RESUMO
Nonlinear mixed effects models were developed to describe the relationship between cabozantinib exposure and target lesion tumor size in a phase III study of patients with progressive metastatic medullary thyroid cancer. These models used cabozantinib exposure estimates from a previously published population pharmacokinetic model for cabozantinib in cancer patients that was updated with data from healthy-volunteer studies. Semi-mechanistic models predict well for tumors with static, increasing, or decreasing growth over time, but they were not considered adequate for predicting tumor sizes in medullary thyroid cancer patients, among whom an early reduction in tumor size was followed by a late stabilization phase in those receiving cabozantinib. A semi-empirical tumor model adequately predicted tumor profiles that were assumed to have a net growth rate constant that was piecewise continuous in the regions of 0-110 and 110-280 days. Emax models relating average concentration to average change in tumor size predicted that an average concentration of 79 and 58 ng/ml, respectively, would yield 50% of the maximum possible tumor reduction during the first 110 days of dosing and during the subsequent 110-280 days of dosing. Simulations of tumor responses showed that daily doses of 60 mg or greater are expected to provide a similar tumor reduction. Both model evaluation of observed data and simulation results suggested that the two protocol-defined cabozantinib dose reductions from 140 to 100 mg/day and from 100 to 60 mg/day are not projected to result in a marked reduction in target lesion regrowth.
Assuntos
Anilidas/farmacocinética , Antineoplásicos/farmacocinética , Carcinoma Neuroendócrino/tratamento farmacológico , Modelos Biológicos , Piridinas/farmacocinética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Anilidas/farmacologia , Antineoplásicos/farmacologia , Carcinoma Neuroendócrino/patologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Humanos , Piridinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias da Glândula Tireoide/patologia , Carga Tumoral/efeitos dos fármacosRESUMO
Treatment of seasonal influenza viral infections using antivirals such as neuraminidase inhibitors (NAIs) has been proven effective if administered within 48h post-infection. However, there is growing evidence that antiviral treatment of infections with avian-derived strains even as late as 6 days post-infection (dpi) can significantly reduce infection severity and duration. Using a mathematical model of in-host influenza viral infections which can capture the kinetics of both a short-lived, typical, seasonal infection and a severe infection exhibiting sustained viral titer, we explore differences in the effects of NAI treatment on both types of influenza viral infections. Comparison of our model's behavior against experimental data from patients naturally infected with avian strains yields estimates for the times at which patients were infected that are consistent with those reported by the patients, and estimates of drug efficacies that are lower for patients who died than for those who recovered. In addition, our model suggests that the sustained, high, viral titers often seen in more severe influenza virus infections are the reason why antiviral treatment delayed by as much as 6 dpi will still lead to reduced viral titers and shortened illness. We conclude that NAIs may be an effective and beneficial treatment strategy against more severe strains of influenza virus characterized by high, sustained, viral titers. We believe that our mathematical model will be an effective tool in guiding treatment of severe influenza viral infections with antivirals.
Assuntos
Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Influenza Aviária/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Modelos Biológicos , Neuraminidase/antagonistas & inibidores , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Aves/virologia , Humanos , Influenza Aviária/epidemiologia , Influenza Aviária/virologia , Influenza Humana/epidemiologia , Influenza Humana/virologia , Neuraminidase/metabolismo , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Carga Viral/efeitos dos fármacosRESUMO
Trastuzumab-DM1 (T-DM1) is a novel antibody-drug conjugate under investigation for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. One challenge in oncologic drug development is determining the optimal dose and treatment schedule. A novel dose regimen-finding strategy was developed for T-DM1 using experimental data and pharmacokinetic/pharmacodynamic modeling. To characterize the disposition of T-DM1, pharmacokinetic studies were conducted in athymic nude and beige nude mice. The pharmacokinetics of T-DM1 were described well by a two-compartment model. Tumor response data were obtained from single-dose, multiple-dose and time-dose-fractionation studies of T-DM1 in animal models of HER2-positive breast cancer, specifically engineered to be insensitive to trastuzumab. A sequential population-based pharmacokinetic/pharmacodynamic modeling approach was developed to describe the anti-tumor activity of T-DM1. A cell-cycle-phase nonspecific tumor cell kill model incorporating transit compartments captured well the features of tumor growth and the activity of T-DM1. Key findings of the model were that tumor cell growth rate played a significant role in the sensitivity of tumors to T-DM1; anti-tumor activity was schedule independent; and tumor response was linked to the ratio of exposure to a concentration required for tumor stasis.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Imunotoxinas/uso terapêutico , Maitansina/análogos & derivados , Modelos Biológicos , Neoplasias/tratamento farmacológico , Ado-Trastuzumab Emtansina , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Maitansina/administração & dosagem , Maitansina/farmacocinética , Camundongos , Camundongos Nus , Fatores de Tempo , Trastuzumab , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Despite the recognition of stunting as a public health priority, nutritional and nonnutritional interventions to reduce or prevent linear growth failure have demonstrated minimal impact. Investigators and policymakers face several challenges that limit their ability to assess the potential benefits of combining available interventions into a linear growth promotion package. We use two common but very different interventions, deworming and multiple micronutrient supplements, to illustrate barriers to recommending an optimal linear growth promotion package based on the currently available literature. These challenges suggest that combining individual- and population-based as well as model-based approaches would complement existing research using systematic review, meta-analysis, and factorial randomized trials, and help integrate existing fields of research to inform the development of optimal linear growth promotion packages for children living in resource-limited settings.
Assuntos
Anti-Helmínticos/uso terapêutico , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/prevenção & controle , Helmintíase/tratamento farmacológico , Micronutrientes/uso terapêutico , Criança , Suplementos Nutricionais , Humanos , Micronutrientes/administração & dosagemRESUMO
The worldwide increase in the prevalence of multi-antibiotic-resistant bacteria has threatened the physician's ability to provide appropriate therapy for infections. The relationship between antimicrobial drug concentration and infecting pathogen population reduction is of primary interest. Using data derived from mice infected with the bacterium Pseudomonas aeruginosa and treated with a fluoroquinolone antibiotic, a mathematical model was developed that described relationships between antimicrobial drug exposures and changes in drug-susceptible and -resistant bacterial subpopulations at an infection site. Dosing regimens and consequent drug exposures that amplify or suppress the emergence of resistant bacterial subpopulations were identified and prospectively validated. Resistant clones selected in vivo by suboptimal regimens were characterized. No mutations were identified in the quinolone resistance-determining regions of gyrA/B or parC/E. However, all resistant clones demonstrated efflux pump overexpression. At base line, MexAB-OprM, MexCD-OprJ, and MexEF-OprN were represented in the drug-resistant population. After 28 hours of therapy, MexCD-OprJ became the predominant pump expressed in the resistant clones. The likelihood of achieving resistance-suppression exposure in humans with a clinically prescribed antibiotic dose was determined. The methods developed in this study provide insight regarding how mathematical models can be used to identify rational dosing regimens that suppress the amplification of the resistant mutant population.
Assuntos
Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos , Infecções por Pseudomonas/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos , Feminino , Cinética , Camundongos , Camundongos Endogâmicos ICR , Modelos Teóricos , Método de Monte Carlo , Mutação , Ofloxacino/farmacologia , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/patogenicidade , Quinolonas/farmacologia , Fatores de TempoRESUMO
CONTEXT: Some members of the Wnt family, including ligands, receptors, inhibitors, and signaling components, are expressed in human endometrium. Dickkopf-1 (Dkk-1), a potent inhibitor of the Wnt signaling pathway, was recently found to be up-regulated in decidualizing endometrial stromal cells during the secretory phase of the menstrual cycle, suggesting regulation by progesterone. OBJECTIVES: To test the hypothesis that progesterone regulates Dkk-1 expression in human endometrial stromal cells, we investigated the following effects on stromal cell expression of Dkk-1 mRNA and protein: decidualizing stimuli (progesterone or cAMP), RU486 (an inhibitor of progesterone action), and withdrawal of progesterone. RESULTS: Short-term treatment (up to 72 h, which corresponds to the full decidualized phenotype in response to cAMP and an early response to progesterone) did not reveal regulation of Dkk-1 mRNA or protein by cAMP but did show induction of Dkk-1 expression when the cells were treated with progesterone, an effect that was blocked by RU486. In long-term cultures (from 14 to 23 d, which corresponds to the full decidualized phenotype in response to progesterone), a significant increase in Dkk-1 mRNA and protein production was observed. Addition of RU486 or withdrawal of progesterone after long-term decidualization resulted in a decrease of Dkk-1 mRNA and protein to control levels. Estradiol alone had no effect on stromal Dkk-1 expression. CONCLUSIONS: These data strongly support regulation by progesterone of Dkk-1 mRNA synthesis and protein expression in human endometrial stromal cells and that the response is specific for progesterone and independent of cAMP and estradiol.
Assuntos
Endométrio/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Progesterona/farmacologia , Transdução de Sinais/fisiologia , Proteínas Wnt/fisiologia , Adulto , Northern Blotting , Western Blotting , Células Cultivadas , AMP Cíclico/fisiologia , Endométrio/citologia , Endométrio/efeitos dos fármacos , Feminino , Antagonistas de Hormônios/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mifepristona/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: Cabozantinib is a tyrosine kinase inhibitor approved in the USA and EU for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). The indicated cabozantinib dose is 140 mg/day, with dose modifications allowed for patients who develop adverse events (AEs). The analysis objective was to develop a population pharmacokinetic (PopPK) model in MTC patients and to use the model for exposure-response (ER) analysis of dose modifications. METHODS: A PopPK model for cabozantinib was developed using data from three clinical trials (2079 evaluations from 289 patients), including a randomized, double-blind, placebo-controlled phase III study of patients with progressive, metastatic MTC. The PopPK model predictions [model-predicted steady-state area under the plasma concentration-time curve (AUCss,pred)] were used for an ER analysis of the time to first dose modification. RESULTS: The final PopPK model was a one-compartment model with first-order absorption and first-order elimination. Estimated cabozantinib apparent oral clearance (CL/F) and apparent volume of distribution (V c/F) were 106 L/day [±2.98 % relative standard error (RSE)] (males) and 349 L (±2.73 % RSE), respectively. CL/F was reduced by 22 % (to 83 L/day) in females. Sex and body mass index (BMI) were significant covariates that combined contributed 15 % to the variability in cabozantinib CL/F, but did not warrant dose adjustment. Higher cabozantinib AUCss,pred was correlated to an increased risk of early dose modification and a lower average dose through to Day 85. Early cabozantinib dose modification was not associated with a reduction in progression-free survival (PFS). CONCLUSION: A PopPK model was developed for cabozantinib pharmacokinetics in MTC patients. Higher cabozantinib exposure was associated with earlier first dose modification and a lower average administered dose through to Day 85. Early first dose modification did not appear to impact PFS.
Assuntos
Anilidas/administração & dosagem , Anilidas/farmacocinética , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto JovemRESUMO
Studies have suggested that erythropoietin (EPO) may be used to treat stroke in both animals and humans. It is thought to exert its effects directly on the brain and studies with therapeutic doses have shown that it can cross the blood-brain barrier. Here, we compared in a blinded fashion the ability of three erythropoietic agents (murine erythropoietin, human erythropoietin, and darbepoetin alfa, an analog of human erythropoietin in clinical use) to cross the blood-brain barrier of the mouse. High-performance liquid chromatography (HPLC) results showed that all three erythropoietic agents were enzymatically resistant in brain and blood. The unidirectional blood-to-brain influx rates (Ki) as measured by multiple-time regression analysis showed that all the erythropoietic agents crossed the blood-brain barrier at about the same rate as albumin, suggesting that they cross the blood-brain barrier by way of the extracellular pathways. No saturable component to influx was found, but indirect evidence suggested a brain-to-blood efflux system. The percent of the intravenously injected dose taken up per gram of brain (%Inj/g) ranged from 0.05 to 0.1 %Inj/g among the three erythropoietic agents and peaked about 3 h after IV injection. For other substances, this range of %Inj/g is known to produce direct effects on brain function. We conclude that erythropoietic agents cross the blood-brain barrier by way of the extracellular pathways in amounts that are likely sufficient to explain their neuroprotective effects.
Assuntos
Barreira Hematoencefálica/metabolismo , Eritropoetina/análogos & derivados , Eritropoetina/farmacocinética , Algoritmos , Animais , Encéfalo/metabolismo , Capilares/metabolismo , Cromatografia Líquida de Alta Pressão , Darbepoetina alfa , Eritropoetina/metabolismo , Humanos , Radioisótopos do Iodo , Masculino , Taxa de Depuração Metabólica , CamundongosRESUMO
Erythropoietin is the primary physiological regulator of erythropoiesis, and it exerts its effect by binding to cell surface receptors. It has recently been shown that both erythropoietin and its receptor are found in the human cerebral cortex, and that, in vitro, the cytokine is synthesized by astrocytes and neurons, has neuroprotective activity, and is up-regulated following hypoxic stimuli. In animal models, exogenous recombinant human erythropoietin has been reported to be beneficial in treating experimental global and focal cerebral ischemia and reducing nervous system inflammation. These findings suggest that exogenous administration of erythropoietic agents (darbepoetin alfa [Aranesp], epoetin alfa [Epogen, Procrit], and epoetin beta [NeoRecormon]) may be a potential therapeutic tool for central nervous system injury. However, transport of protein therapeutics to the brain's extracellular environment via systemic blood supply generally does not occur due to the negligible permeability of the brain capillary endothelial wall. Therefore, in order to pharmacologically exploit and fully realize the therapeutic benefits of exogenous erythropoietic agents in CNS dysfunction, mechanisms of action and the potential impact of biodistribution barriers need to be elucidated.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Encefalopatias/prevenção & controle , Encéfalo/efeitos dos fármacos , Eritropoetina/análogos & derivados , Eritropoetina/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Ensaios Clínicos como Assunto , Darbepoetina alfa , Modelos Animais de Doenças , Epoetina alfa , Eritropoese/fisiologia , Humanos , Receptores da Eritropoetina/metabolismo , Proteínas RecombinantesRESUMO
Our objective was to assess, using clinical trial simulation, the feasibility of a fixed 200-microg dose of darbepoetin alfa (Aranesp) administered every 2 weeks in chemotherapy-induced anemia. A pharmacokinetic/pharmacodynamic model was developed using clinical data from 547 cancer patients who received darbepoetin alfa at various doses and schedules. Monte Carlo simulations were performed for weight-based (3 microg/kg every 2 weeks) and fixed-dose (200 microg every 2 weeks) regimens and were compared with observed clinical data. Mean hemoglobin changes from baseline to end of treatment were +1.61 g/dL, +1.83 g/dL, and +1.79 g/dL for observed data, the weight-based simulation, and the fixed-dose simulation, respectively. The rates of required transfusions (hemoglobin < or = 8 g/dL) were also similar between groups. For patients between 45 and 95 kg (over 90% of the population), the impact of a fixed dose on mean hemoglobin change was negligible. There was a slight weight effect at body weight extremes (< 45 kg and > 95 kg). Clinical outcomes from simulations of weight-based andfixed dosing of darbepoetin alfa were similar to those of observed weight-based data. Given the weight distribution of a typical cancer population, the majority would be expected to benefit equally from weight-based and fixed-dose darbepoetin alfa in the amelioration of chemotherapy-induced anemia.
Assuntos
Anemia/induzido quimicamente , Anemia/tratamento farmacológico , Ensaios Clínicos como Assunto/métodos , Simulação por Computador , Eritropoetina/análogos & derivados , Eritropoetina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Peso Corporal/efeitos dos fármacos , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Darbepoetina alfa , Esquema de Medicação , Eritropoetina/farmacocinética , Eritropoetina/farmacologia , Feminino , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias dos Genitais Femininos/sangue , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Masculinos/sangue , Neoplasias dos Genitais Masculinos/tratamento farmacológico , Hemoglobinas/metabolismo , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Método de Monte CarloRESUMO
PURPOSE: To characterize ranibizumab pharmacokinetics in patients with AMD. METHODS: A population approach of nonlinear mixed-effect pharmacokinetic modeling based on concentration-time data from 2993 serum samples from 674 AMD patients enrolled in 5 phase 1 to 3 clinical trials of single or multiple intravitreal (ITV) doses of ranibizumab (0.3-2.0 mg/eye) administered biweekly or monthly for up to 24 months. RESULTS: A TOTAL OF 696 CONCENTRATION-TIME RECORDS FROM 229 SUBJECTS WITH ONE OR MORE MEASURABLE TOTAL SERUM RANIBIZUMAB CONCENTRATIONS WERE ANALYZED. THE SYSTEMIC CONCENTRATION-TIME DATA FOR RANIBIZUMAB WERE BEST DESCRIBED BY A ONE-COMPARTMENT MODEL WITH FIRST-ORDER ABSORPTION INTO AND FIRST-ORDER ELIMINATION FROM THE SYSTEMIC CIRCULATION. VITREOUS ELIMINATION HALF-LIFE (T1/2) WAS CALCULATED TO BE 9 DAYS AND THE INTRINSIC SYSTEMIC ELIMINATION T1/2 WAS CALCULATED TO BE APPROXIMATELY 2 HOURS. FOLLOWING ITV ADMINISTRATION, RANIBIZUMAB EGRESSES SLOWLY INTO THE SYSTEMIC CIRCULATION, RESULTING IN AN APPARENT SERUM T1/2 OF 9 DAYS. SYSTEMIC-TO-VITREOUS EXPOSURE RATIO WAS ESTIMATED TO BE 1: 90,000. With monthly and quarterly ITV regimens, the serum concentrations of ranibizumab at steady-state for both the 0.3 and 0.5 mg/eye dose levels were estimated to be below the range needed to inhibit VEGF-A-induced endothelial cell proliferation in vitro by 50% at all times. CONCLUSIONS: Systemic exposure to ranibizumab after ITV injection was very low due to elimination on reaching systemic circulation from the vitreous. Population pharmacokinetic analysis of data from a representative sample of AMD patients did not identify clinically significant sources or correlates of variability in ranibizumab exposure. (ClinicalTrials.gov numbers, NCT00056836, NCT00056823.).
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Degeneração Macular/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Ensaios Clínicos como Assunto , Feminino , Meia-Vida , Humanos , Injeções Intravítreas , Masculino , Ranibizumab , Corpo Vítreo/metabolismoRESUMO
PURPOSE: We characterized the pharmacokinetics of onartuzumab (MetMAb) in animals and determined a concentration-effect relationship in tumor-bearing mice to enable estimation of clinical pharmacokinetics and target doses. EXPERIMENTAL DESIGN: A tumor growth inhibition model was used to estimate tumoristatic concentrations (TSC) in mice. Human pharmacokinetic parameters were projected from pharmacokinetics in cynomolgus monkeys by the species-invariant time method. Monte Carlo simulations predicted the percentage of patients achieving steady-state trough serum concentrations (Ctrough ss) ≥TSC for every 3-week (Q3W) dosing. RESULTS: Onartuzumab clearance (CL) in the linear dose range was 21.1 and 12.2 mL/d/kg in mice and cynomolgus monkeys with elimination half-life at 6.10 and 3.37 days, respectively. The estimated TSC in KP4 pancreatic xenograft tumor-bearing mice was 15 µg/mL. Projected CL for humans in the linear dose range was 5.74 to 9.36 mL/d/kg with scaling exponents of CL at 0.75 to 0.9. Monte Carlo simulations projected a Q3W dose of 10 to 30 mg/kg to achieve Ctrough ss of 15 µg/mL in 95% or more of patients. CONCLUSIONS: Onartuzumab pharmacokinetics differed from typical bivalent glycosylated monoclonal antibodies with approximately 2-times faster CL in the linear dose range. Despite this higher CL, xenograft efficacy data supported dose flexibility with Q1W to Q3W dose regimens in the clinical setting with a TSC of 15 µg/mL as the Ctrough ss target. The projected human efficacious dose of 10 to 30 mg/kg Q3W should achieve the target TSC of 15 µg/mL. These data show effective pharmacokinetic/pharmacodynamic modeling to project doses to be tested in the clinic.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Western Blotting , Carcinoma Ductal Pancreático/metabolismo , Simulação por Computador , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Macaca fascicularis , Camundongos , Camundongos Nus , Método de Monte Carlo , Neoplasias Pancreáticas/metabolismo , Valor Preditivo dos Testes , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Several mechanisms have been proposed to account for the marked increase in severity of human infections with avian compared to human influenza strains, including increased cytokine expression, poor immune response, and differences in target cell receptor affinity. Here, the potential effect of target cell tropism on disease severity is studied using a mathematical model for in-host influenza viral infection in a cell population consisting of two different cell types. The two cell types differ only in their susceptibility to infection and rate of virus production. We show the existence of a parameter regime which is characterized by high viral loads sustained long after the onset of infection. This finding suggests that differences in cell tropism between influenza strains could be sufficient to cause significant differences in viral titer profiles, similar to those observed in infections with certain strains of influenza A virus. The two target cell mathematical model offers good agreement with experimental data from severe influenza infections, as does the usual, single target cell model albeit with biologically unrealistic parameters. Both models predict that while neuraminidase inhibitors and adamantanes are only effective when administered early to treat an uncomplicated seasonal infection, they can be effective against more severe influenza infections even when administered late.
Assuntos
Vírus da Influenza A/patogenicidade , Influenza Aviária/virologia , Influenza Humana/virologia , Infecções por Orthomyxoviridae/virologia , Algoritmos , Animais , Aves , Linhagem Celular , Humanos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Vírus da Influenza A Subtipo H3N2/patogenicidade , Virus da Influenza A Subtipo H5N1/patogenicidade , Influenza Aviária/patologia , Influenza Humana/patologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Biológicos , Infecções por Orthomyxoviridae/patologia , Índice de Gravidade de Doença , Especificidade da EspécieRESUMO
HAE1, a high-affinity anti-IgE monoclonal antibody, is discussed here as a case study in the use of quantitative pharmacology in the development of a second-generation molecule. In vitro, preclinical, and clinical data from the first-generation molecule, omalizumab, were heavily leveraged in the HAE1 program. A preliminary mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for HAE1 was developed using an existing model for omalizumab, together with in vitro binding data for HAE1 and omalizumab. When phase I data were available, the model was refined by simultaneously modeling PK/PD data from omalizumab studies with the available HAE1 phase I data. The HAE1 clinical program was based on knowledge of the quantitative relationship between a pharmacodynamic biomarker, suppression of free IgE, and clinical response (e.g., lower exacerbation rates) obtained in pivotal studies with omalizumab. A clinical trial simulation platform was developed to predict free IgE levels and clinical responses following attainment of a target free IgE level (=10 IU/ml). The simulation platform enabled selection of four doses for the phase II dose-ranging trial by two independent methods: dose-response non-linear fitting and linear mixed modeling. Agreement between the two methods provided confidence in the doses selected. Modeling and simulation played a large role in supporting acceleration of the HAE1 program by enabling data-driven decision-making, often based on confirmation of projections and/or learning from incoming new data.
Assuntos
Anticorpos Monoclonais , Afinidade de Anticorpos/imunologia , Desenho de Fármacos , Imunoglobulina E/imunologia , Anticorpos Anti-Idiotípicos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Asma/tratamento farmacológico , Linhagem Celular , Humanos , Omalizumab , Receptores de IgE/imunologiaRESUMO
The preferential use of older antimicrobial agents is, in general, sound public health policy and is meant to maintain susceptibility to newer agents. In the case of fluoroquinolones, however, this strategy is flawed and may actually hasten the spread of Streptococcus pneumoniae strains resistant to newer members of the class. In a mouse thigh infection model, we were unable to isolate clones of pneumococci resistant to the newer fluoroquinolone levofloxacin at 2 x or 4 x the baseline MIC. An initial exposure in vivo to the older agent, ciprofloxacin, allowed straightforward selection of clones resistant to levofloxacin in a subsequent experiment. The original ciprofloxacin exposure generated clones without changes in the parC/E and gyrA/B quinolone target sites almost exclusively but did allow overexpression of a reserpine-responsive pump. While this caused only minimal change in the levofloxacin MIC (0.6 mg/liter to 0.8 mg/liter), it allowed a major change in the mutational frequency to resistance for levofloxacin (<1/10(8.5) to approximately 1/10(4.5)), which allowed levofloxacin-resistant clones to be isolated in a subsequent in vivo experiment. The reason underlying ciprofloxacin's propensity to select for pump-overexpressed clones is likely related to its hydrophilicity. To preserve the susceptibility of Streptococcus pneumoniae to newer members of the class of quinolones, use of ciprofloxacin for community-acquired respiratory infections should be minimized.