Continuous Renal Replacement Therapy (CRRT) is more and more widely used in patients for various indications recent years. It is still intricate for clinicians to decide a suitable empiric antimicrobial dosing for patients receiving CRRT. Inappropriate doses of antimicrobial agents may lead to treatment failure or drug resistance of pathogens. CRRT factors, patient individual conditions and drug pharmacokinetics/pharmacodynamics are the main elements effecting the antimicrobial dosing adjustment. With the development of CRRT techniques, some antimicrobial dosing recommendations in earlier studies were no longer appropriate for clinical use now. Here, we reviewed the literatures involving in new progresses of antimicrobial dosages, and complied the updated empirical dosing strategies based on CRRT modalities and effluent flow rates. The following antimicrobial agents were included for review:

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BACKGROUND: Imatinib is the standard treatment for patients with gastrointestinal stromal tumors (GISTs), but there is significant variation in imatinib plasma trough concentrations (C min ) among patients. The imatinib C min distribution at different doses and the correlation of adverse reactions with C min in Chinese patients with GIST from a high-volume center were evaluated. METHODS: From July 1, 2017 to December 31, 2018, patients who were receiving imatinib treatment for GIST were prospectively enrolled. Steady-state blood samples were obtained from patients who had received same-dose imatinib treatment for ≥1 month with good compliance. Adverse reactions were recorded during regular follow-up, and blood samples were collected 24 ± 2 hours after dosing. Liquid chromatography-tandem mass spectrometry was used to measure drug concentrations. RESULTS: In total, 307 patients who received 367 dose levels were investigated. The imatinib C min was 1315 ± 716 ng/mL, 2117 ± 597 ng/mL, and 3844 ± 987 ng/mL in patients who were receiving imatinib 400 mg, 600 mg, and 800 mg daily, respectively. The C min was significantly correlated with periorbital and limb edema (P < .001), anemia (P < .001), and rash (P = .037). Nausea and vomiting, diarrhea, and conjunctival hemorrhage also were correlated, but not significantly. A much higher C min was observed with severe adverse reactions. There was no correlation between the imatinib C min and leukopenia, muscle cramps, or hepatobiliary dysfunction. CONCLUSIONS: In Chinese patients with GIST, the imatinib C min was higher than that reported for Western populations, especially at higher doses. The C min was correlated with periorbital and limb edema, anemia, and rash, suggesting that monitoring the imatinib C min should be considered when patients develop severe adverse reactions caused by excessive imatinib plasma concentrations.

To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction. Methods: Patients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The Child-Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17 patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis. Results: There were good correlations between the area under the curve (AUC 0-12 ) of PK curve 2 and the corresponding trough concentration (C 0 ) and peak concentration (C max ) (r 2 = 0.951 and 0.963, respectively; both p < 0.001). The median half-life (t 1/2 ) and clearance (CL) of patients in Child-Pugh class A (n = 3), B (n = 5), and C (n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and 2.04 l/h, respectively. In the different Child-Pugh classes, the CL (median) of PK curve 2 were all lower than those of PK curve 1. The apparent steady-state volume of distribution (V ss ) of PK curve 1 was positively correlated with actual body weight (r 2 = 0.450, p = 0.004). The median first C 0 of 17 patients determined on day 5 was 5.27 (2.61) mg/ml, and 29.4% of C 0 exceeded the upper limit of the therapeutic window (2-6 mg/ml). Conclusions:The CL of VRC decreased with increasing severity of liver dysfunction according to the Child-Pugh classification, along with an increased t 1/2 , which resulted in high plasma exposure of VRC. Adjusted dosing regimens of intravenous VRC should be established based on Child-Pugh classes for these ICU patients, and plasma concentrations should be monitored closely to avoid serious adverse events.

Study Objectives This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. Design Prospective pharmacokinetics study. Setting The intensive care unit in a tertiary‐care medical center. Patients A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. Methods Model‐based simulations with therapeutic range of 2–6 mg/L as the plasma trough concentration (Cmin) target and the free area under the concentration‐time curve from 0 to 24 h (ƒAUC24) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24/MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child‐Pugh class A and B (CP‐A/B) and Child‐Pugh class C (CP‐C) patients. Results A two‐compartment model with first‐order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child‐Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP‐A/B and CP‐C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP‐A/B patients and 50 mg q12h or 100 mg q24h for CP‐C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP‐A/B and CP‐C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. Conclusions For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP‐A/B and CP‐C patients.

Background/Aims: Multidrug resistance (MDR) is a critical issue during chemotherapy of cancers. Phorbol 12-myristate 13-acetate (PMA), a diester of phorbol, is a typical activator of protein kinase C (PKC). In the present study, we investigated the effect of PMA on MDR and P-glycoprotein (P-gp) gene expression in K562/ADM cells. Methods: 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay was used to assess adriamycin (Adr)-induced cytotoxicity towards K562/ADM cells in the absence or presence of PMA. The intracellular accumulation of Adr was measured by determining the mean fluorescence intensity. The effect of PMA on P-gp activity was investigated by rhodamine-123 accumulation and efflux experiment. Protein expression and mRNA expression of P-gp in K562/ADM cells were determined by Western blot analysis and real-time qPCR, respectively. Results: Adr-induced cytotoxicity towards K562/ADM cells was significantly decreased by PMA at 5 μmol/l. Furthermore, intracellular Adr-associated mean fluorescence intensity was attenuated by 53.8% 1 h after exposure to PMA at 5 μmol/l compared with the control group (p < 0.05). A dose-dependent decrease of intracellular rhodamine-123 and increase of efflux activity of P-gp were also observed in K562/ADM cells incubation with PMA. In addition, P-gp mRNA and protein expression were significantly induced by PMA. Conclusion: Activation of PKC pathway by PMA can significantly induce expression and activity of P-gp, and thus decrease intracellular Adr level and strengthen MDR in K562/ADM cells.

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11537 Background: The relationship between primary and secondary mutational status and efficacy of regorafenib in third-line therapy on GISTs is yet clear. Methods: From Jun 2017 to Dec 2021, a total of 62 patients with advanced GIST refractory to imatinib and/or sunitinib were enrolled in this study from the First Affiliated Hospital, Sun Yat-sen University. Results: Primary mutational was most common in KIT exon 11(40/62, 64.5%), followed by exon 9 (19.4%), exon 17 (4.8%). Six cases (9.7%) belonged to SDH deficiency and one case (1.6%) was NF1-associated GISTs. Before receiving treatment of regorafenib, specimens obtaining for secondary mutations were as follows: 39 cases from surgery，12 from core-needle biopsy; ctDNA alone was performed in 9 cases and 2 patients refused to secondary mutational test. Excluding 6 patients with SDH deficiency, 14 patients (25.8%) had mutations in exon 11+13, 15 (27.7%) in exon 11+17, 7 (13.0%) in exon 9+17, 4 (7.4%) in exon 11+13+17. Exon 11 + 18, exon 11 + 13 + 18, exon 11 + 13 + 17 + 18, exon 9 + 16, exon 11 + 17 + 18 and NF-1 were found in 1 case, respectively (1.9%). Eight (14.7%) patients with primary KIT mutation were not detected any secondary mutation（2nd-not-detected）. There was no complete response, 4 of partial response (4/54, 7.4%), 27 of stable disease (50.0%). Progression disease was seen in 23 patients (42.6%) and 8 were not applicable (no assessable lesion) to imaging response assessment due to R0/1 surgery before using regorafenib. The median follow-up time was 19.0 months. The median progression-free survival (mPFS) was 5.4 months (0.2-29.1 months) and the median overall survival (mOS) was 20.3 months (0.2-37.0 months). For primary mutation analysis, it was found that SDH-deficient patients had longer mPFS (29.1 months) than those with mutations in exon 9 or exon 11 (5.4 and 4.8 months, respectively; P= 0.013). In terms of secondary mutations, patients with activation loop mutations (exon 17+18) showed both longer mPFS (7.3 months vs 1.9 months, P= 0.001) and longer mOS (20.3 months vs 7.7 months, P= 0.059) than those patients with non-activation loop mutations. Not any specific or new adverse reaction was found in all patients. By Cox-regression analysis, response to regorafenib and mutational status were independent predictors of PFS，response to regorafenib was also an independent predictor of OS. Conclusions: Regorafenib seems to have better treatment efficacy in GIST patients with SDH deficiency compared to those with primary KIT mutations, and better with secondary mutations in activation loop than those with non-activation loop mutations. It is necessary to carry out clinical research for later-line treatment choice based on different genotypes for imatinib-resistant GISTs.