RESUMO
Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies, including elexacaftor-tezacaftor-ivacaftor, are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of coronavirus disease 2019 (COVID-19) with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDIs). However, the population with CF is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options. CYP3A-mediated DDI of elexacaftor-tezacaftor-ivacaftor was evaluated using a physiologically-based pharmacokinetic modeling approach. Modeling was performed incorporating physiological information and drug-dependent parameters of elexacaftor-tezacaftor-ivacaftor to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on the pharmacokinetics of elexacaftor-tezacaftor-ivacaftor. The elexacaftor-tezacaftor-ivacaftor models were verified using independent clinical pharmacokinetic and DDI data of elexacaftor-tezacaftor-ivacaftor with a range of CYP3A modulators. When ritonavir was administered on Days 1 through 5, the predicted area under the curve (AUC) ratio of ivacaftor (the most sensitive CYP3A substrate) on Day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of elexacaftor-tezacaftor-ivacaftor should be reduced when coadministered with nirmatrelvir-ritonavir to elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg on Days 1 and 5, with delayed resumption of full-dose elexacaftor-tezacaftor-ivacaftor on Day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. The simulation predicts a regimen of elexacaftor-tezacaftor-ivacaftor administered concomitantly with nirmatrelvir-ritonavir in people with CF that will likely decrease the impact of the drug interaction.
Assuntos
Tratamento Farmacológico da COVID-19 , Fibrose Cística , Aminofenóis/farmacologia , Benzodioxóis/farmacologia , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística , Citocromo P-450 CYP3A/metabolismo , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Indóis/farmacologia , Lactamas/farmacocinética , Leucina/farmacocinética , Mutação , Nitrilas/farmacocinética , Prolina/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacologia , Pirrolidinas , Quinolinas/farmacologia , Quinolonas , Ritonavir/farmacocinéticaRESUMO
There is an urgent need for potent and selective antivirals against SARS-CoV-2. Pfizer developed PF-07321332 (PF-332), a potent inhibitor of the viral main protease (Mpro, 3CLpro) that can be dosed orally and that is in clinical development. We here report that PF-332 exerts equipotent in vitro activity against the four SARS-CoV-2 variants of concerns (VoC) and that it can completely arrest replication of the alpha variant in primary human airway epithelial cells grown at the air-liquid interface. Treatment of Syrian Golden hamsters with PF-332 (250 mg/kg, twice daily) completely protected the animals against intranasal infection with the beta (B.1.351) and delta (B.1.617.2) SARS-CoV-2 variants. Moreover, treatment of SARS-CoV-2 (B.1.617.2) infected animals with PF-332 completely prevented transmission to untreated co-housed sentinels.
Assuntos
Tratamento Farmacológico da COVID-19 , Modelos Animais de Doenças , Lactamas/administração & dosagem , Leucina/administração & dosagem , Nitrilas/administração & dosagem , Prolina/administração & dosagem , SARS-CoV-2/efeitos dos fármacos , Inibidores de Protease Viral/administração & dosagem , Células A549 , Administração Oral , Animais , COVID-19/prevenção & controle , COVID-19/transmissão , COVID-19/virologia , Chlorocebus aethiops , Proteases 3C de Coronavírus/antagonistas & inibidores , Cricetinae , Humanos , Lactamas/farmacocinética , Leucina/farmacocinética , Mesocricetus , Nitrilas/farmacocinética , Prolina/farmacocinética , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/virologia , SARS-CoV-2/enzimologia , SARS-CoV-2/fisiologia , Células Vero , Inibidores de Protease Viral/farmacocinética , Replicação Viral/efeitos dos fármacosRESUMO
The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part of the healthcare response to countering the ongoing threat presented by COVID-19. Here, we report the discovery and characterization of PF-07321332, an orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human coronavirus antiviral activity and excellent off-target selectivity and in vivo safety profiles. PF-07321332 has demonstrated oral activity in a mouse-adapted SARS-CoV-2 model and has achieved oral plasma concentrations exceeding the in vitro antiviral cell potency in a phase 1 clinical trial in healthy human participants.
Assuntos
Tratamento Farmacológico da COVID-19 , Lactamas/farmacologia , Lactamas/uso terapêutico , Leucina/farmacologia , Leucina/uso terapêutico , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Prolina/farmacologia , Prolina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Inibidores de Protease Viral/farmacologia , Inibidores de Protease Viral/uso terapêutico , Administração Oral , Animais , COVID-19/virologia , Ensaios Clínicos Fase I como Assunto , Coronavirus/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Lactamas/administração & dosagem , Lactamas/farmacocinética , Leucina/administração & dosagem , Leucina/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Nitrilas/administração & dosagem , Nitrilas/farmacocinética , Prolina/administração & dosagem , Prolina/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , SARS-CoV-2/fisiologia , Inibidores de Protease Viral/administração & dosagem , Inibidores de Protease Viral/farmacocinética , Replicação Viral/efeitos dos fármacosRESUMO
Faldaprevir (FDV), a substrate of CYP3A/P-glycoprotein (P-gp), is a selective inhibitor of the hepatitis C virus (HCV) NS3/4 protease. FDV is currently under clinical development for application in interferon-free treatment regimens for patients with chronic HCV infection. Understanding the drug-drug interaction potential of FDV is critical, as certain drug combinations may facilitate the more rapid achievement of steady-state-that is, the ideal drug concentration and balanced metabolic cycle of absorption and elimination that optimize drug efficacy. We thus conducted this study to investigate the effect of itraconazole (ICZ), a strong inhibitor of CYP3A and a moderate inhibitor of P-gp, on the pharmacokinetics (PK) of FDV. Eighteen healthy male and female volunteers participated in this open-label, fixed-sequence study. FDV 120 mg twice daily (BID) was administered on Day 1, followed by 120 mg once daily (QD) from Day 2 until the end of the 10-day study; after 6 days of FDV alone, ICZ 200 mg was added to FDV for an additional 4 days (BID on Day 7 and QD from Day 8 to Day 10). Intensive PK sampling was performed after 6 days of FDV treatment and again after 4 days of combined FDV/ICZ treatment. The adjusted geometric mean (gMean) ratios (%) of area under the concentration curve over dosing interval at steady-state (AUCτ, ss) and maximal concentration at steady-state (Cmax, ss) for combined FDV/ICZ treatment vs. FDV treatment alone were 198.6% and 180.6%, respectively, with 90% confidence intervals (CIs) of 182.4-216.1 and 165.7-196.9. Administration of FDV alone or in combination with ICZ was observed to be safe and well-tolerated. Co-administration with ICZ, however, resulted in an approximately two-fold increase in FDV steady-state exposure. Furthermore, FDV required no dosage adjustment when co-administered with ICZ.
Assuntos
Ácidos Aminoisobutíricos/farmacocinética , Itraconazol/farmacologia , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinolinas/farmacocinética , Tiazóis/farmacocinética , Adulto , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Leucina/farmacocinética , Masculino , Pessoa de Meia-Idade , Prolina/farmacocinéticaRESUMO
BACKGROUND: Vixotrigine is a voltage and use dependent sodium channel blocker currently under development for treatment of various neuropathic pain indications. OBJECTIVE: The objective of this work was to develop a population pharmacokinetic model and assess effects of various covariates on pharmacokinetic parameters of vixotrigine. METHOD: Plasma concentration-time data from 12 Phase 1 or 2 studies were included in the analyses. The data were obtained following administration of single or multiple doses of vixotrigine in healthy volunteers and patients. One- and two-compartment pharmacokinetic models were evaluated as base structural pharmacokinetic models. The inclusion of selected covariates was assessed using a stepwise backward elimination approach (α = 0.001) once the base/full model was developed. The predictive ability of the model was evaluated using a visual predictive check (VPC). The final model was used to evaluate effect of covariates on exposure of vixotrigine. RESULTS: A total of 10,263 pharmacokinetic samples collected from 465 subjects were included in the analyses. The pharmacokinetics of vixotrigine was adequately described by a two-compartment model with two transit absorption compartments and first-order elimination. Predictability of the model was also established by VPC. The final model included covariates of age, weight and carbamazepine co-administration on clearance, weight on central volume of distribution, food on absorption rate constant and formulation and Japanese race on bioavailability. None of the covariates identified had a clinically relevant effect, as impact on area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) was within ± 25%. CONCLUSION: The model characterizes the pharmacokinetics of vixotrigine well, and the exposure of vixotrigine was comparable between healthy subjects and patients. None of the covariates evaluated have a clinically relevant impact on the pharmacokinetics of vixotrigine.
Assuntos
Modelos Biológicos , Éteres Fenílicos/farmacocinética , Prolina/análogos & derivados , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Povo Asiático , Disponibilidade Biológica , Eritromelalgia/tratamento farmacológico , Feminino , Interações Alimento-Droga , Humanos , Masculino , Pessoa de Meia-Idade , Éteres Fenílicos/administração & dosagem , Prolina/administração & dosagem , Prolina/farmacocinética , Radiculopatia/tratamento farmacológico , Distribuição Tecidual , Neuralgia do Trigêmeo/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/administração & dosagem , Adulto JovemRESUMO
Neuropathic pain affects ~ 6.9-10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, and pharmacokinetics of a voltage-dependent and use-dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo-controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7-day washout period for up to 5 dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (Cmax ), area under the concentration-time curve from predose to 24 hours postdose (AUC0-24 ), time to Cmax (Tmax ), and terminal half-life (t1/2), among others, were assessed. Drug-related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug-related AE. SAD results showed that Cmax and AUC increased with dose, Tmax was 1-2 hours, and t1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady-state was achieved from day 5 onward. These data indicate that oral vixotrigine is well-tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.
Assuntos
Tontura/epidemiologia , Éteres Fenílicos/efeitos adversos , Prolina/análogos & derivados , Bloqueadores dos Canais de Sódio/efeitos adversos , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/tratamento farmacológico , Éteres Fenílicos/administração & dosagem , Éteres Fenílicos/farmacocinética , Prolina/administração & dosagem , Prolina/efeitos adversos , Prolina/farmacocinética , Bloqueadores dos Canais de Sódio/administração & dosagem , Bloqueadores dos Canais de Sódio/farmacocinética , Adulto JovemRESUMO
Tumor targeting with bivalent radiolabeled ligands for GPCRs is an attractive means for cancer imaging and therapy. Here, we studied and compared the distance dependence of homobivalent ligands for the human gastrin-releasing peptide receptor (hGRP-R) and the somatostatin receptor subtype II (hSstR2a). Oligoprolines were utilized as molecular scaffolds to enable distances of 10, 20, or 30 Å between two identical, agonistic recognition motifs. In vitro internalization assays revealed that ligands with a distance of 20 Å between the recognition motifs exhibit the highest cellular uptake in both ligand series. Structural modeling and molecular dynamics simulations support an optimal distance of 20 Å for accommodating ligand binding to both binding sites of a GPCR dimer. Translation of these findings to the significantly higher complexity in vivo proved difficult and showed only for the hGRP-R increased tumor uptake of the bivalent ligand.
Assuntos
Oligopeptídeos/química , Oligopeptídeos/farmacocinética , Prolina/análogos & derivados , Prolina/farmacocinética , Receptores da Bombesina/agonistas , Receptores de Somatostatina/agonistas , Animais , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Ligantes , Camundongos SCID , Simulação de Dinâmica Molecular , Neoplasias/metabolismo , Oligopeptídeos/farmacologia , Prolina/farmacologia , Receptores da Bombesina/metabolismo , Receptores de Somatostatina/metabolismoRESUMO
PURPOSE: Fixed-dose combination glecaprevir (GLE) 300 mg + pibrentasvir (PIB) 120 mg is an orally administered once daily antiviral regimen approved for the treatment of hepatitis C virus (HCV) infection. The objective of this study was to evaluate the potential for cardiac repolarization following GLE + PIB administration in healthy adults. METHODS: This placebo- and active-controlled, randomized, single-dose, 4-period, 4-sequence crossover study enrolled 48 healthy subjects. The doses of GLE 400 mg + PIB 120 mg were selected to provide exposures comparable to those with the doses that are therapeutic in the HCV-infected population, GLE 300 mg + PIB 120 mg. The doses of GLE 600 mg + PIB 240 mg were selected to provide supratherapeutic exposures without exceeding the exposures of the GLE + PIB maximal tolerated doses. Moxifloxacin 400 mg (active control/open label) was used for confirming the sensitivity of the ECG assay in detecting QTc prolongation. Time-matched plasma concentrations and triplicate ECGs were obtained on treatment days -1 and 1. The primary end point was time-matched, placebo-corrected, baseline-adjusted Fridericia-corrected QT interval (ΔΔQTcF). Pharmacokinetic-pharmacodynamic analyses characterized the relationship between GLE and PIB plasma concentrations and ΔΔQTcF using a linear regression model and linear mixed-effects model. Findings from categorical analyses of ECG-interval data were also summarized. Tolerability was evaluated through adverse-events monitoring, physical examination including vital sign measurements, ECGs, and laboratory tests. FINDINGS: A total of 48 subjects (22 women [46%], 26 men [54%]), were enrolled in the study, and 47 subjects completed all 4 periods. None of the subjects had a change from baseline in QTcF interval of >30 msec or an absolute QTcF interval of >450 msec. Peak ΔΔQTcF values observed at 5 h postdose (Tmax) were 2.9 msec (upper 95% confidence limit, 4.9 msec) with the therapeutic dose and 3.1 msec (upper 95% confidence limit, 5.1 msec) with the supratherapeutic dose, with both upper 95% confidence limits well below the 10-msec threshold. Assay sensitivity was confirmed by peak ΔΔQTcF in the positive control (12.8 ms at 2 h postdose). No statistically significant GLE or PIB concentration-dependent effects on ΔΔQTcF were observed. Headache and skin irritation from ECG electrodes were the most commonly reported AEs. No clinically significant vital sign measurements, ECG findings, or laboratory measurements were observed. There were no patterns of T- and U-wave morphologic abnormalities. IMPLICATIONS: The fixed-dose combination regimen of GLE/PIB does not prolong the QTc interval. ClinicalTrials.gov identifier.
Assuntos
Ácidos Aminoisobutíricos/administração & dosagem , Benzimidazóis/administração & dosagem , Ciclopropanos/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Coração/efeitos dos fármacos , Lactamas Macrocíclicas/administração & dosagem , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Ácidos Aminoisobutíricos/sangue , Ácidos Aminoisobutíricos/farmacocinética , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Estudos Cross-Over , Ciclopropanos/sangue , Ciclopropanos/farmacocinética , Método Duplo-Cego , Combinação de Medicamentos , Eletrocardiografia/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Coração/fisiologia , Humanos , Lactamas Macrocíclicas/sangue , Lactamas Macrocíclicas/farmacocinética , Leucina/administração & dosagem , Leucina/sangue , Leucina/farmacocinética , Síndrome do QT Longo , Masculino , Pessoa de Meia-Idade , Prolina/administração & dosagem , Prolina/sangue , Prolina/farmacocinética , Pirrolidinas , Quinoxalinas/sangue , Quinoxalinas/farmacocinética , Método Simples-Cego , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , Adulto JovemRESUMO
Stachydrine is extracted from the leaves of Leonurus japonicus Houtt (or Motherwort, "Yi Mu Cao" in Traditional Chinese Medicine) and is the major bioactive ingredient. So far, stachydrine has demonstrated various bioactivities for the treatment of fibrosis, cardiovascular diseases, cancers, uterine diseases, brain injuries, and inflammation. The pharmacological and pharmacokinetic properties of stachydrine up to 2019 have been comprehensively searched and summarized. This review provides an updated summary of recent studies on the pharmacological activities of stachydrine. Many studies have demonstrated that stachydrine has strong anti-fibrotic properties (on various types of fibrosis) by inhibiting ECM deposition and decreasing inflammatory and oxidative stress through multiple molecular mechanisms (including TGF-ß, ERS-mediated apoptosis, MMPs/TIMPs, NF-κB, and JAK/STAT). The cardioprotective and vasoprotective activities of stachydrine are related to its inhibition of ß-MHC, excessive autophagy, SIRT1, eNOS uncoupling and TF, promotion of SERCA, and angiogenesis. In addition to its anticancer action, regulation of the uterus, neuroprotective effects, etc. the pharmacokinetic properties of stachydrine are also discussed.
Assuntos
Prolina/análogos & derivados , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/toxicidade , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Cardiotônicos/farmacocinética , Cardiotônicos/farmacologia , Cardiotônicos/toxicidade , Feminino , Fibrose , Humanos , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/toxicidade , Prolina/farmacocinética , Prolina/farmacologia , Prolina/toxicidade , Útero/efeitos dos fármacosRESUMO
Fine-needle aspiration (FNA) for serial hepatic sampling may be an efficient and less invasive alternative to core needle biopsy (CNB), the current standard for liver tissue sampling. In this randomized, open-label trial in 31 participants with hepatitis C virus genotype 1 infection (NCT01678131/Merck protocol PN048), we evaluated the feasibility of using FNA to obtain human liver tissue samples appropriate for measuring hepatic pharmacokinetics (PK), using vaniprevir as a tool compound. The primary end point was successful retrieval of liver tissue specimens with measurable vaniprevir concentrations at two of three specified FNA time points. Twenty-nine patients met the primary end point and, therefore, were included in the PK analyses. Hepatic vaniprevir concentrations obtained with FNA were consistent with known vaniprevir PK properties. The shape of liver FNA and CNB concentration-time profiles were comparable. In conclusion, FNA may be effective for serial tissue sampling to assess hepatic drug exposure in patients with liver disease.
Assuntos
Antivirais/farmacocinética , Biópsia por Agulha Fina/métodos , Ciclopropanos/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Isoindóis/farmacocinética , Lactamas Macrocíclicas/farmacocinética , Leucina/análogos & derivados , Fígado/metabolismo , Prolina/análogos & derivados , Sulfonamidas/farmacocinética , Adulto , Antivirais/administração & dosagem , Ciclopropanos/administração & dosagem , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Isoindóis/administração & dosagem , Lactamas Macrocíclicas/administração & dosagem , Leucina/administração & dosagem , Leucina/farmacocinética , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Prolina/administração & dosagem , Prolina/farmacocinética , Sulfonamidas/administração & dosagem , Distribuição Tecidual , Adulto JovemRESUMO
Transporter gene knockout models are a practical and widely used tool for pharmacokinetic studies in drug discovery. P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) are major efflux transporters that control absorption and bioavailability, and are important when determining oral drug disposition. To the best of our knowledge, beyond the rule of five (bRo5) molecules launched on the market to date tend to be substrates for efflux transporters. The purpose of this study is to evaluate in vivo the impact of efflux transporters on the oral absorption process and systemic clearance using rats which lack P-gp and/or Bcrp expression. We administered five bRo5 substrates (asunaprevir, cyclosporine, danoprevir, ledipasvir, and simeprevir) intravenously or orally to wild-type and Mdr1a, Bcrp, and Mdr1a/Bcrp knockout rats, calculated the clearance, oral bioavailability, and absorption rate profile of each substrate, and compared the results. Systemic clearance of the substrates in knockout rats changed within approximately ±40% compared to wild-types, suggesting the efflux transporters do not have a significant influence on clearance in rats. On the other hand, the oral absorption of substrates in the knockout rats, especially those lacking Mdr1a, increased greatly-between 2- and 5-fold more than in wild-types. This suggests that rat efflux transporters, especially P-gp, greatly reduce the oral exposure of these substrates. Moreover, results on the absorption rate-time profile suggest that efflux transporters are constantly active during the absorption period in rats. Transporter knockout rats are a useful in vivo tool for estimating the transporter-mediated disposition of bRo5 molecules in drug discovery.
Assuntos
Transportadores de Cassetes de Ligação de ATP/deficiência , Benzimidazóis/farmacocinética , Ciclopropanos/farmacocinética , Ciclosporina/farmacocinética , Fluorenos/farmacocinética , Isoindóis/farmacocinética , Isoquinolinas/farmacocinética , Lactamas Macrocíclicas/farmacocinética , Prolina/análogos & derivados , Simeprevir/farmacocinética , Sulfonamidas/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Administração Oral , Animais , Benzimidazóis/administração & dosagem , Benzimidazóis/sangue , Disponibilidade Biológica , Ciclopropanos/administração & dosagem , Ciclopropanos/sangue , Ciclosporina/administração & dosagem , Ciclosporina/sangue , Fluorenos/administração & dosagem , Fluorenos/sangue , Técnicas de Inativação de Genes , Isoindóis/administração & dosagem , Isoindóis/sangue , Isoquinolinas/administração & dosagem , Isoquinolinas/sangue , Lactamas Macrocíclicas/administração & dosagem , Lactamas Macrocíclicas/sangue , Masculino , Taxa de Depuração Metabólica/genética , Absorção pela Mucosa Oral/genética , Prolina/administração & dosagem , Prolina/sangue , Prolina/farmacocinética , Ratos , Ratos Sprague-Dawley , Simeprevir/administração & dosagem , Simeprevir/sangue , Sulfonamidas/administração & dosagem , Sulfonamidas/sangueRESUMO
Glecaprevir (GLE)/pibrentasvir (PIB) 300 mg/120 mg once daily (Mavyret/Maviret) is an all-oral, pangenotypic, interferon- and ribavirin-free combination regimen approved for the treatment of chronic hepatitis C virus (HCV) infection. The objective of the current analyses was to characterize the pharmacokinetics (PK) of GLE/PIB in HCV-infected Japanese patients. Data from 332 subjects enrolled in 2 Japan phase 3 trials, CERTAIN-1 and CERTAIN-2, were used in the analyses. Pharmacokinetics of GLE/PIB were characterized using a nonlinear mixed-effects modeling. The analyses evaluated the impact of covariates (concomitant medications and demographic and clinical covariates such as renal impairment, effect of cirrhotic status) on GLE/PIB PK. GLE and PIB PK were described by 1- and 2-compartment models, respectively. Presence of cirrhosis, age, and body weight were identified as significant covariates on GLE/PIB PK. A trend toward higher GLE and PIB exposures in older patients and higher PIB exposures in heavier patients was observed; however, these increases were not considered clinically meaningful. GLE and PIB exposures were higher in HCV-infected subjects with cirrhosis (Child-Pugh A; GLE area under the plasma concentration-time curve was 160% higher, and PIB area under the plasma concentration-time curve was 21% higher) compared to subjects without cirrhosis. Renal function (including subjects with end-stage renal disease with dialysis) had no impact on GLE or PIB exposures. The GLE/PIB dose was well tolerated in the Japanese population, and no dose adjustment is needed for the evaluated intrinsic and extrinsic factors.
Assuntos
Ácidos Aminoisobutíricos/farmacocinética , Antivirais/farmacocinética , Benzimidazóis/farmacocinética , Ciclopropanos/farmacocinética , Hepatite C Crônica/tratamento farmacológico , Lactamas Macrocíclicas/farmacocinética , Leucina/análogos & derivados , Prolina/análogos & derivados , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Administração Oral , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Ácidos Aminoisobutíricos/administração & dosagem , Ácidos Aminoisobutíricos/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Área Sob a Curva , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Disponibilidade Biológica , Peso Corporal , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Esquema de Medicação , Combinação de Medicamentos , Feminino , Hepatite C Crônica/sangue , Humanos , Japão , Lactamas Macrocíclicas/administração & dosagem , Lactamas Macrocíclicas/efeitos adversos , Leucina/administração & dosagem , Leucina/efeitos adversos , Leucina/farmacocinética , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Prolina/administração & dosagem , Prolina/efeitos adversos , Prolina/farmacocinética , Pirrolidinas , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Adulto JovemRESUMO
Vixotrigine is a voltage- and use-dependent Nav1.7 channel blocker under investigation for the treatment of peripheral neuropathic pain conditions, including trigeminal neuralgia. Vixotrigine is metabolized primarily via uridine diphosphate-glucuronosyltransferases (UGTs). Carbamazepine, a UGT and cytochrome P450 3A4 inducer, is a first-line treatment for trigeminal neuralgia. We conducted a double-blind, randomized, placebo-controlled, parallel-group, single-center phase 1 study to investigate the impact of coadministering vixotrigine and carbamazepine on their respective pharmacokinetics (PK) in healthy volunteers, the safety and tolerability of combined treatment, and PK recovery of vixotrigine following carbamazepine discontinuation. Randomly assigned treatments were carbamazepine (100 mg twice a day, days 1-3 and 200 mg twice a day, days 4-21) or placebo on days 1 to 21. All volunteers received vixotrigine 150 mg 3 times a day on days 16 to 28. At prespecified times, whole-blood samples were collected for PK assessment. Statistical analyses were performed on the log-transformed PK parameters area under the concentration-time curve within a dosing interval (AUC0-tau ) and maximum observed concentration (Cmax ) for vixotrigine, carbamazepine, and metabolites. Vixotrigine AUC0-tau and Cmax were reduced by 31.6% and 26.3%, respectively, when coadministered with carbamazepine compared with placebo. Seven days after carbamazepine discontinuation, vixotrigine AUC0-tau and Cmax remained 24.5% and 21.4% lower compared with placebo. Carbamazepine AUC0-tau and Cmax were <10% lower when coadministered with vixotrigine compared on days 15 and 21. Vixotrigine/carbamazepine coadministration was well tolerated. These results suggest that vixotrigine does not have an effect on carbamazepine PK, and although carbamazepine has an effect on the exposure of vixotrigine, the effect is not considered clinically relevant.
Assuntos
Analgésicos não Narcóticos/farmacologia , Carbamazepina/farmacologia , Éteres Fenílicos/farmacocinética , Prolina/análogos & derivados , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Adulto , Analgésicos não Narcóticos/efeitos adversos , Analgésicos não Narcóticos/farmacocinética , Carbamazepina/efeitos adversos , Carbamazepina/farmacocinética , Método Duplo-Cego , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Voluntários Saudáveis , Humanos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.7 , Éteres Fenílicos/efeitos adversos , Éteres Fenílicos/sangue , Éteres Fenílicos/farmacologia , Prolina/efeitos adversos , Prolina/sangue , Prolina/farmacocinética , Prolina/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos , Bloqueadores do Canal de Sódio Disparado por Voltagem/sangue , Adulto JovemRESUMO
Leonurus japonicus houtt, a well-known herb of traditional Chinese medicine, is widely used to treat gynaecological diseases. In this study, a rapid and sensitive liquid chromatography with tandem mass spectrometry method for simultaneously quantifying leonurine and stachydrine, the two main bioactive components in Leonurus japonicus houtt, was developed and validated. Plasma samples were prepared by protein precipitation with acetonitrile and separation by a Hewlett Packard XDB-C8 column (150 × 4.6 mm, id, 5 µm) equipped with a gradient elution system containing methanol-water and 0.1% formic acid at a flow-rate of 0.4 mL/min. Components were then detected by a mass spectrometer in positive electrospray ionization mode. This method showed good linearity, precision, accuracy, recovery, stability, and negligible matrix effects, which were within acceptable ranges. The method was successfully applied to compare the pharmacokinetics in normal rats and rats with cold-stagnation and blood-stasis primary dysmenorrhoea treated with Leonurus japonicus houtt electuary. The result showed significant differences (p < 0.05) in the pharmacokinetic parameters between the primary dysmenorrhoea and normal groups. This result implied that Leonurus japonicus houtt electuary remained longer and was absorbed slower in rats with primary dysmenorrhoea and exhibited higher bioavailability and peak concentration.
Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Dismenorreia/tratamento farmacológico , Ácido Gálico/análogos & derivados , Leonurus/química , Prolina/análogos & derivados , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Dismenorreia/sangue , Feminino , Ácido Gálico/administração & dosagem , Ácido Gálico/farmacocinética , Humanos , Prolina/administração & dosagem , Prolina/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
Vixotrigine is a state- and use-dependent Nav1.7 channel blocker being investigated for the treatment of neuropathic pain conditions. This randomized, double-blind, placebo-controlled crossover trial was designed to evaluate changes in blood pressure with the administration of vixotrigine using ambulatory blood pressure monitoring (ABPM). Eligible participants were healthy adults 18 to 65 years of age without evidence of baseline systolic blood pressure (SBP) persistently > 140 mm Hg or diastolic blood pressure (DBP) persistently > 90 mm Hg. Vixotrigine (400 mg [men], 300 mg [women]) or placebo was administered orally twice daily for 36 days. Following a 7-day washout period, participants crossed over to the other treatment. Each dosing period was preceded by 1 inpatient visit and 1 outpatient baseline visit. Two 14-hour inpatient ABPM sessions occurred on days 14 and 35, with a return to the clinic the morning of days 15 and 36 for initiation of outpatient ABPM, which assessed blood pressure and heart rate every 15 minutes. Adverse events were collected throughout the study. The primary end point was the change from baseline in 24-hour mean SBP and DBP on day 36. Sixty participants were enrolled; 10 withdrew from the study owing to adverse events, investigator discretion, or withdrawal of consent. From baseline to day 36, mean changes in average SBP and DBP (vixotrigine treated) were -0.33 and 0.20 mm Hg, respectively. Adverse event rates were comparable for vixotrigine and placebo; the most common adverse events were headache, dizziness, and nausea. Vixotrigine administration is not associated with a clinically important increase in blood pressure.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Éteres Fenílicos/farmacologia , Prolina/análogos & derivados , Bloqueadores dos Canais de Sódio/farmacologia , Adulto , Monitorização Ambulatorial da Pressão Arterial , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Canal de Sódio Disparado por Voltagem NAV1.7/fisiologia , Éteres Fenílicos/efeitos adversos , Éteres Fenílicos/farmacocinética , Prolina/efeitos adversos , Prolina/farmacocinética , Prolina/farmacologia , Bloqueadores dos Canais de Sódio/efeitos adversos , Bloqueadores dos Canais de Sódio/farmacocinética , Adulto JovemRESUMO
In the small intestine transcellular and paracellular pathways are implicated in water-soluble nutrient absorption. In small birds the paracellular pathway is quantitatively important while transcellular pathway is much more important in terrestrial mammals. However, there is not a clear understanding of the mechanistic underpinnings of the differences among taxa. This study was aimed to test the hypothesis that paracellular permeability in perfused intestinal segments is higher in passerine birds than rodents. We performed in situ intestinal perfusions on individuals of three species of passerine birds (Passer domesticus, Taeniopygia guttata and Furnarius rufus) and two species of rodents (Mus musculus and Meriones ungiculatus). Using radio-labelled molecules, we measured the uptake of two nutrients absorbed by paracellular and transcellular pathways (L-proline and 3-O-methyl-D-glucose) and one carbohydrate that has no mediated transport (L-arabinose). Birds exhibited ~2 to ~3 times higher L-arabinose clearance per cm2 epithelium than rodents. Moreover, paracellular absorption accounted for proportionally more of 3-O-methyl-D-glucose and L-proline absorption in birds than in rodents. These differences could be explained by differences in intestinal permeability and not by other factors such as increased retention time or higher intestinal nominal surface area. Furthermore, analysis of our results and all other existing data on birds, bats and rodents shows that insectivorous species (one bird, two bats and a rodent) had only 30% of the clearance of L-arabinose of non-insectivorous species. This result may be explained by weaker natural selection for high paracellular permeability in animal- than in plant-consumers. Animal-consumers absorb less sugar and more amino acids, whose smaller molecular size allow them to traverse the paracellular pathway more extensively and faster than glucose.
Assuntos
3-O-Metilglucose/farmacocinética , Arabinose/farmacocinética , Gerbillinae/fisiologia , Mucosa Intestinal/fisiologia , Camundongos/fisiologia , Passeriformes/fisiologia , Prolina/farmacocinética , Animais , Transporte Biológico , Permeabilidade , Especificidade da EspécieRESUMO
PURPOSE: Cis-4-[18F]fluoro-D-proline (D-cis-[18F]FPro) has been shown to pass the intact blood-brain barrier and to accumulate in areas of secondary neurodegeneration and necrosis in the rat brain while uptake in experimental brain tumors is low. This pilot study explores the uptake behavior of D-cis-[18F]FPro in human brain tumors after multimodal treatment. PROCEDURES: In a prospective study, 27 patients with suspected recurrent brain tumor after treatment with surgery, radiotherapy, and/or chemotherapy (SRC) were investigated by dynamic positron emission tomography (PET) using D-cis-[18F]FPro (22 high-grade gliomas, one unspecified glioma, and 4 metastases). Furthermore, two patients with untreated lesions were included (one glioblastoma, one reactive astrogliosis). Data were compared with the results of PET using O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) which detects viable tumor tissue. Tracer distribution, mean and maximum lesion-to-brain ratios (LBRmean, LBRmax), and time-to-peak (TTP) of the time activity curve (TAC) of tracer uptake were evaluated. Final diagnosis was determined by histology (n = 9), clinical follow-up (n = 10), or by [18F]FET PET (n = 10). RESULTS: D-cis-[18F]FPro showed high uptake in both recurrent brain tumors (n = 11) and lesions classified as treatment-related changes (TRC) only (n = 16) (LBRmean 2.2 ± 0.7 and 2.1 ± 0.6, n.s.; LBRmax 3.4 ± 1.2 and 3.2 ± 1.3, n.s.). The untreated glioblastoma and the lesion showing reactive astrogliosis exhibited low D-cis-[18F]FPro uptake. Distribution of [18F]FET and D-cis-[18F]FPro uptake was discordant in 21/29 cases indicating that the uptake mechanisms are different. CONCLUSION: The high accumulation of D-cis-[18F]FPro in pretreated brain tumors and TRC supports the hypothesis that tracer uptake is related to cell death. Further studies before and after therapy are needed to assess the potential of D-cis-[18F]FPro for treatment monitoring.
Assuntos
Neoplasias Encefálicas/terapia , Prolina/análogos & derivados , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Terapia Combinada , Feminino , Glioma/diagnóstico por imagem , Glioma/patologia , Glioma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prolina/farmacocinética , Fatores de TempoRESUMO
Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel expressed in sensory neurons where it functions as an irritant sensor for a plethora of electrophilic compounds and is implicated in pain, itch, and respiratory disease. To study its function in various disease contexts, we sought to identify novel, potent, and selective small-molecule TRPA1 antagonists. Herein we describe the evolution of an N-isopropylglycine sulfonamide lead (1) to a novel and potent (4 R,5 S)-4-fluoro-5-methylproline sulfonamide series of inhibitors. Molecular modeling was utilized to derive low-energy three-dimensional conformations to guide ligand design. This effort led to compound 20, which possessed a balanced combination of potency and metabolic stability but poor solubility that ultimately limited in vivo exposure. To improve solubility and in vivo exposure, we developed methylene phosphate prodrug 22, which demonstrated superior oral exposure and robust in vivo target engagement in a rat model of AITC-induced pain.
Assuntos
Pró-Fármacos/farmacologia , Prolina/análogos & derivados , Prolina/farmacologia , Sulfonamidas/farmacologia , Canal de Cátion TRPA1/antagonistas & inibidores , Animais , Cães , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Ligantes , Células Madin Darby de Rim Canino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Conformação Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Prolina/síntese química , Prolina/farmacocinética , Ratos , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Canal de Cátion TRPA1/químicaRESUMO
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. Inhibition of GABA aminotransferase (GABA-AT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme that degrades GABA, has been established as a possible strategy for the treatment of substance abuse. The raised GABA levels that occur as a consequence of this inhibition have been found to antagonize the rapid release of dopamine in the ventral striatum (nucleus accumbens) that follows an acute challenge by an addictive substance. In addition, increased GABA levels are also known to elicit an anticonvulsant effect in patients with epilepsy. We previously designed the mechanism-based inactivator (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (2), now called CPP-115, that is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved drug that is an inactivator of GABA-AT. CPP-115 was found to have high therapeutic potential for the treatment of cocaine addiction and for a variety of epilepsies, has successfully completed a Phase I safety clinical trial, and was found to be effective in the treatment of infantile spasms (West syndrome). Herein we report the design, using molecular dynamics simulations, synthesis, and biological evaluation of a new mechanism-based inactivator, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (5), which was found to be almost 10 times more efficient as an inactivator of GABA-AT than CPP-115. We also present the unexpected crystal structure of 5 bound to GABA-AT, as well as computational analyses used to assist the structure elucidation process. Furthermore, 5 was found to have favorable pharmacokinetic properties and low off-target activities. In vivo studies in freely moving rats showed that 5 was dramatically superior to CPP-115 in suppressing the release of dopamine in the corpus striatum, which occurs subsequent to either an acute cocaine or nicotine challenge. Compound 5 also attenuated increased metabolic demands (neuronal glucose metabolism) in the hippocampus, a brain region that encodes spatial information concerning the environment in which an animal receives a reinforcing or aversive drug. This multidisciplinary computational design to preclinical efficacy approach should be applicable to the design and improvement of mechanism-based inhibitors of other enzymes whose crystal structures and inactivation mechanisms are known.
Assuntos
4-Aminobutirato Transaminase/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Prolina/análogos & derivados , 4-Aminobutirato Transaminase/química , 4-Aminobutirato Transaminase/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Domínio Catalítico/efeitos dos fármacos , Cristalografia por Raios X , Dopamina/metabolismo , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacologia , Inibidores Enzimáticos/farmacocinética , Glucose/metabolismo , Humanos , Masculino , Modelos Moleculares , Prolina/química , Prolina/farmacocinética , Prolina/farmacologia , Ratos , Ratos Sprague-Dawley , Ácido gama-Aminobutírico/metabolismoRESUMO
Pharmacokinetic (PK) extension is no longer just a means to create improved second generation biologics (so-called biobetters), but constitutes an accepted strategy in biopharmaceutical drug development today. Although PEGylation has become a widely applied methodology to furnish therapeutic proteins and peptides with prolonged plasma half-life, the immunogenicity and missing biodegradability of this synthetic polymer has prompted an evident need for alternatives. PASylation is based on biological polypeptides made of the small l-amino acids Pro, Ala and/or Ser (PAS), which adopt a random coil structure in aqueous buffers with surprisingly similar biophysical properties as PEG. In contrast, PAS sequences can be conjugated to pharmaceutically active proteins and peptides both via chemical coupling and at the genetic level, as so-called fusion proteins. PASylation has been successfully applied to numerous biologics, including cytokines, growth factors, antibody fragments, enzymes as well as various peptides, and validated in diverse animal models, from mice to monkeys. Here we compare PASylation with other current strategies for half-life extension and we discuss the utility of these approaches for the design of innovative peptide-based therapeutics.