Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, CA, USA.
Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, CA, USA.
J Control Release. 2024 Sep;373:564-567. doi: 10.1016/j.jconrel.2024.07.040. Epub 2024 Jul 29.
When a new molecular entity is predicted to exhibit high clearance in humans, pharmaceutical sponsors almost universally search for similar acting back-up compounds that will demonstrate low clearance. Here we show that, except for oral dosing, there can be marked advantages to developing and commercializing controlled release formulations of high clearance drugs, the expertise of readers of this journal. Our recent publications demonstrate that the universally held pharmacokinetic principle that drug delivery rate has no effect on measured drug clearance is not correct. Rather, we show that if clearance from the drug delivery site is markedly less than the iv bolus clearance of a drug, the in vivo drug clearance can be the drug delivery clearance controlled by the designed dosage form. This approach will be especially advantageous for high hepatic clearance drugs. These advantages include not being concerned with: a) saturable nonlinear kinetics, b) significant pharmacogenomic differences, c) drug-drug induction mechanisms, and d) in many cases drug-drug inhibition interactions. This is due to the ability of a drug sponsor to design clearance, independent of the pharmacokinetic characteristics for high clearance compounds, where clearance from the dosage form becomes the drug clearance from the patient. Recognition of this principle, as described here, results from our development of the use of Kirchhoff's Laws from physics to derive rate-defining clearance and rate constant elimination processes independent of differential equation derivations. The key message for readers of this journal is that high clearance drugs are potentially drugable through formulation design and should not be outright disregarded, since for such drugs the dose-corrected area under the curve can be increased if the release rate from the injection site is controlled and slow resulting in drug clearance from the body controlled by clearance from the dosage form. The concepts presented here describe previously unrecognized advantages of controlled release formulations.
当一种新的分子实体被预测在人体中具有高清除率时，制药赞助商几乎普遍寻找具有相似作用的后备化合物，这些化合物将表现出低清除率。在这里，我们表明，除了口服给药外，开发和商业化高清除率药物的控释制剂可能具有显著优势，这是本期刊读者的专业知识。我们最近的出版物表明，药物传递率对测量的药物清除率没有影响的普遍持有的药代动力学原则是不正确的。相反，我们表明，如果从药物传递部位的清除率明显低于药物的静脉推注清除率，则体内药物清除率可以是由设计的剂型控制的药物传递清除率。这种方法对于高肝清除率药物尤其有利。这些优势包括：a）不考虑饱和非线性动力学；b）显著的药物基因组差异；c）药物诱导机制；以及 d）在许多情况下，药物抑制相互作用。这是由于药物赞助商能够设计清除率，独立于高清除率化合物的药代动力学特征，其中剂型的清除率成为患者的药物清除率。这里描述的这个原则的认识，是由于我们开发了从物理学中利用基尔霍夫定律来推导独立于微分方程推导的速率定义清除率和速率常数消除过程。本期刊读者的关键信息是，高清除率药物通过制剂设计具有潜在可开发性，不应完全忽视，因为对于此类药物，如果控制注射部位的释放速率并使其缓慢，从而控制从体内清除药物，则剂量校正后的曲线下面积可以增加，从而控制由剂型清除率控制的药物清除率。这里提出的概念描述了控释制剂以前未被认识到的优势。
