Clinical Pharmacology and Pharmacokinetics, Shire Development Inc., Wayne, Pennsylvania, USA.
CNS Drugs. 2010 Dec;24(12):1009-25. doi: 10.2165/11539410-000000000-00000.
Methylphenidate- and amfetamine-based stimulants are first-line pharmacotherapies for attention-deficit hyperactivity disorder, a common neurobehavioural disorder in children and adults. A number of long-acting stimulant formulations have been developed with the aim of providing once-daily dosing, employing various means to extend duration of action, including a transdermal delivery system, an osmotic-release oral system, capsules with a mixture of immediate- and delayed-release beads, and prodrug technology. Coefficients of variance of pharmacokinetic measures can estimate the levels of pharmacokinetic variability based on the measurable variance between different individuals receiving the same dose of stimulant (interindividual variability) and within the same individual over multiple administrations (intraindividual variability). Differences in formulation clearly impact pharmacokinetic profiles. Many medications exhibit wide interindividual variability in clinical response. Stimulants with low levels of inter- and intraindividual variability may be better suited to provide consistent levels of medication to patients. The pharmacokinetic profile of stimulants using pH-dependent bead technology can vary depending on food consumption or concomitant administration of medications that alter gastric pH. While delivery of methylphenidate with the transdermal delivery system would be unaffected by gastrointestinal factors, intersubject variability is nonetheless substantial. Unlike the beaded formulations and, to some extent (when considering total exposure) the osmotic-release formulation, systemic exposure to amfetamine with the prodrug stimulant lisdexamfetamine dimesylate appears largely unaffected by such factors, likely owing to its dependence on systemic enzymatic cleavage of the precursor molecule, which occurs primarily in the blood involving red blood cells. The high capacity but as yet unidentified enzymatic system for conversion of lisdexamfetamine dimesylate may contribute to its consistent pharmacokinetic profile. The reasons underlying observed differential responses to stimulants are likely to be multifactorial, including pharmacodynamic factors. While the use of stimulants with low inter- and intrapatient pharmacokinetic variability does not obviate the need to titrate stimulant doses, stimulants with low intraindividual variation in pharmacokinetic parameters may reduce the likelihood of patients falling into subtherapeutic drug concentrations or reaching drug concentrations at which the risk of adverse events increases. As such, clinicians are urged both to adjust stimulant doses based on therapeutic response and the risk for adverse events and to monitor patients for potential causes of pharmacokinetic variability.
哌醋甲酯和苯丙胺类兴奋剂是治疗注意缺陷多动障碍（一种常见的儿童和成人神经行为障碍）的一线药物疗法。为了实现每日一次给药，人们开发了许多长效兴奋剂制剂，采用各种方法来延长作用持续时间，包括透皮给药系统、渗透压控释口服系统、包含速释和缓释珠粒混合物的胶囊，以及前药技术。药代动力学指标的变异系数可根据接受相同剂量兴奋剂的不同个体之间（个体间变异性）和同一个体多次给药之间（个体内变异性）可测量的差异来估计药代动力学变异性的水平。制剂的差异显然会影响药代动力学特征。许多药物在临床反应方面表现出很大的个体间变异性。个体间和个体内变异性较低的兴奋剂可能更适合为患者提供稳定的药物水平。使用 pH 依赖性珠粒技术的兴奋剂的药代动力学特征可能会因食物消耗或同时使用改变胃 pH 值的药物而发生变化。虽然使用透皮给药系统递送哌醋甲酯不会受到胃肠道因素的影响，但个体间的变异性仍然很大。与珠粒制剂不同，并且在某种程度上（考虑到总暴露量）与渗透压控释制剂不同，前药司来吉兰二甲酯的阿莫特林的全身暴露似乎基本不受这些因素的影响，这可能是由于其对前体分子的系统酶裂解的依赖性，该过程主要发生在血液中，涉及红细胞。用于司来吉兰二甲酯转化的高容量但尚未确定的酶系统可能是其稳定药代动力学特征的原因。观察到对兴奋剂的不同反应的原因可能是多因素的，包括药效学因素。虽然使用个体间和个体内药代动力学变异性低的兴奋剂并不能免除滴定兴奋剂剂量的需要，但药代动力学参数个体内变异低的兴奋剂可能会降低患者落入治疗药物浓度以下或达到不良反应风险增加的药物浓度的可能性。因此，临床医生不仅要根据治疗反应和不良反应风险调整兴奋剂剂量，还要监测患者潜在的药代动力学变异性原因。
