MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
BlueClinical, Porto, Portugal.
Pharm Res. 2021 Dec;38(12):2047-2063. doi: 10.1007/s11095-021-03136-3. Epub 2021 Dec 21.
Both inter-individual (IIV) and inter-occasion (IOV) variabilities are observed in bioequivalence studies. High IOV may be a cause of problems on the demonstration of bioequivalence, despite strict measures are taken to control it. The objective of this study is to investigate further means of controlling IIV by optimizing study design of crossover studies.
Data from 18 bioequivalence studies were used to develop population pharmacokinetics (popPK) models to characterize the absorption and disposition processes of 14 drugs, to estimate IOV for each drug substance and to evaluate possible correlations with biopharmaceutical properties of drug substances, classified in accordance to the Biopharmaceutics Drug Disposition Classification System (BDDCS).
Plasma-pharmacokinetics profiles for the 14 drugs analyzed were successfully described using popPK. The pharmacokinetic parameters that showed greater variability were first-order rate constant of absorption, duration of the zero-order absorption process, relative bioavailability and time of latency. ISCV% estimated for C seems to correlate with the log-Dose-Number for Class 1, 2 and 3, despite no direct correlation was observed between popPK model residual variability (RUV) and ISCV%. Nevertheless, higher RUV estimates were observed for Class 2 drugs in comparison to Class 1 and 3.
Pharmacokinetic parameters related to drug absorption showed greater variability. Ingestion of the IMP along with 240 mL of water showed to standardize gastric emptying. Given the dependency between C variability and dose-solubility ratio, for classes 2 and 4, ad libitum water intake may increase C and AUC ISCV%. A water ingestion standardization until the expected T of the drug is suggested.
个体间（IIV）和个体间（IOV）变异性均在生物等效性研究中观察到。尽管采取了严格的措施来控制变异性，但高 IOV 可能是证明生物等效性存在问题的原因。本研究的目的是通过优化交叉研究设计进一步控制 IIV。
使用来自 18 项生物等效性研究的数据来开发群体药代动力学（popPK）模型，以描述 14 种药物的吸收和处置过程，估计每种药物的 IOV，并根据生物药剂学药物处置分类系统（BDDCS）评估与药物物质的生物制药特性的可能相关性。
成功使用 popPK 描述了 14 种分析药物的血浆药代动力学谱。吸收的一级速率常数、零级吸收过程的持续时间、相对生物利用度和潜伏期时间等显示出更大变异性的药代动力学参数。尽管没有观察到 popPK 模型残留变异性（RUV）与 ISCV%之间的直接相关性，但估计的 C 的 ISCV%似乎与分类 1、2 和 3 的对数剂量数相关。然而，与分类 1 和 3 相比，分类 2 药物的 RUV 估计值更高。
与药物吸收相关的药代动力学参数显示出更大的变异性。与 240 毫升水一起摄入 IMP 可标准化胃排空。鉴于 C 变异性和剂量溶解度比之间的依赖性，对于 2 类和 4 类药物，随意饮水可能会增加 C 和 AUC 的 ISCV%。建议标准化水的摄入，直到药物的预期 T 为止。
