Posada Maria M, Bacon James A, Schneck Karen B, Tirona Rommel G, Kim Richard B, Higgins J William, Pak Y Anne, Hall Stephen D, Hillgren Kathleen M
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.M.P., J.A.B., K.B.S., J.W.H., Y.A.P., S.D.H., K.M.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.G.T., R.B.K.)
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (M.M.P., J.A.B., K.B.S., J.W.H., Y.A.P., S.D.H., K.M.H.); and Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.G.T., R.B.K.).
Drug Metab Dispos. 2015 Mar;43(3):325-34. doi: 10.1124/dmd.114.059618. Epub 2014 Dec 12.
Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (Vmax) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m(2) of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and the area under the plasma-concentration time curve (AUC0-inf) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen.
培美曲塞是一种治疗指数狭窄的阴离子抗癌药物，主要通过肾小管主动分泌消除。本研究采用的体外到体内外推法用于预测培美曲塞与非甾体抗炎药（NSAIDs）合用时可能发生的药物相互作用（DDIs），该方法包括体外试验、风险评估模型和基于生理的药代动力学（PBPK）模型。使用表达有机阴离子转运体（OAT）3或OAT4的HEK-PEAK细胞对几种NSAIDs对培美曲塞转运及其抑制参数进行了定量。根据其DDI指数对NSAIDs进行排名，DDI指数计算为其血浆中最大非结合浓度与抑制培美曲塞主动转运50%（IC50）的浓度之比。在Simcyp模拟器中建立了DDI指数最高的NSAID布洛芬的PBPK模型，该模型纳入了主动肾分泌。培美曲塞的自下而上模型对清除率的预测低了2倍。我们使用OAT3最大摄取率（Vmax）的缩放因子5.3建立的模型（该缩放因子是根据接受500mg/m²培美曲塞10分钟输注并补充叶酸和维生素B12的患者的血浆浓度曲线估算得出）充分恢复了临床数据。布洛芬合用时培美曲塞的Cmax和血浆浓度-时间曲线下面积（AUC0-inf）的观察值/预测值分别为1.1和1.0。根据其他所有NSAIDs的DDI指数预测，它们的合用时对AUC0-inf没有显著影响。PBPK模型合理地再现了癌症患者中培美曲塞的浓度-时间曲线及其与布洛芬的相互作用。
