Affiliated Hospital of Jiangxi University of Chinese Medicine, Jiangxi Province, Nanchang, 330006, China.
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100102, China.
Eur J Clin Pharmacol. 2022 Sep;78(9):1435-1446. doi: 10.1007/s00228-022-03338-7. Epub 2022 Jun 9.
To develop a mathematical model combined between physiologically based pharmacokinetic and BTK occupancy (PBPK-BO) to simultaneously predict pharmacokinetic (PK) and pharmacodynamic (PD) changes of acalabrutinib (ACA) and active metabolite ACP-5862 in healthy humans as well as PD in patients. Next, to use the PBPK-BO to determine the optimal dosing regimens in patients alone, with different CYP3A4 variants, when co-administration with four CYP3A4 modulators and in patients with hepatic impairment, respectively.
The PBPK-BO model was built using physicochemical and biochemical properties of ACA and ACP-5862 and then verified by observed PK and PD data from healthy humans and patients. Finally, the model was applied to determine optimal dosing regimens in various clinical situations.
The simulations demonstrated that 100 mg ACA twice daily (BID) was the optimal dosing regimen in patients alone. Additionally, dosage regimens might be reduced to 50 mg BID in patients with five CYP3A4 variants. Moreover, the dosing regimen should be modified to 100 mg (even to 50 mg) once daily (QD) when co-administration with erythromycin or clarithromycin, and be increased to 200 mg BID with rifampicin, and but be avoided co-administration with itraconazole. Furthermore, dosage regimen simulations showed that optimal dosing might be decreased to 50 mg BID in patients with mild and moderate hepatic impairment, and be avoided taking ACA in severely hepatically impaired patients.
This PBPK-BO model can predict PK and PD in healthy humans and patients and also predict the optimal dosing regimens in various clinical situations.
开发一种结合了基于生理的药代动力学（PBPK）和 BTK 占有率（BO）的数学模型，以同时预测阿卡鲁替尼（ACA）和其活性代谢物 ACP-5862 在健康人体中的药代动力学（PK）和药效学（PD）变化，以及患者的 PD。接下来，使用 PBPK-BO 模型分别确定在单独使用时、与四种 CYP3A4 调节剂共同使用时、在具有不同 CYP3A4 变体的患者中以及在肝损伤患者中的最佳给药方案。
使用 ACA 和 ACP-5862 的物理化学和生化特性构建 PBPK-BO 模型，然后使用来自健康人体和患者的观察到的 PK 和 PD 数据对其进行验证。最后，应用该模型确定各种临床情况下的最佳给药方案。
模拟表明，100mg ACA 每日两次（BID）是单独使用时的最佳给药方案。此外，对于具有五种 CYP3A4 变体的患者，剂量方案可能减少至 50mg BID。此外，当与红霉素或克拉霉素联合使用时，给药方案应修改为 100mg（甚至 50mg）QD，当与利福平联合使用时，应增加至 200mg BID，但应避免与伊曲康唑联合使用。此外，剂量方案模拟表明，在轻度和中度肝损伤的患者中，最佳剂量可能减少至 50mg BID，并且应避免在严重肝损伤的患者中使用 ACA。
该 PBPK-BO 模型可以预测健康人体和患者的 PK 和 PD，并预测各种临床情况下的最佳给药方案。
