PURPOSE: The population PK/PD approach was prospectively used to determine the PK/PD of cisatracurium in various subgroups of healthy surgical patients. METHODS:Plasma concentration (Cp) and neuromuscular block data from 241 patients in 8 prospectively-designed Phase I-III trials were pooled and analyzed using NONMEM. The analyses included limited Cp-time data randomly collected from 186 patients in efficacy/safety studies and full Cp-time data from 55 patients in pharmacokinetic studies. The effects of covariates on the PK/PD parameters of cisatracurium were evaluated. The time course of neuromuscular block was predicted for various patient subgroups. RESULTS: The population PK/PD model for cisatracurium revealed that anesthesia type, gender, age, creatinine clearance, and presence of obesity were associated with statistically significant (p < 0.01) effects on the PK/PD parameters of cisatracurium. These covariates were not associated with any clinically significant changes in the predicted recovery profile of cisatracurium. Slight differences in onset were predicted in patients with renal impairment and patients receiving inhalation anesthesia. Based on the validation procedure, the model appears to be accurate and precise. CONCLUSIONS: The prospective incorporation of a population PK/PD strategy into the clinical development of cisatracurium generated information which influenced product labeling and reduced the number of studies needed during development.
RCT Entities:
PURPOSE: The population PK/PD approach was prospectively used to determine the PK/PD of cisatracurium in various subgroups of healthy surgical patients. METHODS: Plasma concentration (Cp) and neuromuscular block data from 241 patients in 8 prospectively-designed Phase I-III trials were pooled and analyzed using NONMEM. The analyses included limited Cp-time data randomly collected from 186 patients in efficacy/safety studies and full Cp-time data from 55 patients in pharmacokinetic studies. The effects of covariates on the PK/PD parameters of cisatracurium were evaluated. The time course of neuromuscular block was predicted for various patient subgroups. RESULTS: The population PK/PD model for cisatracurium revealed that anesthesia type, gender, age, creatinine clearance, and presence of obesity were associated with statistically significant (p < 0.01) effects on the PK/PD parameters of cisatracurium. These covariates were not associated with any clinically significant changes in the predicted recovery profile of cisatracurium. Slight differences in onset were predicted in patients with renal impairment and patients receiving inhalation anesthesia. Based on the validation procedure, the model appears to be accurate and precise. CONCLUSIONS: The prospective incorporation of a population PK/PD strategy into the clinical development of cisatracurium generated information which influenced product labeling and reduced the number of studies needed during development.
Authors: Thaddeus H Grasela; Jill Fiedler-Kelly; Cynthia A Walawander; Joel S Owen; Brenda B Cirincione; Kathleen E Reitz; Elizabeth A Ludwig; Julie A Passarell; Charles W Dement Journal: AAPS J Date: 2005-10-05 Impact factor: 4.009
Authors: Josh D Kaullen; Joel S Owen; Kim L R Brouwer; Paul M Heerdt; Cynthia A Lien; John J Savarese; Virginia D Schmith Journal: Anesthesiology Date: 2018-06 Impact factor: 7.892