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Doravirine is a non-nucleoside reverse transcriptase inhibitor for treatment of human immunodeficiency virus type 1 (HIV-1) infection. A population pharmacokinetic (PK) model for treatment-naive participants in doravirine clinical studies was updated with data from switch participants in the DRIVE-SHIFT trial and used to estimate individual post hoc PK parameter values and evaluate the efficacy exposure-response relationship. The results support the 100-mg dose for people living with HIV switching to a doravirine-based regimen (This study has been registered at ClinicalTrials.gov under ClinicalTrials registration no. NCT02397096.).
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Fumaratos , Infecções por HIV/tratamento farmacológico , Humanos , Lamivudina/uso terapêutico , Piridonas , Tenofovir/uso terapêutico , TriazóisRESUMO
Doravirine is a non-nucleoside reverse transcriptase inhibitor approved for the treatment of HIV-1. In a phase 1 trial, doravirine exposure was transiently decreased when treatment was started immediately after stopping efavirenz. In a post-hoc subgroup analysis of participants who switched from an efavirenz-based regimen to doravirine/lamivudine/tenofovir disoproxil fumarate in the phase 3 DRIVE-SHIFT trial, doravirine plasma levels at week 4 were similar to non-induced levels, and HIV-1 suppression was maintained at weeks 24 and 48.
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To replace the conventional maximum tolerated dose (MTD) approach, a paradigm for dose optimization and dose selection that relies on model-informed drug development (MIDD) approaches has been proposed in oncology. Here, we report our application of an MIDD approach during phase I to inform dose selection for the late-stage development of datopotamab deruxtecan (Dato-DXd). Dato-DXd is a TROP2-directed antibody-drug conjugate being developed for advanced/metastatic non-small cell lung cancer (NSCLC) and other tumors. Data on pharmacokinetics (PKs), efficacy, and safety in NSCLC were collected in the TROPION-PanTumor01 phase I dose-expansion and -escalation study over a wide dose range of 0.27-10 mg/kg administered every 3 weeks. Population PK and exposure-response analyses were performed iteratively at three data cutoffs to inform dose selection. The 6 mg/kg dose was identified as the optimal dose by the second data cutoff analysis and confirmed by the subsequent third data cutoff analysis. The 6 mg/kg dose was more tolerable (i.e., lower rates of interstitial lung disease, stomatitis, and mucosal inflammation) than the MTD (8 mg/kg) and was more efficacious than 4 mg/kg (simulated mean objective response rate: 23.8% vs. 18.6%; mean hazard ratio of progression-free survival: 0.74) - a candidate dose studied just below 6 mg/kg. Therefore, the 6 mg/kg dose was judged to afford the optimal benefit-risk balance. This case study demonstrated the utility of an MIDD approach for dose optimization and dose selection.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Imunoconjugados , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/uso terapêutico , Desenvolvimento de Medicamentos , Imunoconjugados/farmacocinéticaRESUMO
Recent breakthroughs in artificial intelligence (AI) and machine learning (ML) have ushered in a new era of possibilities across various scientific domains. One area where these advancements hold significant promise is model-informed drug discovery and development (MID3). To foster a wider adoption and acceptance of these advanced algorithms, the Innovation and Quality (IQ) Consortium initiated the AI/ML working group in 2021 with the aim of promoting their acceptance among the broader scientific community as well as by regulatory agencies. By drawing insights from workshops organized by the working group and attended by key stakeholders across the biopharma industry, academia, and regulatory agencies, this white paper provides a perspective from the IQ Consortium. The range of applications covered in this white paper encompass the following thematic topics: (i) AI/ML-enabled Analytics for Pharmacometrics and Quantitative Systems Pharmacology (QSP) Workflows; (ii) Explainable Artificial Intelligence and its Applications in Disease Progression Modeling; (iii) Natural Language Processing (NLP) in Quantitative Pharmacology Modeling; and (iv) AI/ML Utilization in Drug Discovery. Additionally, the paper offers a set of best practices to ensure an effective and responsible use of AI, including considering the context of use, explainability and generalizability of models, and having human-in-the-loop. We believe that embracing the transformative power of AI in quantitative modeling while adopting a set of good practices can unlock new opportunities for innovation, increase efficiency, and ultimately bring benefits to patients.
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Inteligência Artificial , Descoberta de Drogas , Humanos , Aprendizado de Máquina , Algoritmos , Processamento de Linguagem NaturalRESUMO
The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively.
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Antineoplásicos , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Neoplasias , Humanos , Desenvolvimento de Medicamentos/métodos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Estados Unidos , United States Food and Drug Administration , Dose Máxima Tolerável , BrancosRESUMO
Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.
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Infecções Bacterianas , Infecções por Bactérias Gram-Negativas , Adulto , Criança , Humanos , Imipenem/farmacocinética , Cilastatina/efeitos adversos , Cilastatina/farmacocinética , Antibacterianos , Compostos Azabicíclicos/efeitos adversos , Combinação de Medicamentos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Testes de Sensibilidade Microbiana , Infecções Bacterianas/tratamento farmacológicoRESUMO
Insulin molecules of size much greater than natural insulin have been synthesized and studied with the intention of widening the therapeutic window between adequate glycemic control and hypoglycemia as compared with conventional insulins. MK-1092 is a synthetic insulin dimer with favorable properties demonstrated in preclinical studies. Here, we report the results of the first-in-human, randomized, double-blind, active-control, single ascending dose trial of MK-1092, conducted in healthy adults, adults with type 1 diabetes (T1D), and adults with type 2 diabetes (T2D). MK-1092 was well tolerated in all study populations, and no dose-related adverse events were identified across the evaluated dose range (4-64 nmol/kg). Circulating concentrations of MK-1092 were approximately dose-proportional. Maximum glucose infusion rate (GIR) and 24-hour time-weighted average GIR were evaluated under euglycemic clamp conditions. These pharmacodynamic measurements were approximately dose-proportional in all study populations; at similar doses, the GIR parameters were lower in adults with T2D than in healthy adults or adults with T1D, likely due to the influence of insulin resistance. At doses ≥ 16 nmol/kg, MK-1092 had similar or greater effects than glargine 3 nmol/kg (0.5 units/kg) on increasing GIR in each study population and on suppressing free fatty acids and ketone generation in adults with T1D. MK-1092 did not prevent a subsequent high dose of lispro from increasing the GIR in healthy adults. Additional studies in adults with T1D and T2D are needed to further evaluate the safety, tolerability, and efficacy profile of MK-1092 and its potential for differentiation from more conventional insulins. (ClinicalTrials.gov: NCT03170544).
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Adulto , Glicemia , Estudos Cross-Over , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Glucose , Humanos , Hipoglicemiantes/efeitos adversos , InsulinaRESUMO
For pharmacokinetics characterization of a therapeutic insulin dimer, an ultrasensitive plasma method was required due to the expected low circulating levels in humans. A bioanalytical strategy combining immunoprecipitation enrichment with liquid chromatography - tandem mass spectrometry (LC-MS/MS) analysis of the intact protein offers the opportunity to resolve the analyte from endogenous and exogenous insulin and insulin analogs. Nonetheless, interference from complex background matrix was observed limiting reliable measurements at the low concentration range. A sample preparation approach incorporating protein precipitation and immunoprecipitation was developed and optimized to further reduce sample complexity prior to LC-MS/MS analysis. This approach enabled a deeper level of selectivity and presented a cleaner mass spectrometric detection that may otherwise be confounded. Sample preparation was automated to allow high throughput analysis. The method reached a limit of quantitation at 0.3 ng/mL (25 pM), and a linear dynamic range from 0.3 to 300 ng/mL. Results were highly reproducible, with intra-day and inter-day precision and bias below 11%. Furthermore, the organic solvent treatment involved in protein precipitation is expected to improve assay resistance to the bias introduced by endogenous protein binding such as that exerted by anti-drug antibodies. The method was successfully applied to support clinical pharmacokinetics studies. This approach may potentially be adapted to bioanalysis of low abundance proteins.
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Insulina , Espectrometria de Massas em Tandem , Cromatografia Líquida/métodos , Humanos , Proteínas , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodosRESUMO
Hemorrhagic shock involves loss of a substantial portion of circulating blood volume leading to diminished cardiac output and oxygen delivery to peripheral tissues. In situations where an immediate resuscitation cannot be provided, pharmacotherapy with a novel combination of Δ9-tetrahydro-cannabinol (THC) and celecoxib (CEL) is currently investigated as an alternative strategy to prevent organ damage. In the present study, 28 Yorkshire×Landrace pigs were used to study the pharmacokinetics of THC and CEL in an established porcine model of hemorrhagic shock. Pigs in hemorrhagic shock received 0.5, 1 or 4 mg/kg THC and 2 mg/kg CEL, while normotensive pigs received 1 mg/kg THC and 2 mg/kg CEL by intravenous injection. THC and CEL plasma concentrations were simultaneously determined by LC-MS/MS. Pharmacokinetic parameters and their between animal variability were obtained using standard non-compartmental analysis as well as a compartmental analysis using nonlinear mixed effects modeling. The concentration-time profiles of THC and CEL followed a multi-exponential decline and their pharmacokinetics were similar in hemorrhagic shock and normotensive conditions, despite the substantial change in hemodynamics in the animals with shock. This interesting finding might be due to the pharmacologic effect of the THC/CEL combination, which is intended to maintain adequate perfusion of vital organs in shock. Overall, this study established THC and CEL pharmacokinetics in a porcine shock model and provides the basis for dose selection in further studies of THC and CEL in this indication.
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Inibidores de Ciclo-Oxigenase 2/farmacocinética , Dronabinol/farmacocinética , Pirazóis/farmacocinética , Choque Hemorrágico/tratamento farmacológico , Sulfonamidas/farmacocinética , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/farmacocinética , Analgésicos não Narcóticos/farmacologia , Animais , Volume Sanguíneo , Débito Cardíaco , Celecoxib , Cromatografia Líquida , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Quimioterapia Combinada , Feminino , Injeções Intravenosas , Dinâmica não Linear , Oxigênio/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Choque Hemorrágico/fisiopatologia , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologia , Suínos , Espectrometria de Massas em TandemRESUMO
ModVizPop is an interactive and dynamic visualization tool developed for simulating differential equation-based population pharmacokinetic (PK) and pharmacodynamic (PD) models with variability. It has a built-in PK/PD ordinary differential equations library of models to choose from alongside the ability to plug in a user-defined model from a local or project directory. The user interface consists of several key inputs for performing the simulations as well as options to visualize the plots, perform simple noncompartmental analysis, and review inputs and model code. It also provides the ability to download the underlying model, plots, simulated data, or a comprehensive report consisting of all the key inputs and outputs of the simulations. The interface includes advanced features where users can overlay external data on a simulation, set a certain simulation scenario as a reference, or carry out sensitivity analysis-based simulations. This easy-to-use interface can serve as a valuable tool to project teams to evaluate potential scenarios facilitating collaborative decision making in the drug discovery and development paradigm.
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Descoberta de Drogas , Software , Simulação por Computador , Humanos , Modelos Biológicos , Poder PsicológicoRESUMO
Spectinamides are a novel class of antibiotics under development for the treatment of MDR- and XDR-tuberculosis, with 1599 and 1445 as early lead candidates within this group. In order to evaluate and differentiate the pharmacological properties of these compounds and assist in candidate selection and design of optimal dosing regimens in animal models of Mtb infection, time kill curve assessments were performed in a previously established in vitro PK/PD model system. The performed studies and subsequent pharmacometric analysis indicate that the anti-mycobacterial activity of 1599 exhibits concentration-dependent killing whereas 1445 shows time-dependent killing. These findings are supported by the fact that the PKPD index that best describes bacterial killing is Tâ¯>â¯MIC for 1445, but fCmax/AUC for 1599. The differential killing behavior among the lead candidates can be rationalized by the differences in post-antibiotic effect: 15.7â¯h for 1445 compared the 133â¯h for 1599. Overall, the PK/PD based analysis of the in vitro pharmacologic killing profile of spectinamides 1599 and 1445 on mycobacteria provided valuable insights that contributed to lead candidate selection and preclinical development of these compounds.
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Antituberculosos/farmacologia , Mycobacterium bovis/efeitos dos fármacos , Espectinomicina/análogos & derivados , Espectinomicina/farmacologia , Relação Dose-Resposta a Droga , Testes de Sensibilidade MicrobianaRESUMO
We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK-8742-P010 and MK-5172-P030) in non-hepatitis C virus (HCV)-infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R- and S-methadone AUC0-24 were 1.03 (90% confidence interval (CI), 0.92-1.15) and 1.09 (90% CI, 0.94-1.26) in the presence/absence of EBR; and 1.09 (90% CI, 1.02-1.17) and 1.23 (90% CI, 1.12-1.35) in the presence/absence of GZR. The GMRs for EBR and GZR AUC0-24 in participants receiving methadone relative to a healthy historical cohort not receiving methadone were 1.20 (90% CI, 0.94-1.53) and 1.03 (90% CI, 0.76-1.41), respectively. These results indicate that no dose adjustment is required for individuals with HCV infection receiving stable methadone therapy and the EBR/GZR fixed-dose regimen.
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Analgésicos Opioides/agonistas , Antivirais/farmacocinética , Benzofuranos/farmacocinética , Imidazóis/farmacocinética , Metadona/farmacocinética , Quinoxalinas/farmacocinética , Adulto , Amidas , Antivirais/administração & dosagem , Área Sob a Curva , Benzofuranos/administração & dosagem , Carbamatos , Ciclopropanos , Interações Medicamentosas , Quimioterapia Combinada/métodos , Feminino , Voluntários Saudáveis , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Humanos , Imidazóis/administração & dosagem , Masculino , Metadona/administração & dosagem , Pessoa de Meia-Idade , Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/complicações , Transtornos Relacionados ao Uso de Opioides/reabilitação , Quinoxalinas/administração & dosagem , Sulfonamidas , Adulto JovemRESUMO
The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single-dose trial in healthy participants. Trial 2 was a multiple-dose trial in participants on BUP/NAL maintenance therapy. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC0-∞ were 0.98 (0.89-1.08), 0.97 (0.86-1.09), and 0.88 (0.78-1.00) in the presence/absence of EBR; 0.98 (0.81-1.19), 1.13 (0.97-1.32), and 1.10 (0.82-1.47) in the presence/absence of GZR. The GMRs (90% CI) for EBR and GZR AUC0-∞ in the absence/presence of BUP/NAL were 1.22 (0.98-1.52) and 0.86 (0.63-1.18). In conclusion, no dose adjustment for BUP/NAL, EBR, or GZR is required for patients with HCV infection receiving EBR/GZR and BUP/NAL maintenance therapy.
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Analgésicos Opioides/agonistas , Antivirais/farmacocinética , Benzofuranos/farmacocinética , Combinação Buprenorfina e Naloxona/farmacocinética , Imidazóis/farmacocinética , Quinoxalinas/farmacocinética , Adulto , Amidas , Antivirais/administração & dosagem , Área Sob a Curva , Benzofuranos/administração & dosagem , Combinação Buprenorfina e Naloxona/administração & dosagem , Carbamatos , Ciclopropanos , Interações Medicamentosas , Quimioterapia Combinada/métodos , Feminino , Voluntários Saudáveis , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Humanos , Imidazóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Tratamento de Substituição de Opiáceos/métodos , Transtornos Relacionados ao Uso de Opioides/complicações , Transtornos Relacionados ao Uso de Opioides/reabilitação , Quinoxalinas/administração & dosagem , Sulfonamidas , Adulto JovemRESUMO
Although the classical antibiotic spectinomycin is a potent bacterial protein synthesis inhibitor, poor antimycobacterial activity limits its clinical application for treating tuberculosis. Using structure-based design, we generated a new semisynthetic series of spectinomycin analogs with selective ribosomal inhibition and excellent narrow-spectrum antitubercular activity. In multiple murine infection models, these spectinamides were well tolerated, significantly reduced lung mycobacterial burden and increased survival. In vitro studies demonstrated a lack of cross resistance with existing tuberculosis therapeutics, activity against multidrug-resistant (MDR) and extensively drug-resistant tuberculosis and an excellent pharmacological profile. Key to their potent antitubercular properties was their structural modification to evade the Rv1258c efflux pump, which is upregulated in MDR strains and is implicated in macrophage-induced drug tolerance. The antitubercular efficacy of spectinamides demonstrates that synthetic modifications to classical antibiotics can overcome the challenge of intrinsic efflux pump-mediated resistance and expands opportunities for target-based tuberculosis drug discovery.
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Amidas/farmacologia , Antituberculosos/farmacologia , Desenho de Fármacos , Modelos Moleculares , Mycobacterium tuberculosis/efeitos dos fármacos , Espectinomicina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Transportadores de Cassetes de Ligação de ATP/metabolismo , Amidas/síntese química , Amidas/química , Animais , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Camundongos , Ribossomos/efeitos dos fármacos , Espectinomicina/química , Relação Estrutura-AtividadeRESUMO
For rapid anti-tuberculosis (TB) drug development in vitro pharmacokinetic/pharmacodynamic (PK/PD) models are useful in evaluating the direct interaction between the drug and the bacteria, thereby guiding the selection of candidate compounds and the optimization of their dosing regimens. Utilizing in vivo drug-clearance profiles from animal and/or human studies and simulating them in an in vitro PK/PD model allows the in-depth characterization of antibiotic activity of new and existing antibacterials by generating timekill data. These data capture the dynamic interplay between mycobacterial growth and changing drug concentration as encountered during prolonged drug therapy. This review focuses on important PK/PD parameters relevant to anti-TB drug development, provides an overview of in vitro PK/PD models used to evaluate the efficacy of agents against mycobacteria and discusses the related mathematical modeling approaches of timekill data. Overall, it provides an introduction to in vitro PK/PD models and their application as critical tools in evaluating anti-TB drugs.
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Antituberculosos/farmacologia , Antituberculosos/farmacocinética , Descoberta de Drogas/tendências , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Animais , Descoberta de Drogas/economia , Humanos , Modelos BiológicosRESUMO
A series of 2-aryl-4-benzoyl-imidazoles (ABI) was synthesized as a result of structural modifications based on the previous set of 2-aryl-imidazole-4-carboxylic amide (AICA) derivatives and 4-substituted methoxylbenzoyl-aryl-thiazoles (SMART). The average IC(50) of the most active compound (5da) was 15.7 nM. ABI analogues have substantially improved aqueous solubility (48.9 µg/mL for 5ga vs 0.909 µg/mL for SMART-1, 0.137 µg/mL for paclitaxel, and 1.04 µg/mL for combretastatin A4). Mechanism of action studies indicate that the anticancer activity of ABI analogues is through inhibition of tubulin polymerization by interacting with the colchicine binding site. Unlike paclitaxel and colchicine, the ABI compounds were equally potent against multidrug resistant cancer cells and the sensitive parental melanoma cancer cells. In vivo results indicated that 5cb was more effective than DTIC in inhibiting melanoma xenograph tumor growth. Our results suggest that the novel ABI compounds may be developed to effectively treat drug-resistant tumors.