Cai Qing, Azarpanah Armita, Bhatt Jayshil A, Wei Hui, Carr Jamie, Morris Kenneth R, Strasinger Caroline, Brogden Nicole K
Lachman Institute for Pharmaceutical Analysis, Long Island University, Brooklyn, NY, USA.
Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA.
Pharm Res. 2024 Jan;41(1):39-50. doi: 10.1007/s11095-023-03617-7. Epub 2023 Oct 17.
This study aimed to determine the extent and rate of lidocaine released in vivo from two bioequivalent topical delivery systems (TDS) by using complementary assessments: pharmacokinetic analysis in healthy human volunteers, and residual lidocaine in TDS following 12 h of wear. The goal was to explore a potentially more clinically meaningful strength presentation than percent active pharmaceutical ingredient loaded in topical systems.
A three-arm, open-label, crossover clinical study was conducted in 23 human subjects, with 5% lidocaine topical systems from two manufacturers, and intravenous lidocaine administration. Residual drug and LC-MS/MS analyses were performed on worn TDS and serum samples. The rate and extent of drug released from the TDS during wear were determined through (1) calculations of consumed lidocaine via analysis of residual drug in worn TDS, and (2) a pharmacokinetic approach via derivation of the absolute clearance and serum lidocaine concentration at steady state.
Overall the pharmacokinetic approach underestimated the amount transferred to the subject and exhibited greater variability, which may relate to natural inter-subject variability in pharmacokinetic parameters. Further, lidocaine TDS are intended for localized, not systemic, delivery and this may also explain some of the variability seen in the systemic serum concentrations.
The residual drug and pharmacokinetic approaches align well for transdermal formulations, but the differences in administration route (topical versus transdermal) all but eliminates the potential use of the pharmacokinetic approach unless additional compartmental modeling is explored.
本研究旨在通过互补评估确定两种生物等效的局部给药系统（TDS）在体内释放利多卡因的程度和速率：对健康人类志愿者进行药代动力学分析，以及佩戴12小时后TDS中的残留利多卡因。目标是探索一种可能比局部系统中活性药物成分加载百分比更具临床意义的强度表述方式。
在23名人类受试者中进行了一项三臂、开放标签、交叉临床研究，使用来自两家制造商的5%利多卡因局部给药系统，并静脉注射利多卡因。对佩戴过的TDS和血清样本进行残留药物和液相色谱-串联质谱（LC-MS/MS）分析。通过以下方法确定TDS在佩戴期间释放药物的速率和程度：（1）通过分析佩戴过的TDS中的残留药物来计算消耗的利多卡因；（2）通过推导稳态下的绝对清除率和血清利多卡因浓度的药代动力学方法。
总体而言，药代动力学方法低估了转移到受试者体内的量，并且表现出更大的变异性，这可能与药代动力学参数的个体间自然变异性有关。此外，利多卡因TDS旨在进行局部而非全身给药，这也可能解释了全身血清浓度中观察到的一些变异性。
残留药物和药代动力学方法对于透皮制剂的结果吻合良好，但给药途径（局部与透皮）的差异几乎消除了药代动力学方法的潜在用途，除非探索额外的房室模型。
