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Pharmacoimmunodynamic interactions of interleukin-10 and prednisolone.

机译：白介素10和泼尼松龙的药物免疫动力学相互作用。

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摘要

Corticosteroids have been the mainstay for treatment of various immune-related disorders. However, the prolonged use of corticosteroids or other immunosuppressants causes severe side-effects. Hence, current strategy for immunosuppressive therapy involves use of combination regimens which has non-overlapping side-effects, whose dual effects are synergistic or at least additive, enabling reduced individual doses in the joint regimen. Interleukin-10 (IL-10) is a cytokine possessing strong anti-inflammatory properties which holds promise for future use in the clinic. With its discovery, there was a need for examining its joint efficacy with another immunosuppressant. Prednisolone, a commonly used systemic corticosteroid was the choice in the joint regimen. We have addressed this important therapeutic area with the aid of various approaches that include use of cell cultures, whole animals, and in vivo human systems.;A wide range of pharmacodynamic endpoints were selected that correlate to actual therapeutic outcomes. These include ex vivo and in vitro lymphocyte proliferation, ex vivo and in vivo proinflammatory cytokine (such as TNF-alpha, IL-1beta and IFN-gamma) and nitric oxide (NO) production, cell trafficking, and endogenous cortisol concentrations. As part of the interaction study, we have also examined the possibility of pharmacokinetic interactions between IL-10 and prednisolone. Data analysis was performed with the use of extensive PD modeling and statistical tools. Innovative pharmacodynamic models based on indirect response models were developed to describe in vivo PD interactions.;There were no pharmacokinetic interactions between IL-10 and prednisolone in humans. Both IL-10 and prednisolone showed appreciable anti-inflammatory effects, causing significant degrees of suppression of lymphocyte proliferation, and downregulation of proinflammatory cytokines and NO production. Prednisolone suppresses adrenal function, while IL-10 elevates endogenous cortisol concentration significantly. This may be an added benefit to long-term immunosuppressive therapy for IL-10. Both agents cause significant changes in the trafficking of various leukocyte subsets. Based on pharmacodynamic interaction models, they usually act additively during joint administration with net responses that were similar to or greater than effects produced by the more strongly acting agent. Thus IL-10 and prednisolone can offer potentially favorable joint immunosuppression.;A unique PK model for subcutaneously administered macromolecules was developed that takes into account the physiological basis for absorption-rate limited disposition for macromolecules. Based on our model, we have proposed that upon SC dosing, macromolecules owing to their molecular size are taken up from the injection site into the lymphatic compartment and then transported into the systemic circulation by the slowly flowing lymphatic fluid resulting extended profiles of serum drug concentrations. We have concluded that when extended concentrations are desired, the preferred dosing route may be SC for therapeutic proteins.;Two new approaches were introduced for characterizing biorhythmic baselines in reference to endogenous cortisol concentrations: (i) A dual cosine function which describes the circadian cortisol secretion rate, (ii) A Fourier method that describes the baseline cortisol concentration by the Fourier series and develops the equations for endogenous cortisol secretion rate from predicted baseline cortisol concentration data. The circadian model based on Fourier method was found to be most accurate and provide unbiased estimate for baseline patterns. The Fourier method can be extended to other drug-induced changes in normal periodic rhythms.;These studies have thus characterized the interactions between two important immunosuppressive and antinflammatory agents and provided improved methods of modeling pharmacokinetic and pharmacodynamic properties and interactions of these drugs.
机译：皮质类固醇一直是各种免疫相关疾病的治疗主体。但是，长期使用皮质类固醇或其他免疫抑制剂会导致严重的副作用。因此，当前的免疫抑制疗法策略涉及使用具有非重叠副作用的联合方案，其双重作用是协同的或至少是累加的，从而可以减少联合方案中的个体剂量。白细胞介素10（IL-10）是一种具有强抗炎特性的细胞因子，有望在临床上进一步应用。随着其发现，需要检查其与另一种免疫抑制剂的联合功效。泼尼松龙，一种常用的全身性皮质类固醇激素是关节疗法的选择。我们已经通过多种方法解决了这一重要的治疗领域，包括使用细胞培养物，整个动物和体内人类系统。选择了与实际治疗结果相关的多种药效学终点。这些包括离体和体外淋巴细胞增殖，离体和体内促炎细胞因子（例如TNF-α，IL-1beta和IFN-γ）和一氧化氮（NO）的产生，细胞运输和内源性皮质醇浓度。作为相互作用研究的一部分，我们还检查了IL-10与泼尼松龙之间药代动力学相互作用的可能性。使用广泛的PD建模和统计工具进行数据分析。建立了基于间接反应模型的创新药效学模型来描述体内PD相互作用。IL-10与泼尼松龙在人体中没有药代动力学相互作用。 IL-10和泼尼松龙均显示出明显的抗炎作用，导致明显程度的抑制淋巴细胞增殖，并下调促炎性细胞因子和NO的产生。泼尼松龙可抑制肾上腺功能，而IL-10可显着提高内源性皮质醇浓度。这可能是IL-10长期免疫抑制治疗的额外好处。两种药剂都导致各种白细胞亚群的运输发生显着变化。基于药效相互作用模型，它们通常在联合给药过程中具有相加作用，其净反应与或更强作用剂产生的作用相似或更大。因此，IL-10和泼尼松龙可以提供潜在的有利的联合免疫抑制作用。皮下给药大分子的独特PK模型被开发出来，该模型考虑了大分子吸收速率受限的生理基础。根据我们的模型，我们建议在SC给药后，由于分子大小，大分子将从注射部位吸收到淋巴腔中，然后通过缓慢流动的淋巴液转运到全身循环中，从而导致血清药物浓度的分布延长。我们得出的结论是，当需要扩展浓度时，治疗性蛋白质的首选给药途径可能是SC。;引入了两种新方法来针对内源性皮质醇浓度表征生物节律基线：（i）双重余弦函数，描述了昼夜皮质醇（ii）一种傅立叶方法，该傅立叶方法通过傅立叶级数描述基线皮质醇浓度，并根据预测的基线皮质醇浓度数据建立内源皮质醇分泌率的方程式。发现基于傅立叶方法的昼夜节律模型最准确，可为基线模式提供无偏估计。傅里叶方法可以扩展到正常周期节律中其他药物引起的变化。因此，这些研究表征了两种重要的免疫抑制剂和抗炎剂之间的相互作用，并提供了建模药物动力学和药效特性以及这些药物相互作用的改进方法。

著录项

  • 作者

    Chakraborty, Abhijit.;

  • 作者单位

    State University of New York at Buffalo.;

  • 授予单位 State University of New York at Buffalo.;
  • 学科 Health Sciences Pharmacy.;Health Sciences Immunology.;Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 1999
  • 页码 312 p.
  • 总页数 312
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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