Table_2_Pharmacokinetics of a continuous intravenous infusion of hydromorphone in healthy dogs.DOCX

IntroductionDosing recommendations for hydromorphone intravenous constant rate infusion (IV CRI) are derived from simulations following IV bolus administration. While this extrapolated dose regimen has been described clinically, pharmacokinetics (PK) of hydromorphone infusions in dogs are not yet described. The study objective was to describe the PK of hydromorphone in healthy dogs receiving an IV bolus followed by an IV CRI for 48 h.
MethodsA prospective, experimental study was performed involving the administration of hydromorphone (0.1 mg/kg IV bolus then IV CRI 0.01 mg/kg/h over a 48 h period) to 6 healthy Beagle dogs. Blood samples were collected at 16 time points between 0 and 58 h relative to the initial bolus. Plasma hydromorphone concentrations were analyzed by high pressure liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameter estimates were obtained with compartmental methods using commercially available software.
ResultsA two-compartment model with first order elimination was used. At the end of the infusion, median (range) plasma hydromorphone concentrations were 6.8 (5.5–19.6) ng/mL. The median total body clearance was 30.4 (19.8–36.7) mL/min/kg; volume of distribution at steady state was 4.5 (3.2–7.8) L/kg; and terminal elimination half-life was 11.2 (7.6–24.3) h.
ConclusionHydromorphone (0.1 mg/kg IV bolus then IV CRI of 0.01 mg/kg/h) maintained steady-state plasma concentrations above the minimum human analgesic target in healthy Beagle dogs with minimal side effects. Further studies are needed to determine the effective plasma concentrations of hydromorphone in painful dogs.

引言
氢吗啡酮静脉持续输注（intravenous constant rate infusion, IV CRI）的给药方案多源自静脉推注（intravenous bolus, IV bolus）后的模拟数据。尽管该外推给药方案已有临床相关报道，但犬氢吗啡酮持续输注的药代动力学（pharmacokinetics, PK）特征尚未见公开描述。本研究旨在描述健康犬经静脉推注后行48小时IV CRI的氢吗啡酮药代动力学特征。
方法
本研究为前瞻性实验研究，纳入6只健康比格犬，给予氢吗啡酮给药方案：0.1 mg/kg静脉推注，随后以0.01 mg/kg/h的速率行48小时IV CRI。于初始推注后0至58小时内的16个时间点采集血液样本。采用高效液相色谱-串联质谱法检测血浆氢吗啡酮浓度。借助商用软件通过房室模型法估算药代动力学参数。
结果
本研究采用一级消除二室模型。输注结束时，血浆氢吗啡酮浓度的中位数（范围）为6.8（5.5~19.6）ng/mL。总体清除率中位数为30.4（19.8~36.7）mL/min/kg；稳态表观分布容积为4.5（3.2~7.8）L/kg；终末消除半衰期为11.2（7.6~24.3）h。
结论
在健康比格犬中，采用0.1 mg/kg静脉推注联合0.01 mg/kg/h IV CRI的给药方案，可维持血浆稳态浓度高于人类镇痛最低靶浓度，且不良反应轻微。后续仍需开展研究以明确疼痛犬体内氢吗啡酮的有效血浆浓度。