more specific strategy to target inflammation. However, mPGES-1 inhibitor development is hampered by the large differences in cross-species activity due to the structural differences between the human and murine mPGES-1. Here, we report that our thiazole-based mPGES-1 inhibitors, compounds 11 (UT-11) and 19 derived from two novel scaffolds, were able to suppress PGE2 production in human (SK-N-AS) and murine (BV2) cells. The IC50 values of inhibiting PGE2 production in human and murine cells were 0.10 and 2.00 µM for UT-11 and 0.43 and 1.55 µM for compound 19, respectively. Based on in vitro and in vivo pharmacokinetic data, we selected UT-11 for evaluation in a lipopolysaccharide (LPS)-induced inflammation model. We found that our compound significantly suppressed proinflammatory cytokines and chemokines in the hippocampus but not in the kidney. Taken together, we demonstrated the potential of UT-11 in treating neuroinflammatory conditions, including epilepsy and stroke, and warrant further optimization.

6.
Tuberculosis (Edinb) ; 140: 102342, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37120915

RESUMO

Spectinamides are a novel series of spectinomycin analogs being developed for the treatment of tuberculosis. The preclinical lead spectinamide 1599 is an antituberculosis drug that possesses robust in vivo efficacy, good pharmacokinetic properties, and excellent safety profiles in rodents. In individuals infected with Mycobacterium tuberculosis or Mycobacterium bovis, causative agents of tuberculosis, the host immune system is capable of restraining these mycobacteria within granulomatous lesions. The harsh microenvironmental conditions of these granuloma lead to phenotypic transformation of mycobacteria. Phenotypically transformed bacteria display suboptimal growth, or complete growth arrest and are frequently associated with drug tolerance. Here we quantified the effect of spectinamide 1599 on log-phase and phenotypically tolerant isoforms of Mycobacterium bovis BCG using various in vitro approaches as a first indicator of spectinamide 1599 activity against various mycobacterial isoforms. We also used the hollow fiber infection model to establish time-kill curves and deployed pharmacokinetic/pharmacodynamic modeling to characterize the activity differences of spectinamide 1599 towards the different phenotypic subpopulations. Our results indicate that spectinamide 1599 is more efficacious against log phase bacteria when compared to its activity against other phenotypically tolerant forms such as acid phase bacteria and hypoxic phase bacteria, a behavior similar to the established antituberculosis drug isoniazid.


Assuntos
Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculose , Humanos , Espectinomicina , Mycobacterium tuberculosis/genética , Antituberculosos/uso terapêutico
7.
PLoS One ; 17(11): e0278111, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36441753

RESUMO

Dimethyl fumarate (DMF) is a first-line prodrug for the treatment of relapsing-remitting multiple sclerosis (RRMS) that is completely metabolized to monomethyl fumarate (MMF), the active metabolite, before reaching the systemic circulation. Its metabolism has been proposed to be due to ubiquitous esterases in the intestines and other tissues, but the specific enzymes involved are unknown. We hypothesized based on its structure and extensive presystemic metabolism that DMF would be a carboxylesterase substrate subject to interaction with alcohol. We sought to determine the enzymes(s) responsible for the extensive presystemic metabolism of DMF to MMF and the effect of alcohol on its disposition by conducting metabolic incubation studies in human recombinant carboxylesterase-1 (CES1), carboxylesterase-2 (CES2) and human intestinal microsomes (HIM), and by performing a follow-up study in an in vivo mouse model. The in vitro incubation studies demonstrated that DMF was only metabolized to MMF by CES1. Consistent with the incubation studies, the mouse pharmacokinetic study demonstrated that alcohol decreased the maximum concentration and area-under-the-curve of MMF in the plasma and the brain after dosing with DMF. We conclude that alcohol may markedly decrease exposure to the active MMF metabolite in the plasma and brain potentially decreasing the effectiveness of DMF in the treatment of RRMS.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Animais , Camundongos , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Seguimentos , Etanol , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Doença Crônica , Hidrolases de Éster Carboxílico , Recidiva
8.
J Clin Pharmacol ; 61 Suppl 1: S193-S206, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34185910

RESUMO

In selecting optimal dosing regimens in support of the clinical use of monoclonal antibodies and other therapeutic proteins in pediatric indications, the unique pharmacokinetic properties of this class of biologics, as well as the underlying physiologic and pathophysiologic processes and their modulation by childhood growth and development, needs to be appreciated. During drug development, first-in-pediatric dose selection is a capstone event in the pediatric investigation plan that relies heavily on extrapolation of pharmacokinetic and pharmacodynamic data from adult to pediatric populations. It is facilitated by combinations of pharmacometric approaches, including allometry, physiologically based pharmacokinetic modeling, and population pharmacokinetic analyses, although data on reliability and qualification of some of these tools in the context of therapeutic proteins are still limited but emerging. Presented data suggest nonlinear relationships between body weight and both clearance and volume of distribution for therapeutic proteins in pediatric populations, with allometric exponents of 0.75 and 0.8, respectively. For newborns and infants (<1 year), even higher nonlinearity seems to occur. Translation of the quantitative characterization of the pediatric pharmacokinetics of therapeutic proteins into dosing regimens for the drug label requires compromising between precision dosing and clinical practicability, with tiered dosing algorithms based on size or age strata being the currently most frequently applied methodology.


Assuntos
Produtos Biológicos/administração & dosagem , Produtos Biológicos/farmacocinética , Pediatria/métodos , Tamanho Corporal , Peso Corporal , Criança , Ensaios Clínicos como Assunto , Esquema de Medicação , Rotulagem de Medicamentos , Humanos , Modelos Biológicos
9.
Paediatr Drugs ; 22(2): 199-216, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32052309

RESUMO

Monoclonal antibodies (mAbs) and their derivatives are increasingly used in pediatric pharmacotherapy, and the number of antibody-based drug products with approved pediatric indications is continuously growing. In most instances, pediatric use is being pursued after the efficacy and safety of novel antibody medications have been established in adult indications. The pediatric extrapolation exercise that is frequently used in this context to bridge efficacy and safety from adults to children is oftentimes challenged through uncertainties and knowledge gaps in how to reliably extrapolate pharmacokinetics and clinical pharmacology of mAbs to different pediatric age groups, and how to derive age-appropriate dosing regimens that strike a balance between precision dosing and practicability. The article highlights some of the pharmacokinetic and clinical pharmacology challenges with regard to therapeutic use of mAbs and antibody derivatives in children, including immunogenicity events. Although considering body size-based differences in drug disposition can account for many of the perceived and actual differences in the distribution and elimination of antibody-based therapeutics between children and adults, increasing evidence suggests potential or actual age-associated differences beyond size differences, especially for young pediatric patients such as newborns and infants. To overcome age-associated differences in antibody disposition, various different dosing approaches have been applied to ensure safe and efficacious antibody exposure for pediatric populations of different ages. The development of such dosing regimens and the associated pathway to pediatric indication approval is illustrated in more detail for two antibody-based biologics, the fusion protein abatacept and the mAb tocilizumab.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/farmacocinética , Neoplasias/tratamento farmacológico , Adolescente , Anticorpos Monoclonais/uso terapêutico , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido
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