The Pharmacokinetics of CPZEN-45, a Novel Anti-Tuberculosis Drug, in Guinea Pigs.
The Pharmacokinetics of CPZEN-45, a Novel Anti-Tuberculosis Drug, in Guinea Pigs.
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DOI：
10.3390/pharmaceutics15122758
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发表时间：
2023-12-12
期刊：
影响因子：
5.4
通讯作者：
Hickey AJ
中科院分区：
文献类型：
--
作者：
Garcia-Contreras L;Hanif SNM;Ibrahim M;Durham P;Hickey AJ
CPZEN-45是一种新的抗结核药物，具有抗结核药物敏感和耐药的活性。本研究旨在确定可吸入CPZEN-45粉末的最佳剂量和给药方案，用于TB感染豚鼠的疗效研究。首先确定静脉内、皮下（SC）和直接肺部施用（INS）后CPZEN-45的处置以获得其基础药代动力学（PK）参数。然后，评价使用连续和顺序剂量被动吸入后CPZEN-45粉末的处置。血浆浓度-时间曲线和PK参数表明，INS后CPZEN-45的吸收快于SC给药后（Ka分别为12.94 ± 5.66 h−1和1.23 ± 0.55 h−1），半衰期较长（2.06 ± 1.01 h vs 0.76 ± 0.22 h），生物利用度较高（分别为67.78%和47.73%）。在1次、2次和3次连续被动吸入给药后，研究期结束时的血药浓度-时间曲线和肺组织浓度与剂量大小不成比例。三次连续被动吸入给药在血浆和肺组织中维持治疗浓度水平的时间长于三次连续给药（分别为10 h和3 h）。未来评估吸入性CPZEN-45粉末疗效的研究应采用连续剂量的粉末，每天三次给予动物一个标称剂量。
CPZEN-45 is a novel compound with activity against drug-susceptible and drug-resistant tuberculosis (TB). The present study was undertaken to determine the best dose and dosing regimen of inhalable CPZEN-45 powders to use in efficacy studies with TB-infected guinea pigs. The disposition of CPZEN-45 after intravenous, subcutaneous (SC), and direct pulmonary administration (INS) was first determined to obtain their basal pharmacokinetic (PK) parameters. Then, the disposition of CPZEN-45 powders after passive inhalation using consecutive and sequential doses was evaluated. Plasma concentration versus time curves and PK parameters indicated that the absorption of CPZEN-45 after INS was faster than after SC administration (Ka = 12.94 ± 5.66 h−1 and 1.23 ± 0.55 h−1, respectively), had a longer half-life (2.06 ± 1.01 h versus 0.76 ± 0.22 h) and had higher bioavailability (67.78% and 47.73%, respectively). The plasma concentration versus time profiles and the lung tissue concentration at the end of the study period were not proportional to the dose size after one, two, and three consecutive passive inhalation doses. Three sequential passive inhalation doses maintained therapeutic concentration levels in plasma and lung tissue for a longer time than three consecutive doses (10 h vs. 3 h, respectively). Future studies to evaluate the efficacy of inhaled CPZEN-45 powders should employ sequential doses of the powder, with one nominal dose administered to animals three times per day.
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