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Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. case example: Naproxen.
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2019-11-27 , DOI: 10.1016/j.ejps.2019.105170 Ioannis Loisios-Konstantinidis 1 , Rodrigo Cristofoletti 2 , Nikoletta Fotaki 3 , David B Turner 4 , Jennifer Dressman 5
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2019-11-27 , DOI: 10.1016/j.ejps.2019.105170 Ioannis Loisios-Konstantinidis 1 , Rodrigo Cristofoletti 2 , Nikoletta Fotaki 3 , David B Turner 4 , Jennifer Dressman 5
Affiliation
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BACKGROUND
Physiologically-based population pharmacokinetic modeling (popPBPK) coupled with in vitro biopharmaceutics tools such as biorelevant dissolution testing can serve as a powerful tool to establish virtual bioequivalence and set clinically relevant specifications. One of several applications of popPBPK modeling is in the emerging field of virtual bioequivalence (VBE), where it can be used to streamline drug development by implementing model-informed formulation design and to inform regulatory decision-making e.g., with respect to evaluating the possibility of extending BCS-based biowaivers beyond BCS Class I and III compounds in certain cases.
METHODS
In this study, Naproxen, a BCS class II weak acid was chosen as the model compound. In vitro biorelevant solubility and dissolution experiments were performed and the resulting data were used as an input to the PBPK model, following a stepwise workflow for the confirmation of the biopharmaceutical parameters. The naproxen PBPK model was developed by implementing a middle-out approach and verified against clinical data obtained from the literature. Once confidence in the performance of the model was achieved, several in vivo dissolution scenarios, based on model-based analysis of the in vitro data, were used to simulate clinical trials in healthy adults. Inter-occasion variability (IOV) was also added to critical physiological parameters and mechanistically propagated through the simulations. The various trials were simulated on a "worst/best case" dissolution scenario and average bioequivalence was assessed according to Cmax, AUC and Tmax.
RESULTS
VBE results demonstrated that naproxen products with in vitro dissolution reaching 85% dissolved within 90 min would lie comfortably within the bioequivalence limits for Cmax and AUC. Based on the establishment of VBE, a dissolution "safe space" was designed and a clinically relevant specification for naproxen products was proposed. The interplay between formulation-related and drug-specific PK parameters (e.g., t1/2) to predict the in vivo performance was also investigated.
CONCLUSION
Over a wide range of values, the in vitro dissolution rate is not critical for the clinical performance of naproxen products and therefore naproxen could be eligible for BCS-based biowaivers based on in vitro dissolution under intestinal conditions. This approach may also be applicable to other poorly soluble acidic compounds with long half-lives, providing an opportunity to streamline drug development and regulatory decision-making without putting the patient at a risk.
中文翻译：
使用体外生物相关的溶出度测试和基于生理的群体药代动力学模型建立虚拟的生物等效性和临床相关的规范。案例：萘普生。
背景技术基于生理学的群体药代动力学模型（popPBPK）与体外生物制药工具（例如与生物相关的溶出度测试）相结合，可以作为建立虚拟生物等效性和设置临床相关规格的有力工具。popPBPK建模的几种应用之一是在虚拟生物等效性（VBE）的新兴领域，在该领域中，它可以通过实施模型信息化的制剂设计来简化药物开发，并为监管决策提供依据，例如，评估可能性在某些情况下将基于BCS的生物豁免扩大到BCS I类和III类化合物之外。方法在本研究中，选择了萘普生（一种BCS II类弱酸）作为模型化合物。进行体外生物相关的溶解度和溶出度实验，并将所得数据用作PBPK模型的输入，随后逐步进行工作流程以确认生物药物参数。萘普生PBPK模型是通过实施一种中效方法开发的，并根据从文献中获得的临床数据进行了验证。一旦获得了对模型性能的信心，就可以基于基于模型的体外数据分析，采用几种体内溶出方案来模拟健康成年人的临床试验。场合间变异性（IOV）也添加到关键的生理参数中，并通过模拟进行机械传播。在“最坏/最佳案例”中模拟了各种试验 根据Cmax，AUC和Tmax评估溶出度和平均生物等效性。结果VBE结果表明，萘普生产品的体外溶出度在90分钟内达到85％，将在Cmax和AUC的生物等效限度内。在建立VBE的基础上，设计了溶出度“安全空间”，并提出了萘普生产品的临床相关规范。还研究了与制剂相关的和药物特异性的PK参数（例如t1 / 2）之间的相互作用，以预测体内性能。结论在广泛的数值范围内，体外溶解速率对于萘普生产品的临床性能不是至关重要的，因此，根据肠道条件下的体外溶解，萘普生可能符合基于BCS的生物豁免。
更新日期：2019-11-28
中文翻译：
使用体外生物相关的溶出度测试和基于生理的群体药代动力学模型建立虚拟的生物等效性和临床相关的规范。案例：萘普生。
背景技术基于生理学的群体药代动力学模型（popPBPK）与体外生物制药工具（例如与生物相关的溶出度测试）相结合，可以作为建立虚拟生物等效性和设置临床相关规格的有力工具。popPBPK建模的几种应用之一是在虚拟生物等效性（VBE）的新兴领域，在该领域中，它可以通过实施模型信息化的制剂设计来简化药物开发，并为监管决策提供依据，例如，评估可能性在某些情况下将基于BCS的生物豁免扩大到BCS I类和III类化合物之外。方法在本研究中，选择了萘普生（一种BCS II类弱酸）作为模型化合物。进行体外生物相关的溶解度和溶出度实验，并将所得数据用作PBPK模型的输入，随后逐步进行工作流程以确认生物药物参数。萘普生PBPK模型是通过实施一种中效方法开发的，并根据从文献中获得的临床数据进行了验证。一旦获得了对模型性能的信心，就可以基于基于模型的体外数据分析，采用几种体内溶出方案来模拟健康成年人的临床试验。场合间变异性（IOV）也添加到关键的生理参数中，并通过模拟进行机械传播。在“最坏/最佳案例”中模拟了各种试验 根据Cmax，AUC和Tmax评估溶出度和平均生物等效性。结果VBE结果表明，萘普生产品的体外溶出度在90分钟内达到85％，将在Cmax和AUC的生物等效限度内。在建立VBE的基础上，设计了溶出度“安全空间”，并提出了萘普生产品的临床相关规范。还研究了与制剂相关的和药物特异性的PK参数（例如t1 / 2）之间的相互作用，以预测体内性能。结论在广泛的数值范围内，体外溶解速率对于萘普生产品的临床性能不是至关重要的，因此，根据肠道条件下的体外溶解，萘普生可能符合基于BCS的生物豁免。
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