{"id":86625,"date":"2019-04-18T00:00:50","date_gmt":"2019-04-23T03:43:06","guid":{"rendered":"http:\/\/www.05921.net\/index.php\/86625\/"},"modified":"2019-04-23T11:43:10","modified_gmt":"2019-04-23T03:43:10","slug":"fd84724f4b","status":"publish","type":"post","link":"https:\/\/www.05921.net\/index.php\/86625\/","title":{"rendered":"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b"},"content":{"rendered":"
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\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b<\/strong><\/p>\n

\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b<\/strong><\/p>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n

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\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n
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\u5bfc\u8bfb<\/strong><\/p>\n<\/section>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/section>\n

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\u4e0a\u7bc7\u6587\u7ae0\u9610\u8ff0\u4e86\u9996\u6b21\u4eba\u4f53PK\u5efa\u6a21\u7684\u7b56\u7565\u3002\u672c\u6587<\/span>\u9009\u53d6\u4e86\u5177\u6709\u4e00\u5b9a\u96be\u5ea6\u7684\u5316\u5408\u7269\u4f5c\u4e3a\u6a21\u578b\u6848\u4f8b\uff0c\u8be6\u7ec6\u89e3\u91ca\u7b56\u7565\u7684\u5e94\u7528\uff1b\u5e76\u4e3aPBPK\u5efa\u6a21\u4eba\u5458\u9047\u5230\u7c7b\u4f3c\u836f\u7269\u6a21\u578b\u63d0\u4f9b\u4e86\u89e3\u51b3\u65b9\u6848\u548c\u601d\u8def\u3002<\/span><\/p>\n

\u901a\u8fc7\u8fd9\u4e9b\u6848\u4f8b\u7684\u5b66\u4e60\uff0c\u53ef\u4ee5\u66f4\u52a0\u6df1\u5165\u5730\u7406\u89e3\u9996\u6b21\u4eba\u4f53PK\u9884\u6d4b\u7684\u7b56\u7565\uff0c\u4ee5\u53ca\u63d0\u9ad8\u89e3\u51b3\u5b9e\u9645\u95ee\u9898\u7684\u80fd\u529b\u3002<\/span><\/p>\n

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\u5fae\u4fe1\u6587\u7ae0\u56fe\u663e\u793a\u4e0d\u6e05\u6670<\/p>\n

\u5982\u9700\u9ad8\u6e05PDF\u7248\u539f\u6587<\/p>\n

\u8bf7\u70b9\u51fb\u9605\u8bfb\u539f\u6587<\/p>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n
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\u53c2\u8003\u6587\u732e\u4f5c\u8005\u5355\u4f4d<\/strong><\/p>\n<\/section>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/section>\n

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Neil A. Miller 1, Micaela B. Reddy 2, Aki T. Heikkinen 3, Viera Lukacova 4, Neil Parrott 5<\/p>\n

1 \u845b\u5170\u7d20\u53f2\u514b\u7814\u53d1\u4e2d\u5fc3(\u82f1\u56fd)\uff0c\u7cfb\u7edf\u5efa\u6a21\u548c\u8f6c\u6362\u751f\u7269\u5b66<\/p>\n

2  Array\u5236\u836f\u516c\u53f8(\u7f8e\u56fd)\uff0c\u4e34\u5e8a\u836f\u7406\u90e8<\/p>\n

3  Admescope\u516c\u53f8(\u82ac\u5170)<\/p>\n

4  Simulations Plus\u516c\u53f8(\u7f8e\u56fd)<\/p>\n

5 \u7f57\u6c0f\u5236\u836f(\u745e\u58eb)\uff0c\u5236\u7a76\u4e0e\u65e9\u671f\u5f00\u53d1\uff0c\u5236\u836f\u79d1\u5b66<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n
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\u6587\u7ae0\u89e3\u8bfb\u4eba<\/strong><\/p>\n<\/section>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/section>\n

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\u9648\u6d9b\uff0c\u4e0a\u6d77\u6280\u672f\u90e8<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n
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\u53c2\u8003\u6587\u732e<\/strong><\/p>\n<\/section>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/section>\n

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Neil A. Miller, Micaela B. Reddy, Aki T. Heikkinen, et al., Physiologically Based Pharmacokinetic Modelling for First-In-Human Predictions: An UpdatedModel Building Strategy Illustrated with Challenging Industry Case Studies. Clin Pharmacokinet. 2019 Feb 7.  <\/p>\n

IF: 4.464<\/p>\n

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\u5efa\u6a21\u7b56\u7565\u90e8\u5206\uff0c<\/p>\n

\u8bf7\u89c1\u300a\uff08\u4e0a\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565<\/span>\u300b<\/span><\/p>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n


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3<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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\u6750\u6599\u4e0e\u65b9\u6cd5<\/strong><\/p>\n<\/section>\n<\/section>\n

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\u6240\u6709\u7684\u6a21\u62df\u5747\u91c7\u7528GastroPlus (Simulations Plus Inc., Lancaster, CA, USA)\u8fdb\u884c\u7684\uff0c\u6b64\u5916ADMET Predictor\u2122(Simulations Plus, Inc.)\u7528\u4e8e\u9884\u6d4b\u5316\u5408\u7269\u7684\u7269\u7406\u5316\u5b66\u53ca\u751f\u7269\u836f\u5242\u5b66\u6027\u8d28\u3002<\/p>\n

Table 2\u8bb0\u5f55\u4e86\u8fd9\u4e9b\u8f6f\u4ef6\u7684\u7248\u672c\u4ee5\u53ca\u6bcf\u4e00\u4e2a\u6848\u4f8b\u7684\u5177\u4f53\u8bbe\u7f6e\u3002FIH PK\u9884\u6d4b\u7684PBPK\u6a21\u578b\u6240\u5fc5\u987b\u7684\u6a21\u578b\u8f93\u5165\u53c2\u6570\u4e5f\u603b\u7ed3\u5728\u4e86Table 2\u3002\u6240\u9009\u62e9\u8fd9\u4e9b\u5316\u5408\u7269\u662f\u4e3a\u4e86\u8bf4\u660e\u6587\u7ae0\u7b56\u7565\u7684\u5e94\u7528\uff0c\u5e76\u7a81\u51fa\u7b56\u7565\u7684\u4e3b\u8981\u6784\u6210(\u5728\u4ed6\u4eec\u5404\u81ea\u6807\u9898\u91cc\u9762\u9648\u8ff0\u7684\u7279\u6b8a\u6027)\u3002<\/p>\n

Compounds 1-3\u662f\u6765\u81ea\u4f01\u4e1a\u7684\u9884\u6d4b\u6848\u4f8b\uff0cCompound 4\u662f\u57fa\u4e8e\u6587\u732e\u62a5\u9053\u7684\u6570\u636e\u8fdb\u884c\u6a21\u578b\u642d\u5efa\u7684\u3002<\/p>\n

Table 2 \u6bcf\u4e2aFIH\u9884\u6d4b\u6848\u4f8b\u6240\u91c7\u7528\u7684\u4e3b\u8981\u7406\u5316\/PK\u53c2\u6570(\u6240\u6709\u7684\u6a21\u578b\u5747\u91c7\u7528ACAT\u6a21\u578b\u5916\u52a0\u7cfb\u7edfPBPK\u6a21\u578b\u5f00\u5c55\uff0c\u6b64\u5916\u90e8\u5206\u5b9e\u6d4b\u7684\u6027\u8d28\u53c2\u6570\u672a\u8fdb\u884c\u5217\u4e3e)<\/span><\/strong><\/p>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n

BPR-<\/span>\u5168\u8840\u8840\u6d46\u6d53\u5ea6\u6bd4\uff1b<\/span>Clint-<\/span>\u56fa\u6709\u6e05\u9664\u7387\uff1b<\/span>ECCS-<\/span>\u6269\u5c55\u6e05\u9664\u5206\u7c7b\u7cfb\u7edf\uff1b<\/span>FaSSIF-<\/span>\u6a21\u62df\u7a7a\u8179\u72b6\u6001\u7684\u80a0\u6db2\uff1b<\/span>FuP-<\/span>\u8840\u6d46\u6e38\u79bb\u836f\u7269\u5206\u6570\uff1b<\/span>IV-<\/span>\u9759\u8109\uff1b<\/span>Kp-<\/span>\u7ec4\u7ec7\u8840\u6d46\u5206\u914d\u7cfb\u6570\uff1b<\/span>Peff-<\/span>\u6709\u6548\u6e17\u900f\u6027\uff1b<\/span>PStc-<\/span>\u7ec4\u7ec7\u6e17\u900f\u6027\u4e0e\u7ec6\u80de\u8868\u9762\u79ef\u4e58\u79ef\uff1b<\/span>QSPR-<\/span>\u5b9a\u91cf\u7ed3\u6784\u6027\u8d28\u5173\u7cfb<\/span><\/p>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n

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4<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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\u5e94\u7528\u6848\u4f8b<\/strong><\/p>\n<\/section>\n<\/section>\n

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4.1 \u6848\u4f8b1<\/strong><\/p>\n

Compound 1: \u901a\u8fc7\u4e34\u5e8a\u524d\u79cd\u5c5e\u7684\u7ecf\u9a8c\u6027PBPK\u6a21\u578b\u56e0\u5b50\u8fdb\u884cFIH\u9884\u6d4b<\/strong><\/p>\n<\/section>\n<\/section>\n<\/section>\n

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Compound 1\u662f\u4e2d\u6027\u548c\u9ad8\u8102\u6eb6\u6027(clogP > 5)\u7684\u5316\u5408\u7269\u3002\u8840\u6d46\u6e38\u79bb\u836f\u7269\u5206\u6570(< 0.1%)\u548c\u4eb2\u6c34\u6027\u6eb6\u89e3\u5ea6(< 1 \u03bcg\/mL)\u5747\u5f88\u4f4e\u4f7f\u5f97\u5f88\u96be\u51c6\u786e\u5b9a\u91cf\u8868\u5f81\u3002<\/p>\n

\u8fd9\u4e9b\u6027\u8d28\u4e5f\u610f\u5473\u7740\u9a8c\u8bc1IVIVE\u65b9\u6cd5\u5177\u6709\u4e00\u5b9a\u7684\u6311\u6218\u6027\u3002\u7136\u800c\uff0c\u8be5\u5316\u5408\u7269\u7531\u4e8e\u9ad8logP\u7b49\u6027\u8d28\u5176\u836f\u7269\u5316\u5b66\u4e0d\u8ba4\u4e3a\u662f\u4e00\u4e2a\u597d\u7684\u6d3b\u6027\u5206\u5b50\uff0c\u4f46\u4e34\u5e8a\u524d\u4f53\u5916\u548c\u4f53\u5185\u7684\u836f\u7406\u5b66\u8fd8\u662f\u6bd4\u8f83\u597d\u7684\u3002\u56e0\u6b64\uff0c\u5f00\u5c55\u4e86PK\u7684\u79cd\u5c5e\u5916\u63a8\u5e76\u8fdb\u884c\u4f30\u7b97\u4e34\u5e8a\u7684\u7ed9\u836f\u5242\u91cf\u3002<\/p>\n

\u5927\u9f20\u3001\u72d7\u548c\u7334\u5b50\u8868\u73b0\u51fa\u76f8\u4f3c\u7684Vss (\u4ece1.5\u52303 L\/kg\u4e4b\u95f4)\u3002\u91c7\u7528Lukacova\u65b9\u6cd5(\u57fa\u4e8e\u836f\u7269\u7684\u7406\u5316\u6027\u8d28\u5e76\u5047\u8bbefup\u7684\u6570\u503c\u4e3a0.1%)\u9884\u6d4b\u7684\u5404\u4e2a\u79cd\u5c5e\u5206\u5e03\u4f53\u79ef\u4e0e\u89c2\u6d4b\u6570\u636e\u8f83\u4e3a\u4e00\u81f4\uff1b\u9884\u6d4b\u7684\u4eba\u4f53Vss\u6570\u503c\u4e3a3.2 L\/kg\u3002<\/p>\n

4.1.1 \u91c7\u7528\u4e34\u5e8a\u524d\u6570\u636e\u9a8c\u8bc1\u7684\u7ecf\u9a8c\u6bd4\u653e\u56e0\u5b50\u8fdb\u884c\u4eba\u4f53\u6e05\u9664\u7387\u7684IVIVE\u9884\u6d4b<\/span><\/strong><\/span><\/span><\/strong><\/p>\n

\u4ece\u4f53\u5916\u6570\u636e\u653e\u5927\u9884\u6d4b\u6e05\u9664\u7387\u5e94\u5f53\u8003\u8651\u4f53\u5916\u548c\u4f53\u5185\u7ed3\u5408\u7684\u5dee\u5f02\u3002\u5bf9\u4e8eCompound 1\uff0c\u56e0\u4e3a\u5f88\u96be\u6d4b\u5b9a\u86cb\u767d\u7ed3\u5408\uff0c\u91c7\u7528\u5047\u8bbe\u4f53\u5916\u6e38\u79bb\u5206\u6570\u7b49\u4e8efup\u7684\u65b9\u6cd5\u5f88\u5927\u7a0b\u5ea6\u5730\u9ad8\u4f30\u5927\u9f20\u6e05\u9664\u7387(10\u500d\u5de6\u53f3)\u3002<\/p>\n

\u56e0\u6b64\uff0c\u4eba\u4f53\u6e05\u9664\u7387\u91c7\u7528\u6765\u81ea\u5927\u9f20\u7814\u7a76\u7684\u7ecf\u9a8c\u6bd4\u653e\u56e0\u5b50\u8fdb\u884c\u9884\u6d4b\u5f97\u5230\u3002\u4e3a\u4e86\u5efa\u7acb\u8be5\u79cd\u65b9\u6cd5\u7684\u4fe1\u5fc3\uff0c\u4f7f\u7528\u6765\u81ea\u540c\u4e00\u7ed3\u6784\u7cfb\u5217\u7684\u5148\u5bfc\u5316\u5408\u7269\u4e14\u5df2\u7ecf\u4f5c\u4e3a\u4e34\u5e8a\u5019\u9009\u5316\u5408\u7269\u7684\u4f53\u5185\u548c\u4f53\u5916\u6570\u636e\u8fdb\u884c\u4e86\u9a8c\u8bc1\u3002<\/p>\n

\u8fd9\u4e9b\u5316\u5408\u7269\u7684\u5b9e\u6d4b\u80be\u810f\u6e05\u9664\u5747\u53ef\u4ee5\u5ffd\u7565\u4e0d\u8ba1\uff0c\u5e76\u5047\u8bbe\u4f53\u5185\u7cfb\u7edf\u603b\u6e05\u9664\u7387(\u4ece<1\u523035 mL\/min\/kg)\u5747\u901a\u8fc7\u809d\u810f\u4ee3\u8c22\u6e05\u9664\u8fdb\u884c\u8868\u5f81\u3002<\/p>\n

\u91c7\u7528\u5145\u5206\u6df7\u5408\u809d\u810f\u6a21\u578b\uff0c\u5316\u5408\u7269\u76f8\u5173\u7684\u6bd4\u653e\u56e0\u5b50\u901a\u8fc7\u5fae\u7c92\u4f53\u548c\u809d\u7ec6\u80de\u56fa\u6709\u6e05\u9664\u7387\u7684\u6570\u636e\u4f30\u7b97\u5f97\u5230\u3002\u8fd9\u4e9b\u6bd4\u653e\u56e0\u5b50\u53c8\u8fdb\u4e00\u6b65\u7528\u4e8e\u7531\u56fa\u6709\u6e05\u9664\u7387(\u6765\u81ea\u4eba\u5fae\u7c92\u4f53\u548c\u809d\u7ec6\u80de\u7684\u6570\u636e)\u63a8\u7b97\u4eba\u4f53\u6e05\u9664\u7387\u3002<\/p>\n

\u901a\u8fc7\u809d\u7ec6\u80de\u548c\u5fae\u7c92\u4f53\u65b9\u6cd5\u9884\u6d4b\u7684\u8fd97\u4e2a\u5316\u5408\u7269\u7684\u4eba\u4f53\u809d\u6e05\u9664\u7387\u8f83\u4e3a\u4e00\u81f4(Fig. 7)\u3002<\/p>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n

Fig. 7<\/span>\u57fa\u4e8e\u6765\u81ea\u5927\u9f20\u7684\u7ecf\u9a8c\u56e0\u5b50\uff0c\u91c7\u7528\u4eba\u5fae\u7c92\u4f53\u548c\u809d\u7ec6\u80de\u56fa\u6709\u6e05\u9664\u7387\u5916\u63a8\u8ba1\u7b97\u4eba\u4f53\u809d\u810f\u6e05\u9664\u7387\u7684\u4e00\u81f4\u6027\u3002<\/span>\u5c06\u8840\u6d46\u548c\u5168\u8840\u86cb\u767d\u7ed3\u5408\u6574\u5408\u5230\u7ecf\u9a8c\u6bd4\u653e\u56e0\u5b50<\/span>(SF)<\/span>\u4ee5\u4fee\u6b63\u5145\u5206\u6df7\u5408\u809d\u810f\u6a21\u578b\uff0c\u5e76\u7528\u4e8e\u5c06\u5fae\u7c92\u4f53\u548c\u809d\u7ec6\u80de\u7684\u56fa\u6709\u6e05\u9664\u7387\u653e\u5927\u5230\u5927\u9f20\u4f53\u5185\u809d\u810f\u6e05\u9664\u7387<\/span>(CL_rat)<\/span>\u3002<\/span>\u5316\u5408\u7269\u76f8\u5173\u7684<\/span>SF<\/span>\u6570\u503c\u5206\u522b\u901a\u8fc7\u5fae\u7c92\u4f53<\/span>(SF_m)<\/span>\u548c\u809d\u7ec6\u80de<\/span>(SF_h)<\/span>\u8fdb\u884c\u4f30\u7b97\u3002<\/span>\u8fd9\u4e9b<\/span>SFs<\/span>\u7136\u540e\u7528\u4e8e\u653e\u5927\u4eba\u5fae\u7c92\u4f53\u548c\u809d\u7ec6\u80de\u6d4b\u5b9a\u7684\u56fa\u6709\u6e05\u9664\u7387\u3002<\/span>\u6240\u9884\u6d4b\u7684<\/span>7<\/span>\u4e2a\u5316\u5408\u7269\u7684\u809d\u810f\u6e05\u9664\u7387\u5177\u6709\u8f83\u597d\u7684\u7ebf\u6027\u5173\u7cfb\u3002<\/span><\/strong><\/span><\/p>\n

Compound 1\u7684\u7ecf\u9a8c\u6bd4\u653e\u56e0\u5b50\u53c8\u8fdb\u4e00\u6b65\u901a\u8fc7\u72d7\u548c\u7334\u5b50\u7684\u809d\u7ec6\u80de\u56fa\u6709\u6e05\u9664\u7387\u8fdb\u884c\u9a8c\u8bc1\u3002\u9884\u6d4b\u72d7\u7684\u6e05\u9664\u7387(0.6 mL\/min\/kg)\u548c\u7334\u5b50\u7684\u6570\u503c(2.0 mL\/min\/kg)\u6bd4\u8f83\u597d\u5730\u53cd\u6620\u4f53\u5185\u89c2\u6d4b\u6570\u503c(\u72d7\uff1a1.5 mL\/min\/kg\uff0c\u7334\u5b50\uff1a1.8 mL\/min\/kg)\u3002\u6700\u540e\uff0c\u6bd4\u653e\u4eba\u809d\u7ec6\u80de\u56fa\u6709\u6e05\u9664\u7387\u6570\u503c\u5e76\u9884\u6d4b\u5f97\u5230\u4eba\u4f53\u5e73\u5747\u7684\u809d\u810f\u6e05\u9664\u6570\u503c\u4e3a0.5 mL\/min\/kg (\u8303\u56f4\uff1a0.2-0.7 mL\/min\/kg)\u3002
<\/p>\n

4.1.2 \u6eb6\u89e3\u5ea6\u4f4e\uff0c\u4e14\u5448\u73b0\u5242\u91cf\u548c\u5242\u578b\u4f9d\u8d56\u578b\u7684\u5438\u6536<\/strong><\/span><\/strong><\/span><\/p>\n

\u7531\u4e8eCompound 1\u7684\u6eb6\u89e3\u5ea6\u4f4e\uff0c\u9884\u6d4b\u5176\u53e3\u670d\u5438\u6536\u5177\u6709\u4e00\u5b9a\u7684\u96be\u5ea6\u3002<\/p>\n

\u4e34\u5e8a\u524d\u7684\u6570\u636e\u663e\u793a\u8be5\u836f\u7269\u7684\u751f\u7269\u5229\u7528\u5ea6\u968f\u7740\u5927\u9f20\u7ed9\u836f\u5242\u91cf\u7684\u589e\u52a0\u800c\u9010\u6e10\u964d\u4f4e\uff0c\u4e14\u8fd8\u53d7\u5230\u5242\u578b\u4ee5\u53ca\u8fdb\u98df\u72b6\u6001\u7684\u5f71\u54cd\u3002\u4e34\u5e8a\u7ed9\u836f\u5242\u578b\u7684\u5438\u6536\u6a21\u578b\u901a\u8fc7\u72d7\u5242\u578b\u7b5b\u9009\u7814\u7a76(\u53d1\u73b0\u7a7a\u8179\u72b6\u6001\u4e0b\u7ed9\u72d7\u5fae\u7c89\u7247\u5242\u7684\u751f\u7269\u5229\u7528\u5ea6\u4e3a7%\uff0c\u800c\u9971\u8179\u72b6\u6001\u53e3\u670d\u7eb3\u7c73\u6df7\u60ac\u6db2\u5219\u4e3a52%)\u5f97\u4ee5\u652f\u6301\u3002\u5c3d\u7ba1\u4eb2\u6c34\u6027\u6eb6\u89e3\u5ea6\u5f88\u4f4e(< 1 \u03bcg\/mL)\uff0c\u4f46\u5728\u751f\u7406\u76f8\u5173\u4ecb\u8d28\u4e2d\u7684\u6eb6\u89e3\u5ea6\u8fd8\u662f\u80fd\u591f\u5f97\u5230\u63d0\u9ad8\u7684(FaSSIF\u4e2d\u7ea6\u4e3a10 \u03bcg\/mL\uff0cFeSSIF\u7ea6\u4e3a35 \u03bcg\/mL)\u3002<\/p>\n

\u642d\u5efa\u4e86\u8fd9\u4e9b\u5236\u5242\u7ed9\u72d7\u670d\u7528\u540e\u7684GastroPlus\u6a21\u578b\uff1a\u8be5\u6a21\u578b\u6574\u5408\u4e86\u5b9e\u6d4b\u7684\u751f\u7269\u4f53\u76f8\u5173\u6eb6\u89e3\u5ea6\uff0c\u5e76\u6839\u636e\u5b9e\u6d4b\u6570\u636e\u8fdb\u884c\u4e24\u6b65\u8c03\u6574\u4f18\u5316\u4e86\u72d7\u7684\u5438\u6536\u6a21\u578b\u3002\u9996\u5148\uff0c\u5c0f\u80a0\u548c\u5927\u80a0\u9694\u5ba4\u4e2d\u6c34\u7684\u767e\u5206\u6570\u5206\u522b\u964d\u4f4e\u81f310 %\u548c0.1%\uff1b\u7136\u540e\uff0c\u5bf9\u4e8e\u7eb3\u7c73\u6df7\u60ac\u6db2\u5c06\u5176\u7c92\u5f84\u8c03\u6574\u81f31 \u03bcm\uff0c\u666e\u901a\u7247\u5242\u7684\u7c92\u5f84\u5219\u4e3a80 \u03bcm\u3002<\/p>\n

\u81f3\u4e8e\u6c34\u542b\u91cf\u7684\u66f4\u6539\uff0c\u5982\u4e00\u4e9b\u751f\u7406\u6a21\u578b\u53c2\u6570\u7684\u66f4\u6539(\u7cfb\u7edf\u53c2\u6570\u7684\u6539\u53d8)\u4ee5\u543b\u5408\u4e00\u4e2a\u7279\u5b9a\u836f\u7269\u7684\u5b9e\u9645\u4f53\u5185\u66b4\u9732\uff0c\u4e00\u822c\u4e0d\u63a8\u8350\u4e3a\u6700\u4f73\u7684\u65b9\u5f0f\u3002\u7136\u800c\uff0c\u53ef\u4ee5\u8003\u8651\u4e0d\u786e\u5b9a\uff0c\u5373\u6000\u7591\u80a0\u9053\u6c34\u5206\u4f53\u79ef\u7684\u76f8\u5173\u53c2\u6570\u548c\u7ed3\u80a0\u6a21\u578b\u9694\u5ba4\u7684\u90e8\u5206\u53c2\u6570\u5177\u6709\u4e0d\u786e\u5b9a\u6027\u3002\u8fd9\u4e9b\u4f18\u5316\u7684\u6570\u503c\u5e76\u8fdb\u4e00\u6b65\u5916\u63a8\u81f3\u4eba\u4f53\u5438\u6536\u6a21\u578b\u4e2d\uff0c\u5e76\u6a21\u62df\u53ef\u80fd\u7684\u4e34\u5e8a\u60c5\u5f62\u3002\u7a7a\u8179\u72b6\u6001\u4e0b\u53e3\u670d50 mg\u7247\u5242\u7684\u53e3\u670d\u5438\u6536\u9884\u6d4b\u503c\u4ec5\u4e3a11%\uff0c\u4f46\u9971\u8179\u72b6\u6001\u4e0b\u53ef\u589e\u52a0\u81f341%\u3002\u56e0\u4e3a\u9884\u6d4b\u51fa\u8be5\u836f\u7269\u6709\u98df\u7269\u6548\u5e94\uff0c\u56e0\u6b64\u9996\u6b21\u4e34\u5e8a\u7814\u7a76\u5728\u9971\u8179\u72b6\u6001\u4e0b\u8fdb\u884c\u5f00\u5c55\u3002<\/p>\n

4.1.3 \u4e34\u5e8a\u6570\u636e\u663e\u793a\u9884\u6d4bPK\u65f6\u8003\u8651\u4e0d\u786e\u5b9a\u6027\u975e\u5e38\u91cd\u8981<\/strong><\/span><\/strong><\/span><\/p>\n

\u5728Fig. 8\u4e2d\uff0c\u6a21\u62df\u7684\u9971\u8179\u72b6\u6001\u7ed9\u836f25 mg\u7247\u5242\u7684\u60c5\u51b5\u4e0e\u9996\u6b216\u4e2a\u4eba\u7ed9\u836f\u540e\u7684\u4e34\u5e8a\u8840\u6d46\u89c2\u6d4b\u6570\u503c\u8fdb\u884c\u4e86\u6bd4\u8f83\u3002\u5c3d\u7ba1\u6700\u5927\u8840\u836f\u6d53\u5ea6\u8fdb\u884c\u4e86\u5f88\u597d\u5730\u9884\u6d4b\uff0c\u4f46\u8fd8\u662f\u53d1\u73b0\u836f\u65f6\u66f2\u7ebf\u4e0b\u7684\u9762\u79ef\u6709\u8d85\u8fc72\u500d\u4ee5\u4e0a\u7684\u4f4e\u4f30\uff0c\u89c2\u6d4b\u7684\u534a\u8870\u671f(10-14\u5929)\u8981\u8fdc\u5927\u4e8e\u9884\u6d4b\u6570\u503c(~3\u5929)\u3002\u5728\u5f00\u53d1\u7684\u540e\u671f\uff0c\u5f00\u5c55\u4e86\u4e00\u4e2a\u5c0f\u5242\u91cf\u7684\u9759\u8109\u7ed9\u836f\u8bd5\u9a8c\u4ee5\u786e\u5b9a\u4e3b\u8981\u7684PK\u53c2\u6570\u3002\u572825 mg\u65f6\uff0c\u89c2\u6d4b\u7684\u53e3\u670d\u7edd\u5bf9\u751f\u7269\u5229\u7528\u5ea6(30-40%)\u548cVss (3.7 L\/kg)\u4e0e\u9884\u6d4b\u7ed3\u679c\u8f83\u4e3a\u4e00\u81f4\uff1b\u7136\u800c\u7cfb\u7edf\u6e05\u9664\u7387(0.18 mL\/min\/kg)\u8981\u7a0d\u5fae\u4f4e\u4e8e\u9884\u6d4b\u7684\u8303\u56f4\u503c(0.2-0.7 mL\/min\/kg)\u3002<\/p>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n

Fig. 8  <\/span>\u7247\u524225 mg<\/span>\u9884\u6d4b\u7684\u5e73\u5747\u8840\u6d46\u836f\u7269\u6d53\u5ea6<\/span>(<\/span>\u5b9e\u7ebf<\/span>)<\/span>\u548c<\/span>6<\/span>\u4e2a\u5065\u5eb7\u5fd7\u613f\u8005\u7684\u89c2\u6d4b\u6570\u636e<\/span>(<\/span>\u70b9<\/span>)<\/span>\u7684\u5bf9\u6bd4\u3002<\/span>\u5d4c\u5165\u7684\u56fe\u4ee5<\/span>log<\/span>\u653e\u5927\u7684\u5f62\u5f0f\u5c55\u793a\u4e86\u76f8\u540c\u7684\u6570\u636e<\/span>(<\/span>\u65f6\u95f4\u8f74\u8d85\u8fc7<\/span>60<\/span>\u5929<\/span>)<\/span>\u3002<\/span>\u9ed1\u8272\u5b9e\u7ebf\u4ee3\u8868\u5e73\u5747\u6e05\u9664\u7387\u4e3a<\/span>0.5mL\/min\/kg<\/span>\u7684\u9884\u6d4b\u7ed3\u679c\uff0c\u800c\u70b9\u865a\u7ebf\u5219\u8868\u793a\u6e05\u9664\u7387\u7684\u8303\u56f4\u5728<\/span>0.2-0.7mL\/min\/kg<\/span>\u65f6\u7684\u9884\u6d4b\u7ed3\u679c\u3002<\/span><\/strong><\/span><\/p>\n

\u5c3d\u7ba1Compound 1\u5177\u6709\u5f88\u6311\u6218\u7684\u6027\u8d28\uff0c\u4f46PK\u8fd8\u662f\u8fdb\u884c\u4e86\u8f83\u597d\u5730\u9884\u6d4b\u3002\u7136\u800cI\u671f\u4e34\u5e8a\u65b9\u6848\u4ec5\u6839\u636e\u9884\u6d4b\u7684\u5e73\u5747\u534a\u8870\u671f(~3\u5929)\u8fdb\u884c\u4e86\u8bbe\u8ba1\uff0c\u8ba1\u5212\u7684\u6837\u54c1\u91c7\u96c6\u65f6\u95f4\u4e0d\u80fd\u5145\u5206\u8868\u5f81PK\u884c\u4e3a\uff0c\u56e0\u6b64\u8fd8\u9700\u8981\u5bf9\u65b9\u6848\u8fdb\u884c\u4fee\u6b63\u3002\u8003\u8651\u5230\u6e05\u9664\u7387\u7684\u4e0d\u786e\u5b9a\u6027\u53ef\u80fd\u907f\u514d\u8be5\u65b9\u6848\u4fee\u6b63\uff0c\u56e0\u6b64\u5728\u9884\u6d4b\u4e2d\u8003\u8651\u4e0d\u786e\u5b9a\u6027\u975e\u5e38\u91cd\u8981\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

\n
\n
\n

4.2 \u6848\u4f8b2
Compound 2\uff1a\u5168\u8840\u8840\u6d46\u836f\u7269\u6d53\u5ea6\u6bd4\u5bf9\u4e8e\u9884\u6d4b\u78b1\u6027\u5316\u5408\u7269\u7a33\u6001\u5206\u5e03\u4f53\u79ef\u7684\u5f71\u54cd-\u56de\u987e\u6027\u5206\u6790<\/span><\/strong><\/p>\n<\/section>\n<\/section>\n<\/section>\n

\n
\n
\n

\u7ed3\u5408QSPR\u548cPBPK\u6a21\u578b\u7684\u8bc4\u4f30\uff0c\u53d1\u73b0Compound 2\u662f\u4e00\u4e2a\u4eb2\u8102\u6027\u3001\u78b1\u6027\u3001\u9ad8\u6eb6\u89e3\u5ea6\u548c\u6e17\u900f\u6027\u7684BCS I\u7c7b\u5316\u5408\u7269\uff1b\u5c5e\u4e8e\u4ee3\u8c22\u6e05\u9664(ECCS)\u5e76\u4e14\u7531\u4e8e\u548c\u7ec4\u7ec7\u9178\u6027\u78f7\u916f\u7684\u7ed3\u5408\u800c\u5bfc\u81f4\u9ad8Vss\u3002\u5bf9\u4e8e\u78b1\u6027\u5316\u5408\u7269\uff0c\u7528\u4e8e\u8bc4\u4f30\u9178\u6027\u78f7\u8102\u7ed3\u5408\u5e38\u6570\u7684BPR\u53ef\u80fd\u662fPBPK\u6a21\u578b\u7684\u4e00\u4e2a\u91cd\u8981\u8f93\u5165\u53c2\u6570\u3002<\/p>\n

\u5047\u8bbe\u4e3a30\u5c81\u300170 Kg\u7684\u4eba\u7fa4\uff0c\u5e76\u8f93\u5165\u5305\u62ecBPR=0.91\u5728\u5185\u7684QSPR\u6a21\u578b\u9884\u6d4b\u7684\u5316\u5408\u7269\u7279\u5f81\u53c2\u6570\uff0c\u91c7\u7528Lukacova\u7684\u65b9\u6cd5\u9884\u6d4b\u5176Vss\u6570\u503c\u4e3a3 L\/kg\u3002PSA\u5206\u6790\u8868\u660eBPR\u662f\u4e00\u4e2a\u654f\u611f\u53c2\u6570\uff1b\u5bf9\u4e8eBPR=0.55\uff0c\u9884\u6d4b\u7684Vss\u6570\u503c\u4e3a0.27 L\/kg\uff1b\u800c\u5047\u8bbeBPR\u4e3a\u66f4\u5927\u6570\u503c\u76842\uff0c\u6240\u9884\u6d4b\u7684Vss\u5219\u4e3a13.1 L\/kg\u3002<\/p>\n

4.2.1 \u9ad8\u7a33\u6001\u5206\u5e03\u4f53\u79ef\u4ee5\u53ca\u79cd\u5c5e\u7279\u5f02\u6027\u7684\u5168\u8840\/\u8840\u6d46\u836f\u7269\u6d53\u5ea6\u6bd4<\/span><\/strong><\/p>\n

\u5df2\u7ecf\u83b7\u5f97\u4e86\u5927\u9f20\u3001\u5154\u5b50\u3001\u72d7\u3001\u7334\u5b50\u3001\u8ff7\u4f60\u732a\u548c\u4eba\u9759\u8109\u7ed9\u836f\u540e\u7684PK\u6570\u636e\u3002\u8fd9\u4e9b\u6570\u636e\u4f5c\u4e3a\u56de\u987e\u6027\u72ec\u7acb\u8bc4\u4f30BPR\u5bf9\u9884\u6d4bVss\u7684\u5f71\u54cd\u3002\u5c06\u6bcf\u4e2a\u79cd\u5c5e\u89c2\u6d4b\u7684\u6e05\u9664\u7387\u6570\u503c\u8f93\u5165\u5230PBPK\u6a21\u578b\u4e2d\u4ee5\u8fdb\u884c\u6a21\u62df\u548c\u89c2\u6d4b\u66f2\u7ebf\u7684\u6bd4\u5bf9\u3002\u91c7\u7528Lukacova\u65b9\u6cd5\u9884\u6d4b\u7684Vss\u6570\u503c\u4e0e\u6240\u6709\u79cd\u5c5e\u7684\u5b9e\u6d4b\u6570\u636e\u8f83\u4e3a\u76f8\u8fd1\u3002<\/p>\n

Compound 2\u5728\u5927\u9f20\u3001\u5154\u5b50\u548c\u72d7\u5168\u8840\u4e2d\u7684\u5206\u914d\u8981\u6bd4\u8840\u6d46\u4e2d\u7684\u591a(Table 3)\u3002<\/p>\n

Table3 Compound 2\u6d4b\u5b9a\u7684\u5168\u8840<\/span>\/\u8840\u6d46\u6d53\u5ea6\u6bd4<\/span>(BPR)\uff0c\u6e38\u79bb\u836f\u7269\u5206\u6570<\/span>(fup)\u4ee5\u53ca\u7a33\u6001\u4e0b\u9759\u8109\u5206\u5e03\u4f53\u79ef<\/span>(Vss\uff0c\u89c2\u6d4b\u548c\u9884\u6d4b\u503c<\/span>)<\/strong><\/span><\/span><\/p>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n

\u6ce8\uff1a<\/span>\u4eba\u4f53\u5b9e\u6d4b\u4e86\u8840\u6d46<\/span>PK<\/span>\uff0c\u4e5f\u91c7\u7528<\/span>GastroPlus<\/span>\u9884\u6d4b\u4e86\u8840\u6d46<\/span>PK<\/span>\uff1b<\/span>\u4ec5\u6709\u4e34\u5e8a\u524d\u79cd\u5c5e\u8fdb\u884c\u5168\u8840<\/span>PK<\/span>\u7684\u68c0\u6d4b\uff0c\u91c7\u7528\u79cd\u5c5e\u7279\u5f81\u7684<\/span>BPR<\/span>\u5c06\u5168\u8840<\/span>Vss<\/span>\u8f6c\u4e3a\u8840\u6d46<\/span>Vss<\/span>\uff0c\u4ee5\u5f97\u5230<\/span>GastroPlus<\/span>\u7684\u8f93\u51fa\u6570\u636e\u3002<\/span><\/span><\/strong><\/p>\n

Vss<\/span>\u7684\u8bef\u5dee<\/span>= \u2212Observed Vss\/Predicted Vss<\/span>\uff0c\u5982\u679c<\/span>Observed Vss > Predicted Vss<\/span><\/span><\/strong><\/p>\n

Vss<\/span>\u7684\u8bef\u5dee<\/span>= +Predicted Vss\/Observed Vss<\/span>\uff0c\u5982\u679c<\/span>Predicted Vss > Observed Vss<\/span><\/strong><\/p>\n

\u5206\u6790\u975e\u623f\u5ba4\u6a21\u578b\u5206\u6790\u9759\u8109\u7ed9\u836f\u540e\u5168\u8840\u4e2d\u7684PK\u6570\u636e\uff0c\u53d1\u73b0\u6240\u6709\u79cd\u5c5e\u7684\u5168\u8840Vss\u90fd\u5f88\u9ad8\uff0c\u540c\u65f6\u4e0eBPR\u4e5f\u4e0d\u80fd\u8868\u73b0\u51fa\u975e\u5e38\u597d\u7684\u7ebf\u6027\u5173\u7cfb\uff0c\u8868\u660eVss\u662f\u53d7\u591a\u4e2a\u8fc7\u7a0b\u9a71\u52a8\u7684\u3002\u4e34\u5e8a\u524d\u79cd\u5c5e(\u9664\u4e86\u7334\u5b50)\u7684\u8840\u6d46\u6e38\u79bb\u836f\u7269\u5206\u6570\u975e\u5e38\u5927\uff0c\u63d0\u793a\u5177\u6709\u4e00\u5b9a\u7684\u79cd\u5c5e\u5dee\u5f02\u3002<\/p>\n

4.2.2 PBPK\u6a21\u578b\u7ec4\u7ec7-\u8840\u6d46\u5206\u914d\u7cfb\u6570\u7684\u9884\u6d4b<\/span><\/strong><\/p>\n

\u901a\u8fc7\u4e24\u79cd\u8272\u8c31\u65b9\u6cd5\u6d4b\u5b9aCompound 2\u7684\u8102\u6eb6\u6027\uff1a\u91c7\u7528C18\u56fa\u5b9a\u76f8\u8fdb\u884c\u7684\u8272\u8c31\u758f\u6c34\u6027\u6307\u6570\uff0c\u4ee5\u53ca\u91c7\u7528\u5316\u5b66\u952e\u5408\u78f7\u8102\u9170\u80c6\u78b1\u5230\u4e8c\u6c27\u5316\u7845\u8868\u9762\u7684\u56fa\u5b9a\u5316\u4eba\u5de5\u819c\u3002\u6240\u6709\u8fd9\u4e9b\u6d4b\u5b9a\u6570\u636e\u53ef\u4ee5\u8fdb\u4e00\u6b65\u8f6c\u4e3a\u8f9b\u9187\/\u6c34 logP\u7cfb\u6570\uff0c\u518d\u8fdb\u4e00\u6b65\u4f5c\u4e3aLukacova\u65b9\u6cd5\u8ba1\u7b97\u7684\u5316\u5408\u7269\u7279\u5f81\u8f93\u5165\u53c2\u6570\u3002\u6700\u540e\u4f7f\u7528\u4e86\u8272\u8c31\u758f\u6c34\u7cfb\u6570(2.9)\u548c\u56fa\u5b9a\u5316\u4eba\u5de5\u819c(5.5)\u6570\u503c\u7684\u5747\u503c4.2. \u5b9e\u6d4b\u7684\u78b1\u6027pKa\u6570\u503c(8.96\uff0c4.12\u548c2.8)\u662f\u5176\u5b83\u4e00\u4e9b\u5316\u5408\u7269\u7279\u5f81\u8f93\u5165\u53c2\u6570\u3002\u5bf9\u4e8e\u6bcf\u4e00\u4e2a\u79cd\u5c5e\uff0c\u91c7\u7528\u4e86\u5b9e\u9645\u7684\u4f53\u91cd\u642d\u5efa\u4e86PBPK\u6a21\u578b\u3002\u5982\u679c\u5728\u8fdb\u884cBPR\u5b9e\u9a8c\u65f6\u6d4b\u5b9a\u4e86\u7ea2\u8840\u7403\u538b\u79ef\u4e5f\u53ef\u4ee5\u8f93\u5165\u5230\u6a21\u578b\u4e2d\uff0c\u5c3d\u7ba1\u8be5\u6570\u503c\u901a\u5e38\u4e0eGastroPlus\u9ed8\u8ba4\u6570\u503c\u57fa\u672c\u4e00\u81f4\u3002\u6240\u6d4b\u5b9a\u7684\u79cd\u5c5e\u7279\u5f81\u53c2\u6570(BPR\u548cfup)\u8f93\u5165\u5230\u5404\u81ea\u7684PBPK\u6a21\u578b\u4e2d\u3002<\/p>\n

4.2.3 \u8bc4\u4f30\u7a33\u6001\u5206\u5e03\u4f53\u79ef\u7684\u9884\u6d4b<\/strong><\/span><\/p>\n

\u91c7\u7528\u76f8\u540c\u7684\u8102\u6eb6\u6027\u548cpKa\u6570\u503c\uff0c\u4ee5\u53ca\u79cd\u5c5e\u7279\u5f81\u7684BPR\u548cfup\u4f5c\u4e3aLukacova\u65b9\u6cd5\u7684\u8f93\u5165\u53c2\u6570\u5e76\u9884\u6d4bVss\uff0c\u7ed3\u679c\u53d1\u73b0\u9664\u4e86\u7334\u5b50\u5916\u6240\u6709\u79cd\u5c5e\u7684\u9884\u6d4b\u503c\u5747\u5728\u89c2\u6d4b\u6570\u636e\u768460%\u4ee5\u5185\uff0c\u7334\u5b50\u7684Vss\u9884\u6d4b\u8bef\u5dee\u5c06\u8fd13\u500d\u5de6\u53f3(Table 3)\u3002\u540c\u6837\u7684\u7b56\u7565\u6210\u529f\u9884\u6d4b\u4e86\u4eba\u4f53\u7684\u5206\u5e03(\u7ea6\u9ad8\u4f3020%)\u3002<\/p>\n

\u8054\u5408QSPR\u548cPBPK PSA\u5206\u6790\u8868\u660eBPR\u662f\u9884\u6d4bCompound 2\u7cfb\u7edf\u5206\u5e03\u7684\u4e00\u4e2a\u5173\u952e\u8f93\u5165\u53c2\u6570\uff0c\u53ef\u80fd\u662f\u56e0\u4e3a\u78b1\u6027\u57fa\u56e2\u548c\u7ec4\u7ec7\u9178\u6027\u78f7\u8102\u7684\u76f8\u4e92\u4f5c\u7528\u3002\u6240\u6709\u79cd\u5c5e\u7684Vss\u90fd\u5f88\u5927\uff0c\u4e14\u6700\u5927\u7684BPR\u5177\u6709\u6700\u9ad8\u7684\u5206\u5e03\u3002\u5c06\u5b9e\u6d4b\u7684BPR\u6570\u503c\u8f93\u5165\u5230\u6a21\u578b\u4e2d\uff0c\u91c7\u7528Lukacova\u65b9\u6cd5\u80fd\u591f\u51c6\u786e\u9884\u6d4b\u836f\u7269\u7684\u5206\u5e03\u3002<\/p>\n

\u6240\u9884\u6d4b\u7684\u7334\u5b50\u5206\u5e03\u4f53\u79ef\u672a\u5728\u901a\u5e38\u53ef\u63a5\u53d7\u76842\u500d\u9884\u6d4b\u8bef\u5dee\u8303\u56f4\u5185\uff0c\u8868\u660e\u5f53\u524d\u53d1\u73b0\u9636\u6bb5\u7684PBPK\u5efa\u6a21\u8fd8\u9700\u8981\u66f4\u6709\u8bc1\u636e\u529b\u7684\u65b9\u6cd5\u3002\u5982\u679c\u5f88\u591a\u4e34\u5e8a\u524d\u79cd\u5c5e(\u8fd9\u4e2a\u6848\u4f8b\u4e3a\u4e94\u5206\u4e4b\u56db)\u90fd\u80fd\u51c6\u786e\u9884\u6d4b\uff0c\u90a3\u4e48\u5df2\u7ecf\u53ef\u4ee5\u5bf9\u4eba\u4f53\u7684\u9884\u6d4b\u6709\u4e00\u5b9a\u7684\u4fe1\u5fc3\uff0c\u5c31\u6ca1\u5fc5\u8981\u82b1\u65f6\u95f4\u53bb\u8003\u8651\u4e3a\u4ec0\u4e48\u8fd9\u4e00\u4e2a\u79cd\u5c5e\u4f1a\u51fa\u73b0\u5f02\u5e38\u503c\u3002\u7136\u800c\uff0c\u4e00\u822c\u5f88\u5c11\u67095\u4e2a\u4e34\u5e8a\u524d\u79cd\u5c5e\u7684PK\u6570\u636e\uff0c\u53ef\u80fd\u5728\u540e\u7eed\u7814\u7a76\u79cd\u5c5e\u5dee\u5f02\u65f6\u53ef\u7528\u7684\u6570\u636e\u96c6\u8f83\u5c11\u3002<\/p>\n

4.2.4 \u5168\u8840\/\u8840\u6d46\u6d53\u5ea6\u6bd4\u7684\u529f\u80fd<\/span><\/strong><\/p>\n

\u5728\u7814\u7a76PK\u6027\u8d28\u65f6\u8003\u8651BPR\u6bd4\u8f83\u91cd\u8981\u3002Lukacova\u65b9\u6cd5\u4f7f\u7528BPR\u4f30\u7b97\u78b1\u6027\u5316\u5408\u7269\u4e0e\u9178\u6027\u78f7\u8102\u5728\u6bcf\u4e00\u4e2a\u79cd\u5c5e\u7684\u7ed3\u5408\u5e38\u6570\uff0c\u56e0\u6b64\u4e0d\u540c\u79cd\u5c5e\u7684BPR\u6570\u503c\u4f1a\u5bfc\u81f4\u9884\u6d4b\u7684\u7ed3\u5408\u5e38\u6570\u4e3a\u4e00\u4e2a\u6570\u503c\u8303\u56f4\u3002\u4ec5\u6709\u5927\u9f20\u3001\u72d7\u548c\u4eba\u80fd\u6536\u96c6\u5230\u7ec4\u7ec7\u7279\u5b9a\u7684\u9178\u6027\u78f7\u8102\u6d53\u5ea6\u6570\u636e(\u5bf9\u9884\u6d4b\u6709\u4e00\u5b9a\u7684\u5f71\u54cd\uff0c\u5c3d\u7ba1\u8be5\u6570\u636e\u5728\u79cd\u5c5e\u5185\u7684\u53d8\u5f02\u6bd4\u79cd\u5c5e\u95f4\u8981\u5927)\u3002<\/p>\n

\u5728\u4eba\u4f53\u4e2d\uff0cCompound 2\u7684\u7ec4\u7ec7\u7ed3\u5408\u662f\u5355\u72ec\u6839\u636e\u5316\u5408\u7269\u4e0e\u4e2d\u6027\u8102\u7c7b\u548c\u78f7\u8102\u7684\u4f5c\u7528\u8fdb\u884c\u9884\u6d4b\u7684\uff1b\u901a\u8fc7\u5efa\u6a21\u8fd8\u8868\u660e\u4e34\u5e8a\u524d\u79cd\u5c5e\u89c2\u6d4b\u7684\u8f83\u5927Vss\u53ef\u80fd\u8fd8\u56e0\u4e3a\u4e0e\u9178\u6027\u78f7\u8102\u7684\u989d\u5916\u7ed3\u5408\u3002<\/p>\n

\u5c3d\u7ba1\u672a\u7814\u7a76Compound 2\u5f88\u53ef\u80fd\u5b58\u5728\u7684\u79cd\u5c5e\u7279\u5b9a\u9178\u6027\u78f7\u8102\u7ed3\u5408\u73b0\u8c61\uff0c\u4f46\u8be5\u6848\u4f8b\u5df2\u7ecf\u7a81\u51fa\u5f3a\u8c03\u4e86\u5bf9\u4e8e\u78b1\u6027\u5316\u5408\u7269PBPK\u5efa\u6a21\u6d4b\u5b9aBPR\u7684\u9700\u6c42\u3002\u6700\u8fd1\u7684\u4e00\u4e9b\u6587\u732e\u8d28\u7591\u4e86PBPK\u6a21\u578b\u80cc\u540e\u7684\u4e00\u4e9b\u5047\u8bbe\uff0c\u5e76\u9648\u8ff0\u78b1\u6027\u5316\u5408\u7269\u7684Kps\u975e\u5e38\u5bb9\u6613\u9884\u6d4b\uff0c\u53ef\u80fd\u662f\u56e0\u4e3a\u4f7f\u7528\u4e86BPR\u7684\u6570\u503c\u4ee5\u8ba1\u7b97\u9178\u6027\u78f7\u8102\u7684\u7ed3\u5408\u5e38\u6570\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

\n
\n
\n

4.3 \u6848\u4f8b3<\/strong><\/p>\n

Compound 3\uff1a\u4eb2\u8102\u5f31\u9178\u6027\u5316\u5408\u7269\u7684\u6311\u6218<\/strong><\/p>\n<\/section>\n<\/section>\n<\/section>\n

\n
\n
\n

Compound 3\u662f\u4e00\u4e2a\u4eb2\u8102\u6027(clogP\u7ea6\u4e3a5)\u3001\u5f31\u9178\u3001\u4f4e\u6eb6\u89e3\u5ea6(\u7279\u522b\u662f\u5728\u80c3\u9178\u4e2d\uff0cTable 2)\uff0c\u8868\u660e\u4f53\u5916\u5b9e\u9a8c\u6d4b\u5b9a\u5177\u6709\u4e00\u5b9a\u6311\u6218\u3002\u5c3d\u7ba1Compound 3\u4e3b\u8981\u901a\u8fc7CYP3A4\u4ee3\u8c22\u6e05\u9664\uff0c\u4f46\u7531\u4e8e\u8f83\u9ad8\u7684\u4ee3\u8c22\u7a33\u5b9a\u6027\u4f7f\u5176\u4eba\u4f53\u6e05\u9664\u7387\u7684\u9884\u6d4b\u5177\u6709\u6311\u6218\u3002\u9884\u671f\u642d\u5efa\u7684PBPK\u6a21\u578b\u662f\u4e3a\u4e86\u7406\u89e3\u5316\u5408\u7269\u7684PK\u7279\u6027\uff0c\u5e76\u7528\u4e8e\u652f\u6301\u63a8\u52a8\u5316\u5408\u7269\u8fdb\u4e00\u6b65\u8fdb\u5165\u4e34\u5e8a\u5f00\u53d1\u7684\u51b3\u7b56\u3002<\/p>\n

4.3.1 \u9884\u671f\u4eba\u4f53\u4f4e\u6e05\u9664\u4f46\u5b9e\u9645\u4f30\u7b97\u65f6\u5177\u6709\u4e0d\u786e\u5b9a\u6027<\/span><\/strong><\/p>\n

\u901a\u8fc7\u653e\u5927\u4f53\u5916\u6570\u636e\u9884\u6d4b\u9178\u6027\u5316\u5408\u7269\u7684\u6e05\u9664\u7387\u7ecf\u5e38\u5177\u6709\u6311\u6218\uff0c\u8003\u8651\u7ed3\u5408\u662f\u975e\u5e38\u91cd\u8981\u7684\u3002\u809d\u7ec6\u80de\u63d0\u4f9b\u4e86\u4e00\u79cd\u4eba\u4f53\u6e05\u9664\u7387\u7684\u9884\u6d4b\u65b9\u6cd5\uff0c\u4f46\u4f1a\u53d7\u5230\u4f53\u5916\u5b9e\u9a8c\u7684\u9650\u5236\uff1b\u57fa\u4e8e\u7334\u5b50\u7684\u5355\u79cd\u5c5e\u653e\u5927\u4e5f\u7528\u4e8e\u9884\u6d4b\u4eba\u4f53\u6e05\u9664\u7387\u7684\u8303\u56f4(\u59820.86-4.6 mL\/min\/kg\uff0cTable 4)\u3002<\/p>\n

Table4 Compound 3\u9759\u8109\u7684<\/span>PK\u6570\u636e\u53ca\u9884\u6d4b\u6570\u503c<\/span><\/span><\/strong><\/span><\/p>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n

CL-<\/span>\u6e05\u9664\u7387\uff1b<\/span><\/span>Vss-<\/span>\u7a33\u6001\u5206\u5e03\u4f53\u79ef<\/span><\/span><\/strong><\/p>\n

a <\/span><\/sup>\u5f53\u9178\u6027<\/span>pKa<\/span>\u7528\u4e8e\u4f30\u7b97\u7ec4\u7ec7<\/span>–<\/span>\u8840\u6d46\u5206\u914d\u7cfb\u6570\u65f6\uff0c\u6240\u6709\u79cd\u5c5e\u7684<\/span>Vss<\/span>\u6570\u503c\u5747\u4f4e\u4f30\u4e14\u4e0e\u86cb\u767d\u7ed3\u5408\u4e0d\u654f\u611f\u3002<\/span>\u56e0\u6b64\uff0c\u9178\u6027<\/span>pKa<\/span>\u4e0d\u8ba1\u5165\u7ec4\u7ec7<\/span>–<\/span>\u8840\u6d46\u5206\u914d\u7cfb\u6570\u7684\u8ba1\u7b97\uff1b<\/span><\/span><\/strong><\/p>\n

b <\/span><\/sup>\u5bf9\u4e8e\u4eba\u4f53<\/span>CL<\/span>\u4e5f\u57fa\u4e8e\u7334\u5b50\u5355\u4e2a\u79cd\u5c5e\u8fdb\u884c\u4e86\u9884\u6d4b<\/span>(<\/span>\u91c7\u7528\u7684\u65b9\u6cd5\u662f\u809d\u8840\u6d41\u91cf\u7684\u767e\u5206\u6570<\/span>)<\/span>\uff0c\u4f46\u7ed3\u679c\u662f\u9884\u6d4b\u8303\u56f4\u5185\u7684\u8f83\u4f4e\u503c\u3002<\/span>\u9009\u62e9\u8fd9\u4e2a\u65b9\u6cd5\u662f\u56e0\u4e3a\u8be5\u65b9\u6cd5\u4e0e\u5176\u5b83\u5f02\u901f\u653e\u5927\u7684\u65b9\u6cd5\u76f8\u6bd4\u80fd\u591f\u8f83\u4e3a\u5408\u7406\u5730\u9884\u6d4b<\/span>CL<\/span>\uff0c\u5e76\u4e14\u4f30\u7b97\u5f97\u5230\u4e00\u4e2a\u8f83\u4f4e\u7684<\/span>CL<\/span>\uff1b<\/span>\u800c\u901a\u8fc7\u809d\u7ec6\u80de\u8fdb\u884c\u9884\u6d4b\u65f6\uff0c\u4e34\u5e8a\u524d<\/span>2\/3<\/span>\u7684\u79cd\u5c5e\u5747\u9ad8\u4f30<\/span>CL<\/span>\u3002<\/span><\/strong><\/p>\n

\u5c3d\u7ba1\u6e05\u9664\u7387\u7684\u9884\u6d4b\u7ed3\u679c\u6709\u4e00\u5b9a\u7684\u4e0d\u786e\u5b9a\u6027\uff0c\u4f46\u91c7\u7528\u809d\u7ec6\u80de\u7684\u6570\u636e\u5bf9\u4e34\u5e8a\u524d\u4e09\u4e2a\u79cd\u5c5e\u4e2d\u7684\u4e24\u4e2a\u90fd\u660e\u663e\u7684\u9ad8\u4f30\uff0c\u56e0\u6b64\u4e34\u5e8a\u524d\u591a\u79cd\u5c5e\u7684\u6e05\u9664\u7387\u8f83\u4f4e\u4e14\u4eba\u4f53\u809d\u7ec6\u80de\u8f83\u4e3a\u7a33\u5b9a\uff0c\u4ece\u800c\u5bfc\u81f4\u4eba\u4f53\u6e05\u9664\u7387\u7684\u9884\u6d4b\u4fe1\u5fc3\u53ef\u80fd\u4e0d\u9ad8\u3002<\/p>\n

4.3.2 \u5206\u5e03\u4f53\u79ef\u7684\u5b9e\u9645\u9884\u6d4b<\/span><\/strong><\/p>\n

\u5206\u5e03\u4f53\u79ef\u7684\u9884\u6d4b\u5177\u6709\u4e00\u5b9a\u7684\u6311\u6218\uff0c\u56e0\u4e3a\u4e34\u5e8a\u524d\u591a\u79cd\u5c5e\u7684Vss (0.25-4.5 L\/kg)\u5c55\u73b0\u51fa18\u500d\u7684\u5dee\u5f02\u3002\u91c7\u7528Lukacova\u65b9\u6cd5\u90fd\u4f4e\u4f30\u4e86\u4e34\u5e8a\u524d\u6240\u6709\u79cd\u5c5e\u7684Vss\uff0c\u53ef\u80fd\u4e3b\u8981\u56e0\u4e3a\u91c7\u7528\u4e86\u9884\u6d4b\u7684\u9178\u6027pKa\u6570\u503c\u3002PSA\u7684\u7ed3\u679c\u663e\u793a\u968f\u7740\u9178\u6027pKa\u7684\u79fb\u52a8\u4f1a\u4f7f\u5f97\u8ba1\u7b97\u7684Vss\u5bf9\u5176\u5b83\u53c2\u6570\u975e\u5e38\u654f\u611f\uff0c\u5e76\u4e14\u80fd\u591f\u4f7f\u5f97\u548c\u89c2\u6d4b\u6570\u503c\u4e00\u81f4(Table 4)\u3002\u548cQSPR\u9884\u6d4b\u7684\u9ad8\u86cb\u767d\u7ed3\u5408\u4e00\u6837\uff0c\u4f53\u5916\u5b9e\u6d4b\u7684\u591a\u4e2a\u79cd\u5c5e\u7684fup\u5747\u5c0f\u4e8e0.1%\uff0c\u4f46\u4e0d\u80fd\u51c6\u786e\u786e\u5b9a\u8be5\u6570\u503c\u3002\u770b\u4e0a\u53bb\u53ef\u80fdVss\u7684\u79cd\u5c5e\u5dee\u5f02\u4e0efup\u7684\u5dee\u5f02\u6bd4\u8f83\u76f8\u5173\u3002\u4e3a\u4f7f\u5f97Vss\u7684\u6570\u503c\u4e0e\u89c2\u6d4b\u7ed3\u679c\u4fdd\u6301\u4e00\u81f4\uff0c\u5047\u8bbe\u4e00\u7cfb\u5217\u8303\u56f4\u7684fup (0.01-0.1%)\u5e26\u5165\u6a21\u578b\u8fdb\u884c\u8ba1\u7b97\u3002\u7531\u6b64\u5f97\u5230\u7684\u4eba\u4f53Vss\u6570\u503c(0.48\u52303.6 L\/kg)\u7528\u4e8e\u4eba\u4f53\u6a21\u578b\u7684\u642d\u5efa\u3002<\/p>\n

4.3.3 BCS\u5206\u7c7b\u7684\u4f53\u5916\u548c\u4f53\u5185\u5dee\u5f02<\/strong><\/p>\n

Compound 3\u7684\u5efa\u6a21\u65b9\u6cd5\u5305\u62ec\u6240\u6709\u7684\u79cd\u5c5e(\u5927\u9f20\u3001\u72d7\u548c\u7334\u5b50)\uff0c\u4f46\u56e0\u4e3a\u7334\u5b50\u7ed9\u836f\u7684\u5242\u578b\u548c\u4eba\u4f53\u7ed9\u836f\u6bd4\u8f83\u76f8\u4f3c\uff0c\u6240\u4ee5\u5438\u6536\u6a21\u578b\u66f4\u5173\u6ce8\u4e8e\u7334\u5b50\u3002\u6b63\u5982\u9884\u6d4b\u7684pKa\u7684\u9884\u671f\u4fe1\u606f\uff0c\u8be5\u5316\u5408\u7269\u5728pH 1.0\u7684\u6a21\u62df\u80c3\u6db2\u4e2d\u6eb6\u89e3\u5ea6\u8f83\u4f4e(< 0.05 \u03bcg\/mL)\uff0c\u4f46\u5728FaSSIF\u4e2d\u4e5f\u8f83\u4f4e(4.7 \u03bcg\/mL)\u3002\u4eba\u4f53\u7ed9\u836f\u7684\u5236\u5242\u4e3a\u5fae\u6c89\u6dc0\u6574\u88c5\u7c89\u672b(MBP)\u4ee5\u63d0\u9ad8\u6eb6\u89e3\u5ea6(FaSSIF\u4ecb\u8d28\u4e2d\u7ea650 \u03bcg\/mL\uff0cTable 2)\u3002\u7334\u5b50\u7684\u5438\u6536\u5efa\u6a21\u8bf4\u660eMBP\u5236\u5242\u5728FaSSIF\u4ecb\u8d28\u4e2d\u6eb6\u89e3\u5ea6\u7684\u91cd\u8981\u6027\uff1a\u4e0d\u8003\u8651\u8be5\u4f5c\u7528\u65f6\uff0c\u5728\u9ad8\u5242\u91cf\u4e0b\u4f1a\u663e\u8457\u4f4e\u4f30\u4f53\u5185\u66b4\u9732\u3002\u7531\u4e8eMBP\u5236\u5242\u7684\u4f5c\u7528\u3001\u6240\u4ea7\u751f\u7684\u8fc7\u9971\u548c\u4ee5\u53ca\u6539\u5584\u5236\u5242\u7279\u6027\uff0c\u6a21\u62dfCompound 3 MBP\u5236\u5242\u5728\u4e34\u5e8a\u76f8\u5173\u7684\u5242\u91cf\u6c34\u5e73\u65f6\u7684PK\u66f2\u7ebf\uff0c\u6eb6\u89e3\u5ea6\u672a\u8003\u8651\u4e3a\u4e00\u4e2a\u4e3b\u8981\u7684\u4e0d\u786e\u5b9a\u6027\u6765\u6e90\u3002<\/p>\n

\u5b9e\u6d4b\u7684\u4f53\u5916\u6e17\u900f\u6027\u6570\u503c\u8f83\u4f4e\uff0c\u4f46\u662f\u5728\u4e34\u5e8a\u524d\u79cd\u5c5e\u5374\u89c2\u6d4b\u5230\u8f83\u597d\u7684\u5438\u6536\u3002\u9884\u6d4b\u7684\u9ad8\u6e17\u900f\u6027\u4ee5\u53ca\u4f53\u5916\u4f4e\u6eb6\u89e3\u5ea6\u7684\u9650\u5236\uff0c\u53ef\u80fd\u4f1a\u4f7f\u5f97\u9519\u8bef\u7406\u89e3\u8be5\u5316\u5408\u7269\u7279\u6027\u3002\u56e0\u6b64\uff0c\u57fa\u4e8e\u6bd4\u5bf9\u6a21\u62df\u7684\u5927\u9f20\u548c\u72d7\u53e3\u670d\u5438\u6536\u6570\u636e\uff0c\u8fdb\u884c\u4eba\u4f53PK\u9884\u6d4b\u65f6\u589e\u52a0\u4e86\u836f\u7269\u7684\u6e17\u900f\u6027\u3002\u521d\u59cb\u7334\u5b50\u7684\u53e3\u670dPK\u66f2\u7ebf\u9ad8\u4f30\u4e86\u5176\u4f53\u5185\u66b4\u9732\u3002PSA\u7528\u4e8e\u63a2\u7d22\u662f\u5426\u4e3a\u4f4e\u6e17\u900f\u6216\u80a0\u9053\u6392\u6cc4\u5bfc\u81f4\u7684\u4e0d\u5b8c\u5168\u5438\u6536\u662f\u9ad8\u4f30\u7684\u53ef\u80fd\u539f\u56e0\uff1b\u7ed3\u8bba(\u901a\u8fc7\u4f53\u5916\u4ee3\u8c22\u8868\u578b\u6570\u636e\u63d0\u793aCompound 3\u662fCYP3A4\u4ee3\u8c22\u7684\u7814\u7a76\u8fdb\u884c\u4e86\u652f\u6301)\u662f\u80a0\u9053\u6392\u6cc4\u6709\u53ef\u80fd\u5bfc\u81f4\u7334\u5b50\u53e3\u670dPK\u7684\u66b4\u9732\u964d\u4f4e\u3002\u5438\u6536\u5efa\u6a21\u900f\u9732\u5c3d\u7ba1\u8be5\u5316\u5408\u7269\u57fa\u4e8e\u4f53\u5916\u6570\u636e\u8868\u660e\u662fBCS IV\u7c7b\uff0c\u4f46MBP\u5236\u5242\u80fd\u591f\u4f7f\u5176\u5728\u4e34\u5e8a\u7ed9\u836f\u5242\u91cf\u4e0b\u7684\u4f53\u5185\u884c\u4e3a\u8868\u73b0BCS I\u836f\u7269\u7279\u6027\u3002<\/p>\n

\u7531\u4e8eCompound 3\u662fCYP3A4\u7684\u5e95\u7269\uff0c\u56e0\u6b64\u4eba\u4f53\u80a0\u9053\u4ee3\u8c22\u6709\u5fc5\u8981\u8003\u8651\u8fdb\u6765(Fig. 5)\u3002\u800c\u7334\u5b50\u5efa\u6a21\uff0c\u5c06\u80a0\u9053\u4ee3\u8c22\u7684\u4f5c\u7528\u6dfb\u52a0\u81f3PBPK\u6a21\u578b\u4e2d\u5bf9\u9884\u6d4b\u5176PK\u540c\u6837\u91cd\u8981\u3002\u7531\u4e8e\u5176\u76f8\u5bf9\u8f83\u9ad8\u7684\u4f53\u5185\u6e17\u900f\u548c\u4ee3\u8c22\u7a33\u5b9a\u6027\uff0c\u9884\u4f30\u4eba\u4f53\u80a0\u9053\u6392\u6cc4\u662f\u6bd4\u8f83\u5c0f\u7684\u3002\u7334\u5b50\u7531\u4e8eCYP3A\u7684\u4f5c\u7528\u662f\u8868\u73b0\u663e\u8457\u7684\u80a0\u9053\u4ee3\u8c22\uff0c\u4f46\u4e0e\u4eba\u65e0\u5173\u6216\u8005\u5f88\u5c11\u76f8\u5173\u3002\u8fd9\u4e2a\u6848\u4f8b\u4e0d\u7528\u4f5c\u4e8e\u8bf4\u660eGastroPlus\u5bf9\u80a0\u9053\u4ee3\u8c22\u7684\u9884\u6d4b\uff0c\u4f46\u8be5\u76ee\u7684\u7684\u5e94\u7528\u5df2\u7ecf\u5728\u4e00\u4e9b\u4e34\u5e8a\u524d\u79cd\u5c5e\u548c\u4eba\u4f53\u8fdb\u884c\u4e86\u9610\u660e\u3002<\/p>\n

4.3.4 \u9a8c\u8bc1\u4e34\u5e8a\u524d\u79cd\u5c5ePBPK\u6a21\u578b\u7684\u91cd\u8981\u6027<\/span><\/strong><\/p>\n

FIH PBPK\u5efa\u6a21\u53ef\u4ee5\u5728\u6ca1\u6709\u9a8c\u8bc1\u4e34\u5e8a\u524d\u79cd\u5c5e\u6a21\u578b\u7684\u91cd\u8981\u6b65\u9aa4\u65f6\u4fbf\u8fdb\u884c\u5f00\u5c55\uff0c\u4f46\u662f\u53ef\u4fe1\u5ea6\u4f1a\u6bd4\u8f83\u4f4e\u3002\u8bc4\u4f30\u4f53\u5916\u8f93\u5165\u6570\u636e\u5bf9\u4e34\u5e8a\u524d\u79cd\u5c5e\u4f53\u5185PK\u66f2\u7ebf\u7684\u5f71\u54cd\uff0c\u5e76\u5728\u4f53\u5916\u6570\u636e\u4e0e\u89c2\u6d4b\u6570\u636e\u4e0d\u4e00\u81f4\u65f6\u786e\u5b9a\u53ef\u7528\u7684\u53c2\u6570\uff0c\u4ee5\u4f7f\u5f97Compound 3\u4eba\u4f53PK\u9884\u6d4b\u6709\u8f83\u4e3a\u5408\u7406\u7684\u51c6\u786e\u6027(Fig. 9)\u3002<\/p>\n

4.3.5 \u4e0d\u786e\u5b9a\u6027\u5206\u6790<\/strong><\/span><\/p>\n

\u5bf9\u4e8e\u8fd9\u4e2a\u6848\u4f8b\uff0c\u6e05\u9664\u7387\u548cVss\u4f3c\u4e4e\u6709\u4e9b\u4e0d\u786e\u5b9a\u6027\uff0c\u56e0\u6b64\u5bf9\u6bcf\u4e2a\u53c2\u6570\u5206\u522b\u8fdb\u884c\u4e86\u9ad8\u4f30\u548c\u4f4e\u4f30\u3002\u7136\u800c\uff0c\u8fd0\u884c\u6240\u6709\u53ef\u80fd\u7ec4\u5408\u7684\u6a21\u62df\u53ef\u80fd\u5f97\u5230\u4e00\u4e9b\u65e0\u7528\u7684\u3001\u8f83\u5927\u8303\u56f4\u7684PK\u3002\u6b64\u5916\uff0c\u6e05\u9664\u7387\u548cVss\u4f3c\u4e4e\u8fd8\u53ef\u80fd\u548cfup (\u4e0d\u80fd\u51c6\u786e\u6d4b\u5b9a)\u6709\u4e00\u5b9a\u7684\u5173\u7cfb\uff1a\u5927\u9f20\u7684Vss\u548cCL\u90fd\u8f83\u5927\uff0c\u800c\u72d7\u548c\u7334\u5b50\u5747\u8f83\u4f4e(Table 4)\u3002\u56e0\u6b64\uff0c\u6700\u7ec8\u4ec5\u7528\u4e24\u79cd\u53c2\u6570\u7684\u7ec4\u5408\u4ee5\u8fdb\u884c\u9884\u6d4b\u7684\u63a2\u7d22\u3002\u7b2c\u4e00\u79cd\u60c5\u51b5\u662f\u63a2\u7d22\u7531\u4e8e\u4f4efup (0.01%)\u5bfc\u81f4\u7684\u4f4e\u6e05\u9664\u548c\u4f4e\u5206\u5e03\u7ec4\u5408\uff1b\u7b2c\u4e8c\u79cd\u60c5\u51b5\u5219\u662f\u8003\u8651\u9ad8fup (0.1%)\u4f5c\u7528\u7684\u9ad8\u6e05\u9664\u548c\u9ad8\u5206\u5e03\u7ec4\u5408\u3002<\/p>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n

Fig. 9<\/span>\u6bd4\u8f83<\/span>Compound3<\/span>\u89c2\u6d4b\u548c\u9884\u6d4b\u7684\u8840\u6d46\u6d53\u5ea6<\/span>–<\/span>\u65f6\u95f4\u66f2\u7ebf\u3002<\/span>\u7a7a\u5fc3\u70b9\u4ee3\u8868\u6bcf\u4e2a\u4e2a\u4f53\u7684\u6570\u636e\uff0c\u95ed\u5408\u7684<\/span>x<\/span>\u4ee3\u8868\u4e2d\u503c\uff1b<\/span>\u4ee5\u53ca\u6a21\u62df\u4e86\u5728\u524d\u4e24\u4e2a\u5242\u91cf<\/span>(mg<\/span>\u4e3a\u5355\u4f4d\u7ed9\u836f<\/span>)<\/span>\u6c34\u5e73\u65f6\u4f4e\u6e05\u9664\u3001\u4f4e\u5206\u5e03\u4f53\u79ef\u4ee5\u53ca\u9ad8\u6e05\u9664\u548c\u9ad8\u5206\u5e03\u4f53\u79ef\u7684\u60c5\u51b5\u3002<\/span><\/strong><\/span><\/p>\n

\u60c5\u51b51\u548c2\u7684\u9884\u6d4b\u7ed3\u679c\u5206\u522b\u4e3aFig. 9\u4e2d\u9ad8\u3001\u4f4e\u66f2\u7ebf\u3002\u4e24\u79cd\u60c5\u51b5\u9884\u6d4b\u7684PK\u57fa\u672c\u53ef\u4ee5\u6db5\u76d6\u89c2\u6d4b\u7684PK\u66f2\u7ebf\uff0c\u8868\u660e\u4eba\u4f53\u771f\u5b9e\u7684fup\u6570\u503c\u53ef\u80fd\u57280.01\u548c0.1\u4e4b\u95f4\u3002\u91cd\u8981\u7684\u662f\uff0cPSA\u53ef\u4ee5\u63a2\u7d22\u4e00\u4e2a\u5408\u9002\u7684\u9884\u6d4b\u8303\u56f4\uff0c\u4ee5\u8fdb\u4e00\u6b65\u7406\u89e3\u4e0d\u786e\u5b9a\u6027\u53ca\u63d0\u9ad8\u4eba\u4f53PK\u9884\u6d4b\u7684\u4fe1\u5fc3\uff0c\u5e76\u4f7f\u5f97\u9884\u6d4b\u7684PK\u53ef\u4ee5\u8fbe\u5230\u4e34\u5e8a\u9884\u671f\u7684\u6709\u6548\u66b4\u9732\u3002
<\/p>\n<\/section>\n<\/section>\n<\/section>\n

\n
\n
\n

4.4 \u6848\u4f8b4<\/strong><\/p>\n

Compound 4\uff1a\u9884\u671f\u6162\u901f\u88ab\u52a8\u6269\u6563\u900f\u8fc7\u7ec6\u80de\u819c\u3001\u5206\u5b50\u91cf\u5927\u7684\u5316\u5408\u7269<\/strong><\/p>\n<\/section>\n<\/section>\n<\/section>\n

\n
\n
\n

\u57fa\u4e8eQSPR\u548cPBPK\u6a21\u578b\u7684\u8bc4\u4f30\uff0cCompound 4\u662f\u4e00\u4e2a\u5206\u5b50\u91cf\u5927(> 1000 Da)\u3001\u6709\u5408\u9002\u6eb6\u89e3\u5ea6\u548c\u4f4e\u6e17\u900f\u6027(BCS Class III)\u4ee5\u53ca\u4e3b\u8981\u80be\u810f\u6d88\u9664(ECCS)\u7684\u5316\u5408\u7269\u3002\u8be5\u5316\u5408\u7269\u7531\u4e8e\u4f53\u79ef\u5927\u548c\u542b\u6709\u5927\u91cf\u4e0d\u53ef\u7535\u79bb\u57fa\u56e2\u4f7f\u5176\u5177\u6709\u4e2d\u7b49\u7684\u8102\u6eb6\u6027\uff0c\u56e0\u6b64\u9884\u671f\u53ef\u80fd\u662f\u819c\u9650\u901f\u578b\u7684\u7ec4\u7ec7\u5206\u5e03\u3002\u9884\u6d4b\u7ec4\u7ec7\u7279\u5b9a\u7684\u6e17\u900f\u6027-\u8868\u9762\u79ef\u4e58\u79ef(PStc)\u8fd9\u4e00\u6a21\u578b\u53c2\u6570\u7684\u9a8c\u8bc1\u65b9\u6cd5\u672a\u5efa\u7acb\u8d77\u6765\u3002\u5bf9\u4e8eCompound 4\uff0c\u901a\u8fc7\u5927\u9f20PK\u6570\u636e\u786e\u5b9a\u5f97\u5230GastroPlus\u7684\u7279\u5b9aPStc (\u6bcf\u6beb\u5347\u7ec4\u7ec7\u7ec6\u80de\u4f53\u79ef\u7684PStc)\u6570\u503c\u5e76\u7528\u4e8e\u540e\u7eedFIH PK\u7684\u9884\u6d4b\u3002<\/p>\n

4.4.1 \u57fa\u4e8e\u4e34\u5e8a\u524d\u7684\u7814\u7a76\u786e\u5b9aPBPK\u6a21\u578b\u7684\u6784\u67b6<\/span><\/strong><\/p>\n

\u6536\u96c6\u6587\u732e\u62a5\u9053\u7684\u5927\u9f20\u9759\u8109\u7ed9\u836fCompound 4\u7684PK\u6570\u636e(\u5305\u62ec\u8840\u6d46\u548c\u80be\u810f\u5300\u6d46\u91cc\u7684\u6d53\u5ea6) \u3002\u8fd9\u4e9b\u6570\u636e\u7528\u4e8e\u4f18\u5316\u7279\u5b9aPStc\u7684\u6570\u503c\uff0c\u4ee5\u53ca\u9a8c\u8bc1\u91c7\u7528fup\u548c\u80be\u5c0f\u7403\u6ee4\u8fc7\u7387\u4e58\u79ef\u9884\u6d4b\u7684\u7cfb\u7edf\u6e05\u9664\u7387\u3002\u7279\u5b9aPStc\u8fde\u540c\u6bcf\u4e2a\u7ec4\u7ec7\u7684\u751f\u7406\u7ec6\u80de\u7136\u540e\u7528\u4e8e\u8ba1\u7b97\u5176\u5b83\u7ec4\u7ec7\u7684PStc\u6570\u503c\u3002\u4e3b\u52a8\u8f6c\u8fd0\u4f53\u6682\u65f6\u672a\u5305\u62ec\u5728\u5f53\u524d\u6a21\u578b\u4e2d\uff0c\u4ec5\u8054\u5408\u4e86\u88ab\u52a8\u80be\u5c0f\u7403\u6ee4\u8fc7\u548c\u88ab\u52a8\u819c\u6e17\u900f\u7684\u56e0\u7d20\u4ee5\u8003\u8651\u7ec4\u7ec7\u5206\u5e03\u548c\u80be\u810f\u6e05\u9664\u3002\u6a21\u578b\u672a\u5305\u62ec\u5176\u5b83\u7684\u6e05\u9664\u673a\u7406\u3002<\/p>\n

\u63a2\u5bfb\u4e86\u4e0d\u540c\u7684\u7b56\u7565\u9884\u6d4b\u5927\u9f20\u7684\u5206\u5e03\u7279\u5f81\u3002\u8840\u6d41\u704c\u6ce8\u578b(\u91c7\u7528Poulin-extracellular\u65b9\u6cd5\u8ba1\u7b97Kp\u6570\u503c)\u7684<\/p>\n

PBPK\u6a21\u578b\u76f8\u5bf9\u5408\u7406\u5730\u9884\u6d4b\u8840\u6d46\u6d53\u5ea6\u4ee5\u53ca\u8868\u5f81\u8be5\u836f\u7269\u8f83\u4f4e\u7684Vss\u3002\u8be5\u9884\u6d4b\u65b9\u6cd5\u5047\u8bbe\u5316\u5408\u7269\u4ec5\u5206\u5e03\u5230\u7ec6\u80de\u5916\u7684\u7ec4\u7ec7\u7a7a\u95f4\uff0c\u4e0d\u6269\u6563\u901a\u8fc7\u7ec6\u80de\u819c\u3002\u5c3d\u7ba1\u8be5\u65b9\u6cd5\u5408\u7406\u543b\u5408\u4e86\u8840\u836f\u6d53\u5ea6\uff0c\u4f46\u662f\u80be\u810f\u7ec4\u7ec7\u6d53\u5ea6\u660e\u663e\u7684\u4f4e\u4f30\u3002\u56e0\u6b64\u540e\u7eed\u5c06\u8be5\u6a21\u578b\u66f4\u6539\u4e3a\u819c\u9650\u901f\u578b\u7ec4\u7ec7\uff0c\u5e76\u4f18\u5316\u4e86PStc\u6570\u503c\u4f7f\u5176\u8840\u6d46\u548c\u80be\u810f\u7ec4\u7ec7\u7684\u6d53\u5ea6\u90fd\u543b\u5408\u89c2\u6d4b\u503c(Fig. 10)\u3002<\/p>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n

Fig.10 <\/span>\u5927\u9f20\u8840\u6d41\u704c\u6ce8\u578b\u7ec4\u7ec7<\/span>(<\/span>\u5de6\u56fe<\/span>)<\/span>\u548c\u819c\u9650\u901f\u578b\u7ec4\u7ec7<\/span>(<\/span>\u53f3\u56fe<\/span>)PBPK<\/span>\u6a21\u578b\u6a21\u62df<\/span>5mg\/kg (<\/span>\u4e0a\u8fb9<\/span>)<\/span>\u548c<\/span>100mg\/kg (<\/span>\u4e0b\u8fb9<\/span>)<\/span>\u9759\u8109\u6ce8\u5c04\u7ed9\u836f\u540e\u8840\u6d46<\/span>(<\/span>\u9ed1\u5b9e\u7ebf<\/span>)<\/span>\u548c\u80be\u810f<\/span>(<\/span>\u7eff\u8272\u865a\u7ebf<\/span>)<\/span>\u7684\u836f\u7269\u6d53\u5ea6\uff0c\u4ee5\u53ca\u76f8\u5e94\u7684\u89c2\u6d4b\u6570\u503c<\/span>(<\/span>\u8840\u6d46\uff1a<\/span>\u9ed1\u70b9\uff1b\u80be\u810f\uff1a\u7a7a\u5fc3\u70b9<\/span>)<\/span>\u3002<\/span><\/strong><\/span><\/p>\n

4.4.2 \u9884\u6d4b\u4eba\u4f53\u7684PK<\/span><\/strong>
<\/p>\n

\u5728\u5047\u8bbe\u4e0d\u540c\u79cd\u5c5e\u7684\u7ec6\u80de\u819c\u7ec4\u6210\u76f8\u4f3c\u7684\u524d\u63d0\u4e0b\u8fdb\u884c\u4e86\u4eba\u4f53PK\u7684\u9884\u6d4b\uff0c\u6765\u81ea\u5927\u9f20\u7684\u7279\u5b9aPStc\u6570\u636e(9.15*10\u22125 mL\/s\/mL cell volume)\u7528\u4e8e\u4eba\u4f53\u751f\u7406\u5b66\u6a21\u578b\u642d\u5efa\u5e76\u53ef\u4ee5\u51c6\u786e\u9884\u6d4b\u4eba\u4f53PK (Fig. 11)\u3002<\/p>\n


<\/p>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n

Fig. 11 \u5065\u5eb7\u5fd7\u613f\u8005\u8840\u6d41\u704c\u6ce8\u578b\u7ec4\u7ec7<\/span>(\u5de6\u56fe<\/span>)\u548c\u819c\u9650\u901f\u578b\u7ec4\u7ec7<\/span>(\u53f3\u56fe<\/span>)PBPK\u6a21\u578b\u6a21\u62df\u6bcf<\/span>12\u5c0f\u65f6\uff0c\u7ef4\u6301<\/span>1\u5c0f\u65f6\u9759\u8109\u6ef4\u6ce8<\/span>1000mg \u7ed9\u836f\u540e\u8840\u6d46<\/span>(\u9ed1\u5b9e\u7ebf<\/span>)\u548c\u80be\u810f<\/span>(\u7eff\u8272\u865a\u7ebf<\/span>)\u7684\u836f\u7269\u6d53\u5ea6\uff0c\u4ee5\u53ca\u76f8\u5e94\u7684\u89c2\u6d4b\u6570\u503c<\/span>(\u8840\u6d46\uff1a<\/span><\/span>\u9ed1\u70b9<\/span><\/span>)\u3002<\/span><\/span><\/strong><\/span><\/p>\n

\u4e3a\u4e86\u8fdb\u884c\u5bf9\u6bd4\uff0c\u4eba\u4f53PK\u4e5f\u91c7\u7528\u4e86\u8840\u6d41\u704c\u6ce8\u578b\u6a21\u578b(\u901a\u8fc7Poulin-extracellular\u65b9\u6cd5\u8ba1\u7b97Kps)\u8fdb\u884c\u4e86\u9884\u6d4b\u3002\u548c\u5927\u9f20\u7c7b\u4f3c\uff0c\u8be5\u6a21\u578b\u80fd\u591f\u5408\u7406\u5730\u9884\u6d4b\u8840\u6d46\u836f\u7269\u6d53\u5ea6\u53d8\u5316\uff1b\u4f46\u662f\u80be\u810f\u6d53\u5ea6\u4ee5\u53ca\u5c3f\u6db2\u4e2d\u6392\u6cc4\u7684\u836f\u91cf\u91c7\u7528\u8be5\u7b80\u5355\u7684\u6a21\u578b\u4e0d\u80fd\u51c6\u786e\u9884\u6d4b\u3002\u91c7\u7528\u8840\u6d41\u704c\u6ce8\u578b\u7ec4\u7ec7\u6a21\u578b\u9884\u6d4b\u7b2c\u4e5d\u6b21\u7ed9\u836f\u540e(\u6bcf\u5929\u4e24\u6b21\uff0c\u6ef4\u6ce8\u65f6\u95f4\u7ef4\u63011\u5c0f\u65f6)\u80be\u810f\u548c\u8840\u6d46\u6d53\u5ea6\u6bd4\u503c\u662f0.12\uff0c\u4f46\u662f\u91c7\u7528\u819c\u9650\u901f\u578b\u7ec4\u7ec7\u6a21\u578b\u9884\u6d4b\u7684\u5404\u4e2a\u5242\u91cf\u7ed9\u836f\u540e\u7684\u6bd4\u4f8b\u8303\u56f4\u4e3a12\u5230153\u3002\u6587\u732e\u62a5\u9053\u4e00\u4e2a\u6b63\u5e38\u80be\u529f\u80fd\u53d7\u8bd5\u8005\u5728\u591a\u6b21\u9759\u8109\u7ed9\u836f\u540e\u7684\u7684Kp\u6570\u503c\u4e3a45.8\uff0c\u867d\u7136\u6ca1\u6709\u62a5\u9053\u5177\u4f53\u7684\u6837\u54c1\u91c7\u96c6\u65f6\u95f4\uff0c\u4f46\u89c2\u6d4b\u503c\u5305\u542b\u5728\u819c\u9650\u901f\u578b\u7ec4\u7ec7\u6a21\u578b\u7684\u9884\u6d4b\u8303\u56f4\u5185\u3002
<\/p>\n

\u5065\u5eb7\u5fd7\u613f\u8005\u9759\u8109\u6ef4\u6ce8\u7ed9\u836f1000 mg\u540e\u7684\u89c2\u6d4b\u7ed3\u679c\u4e3a\uff1a24\u5c0f\u65f6\u5185\u5c3f\u6db2\u4e2d\u7d2f\u79ef\u7684\u836f\u7269\u6392\u6cc4\u91cf\u4e3a85%\uff0c72\u5c0f\u65f6\u4e3a91%\u3002\u8840\u6d41\u704c\u6ce8\u578b\u6a21\u578b\u9884\u6d4b24\u5c0f\u65f6\u7684\u5c3f\u6db2\u6392\u6cc4\u91cf\u4e3a100%\uff1b\u7136\u800c\u819c\u9650\u901f\u578b\u6a21\u578b\u9884\u6d4b\u768424\u5c0f\u65f6\u7d2f\u79ef\u6392\u6cc4\u4e3a69%\uff0c72\u5c0f\u65f6\u7684\u7d2f\u79ef\u91cf\u4e3a83%\u3002\u5c3d\u7ba1\u91c7\u7528\u819c\u9650\u901f\u578b\u7ec4\u7ec7\u6a21\u578b\u9884\u6d4b\u7684\u603b\u5c3f\u6db2\u6e05\u9664\u8981\u6bd4\u89c2\u6d4b\u503c\u5c0f\u4e00\u4e9b\uff0c\u4f46\u8fd8\u662f\u80fd\u8f83\u4e00\u81f4\u5730\u9884\u6d4b\u4e86\u7531\u4e8e\u80be\u810f\u6e05\u9664\u7684\u5ef6\u957f\u6240\u63d0\u793a\u5206\u5e03\u548c\u6d88\u9664\u673a\u7406\u7684\u89c2\u6d4b\u8d8b\u52bf\uff0c\u8fd9\u4e9b\u4fe1\u606f\u90fd\u51c6\u786e\u5730\u53cd\u6620\u5728\u5f53\u524d\u7684\u6a21\u578b\u4e2d\u3002<\/p>\n


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5<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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\u8ba8\u8bba\u548c\u7ed3\u8bed<\/strong><\/p>\n<\/section>\n<\/section>\n

<\/section>\n<\/section>\n<\/section>\n<\/section>\n
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\u6240\u5c55\u793a\u8fd9\u4e9b\u6848\u4f8b\u662f\u4e3a\u4e86\u8bf4\u660ePBPK\u5efa\u6a21\u7684\u4ef7\u503c\uff0c\u6a21\u578b\u53ef\u4ee5\u6574\u5408\u591a\u79cd\u6765\u6e90\u7684\u6570\u636e\u4ee5\u63d0\u9ad8\u5728\u836f\u7269FIH\u8bd5\u9a8c\u4e4b\u524d\u5bf9PK\u7279\u6027\u7684\u673a\u5236\u6027\u7406\u89e3\u3002\u4f8b\u5982\uff0c\u89e3\u6790\u591a\u79cd\u673a\u7406\u5bfc\u81f4\u751f\u7269\u5229\u7528\u5ea6\u5dee\u7684\u60c5\u51b5\u6709\u4e00\u5b9a\u7684\u6311\u6218\uff0c\u800cPBPK\u5efa\u6a21\u8ba4\u4e3a\u662f\u63a8\u52a8\u8fd9\u9879\u79d1\u5b66\u7814\u7a76\u7684\u6709\u7528\u5de5\u5177\u3002\u5982\u679c\u8f93\u5165\u7684\u53c2\u6570\u6709\u53d8\u5f02\u6216\u4e0d\u786e\u5b9a\u6027\uff0c\u90a3\u4e48\u5728\u89e3\u91ca\u7ed3\u679c\u7684\u65f6\u5019\u52a1\u5fc5\u5c0f\u5fc3\u8c28\u614e\u3002PBPK\u6a21\u578b\u53ef\u4ee5\u7528\u4e8e\u8bc4\u4f30\u6a21\u578b\u8f93\u5165\u53c2\u6570\u9650\u5236\u7684\u5f71\u54cd\u3002\u8fd9\u4e9b\u6a21\u578b\u7684\u673a\u5236\u6027\u57fa\u7840\uff0c\u80fd\u591f\u89e3\u91ca\u5982\u968f\u9910\u670d\u7528\u6216\u8005CYP\u6291\u5236\u7b49\u662f\u5426\u5bfc\u81f4\u66b4\u9732\u589e\u52a0\u7b49\u76f8\u5173\u673a\u7406\u95ee\u9898\u3002<\/p>\n

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PBPK\u5efa\u6a21\u9884\u6d4b\u4eba\u4f53\u7684\u8868\u73b0\u5df2\u7ecf\u7f8e\u56fd\u836f\u7269\u7814\u7a76\u548c\u5236\u9020\u5546\u534f\u4f1a(Pharmaceutical Research and Manufacturers of America)\u8fdb\u884c\u4e86\u8bc4\u4f30\uff0c\u4ed6\u4eec\u4e5f\u672a\u53d1\u73b0\u6709\u975e\u5e38\u9ad8\u7684\u51c6\u786e\u6027\uff0c\u7279\u522b\u662f\u5bf9\u53e3\u670d\u7ed9\u836f\u3002<\/p>\n

\u7136\u800c\uff0c\u8fd9\u4e9b\u5206\u6790\u4e5f\u6709\u4e00\u4e9b\u975e\u5e38\u660e\u663e\u7684\u9650\u5236\uff0c\u6bd4\u5982\u4f7f\u7528\u4e0d\u540c\u4f01\u4e1a\u7684\u4f53\u5916\u5b9e\u9a8c\u6570\u636e\uff0c\u4f7f\u7528\u5b9a\u5236\u7684PBPK\u6a21\u578b\uff0c\u4ee5\u53ca\u6ca1\u6709\u5728\u4eba\u4f53\u9884\u6d4b\u524d\u5bf9\u5316\u5408\u7269\u76f8\u5173\u7684PBPK\u6a21\u578b\u8fdb\u884c\u4e34\u5e8a\u524d\u9a8c\u8bc1\u7b49\u3002\u7ed9\u51fa\u9884\u6d4b\u4e34\u5e8a\u524d\u79cd\u5c5e\u5316\u5408\u7269\u7684PK\u6027\u8d28\u80fd\u529b\u7684\u8bc4\u4f30\u91cd\u8981\u6027\uff0c\u4ee5\u53ca\u5c06\u5408\u9002\u7684\u673a\u7406\u6574\u5408\u5230PBPK\u6a21\u578b\u4e2d\u662f\u76f8\u5bf9\u6070\u5f53\u7684\uff0c\u6240\u4ee5\u5c31\u4e0d\u5947\u602a\u4e3a\u4ec0\u4e48\u7f8e\u56fd\u836f\u7269\u7814\u7a76\u548c\u5236\u9020\u5546\u534f\u4f1a\u5e94\u7528PBPK\u5efa\u6a21\u5f97\u5230\u8f83\u5dee\u7684\u9884\u6d4b\u7ed3\u679c\u4e86\uff0c\u7279\u522b\u662f\u8ddf\u5de5\u4e1a\u754c\u5176\u5b83\u8f83\u597d\u7684\u65b9\u6cd5\u4e00\u8d77\u6bd4\u8f83\u4e86\u3002\u9884\u6d4b\u4eba\u4f53PK\u4e00\u76f4\u662f\u4e00\u9879\u6311\u6218\u5de5\u4f5c\uff0c\u800c\u4e14\u5982\u679c\u4e0d\u80fd\u901a\u8fc7\u4e34\u5e8a\u524d\u79cd\u5c5ePBPK\u6a21\u578b\u8fdb\u884c\u9a8c\u8bc1\uff0c\u90a3\u4e48\u4eba\u4f53PK\u9884\u6d4b\u7684\u4fe1\u5fc3\u5c31\u66f4\u4f4e\u4e86\u3002<\/p>\n

\u6b27\u76df\u7684\u53e3\u670d\u751f\u7269\u836f\u5242\u5b66\u5de5\u5177(OrBiTo)\u9879\u76ee\u8fd1\u671f\u5bf9\u81ea\u5e95\u5411\u4e0a\u7684PBPK\u6a21\u578b\u9884\u6d4b\u505a\u4e86\u8bc4\u4f30\uff0c\u8bf4\u660e\u4f9d\u7136\u5b58\u5728\u4e00\u4e9b\u6311\u6218\uff0c\u5e76\u4e14\u9884\u6d4b\u6027\u80fd\u4f1a\u4ece\u9759\u8109\u5230\u53e3\u670d\u6eb6\u6db2\u5242\u5230\u7247\u5242\u5448\u73b0\u9010\u5c42\u4e0b\u964d\u7684\u8d8b\u52bf\u3002\u8fd9\u9879\u8bc4\u4f30\u4e5f\u4f53\u73b0\u4e86\u5c11\u4e8e5\u5e74\u7ecf\u9a8c\u7684\u5efa\u6a21\u4eba\u5458\u4f1a\u589e\u52a0\u9884\u6d4b\u7684\u4e0d\u786e\u5b9a\u6027\u3002\u8be5\u6587\u7ae0\u5efa\u8bae\u7684FIH PK\u9884\u6d4b\u7684PBPK\u6a21\u578b\u7b56\u7565(\u5efa\u7acb\u5728\u5bf9\u8fd1\u671f\u5e94\u7528\u6587\u732e\u3001\u77e5\u8bc6\u7684\u7efc\u5408\u5ba1\u9605\u4ee5\u53ca\u8d44\u6df1GastroPlus\u7528\u6237\u7684\u5b9e\u6218\u7ecf\u9a8c\u4e0a)\uff0c\u63d0\u4f9b\u89e3\u6790\u5316\u5408\u7269ADME\u590d\u6742\u6027\u8d28\u7684\u6d41\u7a0b\u56fe\u3002\u4ece\u5316\u5408\u7269\u7ed3\u6784\u5f0f\u51fa\u53d1\u8054\u5408QSPR\u548cPBPK\u6a21\u578b\uff0c\u53ef\u4ee5\u57fa\u4e8e\u5316\u5408\u7269\u7279\u6027\u8fdb\u884c\u98ce\u9669\u8bc4\u4f30\uff0c\u6307\u5bfc\u51b3\u7b56\u4ee5\u53ca\u4f18\u5148\u5206\u914d\u7b26\u5408\u76ee\u6807(fit for purpose)\u7684\u8d44\u6e90\u4ee5\u652f\u6301\u6a21\u578b\u7684\u5f00\u53d1\u3002<\/p>\n

\u5e94\u7528\u6240\u63a8\u8350\u7684PBPK\u7b56\u7565\u5e76\u5728\u591a\u4e2a\u5236\u836f\u4f01\u4e1a\u6574\u5408ADME PBPK\u51b3\u7b56\u6811\uff0c\u80fd\u591f\u5728\u836f\u7269\u65e9\u671f\u9636\u6bb5\u8fdb\u884cPBPK\u5efa\u6a21\u7684\u6b63\u786e\u8bc4\u4f30\uff0c\u4ee5\u514b\u670d\u65e9\u671f\u5206\u6790\u7684\u5c40\u9650\u6027\uff0c\u5e76\u589e\u5f3a\u6cd5\u89c4\u76d1\u7ba1\u90e8\u95e8\u5bf9PBPK\u5efa\u6a21\u9884\u6d4bFIH PK\u7684\u5e94\u7528\u4fe1\u5fc3\u3002\u8be5\u7b56\u7565\u4f7f\u7528\u4e00\u4e2a\u5df2\u7ecf\u5546\u4e1a\u5316\u7684PBPK\u6a21\u578b\u5e73\u53f0\uff0c\u5e76\u5305\u62ec\u5bf9\u4e34\u5e8a\u524dPBPK\u6a21\u578b\u7684\u9a8c\u8bc1\u3002\u4e3a\u5c3d\u91cf\u589e\u52a0PBPK\u5efa\u6a21\u7684\u4ef7\u503c\uff0cPSA\u5206\u6790\u901a\u5e38\u5bf9\u4e8e\u63a2\u7d22\u4e0d\u786e\u5b9a\u662f\u6bd4\u8f83\u91cd\u8981\u7684\u3002\u5c55\u73b0\u7684\u8fd9\u4e9b\u6709\u4e00\u5b9a\u6311\u6218\u6027\u7684\u5e94\u7528\u6848\u4f8b(\u4e4b\u524d\u516c\u5e03\u7684\u5178\u578b\u6570\u636e\u96c6\u4e2d\u5728\u5177\u6709\u6781\u7aef\u8102\u6eb6\u6027\u548cfup\u7684\u836f\u7269)\uff0c\u8fdb\u4e00\u6b65\u7a81\u51fa\u4e86\u5408\u7406\u5e94\u7528\u6a21\u578b\u53ef\u4ee5\u63d0\u9ad8PBPK\u9884\u6d4bFIH PK\u7684\u4ef7\u503c\u3002<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/p>\n
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\u53c2\u8003\u6587\u732e<\/strong><\/p>\n<\/section>\n

\"\uff08\u4e0b\uff09\u57fa\u4e8e\u751f\u7406\u836f\u4ee3\u52a8\u529b\u5b66\u6a21\u578b\u9884\u6d4b\u9996\u6b21\u4eba\u4f53PK\u7684\u65b0\u7b56\u7565-\u5e94\u7528\u6848\u4f8b\"<\/section>\n

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Neil A. Miller, Micaela B. Reddy, Aki T. Heikkinen, et al., Physiologically Based Pharmacokinetic Modelling for First-In-Human Predictions:  An UpdatedModel Building Strategy Illustrated with Challenging Industry Case Studies. Clin Pharmacokinet. 2019 Feb 7.   <\/p>\n

IF: 4.464<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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\u514d\u8d23\u58f0\u660e<\/strong><\/p>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n

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