JK is an employee of Pfizer AB. increase observed for UC patients. CL also showed a negative correlation with baseline albumin concentration. Open in a separate window Physique 1 Relationship between selected covariates and pharmacokinetic parameters in the base model (A) and the final model (B). The solid red line is usually a easy curve fit of the data computed by loess. In the boxplots on the right, the thick line shows median, box shows the first and the third quartiles, and the bars show 1.5 *interquartile range. CL, clearance; were slightly elevated for moderate to severe asthma patients, it suggested that it could be due to the difference in bioavailability. Therefore, having moderate to severe asthma or having moderate to moderate asthma were tested as covariates for were plotted against various covariates for the final model (Physique?(Figure1B)1B) and no trend could be observed suggesting the final model properly captured the EsculentosideA available covariates. The relationship between CL and baseline Mayo score for UC patients was explored graphically (Physique?(Figure2).2). Since no pattern was observed based on the plot, no further covariate analysis on Mayo score was conducted. Open in a separate windows Physique 2 Relationship between baseline Mayo score and CL for ulcerative colitis patients. In the boxplot, the thick line shows median, box shows the first and the third quartiles, and the bars show 1.5 *interquartile range. The parameter values for the final model are listed in Table?Table3.3. Relative standard error (RSE) for all the fixed effect and random effect parameters were all less than 20%. Diagnostic plots for the final model are shown in Figure?Physique3.3. There was no systematic bias or lack of fit as EsculentosideA indicated by these plots. The final model was also evaluated by VPCs from EsculentosideA 1000 simulations stratified by dose. Representative plots from six treatment groups from both i.v. and s.c. routes of administration and different disease says are shown in Figure?Physique4.4. For each of the three percentiles, the observed and simulated data agreed well. To validate the model further, 2000 bootstrap runs were performed. The median values and 95% confidence intervals (CIs) from the bootstrap estimation are listed in Table?Table3.3. The bootstrap results were very similar to the NONMEM estimates from the final model, supporting the stability of the population PK model. The significance of the included covariates was further supported by the bootstrap analysis, as none of the 95% CIs for the covariate effects included zero (if the parameter value for covariate effect is usually zero, it represents the null hypothesis). In the final model, the half-life for non-UC subjects was 567?h (95% CI 548C586 h) and for UC patients, it was 328?h (95% CI 301C352 h). Open in a separate window Physique 3 Goodness-of-fit plots for the final model. A) Observed increased with body weight, which is often observed with other therapeutic monoclonal antibodies 14 and is consistent with the mechanism of metabolism for monoclonal antibodies. The half-life for non-UC subjects was CREB3L4 567?h (95% confidence interval 548C586 h). Overall, the PK properties of anrukinazumab are consistent with a typical monoclonal antibody. Albumin was also identified as a covariate for CL which has been reported before for other monoclonal antibodies []10,15. Since both.