caa a22 4500 477125506 CHVBK 20180405111648.0 cr unu---uuuuu 170330e19970101xx s 000 0 eng 10.1023/A:1012015719694 doi (NATIONALLICENCE)springer-10.1023/A:1012015719694 Prospective Use of Population Pharmacokinetics/ Pharmacodynamics in the Development of Cisatracurium [Elektronische Daten] [Virginia Schmith, Jill Fiedler-Kelly, Luann Phillips, Thaddeus Grasela Jr.] 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. Plenum Publishing Corporation, 1997 pharmacokinetics nationallicence pharmacodynamic modeling nationallicence NONMEM nationallicence model validation nationallicence cisatracurium nationallicence Schmith Virginia Clinical Pharmacokinetics and Dynamics, Glaxo Wellcome Inc., 5 Moore Drive, RTP, 27709, North Carolina aut Fiedler-Kelly Jill Pharmaceutical Outcomes Research, Inc., 435 Lawrence Bell Drive, 14221, Williamsville, New York aut Phillips Luann Pharmaceutical Outcomes Research, Inc., 435 Lawrence Bell Drive, 14221, Williamsville, New York aut Grasela Jr. Thaddeus Pharmaceutical Outcomes Research, Inc., 435 Lawrence Bell Drive, 14221, Williamsville, New York aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/1(1997-01-01), 91-97 0724-8741 14:1<91 1997 14 11095 https://doi.org/10.1023/A:1012015719694 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012015719694 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Schmith Virginia Clinical Pharmacokinetics and Dynamics, Glaxo Wellcome Inc., 5 Moore Drive, RTP, 27709, North Carolina aut NATIONALLICENCE 700 1- Fiedler-Kelly Jill Pharmaceutical Outcomes Research, Inc., 435 Lawrence Bell Drive, 14221, Williamsville, New York aut NATIONALLICENCE 700 1- Phillips Luann Pharmaceutical Outcomes Research, Inc., 435 Lawrence Bell Drive, 14221, Williamsville, New York aut NATIONALLICENCE 700 1- Grasela Jr Thaddeus Pharmaceutical Outcomes Research, Inc., 435 Lawrence Bell Drive, 14221, Williamsville, New York aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/1(1997-01-01), 91-97 0724-8741 14:1<91 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer