Aims Anlotinib is a novel oral tyrosine kinase inhibitor that targets VEGFR-2, VEGFR -3, FGFR1-4, PDGFR-α, PDGFR-β, c-Kit, and Ret. This study aimed to develop a population pharmacokinetic model of anlotinib in patients with malignant tumors and identify various covariates that might affect its pharmacokinetic parameters. Methods 407 plasma concentrations from 16 patients were analyzed to establish a population pharmacokinetic model using the nonlinear mixed-effects model method. All patients were administered anlotinib (12 mg) orally, as a single drug therapy. The potential influence of demographic, hepatic, and renal function data was investigated using automated stepwise covariate model. The final model was evaluated using diagnostic goodness-of-fit plots, bootstrap, and visual predictive check methods. Results A one-compartment model with first-order absorption and elimination adequately described anlotinib pharmacokinetics. The population estimates of apparent total plasma clearance (CL/F) was 9.26 L/h (29.20% IIV), apparent volume of distribution (V/F) was 2010 L (29.20 IIV), and absorption rate constant (Ka) was 0.64 h-1 (56.70% IIV). Total cholesterol (TC) was identified as a covariate affecting CL/F, while alkaline phosphatase (ALP) was found to be statistically significant for V/F. Conclusion The population pharmacokinetic model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors. TC and ALP might have a slight effect on the pharmacokinetic profile of anlotinib.

Information about the concentration of unbound paclitaxel over time following administration of albumin-bound paclitaxel (nab-paclitaxel) and its proportion to total paclitaxel in plasma remains unavailable. The aim of this study was to establish a population pharmacokinetic (PK) model to evaluate the dynamic relationship between total and unbound concentrations of paclitaxel in Chinese patients with metastatic breast cancer. A total of 653 concentrations corresponding to total and 334 to unbound paclitaxel were analyzed in 24 subjects who received two cycles of a single nab-paclitaxel dose of 260 mg/m2/cycle. The time course of the fraction of unbound paclitaxel was analyzed by non-linear mixed-effects modeling and Monte Carlo simulation. A mechanism-based model incorporating linear dissociation of nab-paclitaxel and saturated binding of free paclitaxel to plasma components was established to describe the relationship between total and unbound paclitaxel. Dissociation coefficient of nab-paclitaxel was estimated to be 4.60%, while a maximum unbound fraction value of 2.76% was reached at the end of infusion due to nonlinear binding kinetics of unbound paclitaxel. This is the first study to determine relationship between total and unbound nab-paclitaxel concentrations using a semi-mechanical population PK model, revealing that unbound paclitaxel fraction was expressed as a function of nab-paclitaxel concentration.

Objective: To assess whether dose adjustments of linezolid were needed based on renal function and body weight against methicillin-resistant Staphylococcus aureus (MRSA) infections. Methods: Monte Carlo simulations (MCSs) were conducted to simulate pharmacokinetic/pharmacodynamic (PKPD) model. Area under the concentration time curve (AUC)/ minimum inhibitory concentration (MIC) ratio and percentage of time above the MIC (%T>MIC) were regarded as PKPD targets. The probability of target attainment (PTA) and cumulative fractions of response (CFR) were calculated to assess the efficacy. Regarding safety, trough plasma concentration (Cmin) > 8 mg/L was used to target for toxicity. Results: Using AUC /MIC > 100 as the parameter, the CFR of linezolid at the standard dose [600 mg every 12 h (q12h)] were 57.01%, 93.22% and 99.93% in patients with normal renal function, patients with renal dysfunction and low body weight patients with renal dysfunction, respectively. Using 100%T > MIC as the parameter, all the CFR of three population groups were more than 90% at the standard dose. The percentages of Cmin > 8 mg/L at the standard dose of linezolid were 24.16%, 53.24% and 90.10% in three population groups on day 7. Conclusions: The risk of thrombocytopenia of linezolid was extremely high in low body weight patients with renal impairment when receiving standard linezolid dose. 600 mg q12h might be effective and safe against MRSA infection in patients with normal renal function, while 450mg q12h and 300mg q12h in patients with renal dysfunction and low body weight patients with renal dysfunction, respectively.