Chen Yuan, Zhu Rui, Ma Fang, Mao Jialin, Chen Eugene C, Choo Edna F, Sahasranaman Srikumar, Liu Lichuan
Drug Metabolism and Pharmacokinetics, Genentech Inc., South San Francisco, CA, 94080, USA.
Clinical Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USA.
Biopharm Drug Dispos. 2018 Nov;39(9):420-430. doi: 10.1002/bdd.2159. Epub 2018 Nov 20.
GDC-0810 was under development as an oral anti-cancer drug for the treatment of estrogen receptor-positive breast cancer as a single agent or in combination. In vitro data indicated that GDC-0810 is a potent inhibitor of OATP1B1/1B3. To assess clinical risk, a PBPK model was developed to predict the transporter drug-drug interaction (tDDI) between GDC-0810 and pravastatin in human. The PBPK model was constructed in Simcyp® by integrating in vitro and in vivo data for GDC-0810. The prediction of human pharmacokinetics (PK) was verified using GDC-0810 phase I clinical PK data. The Simcyp transporter DDI model was verified using known OATP1B1/1B3 inhibitors (rifampicin, cyclosporine and gemfibrozil) and substrate (pravastatin), prior to using the model to predict GDC-0810 tDDI. The effect of GDC-0810 on pravastatin PK was then predicted based on the proposed clinical scenarios. Sensitivity analysis was conducted on the parameters with uncertainty. The developed PBPK model described the PK profile of GDC-0810 reasonably well. In the tDDI verification, the model reasonably predicted pravastatin tDDI caused by rifampicin and gemfibrozil OATP1B1/3 inhibition but under-predicted tDDI caused by cyclosporine. The effect of GDC-0810 on pravastatin PK was predicted to be low to moderate (pravastatin C ratios 1.01-2.05 and AUC ratio 1.04-2.23). The observed tDDI (C ratio 1.20 and AUC ratio 1.41) was within the range of the predicted values. This work demonstrates an approach using a PBPK model to prospectively assess tDDI caused by a new chemical entity as an OATP1B1/3 uptake transporter inhibitor to assess clinical risk and to support development strategy.
GDC - 0810正在作为一种口服抗癌药物进行研发，用于单药治疗或联合治疗雌激素受体阳性乳腺癌。体外数据表明，GDC - 0810是OATP1B1/1B3的强效抑制剂。为评估临床风险，构建了一个生理药代动力学（PBPK）模型来预测GDC - 0810与普伐他汀在人体内的转运体介导的药物相互作用（tDDI）。通过整合GDC - 0810的体外和体内数据，在Simcyp®中构建了PBPK模型。使用GDC - 0810的I期临床药代动力学（PK）数据验证了对人体药代动力学（PK）的预测。在使用该模型预测GDC - 0810的tDDI之前，使用已知的OATP1B1/1B3抑制剂（利福平、环孢素和吉非贝齐）和底物（普伐他汀）对Simcyp转运体DDI模型进行了验证。然后根据拟定的临床情况预测GDC - 0810对普伐他汀PK的影响。对具有不确定性的参数进行了敏感性分析。所构建的PBPK模型较好地描述了GDC - 0810的PK特征。在tDDI验证中，该模型合理地预测了利福平和吉非贝齐对OATP1B1/3的抑制所导致的普伐他汀tDDI，但对环孢素所导致的tDDI预测不足。预计GDC - 0810对普伐他汀PK的影响为低到中度（普伐他汀C比值为1.01 - 2.05，AUC比值为1.04 - 2.23）。观察到的tDDI（C比值为1.20，AUC比值为1.41）在预测值范围内。这项工作展示了一种使用PBPK模型前瞻性评估由新化学实体作为OATP1B1/3摄取转运体抑制剂引起tDDI的方法，以评估临床风险并支持研发策略。
