Cacek Anthony T, Gobburu Jogarao V S, Gopalakrishnan Mathangi
ContractKinetica, Columbia, MO, USA.
Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
J Clin Pharmacol. 2017 Feb;57(2):247-254. doi: 10.1002/jcph.799. Epub 2016 Aug 23.
The primary objective of the current investigation was to establish the pharmacokinetic characteristics of oxymetazoline and tetracaine's primary metabolite, para-butylaminobenzoic acid (PBBA), after the intranasal administration of oxymetazoline/tetracaine. Thirty-six subjects contributing a total of 1791 plasma concentration results from 2 open-label trials were utilized. Model development was achieved using data from the second trial (N = 24) in which 0.3 mg oxymetazoline/18 mg tetracaine was administered. External model validation utilized data from the first trial (N = 12), which included doses of 0.3 mg oxymetazoline/18 mg tetracaine and 0.6 mg oxymetazoline/36 mg tetracaine. Oxymetazoline and PBBA dispositions were described by a 2-compartment model with first-order absorption. An allometric model for body weight was included on volumes and clearances to describe unexplained between-subject variability. The final oxymetazoline parameter estimates were k 4.41 h ; peripheral volume 418 L; clearance 66.4 L/h; central volume 6.97 L; and intercompartmental clearance 419 L/h for a 70-kg subject. The final PBBA parameter estimates were k 8.51 h ; peripheral volume 32.0 L; clearance 16.7 L/h; central volume 29.8 L; and intercompartmental clearance 2.43 L/h for a 70-kg subject. Between-subject variability ranged from 14% to 39% for oxymetazoline and from 10% to 94% for PBBA.
本研究的主要目的是确定滴鼻用羟甲唑啉/丁卡因给药后,羟甲唑啉和丁卡因的主要代谢产物对丁氨基苯甲酸(PBBA)的药代动力学特征。利用来自2项开放标签试验的36名受试者共1791个血浆浓度结果。模型开发使用了第二项试验(N = 24)的数据,其中给予了0.3 mg羟甲唑啉/18 mg丁卡因。外部模型验证使用了第一项试验(N = 12)的数据,其中包括0.3 mg羟甲唑啉/18 mg丁卡因和0.6 mg羟甲唑啉/36 mg丁卡因的剂量。羟甲唑啉和PBBA的处置情况用具有一级吸收的二室模型描述。在体积和清除率方面纳入了体重的异速生长模型,以描述受试者间无法解释的变异性。对于一名70 kg的受试者,最终的羟甲唑啉参数估计值为:消除速率常数4.41 h⁻¹;外周室容积418 L;清除率66.4 L/h;中央室容积6.97 L;室间清除率419 L/h。对于一名70 kg的受试者,最终的PBBA参数估计值为:消除速率常数8.51 h⁻¹;外周室容积32.0 L;清除率16.7 L/h;中央室容积29.8 L;室间清除率2.43 L/h。羟甲唑啉的受试者间变异性范围为14%至39%,PBBA为从10%至94%。