Eculizumab precision dosing algorithm for thrombotic microangiopathy in children and young adults undergoing HSCT

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal post-transplant complication of hematopoietic stem cell transplantation (HSCT). We recently reported that survival for TA-TMA has been improved by early intervention with eculizumab, a complement C5 inhibitor, guided by pharmacokinetic/pharmacodynamic (PK/PD) model-informed precision dosing. However, patients with gastrointestinal (GI) bleeding showed poor survival even when treated with more frequent dosing. Our objective was to develop separate models in bleeding and non-bleeding TA-TMA patients and propose precision dosing algorithms. Eculizumab PK/PD were analyzed in 19 bleeding and 38 non-bleeding patients (0.5-29.9 years). A complement activation biomarker (sC5b-9) and bodyweight were identified as significant determinants of eculizumab clearance regardless of bleeding. Eculizumab clearance after the first dose was higher in bleeding patients than in non-bleeding patients (83.8 vs. 61.3 mL/h/70kg, p=0.07). The high clearance was maintained over treatment doses in bleeding patients, whereas non-bleeding patients showed a time-dependent decrease in clearance. sC5b-9 levels were highest before the first dose and decreased over time regardless of bleeding complications. A Monte Carlo Simulation analysis showed that the current dosing protocols recommended for aHUS had less than 15% probability of eculizumab target concentration attainment of >100 g/mL in non-bleeding patients. This study identified an intensified loading protocol to reach 80% target attainment. Our data clearly showed the need for individualized dosing for patients with significant bleeding, and for ongoing dose adjustments to optimize outcomes. The developed models will be incorporated into a clinical decision support for precision dosing to improve outcomes in children and young adults with TA-TMA.

Combination of pharmacokinetic and pathogen susceptibility information to optimize meropenem treatment of gram-negative infections in critically ill patients

Background: Meropenem is one of the most frequently used antibiotics to treat life-threatening infections in critically ill patients. This study aimed to develop a meropenem dosing algorithm for the treatment of gram-negative infections based on intensive care unit (ICU)-specific resistance data. Methods: Antimicrobial susceptibility testing of gram-negative bacteria obtained from critically ill patients was carried out from 2016 to 2020 at a tertiary care hospital. Based on the observed minimal inhibitory concentration (MIC) distribution, stochastic simulations (n=1000) of an evaluated pharmacokinetic meropenem model and a defined pharmacokinetic/pharmacodynamic target (100%T >4xMIC while minimum concentrations <44.5 mg/L), dosing recommendations for patients with varying renal function were derived: Pathogen-specific MIC distributions were used to calculate the cumulative fraction of response (CFR) and the overall MIC distribution was used to calculate the local pathogen-independent mean fraction of response (LPIFR) for the investigated dosing regimens. A CFR/LPIFR >90% was considered adequate. Results: The observed MIC distribution significantly differed from the EUCAST database. Based on the 6520 MIC values included, a three-level dosing algorithm was developed. If the pathogen causing the infection is unknown (level 1), known (level 2), known to be neither Pseudomonas aeruginosa nor Acinetobacter baumannii or classified as susceptible (level 3), a continuous infusion of 1.5 g daily reached sufficient target attainment independent of renal function. In all other cases dosing needs to be adjusted based on renal function. Conclusion: ICU-specific susceptibility data should be assessed regularly and integrated into dosing decisions. The presented workflow may serve as a blueprint for other antimicrobial settings. (250 words)

Development of a system to support warfarin dose decisions using deep neural networks

The first aim of this study was to develop a prothrombin time international normalized ratio (PT INR) prediction model. The second aim was to develop a warfarin maintenance dose decision support system as a precise warfarin dosing platform. Data of 19,719 inpatients from three institutions was analyzed. The PT INR prediction algorithm included dense and recurrent neural networks, and was designed to predict the 5th-day PT INR from data of days 1–4. Data from patients in one hospital (n = 22,314) was used to train the algorithm which was tested with the datasets from the other two hospitals (n = 12,673). The performance of 5th-day PT INR prediction was compared with 2000 predictions made by 10 expert physicians. A generator of individualized warfarin dose-PT INR tables which simulated the repeated administration of varying doses of warfarin was developed based on the prediction model. The algorithm outperformed humans with accuracy terms of within ± 0.3 of the actual value (machine learning algorithm: 10,650/12,673 cases (84.0%), expert physicians: 1647/2000 cases (81.9%), P = 0.014). In the individualized warfarin dose-PT INR tables generated by the algorithm, the 8th-day PT INR predictions were within 0.3 of actual value in 450/842 cases (53.4%). An artificial intelligence-based warfarin dosing algorithm using a recurrent neural network outperformed expert physicians in predicting future PT INRs. An individualized warfarin dose-PT INR table generator which was constructed based on this algorithm was acceptable.

Acenocoumarol Pharmacogenetic Dosing Algorithm versus Usual Care in Patients with Venous Thromboembolism: A Randomised Clinical Trial

Patients with venous thromboembolism (VTE) require immediate treatment with anticoagulants such as acenocoumarol. This multicentre randomised clinical trial evaluated the effectiveness of a dosing pharmacogenetic algorithm versus a standard-of-care dose adjustment at the beginning of acenocoumarol treatment. We included 144 patients with VTE. On the day of recruitment, a blood sample was obtained for genotyping (CYP2C9*2, CYP2C9*3, VKORC1, CYP4F2, APOE). Dose adjustment was performed on day 3 or 4 after the start of treatment according to the assigned group and the follow-up was at 12 weeks. The principal variable was the percentage of patients with an international normalised ratio (INR) within the therapeutic range on day 7. Thirty-four (47.2%) patients had an INR within the therapeutic range at day 7 after the start of treatment in the genotype-guided group compared with 14 (21.9%) in the control group (p = 0.0023). There were no significant differences in the time to achieve a stable INR, the number of INRs within the range in the first 6 weeks and at the end of study. Our results suggest the use of a pharmacogenetic algorithm for patients with VTE could be useful in achieving target INR control in the first days of treatment.

Population Pharmacokinetics and Dose Optimization of Ceftazidime and Imipenem in Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Background: Ceftazidime and imipenem have been increasingly used to treat Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) due to their extended-spectrum covering Pseudomonas aeruginosa. This study aims to describe the population pharmacokinetic (PK) and pharmacodynamic (PD) target attainment for ceftazidime and imipenem in patients with AECOPD. Methods: We conducted a prospective PK study at Bach Mai Hospital (Viet Nam). A total of 50 (ceftazidime) and 44 (imipenem) patients with AECOPD were enrolled. Population PK analysis was performed using Monolix 2019R1 and Monte Carlo simulations were conducted to determine the optimal dose regimen with respect to the attainment of 60% and 40% fT>MIC for ceftazidime and imipenem, respectively. A dosing algorithm was developed to identify optimal treatment doses. Results: Ceftazidime and imipenem PK was best described by a one-compartment population model with a volume of distribution and clearance of 23.7 L and 8.74 L/h for ceftazidime and 15.1 L and 7.88 L/h for imipenem, respectively. Cockcroft–Gault creatinine clearance represented a significant covariate affecting the clearance of both drugs. Increased doses with prolonged infusion were found to cover pathogens with reduced susceptibility. Conclusions: This study describes a novel and versatile three-level dosing algorithm based on patients’ renal function and characteristic of the infective pathogen to explore ceftazidime and imipenem optimal regimen for AECOPD.

Low risk of OHSS with follitropin delta use in women with different polycystic ovary syndrome phenotypes: a retrospective case series

Background To explore the efficacy of follitropin delta in ovarian stimulation of patients with the Rotterdam ESHRE/ASRM 2003 phenotypes of polycystic ovarian syndrome (PCOS) using a retrospective case series with an electronic file search in a reproductive medicine clinic. Case presentation Seventy-four patients with PCOS undergoing ovarian stimulation according to the individualized dosing algorithm of follitropin delta for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI)/oocyte freezing were included. Follitropin delta resulted in a high number of pre-ovulatory follicles at the end of stimulation as expected in patients with PCOS. There was a large number of oocytes retrieved with an acceptable percentage of metaphase II (MII) oocytes. There were no cases of moderate or severe OHSS across all phenotypes. Conclusion Follitropin delta, using the individualized dosing algorithm, appears to be a safe method of ovarian stimulation with a low risk of OHSS in PCOS patients without sacrificing successful stimulation outcomes.

Plasma imatinib levels and ABCB1 polymorphism influences early molecular response and failure-free survival in newly diagnosed chronic phase CML patients

Achieving early molecular response (EMR) has been shown to be associated with better event free survival in patients with chronic phase chronic myeloid leukemia (CP-CML) on Imatinib therapy. We prospectively evaluated the factors influencing the 2-year failure free survival (FFS) and EMR to imatinib therapy in these patients including day29 plasma Imatinib levels, genetic variants and the gene expression of target genes in imatinib transport and biotransformation. Patients with low and intermediate Sokal score had better 2-year FFS compared to those with high Sokal Score (p = 0.02). Patients carrying ABCB1-C1236T variants had high day29 plasma imatinib levels (P = 0.005), increased EMR at 3 months (P = 0.044) and a better 2 year FFS (P = 0.003) when compared to those with wild type genotype. This translates to patients with lower ABCB1 mRNA expression having a significantly higher intracellular imatinib levels (P = 0.029). Higher day29 plasma imatinib levels was found to be strongly associated with patients achieving EMR at 3 months (P = 0.022), MMR at 12 months (P = 0.041) which essentially resulted in better 2-year FFS (p = 0.05). Also, patients who achieved EMR at 3 months, 6 months and MMR at 12 months had better FFS when compared to those who did not. This study suggests the incorporation of these variables in to the imatinib dosing algorithm as predictive biomarkers of response to Imatinib therapy.