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Figure 1 Study flow chart. D0, day of tumour inoculation; D5, 5?days after tumour inoculation; D10, 10?days after tumour inoculation; M, midazolam; P, propranolol. Figure 2 Changes in body weight and body composition from D0 to D10 (mean, standard deviation). D0, day of tumour inoculation; D10, 10?days after tumour inoculation; ** P?Enzalutamide manufacturer variability was more pronounced with oral dosing of midazolam and propranolol compared with intravenous dosing of iohexol (data not shown). For all three compounds, pharmacokinetics was most adequately described by a one-compartment model and a proportional model of residual variability. Pharmacokinetic parameters are summarized in Table?Table1.1. Because find more of rapid absorption and limited data in the absorption phase, we were not able to estimate the variability in the absorption rate. Consequently, the effect of cachexia on absorption rate had to be fixed to 0. With midazolam, we were able to estimate the typical value of absorption rate, while with propranolol, the absorption rate had to be fixed to an arbitrary value of 1?min?1. This assumption was tested with a sensitivity analysis of the final model. Without intravenous pharmacokinetic data for midazolam and propranolol, it was not possible to estimate the absorbed fraction (F) after oral dosing. Consequently, clearance and distribution volume are reported as CL/F (apparent oral clearance) and Vd/F (apparent volume of distribution after oral dosing). Inter-occasion variability of CL/F (150% and 170% for midazolam and propranolol, respectively) and Vd/F (190% and 160% for midazolam and propranolol, respectively) was generally in the range of inter-animal variability. Consequently, inter-animal variability was not included in the final model as suggested by Karlsson and Sheiner.15 With the final model for midazolam, the covariance step was not successful (Table?(Table1,1, Model 1). A non-significant increase in CL/F and Vd/F Histone demethylase on D5 was therefore fixed to 0 to obtain the precision of the parameter estimates (Table?(Table1,1, Model 2). Figure 3 Mean pharmacokinetic profiles of midazolam, propranolol, and iohexol on D0, D5, and D10. D0, day of tumour inoculation, D5, 5?days after tumour inoculation; D10, 10?days after tumour inoculation. Table 1 Pharmacokinetic parameters of midazolam, propranolol, and iohexol on D0 and percentage change on D5 and D10 (mean, standard error) Pharmacokinetics of iohexol was much less variable, with inter-occasion variability of 20% (CL) and 12% (Vd). However, again, inter-animal variability was in the same range and was therefore not included in the model. Midazolam Typical midazolam CL/F on D0 was 463?mL/min, and typical Vd/F was 32.7?L (Table?1).
