Anger G J, Piquette-Miller M
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Clin Pharmacol Ther. 2008 Jan;83(1):184-7. doi: 10.1038/sj.clpt.6100377. Epub 2007 Sep 19.
Prescription and over-the-counter drug use during pregnancy is necessary for many women today. A study of US and Canadian women found that, on average, 2.3 drugs were used during pregnancy; however, 28% reported using more than 4. For some women, this is because they become pregnant with preexisting conditions that require ongoing or intermittent pharmacotherapy. For others, this is because pregnancy itself can give rise to new medical conditions such as gestational diabetes and preeclampsia. The principal concern of prescribing physicians is whether or not agents will harm the fetus (i.e., have teratogenic effects). This concern rose to prominence primarily as a result of the thalidomide disaster. Marketed for use in morning sickness, thalidomide was found to be a potent teratogen capable of producing a variety of birth defects relating to development. Consequently, determining the teratogenicity of new drugs currently dominates the objectives of pregnancy-relevant experiments conducted throughout drug development. This often comes at the expense of valuable pharmacokinetic (PK) studies, which are seldom performed pre-market. Sex differences in PK parameters have been demonstrated in animals and humans since the 1930s. It is, therefore, not surprising that differences also arise in pregnancy. A wide array of physiological and hormonal changes occur during pregnancy; most begin early in the first trimester and increase linearly until parturition. Physicians lacking adequate PK information typically prescribe the standard adult dose in pregnancy, and this can be either inadequate or excessive depending on a variety of factors. The purpose of this report is to highlight this issue and illustrate how current methods used to obtain PK data in pregnancy are insufficient. The steps that are being taken to address this issue will also be discussed.
如今，对许多女性来说，孕期使用处方药和非处方药是必要的。一项针对美国和加拿大女性的研究发现，平均而言，女性在孕期会使用2.3种药物；然而，28%的女性报告使用了超过4种药物。对一些女性来说，这是因为她们怀孕时就患有需要持续或间歇性药物治疗的疾病。对另一些女性来说，这是因为怀孕本身会引发新的医疗状况，如妊娠期糖尿病和先兆子痫。开处方的医生主要关心的是药物是否会伤害胎儿（即是否有致畸作用）。这种担忧主要是由于沙利度胺灾难而变得突出。沙利度胺曾被用于治疗孕吐，后来被发现是一种强效致畸剂，能够导致各种与发育相关的出生缺陷。因此，确定新药的致畸性目前主导着整个药物研发过程中与妊娠相关实验的目标。这往往是以牺牲宝贵的药代动力学（PK）研究为代价的，而PK研究在上市前很少进行。自20世纪30年代以来，动物和人类的PK参数已被证明存在性别差异。因此，孕期出现差异也就不足为奇了。孕期会发生一系列生理和激素变化；大多数变化在孕早期就开始了，并一直呈线性增加直至分娩。缺乏足够PK信息的医生通常会在孕期开出标准的成人剂量，而这可能因各种因素而不足或过量。本报告的目的是强调这一问题，并说明目前用于获取孕期PK数据的方法是如何不足的。还将讨论为解决这一问题正在采取的措施。
