151751-Najiba-Chargi

267 Systemic therapy: the prospective PLATISMA study SUPPLEMENTARY MATERIALS S1. Details of the pharmacokinetic model of cisplatin A schematic overview of the pharmacokinetic model of free and bound cisplatin is shown in the following figure: Vfree, volume of distribution of free cisplatin; CLfree, clearance of free cisplatin; Vp, volume of distribution of the peripheral volume of free cisplatin; Q, intercompartmental clearance; Vbound, volume of distribution of protein-bound cisplatin; CLbound, clearance of protein-bound cisplatin The interindividual variability (IIV) was described with an exponential model according to equation S1: (1) (2) (3) (4) (5) , = , × (1 + ) = ( − + × 6 ) × ( ℎ 70 ) 0.75 = × (1 + × ( − )) (S1) Where θ i represents the parameter estimate for individual i , θ pop represents the typical param- eter estimate for the population, and η i represents the IIV for individual i . The residual unexplained variability was described by a proportional model for free cisplatin and protein-bound cisplatin separately, according to equation 2: (1) (2) (3) (4) (5) , = , × (1 + ) = ( − + × 6 ) × ( ℎ 70 ) 0.75 = × (1 + × ( − )) (S2) Where C obs,ij represents the observed concentration for individual i and observation j , C pred,ij represents the predicted concentration for individual i and observation j , and ε prop represents the proportional error which was assumed to be normally distributed with a mean of zero and a variance of σ 2 . In order to further investigate the effects of SMM on PK of cisplatin, glomerular filtration rate (GFR), and albumin were examined as additional relevant covariates. These potential covari - ates were first tested as covariates on the baseline model. GFR was evaluated on clearance of protein-bound cisplatin as follows: 14