Dependent and independent variables may appear uncorrelated when analyzed in full range in medical data. However, when an independent variable is divided by the cutoff value, the dependent and independent variables may become correlated in each group. Furthermore, researchers often convert independent variables of quantitative data into binary data by cutoff value and perform statistical analysis with the data. Therefore, it is important to select the optimum cutoff value since performing statistical analysis depends on the cutoff value. Our study determines the optimal cutoff value when the data of dependent and independent variables are quantitative. The piecewise linear regression analysis divides an independent variable into two by the cutoff value, and linear regression analysis is performed in each group. However, the piecewise linear regression analysis may not obtain the optimal cutoff value when data follow a non-normal distribution. Unfortunately, medical data often follows a non-normal distribution. We, therefore, performed theWilcoxon-Mann-Whitney (WMW) test with two-sided for all potential cutoff values and adopted the cutoff value that minimizes the P-value (called minimum P-value approach). Calculating the cutoff value using the minimum P-value approach is often used in the log-rank and chi-squared test but not the WMW test. First, using Monte Carlo simulations at various settings, we verified the performance of the cutoff value for the WMW test by the minimum P-value approach. Then, COVID-19 data were analyzed to demonstrate the practical applicability of the cutoff value.

Since trimethoprim (TMP) dose-dependently inhibits the excretion of potassium, a population kinetic-pharmacodynamic analysis was performed to establish an adequate dosing schedule and characterize factors of hyperkalaemia. Dataset was constructed using a retrospective observational cohort of hospitalized patients (>18 years) with oral sulfamethoxazole/trimethoprim formulation. The model integrated a kinetic model for TMP, a urinary TMP concentrationresponse curve and a kinetic model for serum potassium using an indirect response model. The model was a function of body weight, renal function, serum potassium levels and TMP dosing schedule. We evaluated covariates by the stepwise forward and backward selection methods. The Monte Carlo simulation determined the probability of hyperkalaemia (>5.5 or >6.0 meq/L) according to the dosing schedule, renal function and covariates. This study included 317 patients [age 62 (42-72) years] with 4359 serum potassium levels.The significant covariate was non-steroidal anti-inflammatory drugs (NSAIDs), with a 72.3% reduction in 50% inhibitory concentration. Monte Carlo simulation revealed that high-dose TMP (400 mg thrice daily) co-administered with NSAIDs led to mild hyperkalaemia (>10%) and severe hyperkalaemia (approximately 5%), regardless of renal function. In conclusion, clinicians should pay attention to hyperkalaemia with TMP high-dose and co-administered NSAIDs.

Background Phenobarbital (PB) is commonly used as elixir and powder formulations in pediatric care. Its dose adjustment is performed based on individual drug concentration monitoring. Few studies have comprehensively analyzed the variation factors for serum PB concentration. In this study, we retrospectively investigated the factors that influence serum PB concentration and assessed the impacts of dosage formulation and administration route. Methods This retrospective cohort study covered clinical data from January 2007 to September 2019 at Mie University Hospital. The present study included 60 pediatric patients administered the elixir and powder of PB through oral route and enteral tube. Simple and multiple linear regression analyses were performed to identify the risk factors that affect the weight-corrected PB serum concentration/dose (C/D) ratio in pediatric patients. Six subgroups were also established according to the concomitant use of drugs that potentially inhibit PB metabolism, dosage formulation, and administration route to investigate the difference in the PB C/D ratio among the subgroups. Results A significant regression equation to predict the PB C/D ratio was found through simple and multiple linear regression analyses, with an adjusted coefficient of determination of 0.53 (p < 0.001). Further, the concomitant uses of valproic acid (VPA) or amiodarone, which were the only two drugs seen in this study as potential inhibitors of PB, was found to have the greatest effect on the PB C/D ratio (standardized partial regression coefficient (β) = 0.543, p < 0.001). Furthermore, a significant difference in the PB C/D ratio was found between the subgroups classified by the concomitant use of VPA or amiodarone (p = 0.002). However, there were no significant correlations between the PB C/D ratio, dosage formulation, and administration route. Conclusions The most influential factor on the PB C/D ratio was the concomitant use of VPA or amiodarone with PB. This result could provide an important perspective in pediatric drug therapy where elixir and powder formulations are administered via the oral route and enteral tube.

Purpose: Anemia is one of the dose-limiting toxicities of olaparib. The global phase trial con rmed that anemia occurrence in Japanese was relatively high. The factors related to anemia in different nationalities remain unknown. Therefore, this study investigated the factors of olaparib-related anemia in real-world settings using an adverse event reporting system database.Methods: We used data from FDA Adverse Events Reporting System (FAERS) and Japanese Adverse Drug Event Report database (JADER) between 2018 and 2021. FAERS reports from Japan were collected to conduct subgroup analyses, which was de ned as FAERS-Japan. The endpoint was the occurrence of olaparib-related anemia. Disproportionality analysis was conducted to calculate reporting odds ratio (ROR), with a con dence interval of 95%. Adjusted ROR (aROR) was calculated to control for gender differences.Results: In FAERS and JADER, the daily olaparib dose per body weight (DPBW) ≥12 mg/kg was detected to be a positive signal for anemia occurrence (aROR; FAERS, p<0.001, p=0.009, and JADER,], p=0.034). Furthermore, FAERS reports con rmed that females with body weight <50kg, reports from Japan, concomitant use of drugs suppressing vitamin B 12 , and previous platinum treatment history were positive signals of olaparib-related anemia. FAERS-Japan also showed that body weight <50kg and previous platinum treatment history were positive signals for the anemia occurrence. Conclusion: High DPBW poses a signi cant risk of anemia. The co-administration of drugs suppressing vitamin B 12 and previous platinum treatment history are also important information to evaluate the risk of olaparib-related anemia.