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BACKGROUND: A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of multiple doses of modafinil, a moderate CYP3A4 inducer at a 400 mg QD dose, on the multiple oral dose pharmacokinetics (PK) of encorafenib and its metabolite, LHY746 and binimetinib and its metabolite, AR00426032. METHODS: This study was conducted in patients with BRAF V600-mutant advanced solid tumors. Treatment of 400 mg QD modafinil was given on Day 15 through Day 21. Encorafenib 450 mg QD and binimetinib 45 mg BID were administered starting on Day 1. PK sampling was conducted from 0 to 8 h on Day 14 and Day 21. Exposure parameters were calculated for each patient by noncompartmental analysis and geometric least-squares mean ratio. Corresponding 90% confidence intervals were calculated to estimate the magnitude of effects. RESULTS: Among 11 PK evaluable patients, encorafenib Cmax and AUClast were decreased in presence of steady-state modafinil by 20.2% and 23.8%, respectively. LHY746 exposures were not substantially changed in the presence of steady-state modafinil. CONCLUSION: The results from this clinical study indicate modafinil 400 mg QD had a weak effect on encorafenib PK. Based on these results, encorafenib can be coadministered with a moderate CYP3A4 inducer without dosing adjustment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03864042, registered 6 March 2019.
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RAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors. Significance: PF-07799933 treatment was associated with antitumor activity against BRAFV600- and non-V600-mutant cancers preclinically and in treatment-refractory patients, and PF-07799933 could be safely combined with a MEK inhibitor. The novel, rapid pharmacokinetics (PK)-informed dose escalation design provides a new paradigm for accelerating the testing of next-generation targeted therapies early in clinical development.
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Resistencia a Antineoplásicos , Mutación , Neoplasias , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Animales , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Persona de Mediana Edad , Bencimidazoles/farmacocinética , Bencimidazoles/uso terapéutico , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacología , Anciano , Adulto , Línea Celular TumoralRESUMEN
BACKGROUND AND OBJECTIVES: Encorafenib is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma or metastatic colorectal cancer, respectively, with selected BRAF V600 mutations. A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of encorafenib on rosuvastatin, a sensitive substrate of OATP1B1/3 and breast cancer resistance protein (BCRP), and bupropion, a sensitive CYP2B6 substrate. Coproporphyrin I (CP-I), an endogenous substrate for OATP1B1, was measured in a separate study to deconvolute the mechanism of transporter DDI. METHODS: DDI study participants received a single oral dose of rosuvastatin (10 mg) and bupropion (75 mg) on days - 7, 1, and 14 and continuous doses of encorafenib (450 mg QD) and binimetinib (45 mg BID) starting on day 1. The CP-I data were collected from participants in a phase 3 study who received encorafenib (300 mg QD) and cetuximab (400 mg/m2 initial dose, then 250 mg/m2 QW). Pharmacokinetic and pharmacodynamic analysis was performed using noncompartmental and compartmental methods. RESULTS: Bupropion exposure was not increased, whereas rosuvastatin Cmax and area under the receiver operating characteristic curve (AUC) increased approximately 2.7 and 1.6-fold, respectively, following repeated doses of encorafenib and binimetinib. Increase in CP-I was minimal, suggesting that the primary effect of encorafenib on rosuvastatin is through BCRP. Categorization of statins on the basis of their metabolic and transporter profile suggests pravastatin would have the least potential for interaction when coadministered with encorafenib. CONCLUSION: The results from these clinical studies suggest that encorafenib does not cause clinically relevant CYP2B6 induction or inhibition but is an inhibitor of BCRP and may also inhibit OATP1B1/3 to a lesser extent. Based on these results, it may be necessary to consider switching statins or reducing statin dosage accordingly for coadministration with encorafenib. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03864042, registered 6 March 2019.
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Bupropión , Carbamatos , Coproporfirinas , Interacciones Farmacológicas , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Rosuvastatina Cálcica , Sulfonamidas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Bupropión/administración & dosificación , Bupropión/farmacocinética , Carbamatos/administración & dosificación , Carbamatos/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Rosuvastatina Cálcica/farmacocinética , Rosuvastatina Cálcica/administración & dosificación , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Anciano de 80 o más AñosRESUMEN
Combination therapies are often evaluated during the clinical development of oncology investigational agents. A new investigational agent may be combined with one or more approved agent(s) or investigational agent(s). As the initial step to test combination therapies, combination dose escalation of an investigational agent and an approved drug is generally conducted using one of the following designs: sequential design, parallel (staggered) design, healthy participant first-in-human prior to first-in-patient combination escalation, monotherapy lead-in (intra-patient "crossover"), and potentially combination escalation (no monotherapy component). Dose-finding studies for the combinations of two investigational agents may follow similar principles and considerations, and a more conservative approach may be required. A comparison of the characteristics of these designs indicates an efficient design should consider factors including the predicted difference in dose/exposure-response relationships between monotherapy and combination therapy, any potential for pharmacokinetic and pharmacodynamic interactions between the combinatory agents, and the benefit/risk to study participants, etc. In this report, we propose application scenarios for each trial design based on the above considerations and a review of the internal database and published external studies. Generation of robust exposure-response data via an appropriate design will assist the selection of appropriate doses for further assessment to support optimal dose selection as encouraged by the US Food and Drug Administration based on Project Optimus.
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Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Oncología Médica , Protocolos de Quimioterapia Combinada Antineoplásica , Medición de Riesgo , Relación Dosis-Respuesta a Droga , Proyectos de InvestigaciónRESUMEN
Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600-mutant kinase approved for patients with BRAF-mutant melanoma and colorectal cancer. Encorafenib is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro and may be susceptible to drug-drug interactions when co-administered with CYP3A inhibitors or inducers. The primary objective was to assess the impact of the strong CYP3A inhibitor posaconazole (part 1) and the moderate CYP3A and P-gp inhibitor diltiazem (part 2) on encorafenib pharmacokinetics in healthy volunteers following a single 50-mg dose. A total of 32 participants were enrolled (16 each in parts 1 and 2). The area under the curve extrapolated to infinity (AUCinf ) and maximum plasma concentration (Cmax ) geometric mean for encorafenib increased by 183% and 68.4%, respectively, when co-administered with posaconazole. Apparent encorafenib clearance decreased from 26.0 to 9.2 L/h when coadministered with posaconazole, and plasma terminal half-life (t½ ) of encorafenib increased from 4.3 to 7.3 h. The AUCinf and Cmax geometric mean for encorafenib increased by 83.0% and 44.7%, respectively, when co-administered with diltiazem. Similarly, the apparent encorafenib clearance decreased from 29.0 to 16.0 L/h when co-administered with diltiazem, and plasma t½ of encorafenib increased from 6.6 to 7.9 h. There were no deaths, serious adverse events (AEs), or patient discontinuations due to AEs in parts 1 or 2. The most frequently reported treatment-related AEs were erythema (n = 14; 88%) and headache (n = 11; 69%) in part 1 and headache (n = 7; 44%) in part 2. The results of this study indicate that co-administration of encorafenib with strong or moderate CYP3A4 inhibitors should be avoided.
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Antineoplásicos , Neoplasias Colorrectales , Melanoma , Humanos , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Inhibidores del Citocromo P-450 CYP3A/farmacología , Diltiazem/uso terapéutico , Interacciones Farmacológicas , Cefalea/inducido químicamente , Melanoma/tratamiento farmacológico , Melanoma/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/uso terapéuticoRESUMEN
Rationally targeted therapies have transformed cancer treatment, but many patients develop resistance through bypass signaling pathway activation. PF-07284892 (ARRY-558) is an allosteric SHP2 inhibitor designed to overcome bypass-signaling-mediated resistance when combined with inhibitors of various oncogenic drivers. Activity in this setting was confirmed in diverse tumor models. Patients with ALK fusion-positive lung cancer, BRAFV600E-mutant colorectal cancer, KRASG12D-mutant ovarian cancer, and ROS1 fusion-positive pancreatic cancer who previously developed targeted therapy resistance were treated with PF-07284892 on the first dose level of a first-in-human clinical trial. After progression on PF-07284892 monotherapy, a novel study design allowed the addition of oncogene-directed targeted therapy that had previously failed. Combination therapy led to rapid tumor and circulating tumor DNA (ctDNA) responses and extended the duration of overall clinical benefit. SIGNIFICANCE: PF-07284892-targeted therapy combinations overcame bypass-signaling-mediated resistance in a clinical setting in which neither component was active on its own. This provides proof of concept of the utility of SHP2 inhibitors in overcoming resistance to diverse targeted therapies and provides a paradigm for accelerated testing of novel drug combinations early in clinical development. See related commentary by Hernando-Calvo and Garralda, p. 1762. This article is highlighted in the In This Issue feature, p. 1749.
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Neoplasias Pulmonares , Proteínas Tirosina Quinasas , Humanos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Oncogenes , Atención Dirigida al PacienteRESUMEN
PURPOSE: Enhanced MAPK pathway signaling and cell-cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination. PATIENTS AND METHODS: This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with NRAS-mutant melanoma (NCT01781572). Primary objectives were to estimate the MTD/recommended phase II dose (RP2D) of the combination (phase Ib) and to characterize combination antitumor activity at the RP2D (phase II). Tumor genomic characterization and pharmacokinetics/pharmacodynamics were also evaluated. RESULTS: Ten patients (16.4%) experienced dose-limiting toxicities in cycle 1 of phase Ib. Overall response rate in the phase II cohort (n = 41) for the selected RP2D (binimetinib 45 mg twice daily + ribociclib 200 mg once daily, 21 days on/7 days off) was 19.5% [8/41; 95% confidence interval (CI), 8.8-34.9]. The response rate was 32.5% (13/40; 95% CI, 20.1-48.0) in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. Median progression-free survival was 3.7 months (95% CI, 3.5-5.6) and median overall survival was 11.3 months (95% CI, 9.3-14.2) for all patients. Common treatment-related toxicities included creatine phosphokinase elevation, rash, edema, anemia, nausea, diarrhea, and fatigue. Pharmacokinetics and safety were consistent with single-agent data, supporting a lack of drug-drug interaction. CONCLUSIONS: Ribociclib + binimetinib can be safely administered and is clinically active in patients with NRAS-mutant melanoma. Co-mutations of cell-cycle genes may define a population with greater likelihood of treatment benefit. See related commentary by Moschos, p. 2977.
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Melanoma , Aminopiridinas/efectos adversos , Bencimidazoles/administración & dosificación , GTP Fosfohidrolasas/genética , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Proteínas de la Membrana/genética , PurinasRESUMEN
[This corrects the article DOI: 10.1371/journal.pcbi.1007705.].
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The International Consortium for Innovation and Quality (IQ) Physiologically Based Pharmacokinetic (PBPK) Modeling Induction Working Group (IWG) conducted a survey across participating companies around general strategies for PBPK modeling of induction, including experience with its utility to address various questions, regulatory interactions, and regulatory acceptance. The results highlight areas where PBPK modeling is used with high confidence and identifies opportunities where confidence is lower and further evaluation is needed. To enhance the survey results, the PBPK-IWG also collected case studies and analyzed recent literature examples where PBPK models were applied to predict CYP3A induction-mediated drug-drug interactions. PBPK modeling of induction has evolved and progressed significantly, proving to have great potential to accelerate drug discovery and development. With the aim of enabling optimal use for new molecular entities that are either substrates and/or inducers of CYP3A, the PBPK-IWG proposes initial workflows for PBPK application, discusses future trends, and identifies gaps that need to be addressed.
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Citocromo P-450 CYP3A , Modelos Biológicos , Simulación por Computador , Sistema Enzimático del Citocromo P-450 , Interacciones Farmacológicas , Humanos , Flujo de TrabajoRESUMEN
Uridine 5'-diphospho-glucuronosyltransferases (UGTs) are expressed in the small intestines, but prediction of first-pass extraction from the related metabolism is not well studied. This work assesses physiologically based pharmacokinetic (PBPK) modeling as a tool for predicting intestinal metabolism due to UGTs in the human gastrointestinal tract. Available data for intestinal UGT expression levels and in vitro approaches that can be used to predict intestinal metabolism of UGT substrates are reviewed. Human PBPK models for UGT substrates with varying extents of UGT-mediated intestinal metabolism (lorazepam, oxazepam, naloxone, zidovudine, cabotegravir, raltegravir, and dolutegravir) have demonstrated utility for predicting the extent of intestinal metabolism. Drug-drug interactions (DDIs) of UGT1A1 substrates dolutegravir and raltegravir with UGT1A1 inhibitor atazanavir have been simulated, and the role of intestinal metabolism in these clinical DDIs examined. Utility of an in silico tool for predicting substrate specificity for UGTs is discussed. Improved in vitro tools to study metabolism for UGT compounds, such as coculture models for low clearance compounds and better understanding of optimal conditions for in vitro studies, may provide an opportunity for improved in vitro-in vivo extrapolation (IVIVE) and prospective predictions. PBPK modeling shows promise as a useful tool for predicting intestinal metabolism for UGT substrates.
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[This corrects the article DOI: 10.1371/journal.pcbi.1007705.].
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Within the human respiratory tract (HRT), virus diffuses through the periciliary fluid (PCF) bathing the epithelium. But virus also undergoes advection: as the mucus layer sitting atop the PCF is pushed along by the ciliated cell's beating cilia, the PCF and its virus content are also pushed along, upwards towards the nose and mouth. While many mathematical models (MMs) have described the course of influenza A virus (IAV) infections in vivo, none have considered the impact of both diffusion and advection on the kinetics and localization of the infection. The MM herein represents the HRT as a one-dimensional track extending from the nose down towards the lower HRT, wherein stationary cells interact with IAV which moves within (diffusion) and along with (advection) the PCF. Diffusion was found to be negligible in the presence of advection which effectively sweeps away IAV, preventing infection from disseminating below the depth at which virus first deposits. Higher virus production rates (10-fold) are required at higher advection speeds (40 µm/s) to maintain equivalent infection severity and timing. Because virus is entrained upwards, upper parts of the HRT see more virus than lower parts. As such, infection peaks and resolves faster in the upper than in the lower HRT, making it appear as though infection progresses from the upper towards the lower HRT, as reported in mice. When the spatial MM is expanded to include cellular regeneration and an immune response, it reproduces tissue damage levels reported in patients. It also captures the kinetics of seasonal and avian IAV infections, via parameter changes consistent with reported differences between these strains, enabling comparison of their treatment with antivirals. This new MM offers a convenient and unique platform from which to study the localization and spread of respiratory viral infections within the HRT.
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Gripe Humana/epidemiología , Gripe Humana/metabolismo , Sistema Respiratorio/virología , Humanos , Virus de la Influenza A/patogenicidad , Gripe Humana/virología , Modelos Teóricos , Infecciones por Orthomyxoviridae/virología , Replicación ViralRESUMEN
Physiologically based pharmacokinetic modelling is well established in the pharmaceutical industry and is accepted by regulatory agencies for the prediction of drug-drug interactions. However, physiologically based pharmacokinetic modelling is valuable to address a much wider range of pharmaceutical applications, and new regulatory impact is expected as its full power is leveraged. As one example, physiologically based pharmacokinetic modelling is already routinely used during drug discovery for in-vitro to in-vivo translation and pharmacokinetic modelling in preclinical species, and this leads to the application of verified models for first-in-human pharmacokinetic predictions. A consistent cross-industry strategy in this application area would increase confidence in the approach and facilitate further learning. With this in mind, this article aims to enhance a previously published first-in-human physiologically based pharmacokinetic model-building strategy. Based on the experience of scientists from multiple companies participating in the GastroPlus™ User Group Steering Committee, new Absorption, Distribution, Metabolism and Excretion knowledge is integrated and decision trees proposed for each essential component of a first-in-human prediction. We have reviewed many relevant scientific publications to identify new findings and highlight gaps that need to be addressed. Finally, four industry case studies for more challenging compounds illustrate and highlight key components of the strategy.
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Descubrimiento de Drogas/métodos , Modelos Biológicos , Preparaciones Farmacéuticas , Farmacocinética , Absorción Fisiológica , Simulación por Computador , Industria Farmacéutica , Humanos , Tasa de Depuración Metabólica , Preparaciones Farmacéuticas/sangre , Preparaciones Farmacéuticas/química , Relación Estructura-Actividad Cuantitativa , Distribución TisularRESUMEN
1. Idasanutlin (RG7388) is a potent p53-MDM2 antagonist currently in clinical development for treatment of cancer. The purpose of the present studies was to investigate the cause of marked decrease in plasma exposure after repeated oral administration of RG7388 in monkeys and whether the autoinduction observed in monkeys is relevant to humans. 2. In monkey liver and intestinal microsomes collected after repeated oral administration of RG7388 to monkeys, significantly increased activities of homologue CYP3A8 were observed (ex vivo). Investigation using a physiologically based pharmacokinetic (PBPK) model suggested that the loss of exposure was primarily due to induction of metabolism in the gut of monkeys. 3. Studies in monkey and human primary hepatocytes showed that CYP3A induction by RG7388 only occurred in monkey hepatocytes but not in human hepatocytes, which suggests the observed CYP3A induction is monkey specific. 4. The human PK data obtained from the first cohorts confirmed the lack of relevant induction as predicted by the human hepatocytes and the PBPK modelling based on no induction in humans.
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Antineoplásicos/farmacología , Macaca fascicularis/fisiología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Pirrolidinas/farmacología , para-Aminobenzoatos/farmacología , Animales , Antineoplásicos/metabolismo , Humanos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Pirrolidinas/metabolismo , para-Aminobenzoatos/metabolismoRESUMEN
The ferret is a suitable small animal model for preclinical evaluation of efficacy of antiviral drugs against various influenza strains, including highly pathogenic H5N1 viruses. Rigorous pharmacokinetics/pharmacodynamics (PK/PD) assessment of ferret data has not been conducted, perhaps due to insufficient information on oseltamivir PK. Here, based on PK data from several studies on both uninfected and influenza-infected groups (i.e., with influenza A viruses of H5N1 and H3N2 subtypes and an influenza B virus) and several types of anesthesia we developed a population PK model for the active compound oseltamivir carboxylate (OC) in the ferret. The ferret OC population PK model incorporated delayed first-order input, two-compartment distribution, and first-order elimination to successfully describe OC PK. Influenza infection did not affect model parameters, but anesthesia did. The conclusion that OC PK was not influenced by influenza infection must be viewed with caution because the influenza infections in the studies included here resulted in mild clinical symptoms in terms of temperature, body weight, and activity scores. Monte Carlo simulations were used to determine that administration of a 5.08 mg/kg dose of oseltamivir phosphate to ferret every 12 h for 5 days results in the same median OC area under the plasma concentration-time curve 0-12 h (i.e., 3220 mg h/mL) as that observed in humans during steady state at the approved dose of 75 mg twice daily for 5 days. Modeling indicated that PK variability for OC in the ferret model is high, and can be affected by anesthesia. Therefore, for proper interpretation of PK/PD data, sparse PK sampling to allow the OC PK determination in individual animals is important. Another consideration in appropriate design of PK/PD studies is achieving an influenza infection with pronounced clinical symptoms and efficient virus replication, which will allow adequate evaluation of drug effects.
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Antivirales/farmacología , Antivirales/farmacocinética , Hurones , Modelos Biológicos , Oseltamivir/análogos & derivados , Administración Oral , Animales , Antivirales/administración & dosificación , Subtipo H3N2 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Masculino , Método de Montecarlo , Oseltamivir/administración & dosificación , Oseltamivir/farmacocinética , Oseltamivir/farmacologíaRESUMEN
The role of the host immune response in determining the severity and duration of an influenza infection is still unclear. In order to identify severity factors and more accurately predict the course of an influenza infection within a human host, an understanding of the impact of host factors on the infection process is required. Despite the lack of sufficiently diverse experimental data describing the time course of the various immune response components, published mathematical models were constructed from limited human or animal data using various strategies and simplifying assumptions. To assess the validity of these models, we assemble previously published experimental data of the dynamics and role of cytotoxic T lymphocytes, antibodies, and interferon and determined qualitative key features of their effect that should be captured by mathematical models. We test these existing models by confronting them with experimental data and find that no single model agrees completely with the variety of influenza viral kinetics responses observed experimentally when various immune response components are suppressed. Our analysis highlights the strong and weak points of each mathematical model and highlights areas where additional experimental data could elucidate specific mechanisms, constrain model design, and complete our understanding of the immune response to influenza.
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Gripe Humana/inmunología , Modelos Inmunológicos , Animales , Anticuerpos Antivirales/inmunología , Humanos , Huésped Inmunocomprometido , Virus de la Influenza A/inmunología , Gripe Humana/virología , Interferones/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Linfocitos T Citotóxicos/inmunología , Esparcimiento de VirusRESUMEN
BACKGROUND AND OBJECTIVE: Danoprevir, a potent, selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease, is metabolized by cytochrome P450 (CYP) 3A. Clinical studies in HCV patients have shown a potential need for a high danoprevir daily dose and/or dosing frequency. Ritonavir, an HIV-1 protease inhibitor (PI) and potent CYP3A inhibitor, is used as a pharmacokinetic enhancer at subtherapeutic doses in combination with other HIV PIs. Coadministering danoprevir with ritonavir as a pharmacokinetic enhancer could allow reduced danoprevir doses and/or dosing frequency. Here we evaluate the impact of ritonavir on danoprevir pharmacokinetics. METHODS: The effects of low-dose ritonavir on danoprevir pharmacokinetics were simulated using Simcyp, a population-based simulator. Following results from this drug-drug interaction (DDI) model, a crossover study was performed in healthy volunteers to investigate the effects of acute and repeat dosing of low-dose ritonavir on danoprevir single-dose pharmacokinetics. Volunteers received a single oral dose of danoprevir 100 mg in a fixed sequence as follows: alone, and on the first day and the last day of 10-day dosing with ritonavir 100 mg every 12 hours. RESULTS: The initial DDI model predicted that following multiple dosing of ritonavir 100 mg every 12 hours for 10 days, the danoprevir area under the plasma concentration-time curve (AUC) from time zero to 24 hours and maximum plasma drug concentration (C(max)) would increase by about 3.9- and 3.2-fold, respectively. The clinical results at day 10 of ritonavir dosing showed that the plasma drug concentration at 12 hours postdose, AUC from time zero to infinity and C(max) of danoprevir increased by approximately 42-fold, 5.5-fold and 3.2-fold, respectively, compared with danoprevir alone. The DDI model was refined with the clinical data and sensitivity analyses were performed to better understand factors impacting the ritonavir-danoprevir interaction. CONCLUSION: DDI model simulations predicted that danoprevir exposures could be successfully enhanced with ritonavir coadministration, and that a clinical study confirming this result was warranted. The clinical results demonstrate that low-dose ritonavir enhances the pharmacokinetic profile of low-dose danoprevir such that overall danoprevir exposures can be reduced while sustaining danoprevir trough concentrations.
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Lactamas/farmacocinética , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/farmacocinética , Ritonavir/farmacología , Sulfonamidas/farmacocinética , Adulto , Simulación por Computador , Estudios Cruzados , Ciclopropanos , Interacciones Farmacológicas , Femenino , Humanos , Isoindoles , Lactamas/sangre , Lactamas Macrocíclicas , Masculino , Modelos Biológicos , Prolina/análogos & derivados , Inhibidores de Proteasas/sangre , Sulfonamidas/sangre , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adulto JovenRESUMEN
This analysis was conducted to determine whether the hepatitis C virus (HCV) viral kinetics (VK) model can predict viral load (VL) decreases for nonnucleoside polymerase inhibitors (NNPolIs) and protease inhibitors (PIs) after 3-day monotherapy studies of patients infected with genotype 1 chronic HCV. This analysis includes data for 8 NNPolIs and 14 PIs, including VL decreases from 3-day monotherapy, total plasma trough concentrations on day 3 (C(min)), replicon data (50% effective concentration [EC(50)] and protein-shifted EC(50) [EC(50,PS)]), and for PIs, liver-to-plasma ratios (LPRs) measured in vivo in preclinical species. VK model simulations suggested that achieving additional log(10) VL decreases greater than one required 10-fold increases in the C(min). NNPolI and PI data further supported this result. The VK model was successfully used to predict VL decreases in 3-day monotherapy for NNPolIs based on the EC(50,PS) and the day 3 C(min). For PIs, however, predicting VL decreases using the same model and the EC(50,PS) and day 3 C(min) was not successful; a model including LPR values and the EC(50) instead of the EC(50,PS) provided a better prediction of VL decrease. These results are useful for designing phase 1 monotherapy studies for NNPolIs and PIs by clarifying factors driving VL decreases, such as the day 3 C(min) and the EC(50,PS) for NNPolIs or the EC(50) and LPR for PIs. This work provides a framework for understanding the pharmacokinetic/pharmacodynamic relationship for other HCV drug classes. The availability of mechanistic data on processes driving the target concentration, such as liver uptake transporters, should help to improve the predictive power of the approach.
Asunto(s)
Antivirales/farmacocinética , Hepacivirus/efectos de los fármacos , Inhibidores de Proteasas/farmacocinética , Antivirales/farmacología , Humanos , Modelos Teóricos , Inhibidores de Proteasas/farmacologíaRESUMEN
Danoprevir, a potent, selective inhibitor of HCV NS3/4A protease, has a short half-life in humans. Therefore, the feasibility of a controlled release (CR) formulation to allow less frequent dosing was investigated using experimental approaches and physiological modeling to examine whether danoprevir is absorbed in the colon. Danoprevir absorption was studied in portal-vein-cannulated monkeys and in monkeys surgically modified to make intraduodenal, intrajejunal, intracolonic and oral administration possible. In portal-vein-cannulated monkeys, absorption was apparent up to 24 h after administration. The observed relative bioavailability from intracolonic delivery in the monkey was approximately 30% relative to oral administration, consistent with the model prediction of 40%. Human relative bioavailability for a tablet delivered to the colon compared with an immediate release (IR) formulation was predicted to be 4-28%. Preclinical data and modeling suggested that CR development would be challenging for this Biopharmaceutics Classification System Class IV compound. Therefore, a confirmative study in healthy volunteers was conducted to investigate the relative bioavailability of danoprevir in various regions of the gastrointestinal tract. In a randomized, open-label, crossover study, subjects received 100 mg danoprevir IR soft gel capsule, 100 mg danoprevir solution delivered to the distal small bowel and colon via an Enterion™ capsule (a remotely activated capsule for regional drug delivery) and 100 mg danoprevir powder to the colon via an Enterion™ capsule. The relative bioavailability of danoprevir (compared with IR) delivered to the colon was 6.5% for a solution and 0.6% for a powder formulation, indicating that a CR formulation is not feasible.
Asunto(s)
Antivirales/farmacocinética , Absorción Intestinal , Lactamas/farmacocinética , Modelos Biológicos , Sulfonamidas/farmacocinética , Administración Oral , Adulto , Animales , Antivirales/administración & dosificación , Disponibilidad Biológica , Estudios Cruzados , Ciclopropanos , Preparaciones de Acción Retardada , Estudios de Factibilidad , Humanos , Isoindoles , Lactamas/administración & dosificación , Lactamas Macrocíclicas , Macaca fascicularis , Masculino , Prolina/análogos & derivados , Sulfonamidas/administración & dosificación , Adulto JovenRESUMEN
With non-volatile compounds, high lipophilicity (i.e., fat:blood partition coefficients, Pf, in the range of several hundred to a thousand or higher) typically leads to concerns for bioaccumulation. To evaluate the extent to which highly cleared, lipophilic vapors are expected to accumulate in blood and tissues, we conducted pharmacokinetic (PK) analysis, using both a generic physiologically based (PBPK) model for inhalation of volatile compounds (VCs) and a more detailed PBPK model specifically developed for a highly lipophilic volatile (decamethylcyclopentasiloxane, D(5)). The generic PBPK model for inhalation of VCs in humans showed that highly metabolized, lipophilic compounds, with a low blood:air partition coefficient (Pb), do not accumulate in blood or systemic tissues with repeat exposures although a period of days to weeks may be required for fat to reach periodic steady state. VCs with higher Pb (in the hundreds) and lower hepatic extraction accumulate in blood on repeat exposures. The more detailed PBPK model for D(5) also showed that this lipophilc VC does not accumulate in blood and predictions of the increases in D(5) in fat with repeat exposures in rats agreed with experiments. In general, the major characteristic favoring accumulation of VCs in blood and systemic tissues is poor whole-body clearance, not lipophilicty. The term bioaccumulation should be used to refer to cases where repeat exposures lead to increases in VC blood (or central compartment) concentration. Based on this definition, highly cleared VCs, such as D(5), would not be considered to bioaccumulate on repeat exposures.