Based on PK/PD and Monte Carlo Simulation Analysis of the Dosing Regimens of Micafungin in Children with Febrile Neutropenic

Neutropenia with fever is a special group of patients. Due to low immune function, inflammation-related clinical symptoms and signs are often not obvious, and pathogenic bacteria and infection focus are not clear. Fever may be the only sign of infection. If appropriate antimicrobial treatment is not given in time, infection-related mortality is high. In our study, we aimed to optimize the dosage regimen of Micafungin in children with febrile neutropenic against Candida spp. by Mote Carlo Simulation (MCS). Pharmacokinetic parameters and microbiological data of Micafungin were collected. Then we used MCS to calculate Probability of Target Attainment (PTA) and Cumulative Fraction of Response (CFR). With dosages of 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 3 mg/kg, and 4 mg/kg in oral group and dosages of 100 mg, and 200 mg in intravenous administration, all have different degree of antifungal effect. But when the dosage regimen was 50 mg IV, the therapeutic effect of Micafungin against Candida spp. was not good.

A PK/PD model of saxagliptin:to simulate its pharmacokinetics and pharmacodynamics in healthy adults and patients with impaired hepatic function

In this study,we aimed to develop and evaluate a whole-body physiologically based pharmacokinetic(WB-PBPK)/pharmacodynamic(PD)model for saxagliptin,simulate its pharmacokinetic and pharmacodynamic properties in healthy adults and patients with hepatic function impairment,and provide a new method for the research to the clinical pharmacy of special patients.Based on the drug-specific properties,such as log D,plasma protein binding collected by the published literature,the WB-PBPK model and the PD model were established.After comparing the simulated concentration-time profiles and the pharmacokinetic parameters with data in healthy adults from oral and intravenous clinical investigation,the WB-PBPK model could be optimized.After comparing the simulated DPP-4 inhibition profile with the observed pharmacodynamic in healthy subjects,the PD model could be optimized.The PK/PD model was utilized to predict the mean and variability of the pharmacokinetic and pharmacodynamic profiles in subjects with different hepatic impairment.All of the predicted pharmacokinetic curves were comparable to the observed curves both in healthy subjects and hepatic impairment subjects(Cmax and AUC were less than 1.3-fold).The predicted pharmacodynamic curves were comparable to the observed ones in different oral dosage after optimization,and pharmacodynamics of saxagliptin in hepatic impairment subjects were predicted successfully.The WB-PBPK/PD model can accurately simulate the pharmacokinetics and pharmacodynamics of saxagliptin in normal adults and different hepatic impaired patients.

A stochastic population pharmacodynamic model of QAP14 in the treatment of lung metastases of 4T1 breast cancer

Cancer metastasis is a process with multi-step complexity and apparent randomness. In this study, we aimed to establish a stochastic mathematical model to describe the random process of cancer metastasis and predict the drug effect of QAP14 on metastasis in a mouse model. The data of lung metastases on the 22^(nd) day after cancer cell implantation with or without the treatment of QAP14, a new chemical compound, were collected in 4T1 breast cancer BALB/c mice. Based on the exponential growth of the primary tumor and metastatic loci, a joint distribution model of metastasis size and number was developed. Disease progression of metastasis and preclinical efficacy of QAP14 were modeled. Parameters M and m representing maximum and minimum of metastasis volume were 3.24 and 0.0184 mm^(3), respectively. The metastasis growth rate γ and metastasis promotion time ρ were estimated and fixed to be 0.0216 d^(-1) and 7.8 d, respectively. The efficacy of QAP14 acted on metastasis promotion time and metastasis growth rate constant in an exponential term, and the effect parameter Effectρ and Effectγ were 16.6 and 0.327 g/mg, respectively. In the present study, we comprehensively characterized the random process of lung metastasis and efficacy of QAP14 in 4T1 breast cancer mice, which might provide a useful reference for the establishment of a clinical population model of cancer metastasis.