Pharmacokinetics and Adverse Effects of Clofazimine in the Treatment of Pulmonary Non-Tuberculous Mycobacterial Infection.

Clofazimine (CFZ) is used to treat pulmonary non-tuberculous mycobacterial (NTM) infection; however, its pharmacokinetics remain unexplored in patients with pulmonary NTM, and the relationship between CFZ serum concentration and adverse effects has not been investigated. The objectives of this study were to characterize the pharmacokinetics of CFZ in pulmonary NTM disease treatment and to investigate the relationship between the steady-state CFZ serum concentration and adverse effects. A prospective observational study was conducted on 45 patients with pulmonary NTM treated with CFZ (UMIN000041053). A maximum of five serum samples per patient were taken at the CFZ trough, and serum concentration was measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). The pharmacokinetics of CFZ were analyzed using a nonlinear mixed effect model. The relationships among steady-state CFZ serum concentration and adverse effects, pigmentation, and heart rate-corrected QT (QTc) interval were investigated. Twenty-six patients had M. avium or M. intracellulare infection and nineteen had M. abscessus infection. The primary CFZ dosage was 50 mg/day. The estimated apparent CFZ clearance, apparent volume of distribution, and half-life were 2.4 L/h, 2,960 L, and 36 days, respectively. The combined use of rifampicin and CFZ significantly reduced CFZ exposure by 22%. Although there was no relationship between CFZ serum concentration and pigmentation intensity, the QTc interval was significantly correlated with CFZ serum concentration. The estimation of accurate pharmacokinetics for CFZ required approximately 5 months of monitoring. The relationship between the serum concentration and specific adverse effects of CFZ confirmed that CFZ serum concentration was not associated with pigmentation but did affect the QTc interval.

Low-dosage ethambutol, less than 12.5 mg/kg/day, does not worsen the clinical outcomes of pulmonary Mycobacterium avium and Mycobacterium intracellulare disease: a retrospective cohort study.

OBJECTIVES: Multidrug chemotherapy is recommended for treating pulmonary Mycobacterium avium and Mycobacterium intracellulare disease. Although ethambutol has been demonstrated to inhibit macrolide resistance, the ethambutol dosage is sometimes decreased due to concerns about optic neuropathy. We aimed to assess whether lower ethambutol doses impact treatment outcomes. METHODS: Patients treated over 12 months between 2016 and 2020 were collected retrospectively. Clinical outcomes, including negative culture conversion, microbiological cure, adverse events, resistance to macrolides, and recurrence, were compared according to daily ethambutol dosage. RESULTS: Among 146 patients, 42 were treated with ethambutol dosages over 12.5 mg/kg/day, and 104 were treated with lower dosages. Negative culture conversion was achieved for 125 patients, and 90 patients achieved microbiological cure. Recurrence was identified in 16 patients who achieved microbiological cure. No macrolide resistance was observed, and no significant difference was observed in the percentage of negative culture conversion (P = 1.00) or microbiological cure (P = 0.67) between the high- and low-dosage ethambutol groups. Sputum smear positivity was associated with a lower adjusted odds ratio (aOR) of negative culture conversion (aOR: 0.48, 95% CI: 0.29-0.80). A lower aOR of microbiological cure was independently associated with sputum smear positivity (aOR: 0.52, 95% CI: 0.37-0.74) and with the use of an intermittent regimen (aOR: 0.60, 95% CI: 0.41-0.87). Daily ethambutol dosage was not identified as a prognostic factor for any of the outcomes. Optic neuropathy was observed in 7.1% of the high-dose ethambutol group and 1.0% of the low-dosage ethambutol group (P = 0.07). CONCLUSION: An ethambutol dosage of 12.5 mg/kg/day or less in guideline-based chemotherapy may reduce optic neuropathy without worsening clinical outcomes.

Population Pharmacokinetic Model of Amiodarone and N-Desethylamiodarone Focusing on Glucocorticoid and Inflammation.

Some population pharmacokinetic models for amiodarone (AMD) did not incorporate N-desethylamiodarone (DEA) concentration. Glucocorticoids activate CYP3A4 activity, metabolizing AMD. In contrast, CYP3A4 activity may decrease under inflammation conditions. However, direct evidence for the role of glucocorticoid or inflammation on the pharmacokinetics of AMD and DEA is lacking. The pilot study aimed to address this gap using a population pharmacokinetic analysis of AMD and DEA. A retrospective cohort observational study in adult patients who underwent AMD treatment with trough concentration measurement was conducted at Tokyo Women's Medical University, Medical Center East from June 2015 to March 2019. Both structural models of AMD and DEA applied 1-compartment models, which included significant covariates using a stepwise forward selection and backward elimination method. The eligible 81 patients (C-reactive protein level: 0.26 [interquartile range; 0.09-1.92] mg/dL) had a total of 408 trough concentrations for both AMD and DEA. The median trough concentrations were 0.49 [0.31-0.81] µg/mL for AMD and 0.43 [0.28-0.71] µg/mL for DEA during a median follow-up period of 446 [147-1059] d. Three patients received low-dose oral glucocorticoid. The final model identified that AMD clearance was 7.9 L/h, and the apparent DEA clearance was 10.3 L/h. Co-administered glucocorticoids lowered apparent DEA clearance by 35%. These results indicate that co-administered glucocorticoids may increase DEA concentrations in patients without severe inflammation.

Population Pharmacokinetic Analysis and Dose Regimen Optimization in Japanese Infants with an Extremely Low Birth Weight.

Vancomycin is a synthetic antibiotic effective against Gram-positive pathogens. Although the clinical applicability of vancomycin for infants has been increasing, the pharmacokinetic data for vancomycin in extremely low-birth-weight infants are limited. The aim of this study was to construct a population pharmacokinetics model for vancomycin in extremely-low-birth-weight infants and establish an optimal dosage regimen. We enrolled children aged less than 1 year with a birth weight of less than 1,000 g and body weight at vancomycin prescription of less than 1,500 g. Pharmacokinetic data from 19 patients were analyzed, and a population pharmacokinetics model was developed using nonlinear mixed-effects modeling software. Goodness-of-fit plots, a nonparametric bootstrap analysis, and a prediction-corrected visual predictive check were employed to evaluate the final model. The dosage regimen was optimized based on the final model. The pharmacokinetic data fit a one-compartment model with first-order elimination, and body weight and estimated serum creatinine level were used as significant covariates. In a simulation using the final model, the optimal dosage regimen, especially when the serum creatinine level (>0.6 mg/dl) was high, was 5.0 to 7.5 mg/kg of body weight twice a day every 12 h; this was required to reduce the dosage compared with that in previous studies. The recommended doses based on the current target time course concentration curves may not be appropriate for extremely-low-birth-weight infants.

Effect of high-dose sulfamethoxazole/trimethoprim and glucocorticoid use on hyperkalemic event: A retrospective observational study.

INTRODUCTION: Sulfamethoxazole/trimethoprim causes hyperkalemia; however, the effect of sulfamethoxazole/trimethoprim dose and co-administered glucocorticoids on hyperkalemia has not been clarified. METHODS: This single-center, retrospective, observational cohort, chart review study involving patients (>20 years) who were treated with sulfamethoxazole/trimethoprim was conducted at Tokyo Women's Medical University, Medical Center East from June 2015 to May 2019. Multivariate Cox proportional hazard model was used to identify risk factors for hyperkalemia (serum potassium level > 5.5 mEq/L). Additionally, Kaplan-Meier curve analyzed the cumulative incidence of hyperkalemia focusing on sulfamethoxazole/trimethoprim dose and concomitant use of glucocorticoids with mineralocorticoid activity. RESULTS: Among 333 patients, 44 (13%) patients developed hyperkalemia associated with sulfamethoxazole/trimethoprim use for over 49 (interquartile range; 17-233) days. We found associations between the time to hyperkalemia development and sulfamethoxazole/trimethoprim dose (hazard ratio 1.238, 95% confidence interval 1.147-1.338, p < 0.001) and glucocorticoid use (hazard ratio 0.678, 95% confidence interval 0.524-0.877, p = 0.003). Interestingly, the Kaplan-Meier curves revealed that the concomitant use of glucocorticoids did not attenuate the risk of hyperkalemia in patients receiving high-dose sulfamethoxazole/trimethoprim (p = 0.747), whereas concomitant use of glucocorticoids significantly reduced the risk of hyperkalemia in patients receiving non-high dose sulfamethoxazole/trimethoprim (p < 0.001). CONCLUSIONS: High-dose sulfamethoxazole/trimethoprim is a significant predictor of hyperkalemia. The effect of glucocorticoids on hyperkalemia varies depending on the sulfamethoxazole/trimethoprim dose.

Minocycline prevents and repairs the skin disorder associated with afatinib, one of the epidermal growth factor receptor-tyrosine kinase inhibitors for non-small cell lung cancer.

BACKGROUND: While epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) exert a breakthrough effect, the incidence of skin disorders as a side effect has significantly reduced patients' quality of life. This study aimed to develop a treatment for inflammatory ulcers as one of the side effects of afatinib (Giotrif®), a second-generation EGFR-TKI, and established a skin disorder mouse model to investigate the protective effect of minocycline. METHODS: First, under inhalation anesthesia with isoflurane, the back of a male ddy mouse was shaved, and afatinib petrolatum was applied alone or in combination with minocycline to observe the state of the skin and measure transepidermal water transpiration (TEWL). Next, afatinib was administered orally to mice, and minocycline petrolatum was applied to observe whether the skin disorder was prevented and its effect on repair of the skin disorder. RESULTS: Skin injury occurred on the back of the mouse following afatinib (1 mg/g in petrolatum) application, and scab formation was observed. Application of minocycline prevented and improved the skin disorder caused by afatinib. When the minocycline-petrolatum mixture was applied to the mouse that developed the skin disorder, a significant improvement in TEWL was observed, and skin repair was observed macroscopically. CONCLUSIONS: These results suggest that minocycline petrolatum applied locally prevents and repairs afatinib-induced skin disorders of non-small cell lung cancer patients. Histological examination of skin has provided insights into the mechanism of the occurrence of afatinib-related skin disorder and suggested the efficacy of minocycline topical application in clinical practice.

Effects of overweight and underweight on the treatment outcomes of rheumatoid arthritis patients treated with biological drugs: A retrospective observational descriptive study.

WHAT IS KNOWN AND OBJECTIVE: The effects of the body size condition (overweight and underweight) on the outcome of antirheumatic drugs are unclear. The aim of this study was to elucidate the relationship between body size and treatment outcomes in rheumatoid arthritis patients treated with biological antirheumatic drugs. METHODS: A retrospective observational descriptive study was conducted at Tokyo Women's Medical University, Medical Center East, from June 2015 to May 2018. Primary and secondary outcomes were defined as antirheumatic treatment ineffectiveness and antirheumatic treatment discontinuation due to any side effects, respectively. Multivariate logistic regression analysis was used to determine the risk factors for the outcomes and to calculate the odds ratio (OR) and the 95% confidence interval (95% CI). RESULTS AND DISCUSSION: A total of 297 patients were included. Primary and secondary outcomes were observed in 42 (14%) and 11 (4%) of the patients, respectively. Multivariate logistic regression analysis demonstrated that a body mass index (BMI) ≥25 kg/m2 (OR = 4.22, 95% CI; 1.69-10.5, P = .002) was associated with rheumatoid arthritis treatment ineffectiveness and that BMI <18.5 kg/m2 (OR = 5.87, 95% CI; 1.25-27.5, P = .025) and tacrolimus use (OR = 9.06, 95% CI; 1.37-60.1, P = .022) were associated with antirheumatic treatment discontinuation due to any side effects. The cut-off dose for tacrolimus was 0.5 mg/day. WHAT IS NEW AND CONCLUSION: Overweight affects antirheumatic drug efficacy. Underweight and tacrolimus use increased the discontinuation of antirheumatic drugs due to side effects. A validation study is needed to confirm the reliability of these results.

Correction to: Risk factors for vancomycin nephrotoxicity and time course of renal function during vancomycin treatment.

After online publication, we found a typographical error in Table 2. We consider correcting "VCM trough concentration > 20 g/mL" to "VCM trough concentration > 20 µg/mL".

Risk factors for vancomycin nephrotoxicity and time course of renal function during vancomycin treatment.

PURPOSE: Vancomycin (VCM) is used for the treatment of methicillin-resistant Staphylococcus aureus. Although the risk factors for VCM nephrotoxicity have been evaluated, the time course of renal function during VCM treatment is unknown. We assessed risk factors for VCM nephrotoxicity and how renal function varied over time. METHODS: We conducted a retrospective analysis of patients receiving intravenous VCM treatment between June 2015 and August 2017 at Tokyo Women's Medical University, Medical Center East. VCM nephrotoxicity was defined as an increase in serum creatinine levels > 50%. We performed multivariate logistic regression analysis to assess risk factors for VCM nephrotoxicity. The time course of renal function with VCM nephrotoxicity was compared and stratified by risk factors for VCM nephrotoxicity. Clinical course of VCM nephrotoxicity and VCM trough concentration were assessed. RESULTS: In total, 42 (17.3%) of 243 patients developed VCM nephrotoxicity. Risk factors for VCM nephrotoxicity were VCM trough concentration > 20 µg/mL and concomitant use of renal hypoperfusion medications (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, loop/thiazide diuretics, and non-steroidal anti-inflammatory drugs). Although time course of renal function stratified by renal hypoperfusion medications was comparable, the time course of renal function significantly deteriorated in patients with loop/thiazide diuretics. Focusing on patients continuing VCM treatment, VCM nephrotoxicity recovered in 40% of the patients and VCM trough concentration improved to 10-20 µg/mL in 75% of the patients. CONCLUSIONS: VCM trough concentration > 20 µg/mL and concomitant use of renal hypoperfusion medications are associated with VCM nephrotoxicity. Recovery of VCM nephrotoxicity was poor compared to the improvement of VCM trough concentration.

Population pharmacokinetics and pharmacodynamics of fondaparinux in Japanese patients after artificial total knee replacement
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OBJECTIVE: This study was designed to clarify the factors affecting the efficacy, adverse events, and pharmacokinetics of fondaparinux in Japanese patients undergoing artificial knee replacement surgery. MATERIALS AND METHODS: Fondaparinux (1.5 mg/d) was administered subcutaneously to patients (n = 30) at 24 hours after surgery, and blood samples were taken at various time points thereafter. Venous thromboembolism (VTE), presence of bleeding, and pharmacokinetics were evaluated. Multivariate analysis and population pharmacokinetic analysis were performed to detect factors that necessitated withdrawal of fondaparinux and individual differences in its pharmacokinetics. RESULTS: VTE was observed in 9 patients (3 for whom administration was continued and 6 for whom withdrawal was necessary). The maximum plasma concentration of fondaparinux was found to be a significant factor determining withdrawal of the drug. Population pharmacokinetic analysis demonstrated that individual renal function and body weight were significant factors associated with apparent clearance and volume of distribution, respectively. CONCLUSIONS: A high maximum plasma concentration of fondaparinux may result in subcutaneous hemorrhage, necessitating withdrawal of fondaparinux administration. The patient's kidney function and body weight also contribute to individual differences in pharmacokinetics. We recommend considering an adjustment to the dose of fondaparinux based on body weight in patients undergoing artificial knee replacement surgery.
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A quantitative LC/MSMS method for determination of edoxaban, a Xa inhibitor and its pharmacokinetic application in patients after total knee arthroplasty.

Edoxaban was extracted from human plasma by simple protein precipitation with acetonitrile, followed by quantitative determination using a liquid chromatography-mass spectrometry method. The recoveries of edoxaban and the internal standard (ticlopidine) from human plasma were >85%, and the within- and between-day coefficients of variation were within 15%. The limit of quantification in human plasma was 1 ng/mL. The concentration of edoxaban in blood decreased at room temperature, but remained unchanged for 1 week at 4°C. On the other hand, the concentration in plasma at both -20 and -80°C remained unchanged for 5 months. These results indicated that blood samples should be centrifuged immediately or stored at 4°C, and that plasma samples should be stored below -20°C until analysis. This method was applied to human plasma obtained from four patients after total knee arthroplasty. Analysis of edoxaban pharmacokinetics demonstrated an absorption time lag of 4h, a maximum concentration of 110 ± 26 ng/mL and an oral clearance of 37 ± 16 L/h. The analytical methods established in this study will be suitable for determining the concentrations of edoxaban in human plasma.

Evaluation of pharmacokinetics, safety, and efficacy of [211At] meta-astatobenzylguanidine ([211At] MABG) in patients with pheochromocytoma or paraganglioma (PPGL): A study protocol.

BACKGROUND: Pheochromocytoma, or paraganglioma (PPGL), is a tumor that arises from catecholamine-producing chromaffin cells of the adrenal medulla or paraganglion. Systemic therapy, such as the combination of cyclophosphamide, vincristine, and dacarbazine or therapeutic radiopharmaceuticals such as [131I] meta-iodobenzylguanidine (MIBG), may be administered in cases of locally advanced tumors or distant metastases. However, the current therapies are limited in terms of efficacy and implementation. [211At] meta-astatobenzylguanidine (MABG) is an alpha-emitting radionuclide-labeled ligand that has demonstrated remarkable tumor-reducing effects in preclinical studies, and is expected to have a high therapeutic effect on pheochromocytoma cells. METHODS: We are currently conducting an investigator-initiated first-in-human clinical trial to evaluate the pharmacokinetics, safety, and efficacy of [211At] MABG. Patients with locally unresectable or metastatic PPGL refractory to standard therapy and scintigraphically positive [123I] MIBG aggregation are being recruited, and a 3 + 3 dose escalation design was adopted. The initial dose of [211At] MABG is 0.65 MBq/kg, with a dose escalation in a 1:2:4 ratio in each cohort. Dose-limiting toxicity is observed for 6 weeks after a single bolus dose of [211At] MABG, and the patients are observed for 3 months to explore safety and efficacy profiles. The primary endpoint is dose-limiting toxicity to determine both maximum tolerated and recommended doses. The secondary endpoints include radiopharmacokinetics, urinary radioactive excretion rate, urinary catecholamine response rate, objective response rate, progression free survival, [123I] MIBG scintigraphy on reducing tumor accumulation, and quality of life. TRIALS REGISTRATION: jRCT2021220012 registered on 17 June 2022.

Clofazimine serum concentration and safety/efficacy in nontuberculous mycobacterial pulmonary disease treatment.

BACKGROUND: Clofazimine (CFZ) has shown promising effects against Mycobacterium avium-intracellulare complex pulmonary disease (MAC-PD) and Mycobacterium abscessus species pulmonary disease (MABS-PD). However, the optimal CFZ dose remains unknown. We aimed to explore the relationship between steady-state CFZ concentration and its safety and efficacy in MAC-PD and MABS-PD. METHODS: This prospective observational study focused on patients with MAC-PD and MABS-PD treated with CFZ (UMIN 000041053). To understand the safety and efficacy profile of CFZ and elucidate its optimal concentration, we analyzed CFZ-induced pigmentation grade, QTc interval, and culture conversion outcomes in relation to serum CFZ concentration using Student's t-test, a concentration-QTc model, and multivariable logistic regression analysis, respectively. In total, 64 patients (34 with MAC-PD; 30 with MABS-PD) were included. RESULTS: The steady-state concentration of CFZ was higher in the moderate-to-severe pigmentation group than in the none-to-light pigmentation group (P < 0.001). At a CFZ concentration of 1 mg/L, the QTc interval was prolonged by 17.3 ms (95 % confidence interval [CI], 3.9-25.4) from baseline. Culture conversion was achieved in 33 (51.6 %) patients. The only significant predictor of culture conversion was surgery (adjusted odds ratio, 5.4; 95 % CI, 1.3-38.0). CFZ concentration and MIC of CFZ less than 0.25 mg/L were not associated with culture conversion in this study. CONCLUSION: CFZ-induced pigmentation and QT interval prolongation are associated with serum CFZ concentrations. CFZ dosage may be optimized by monitoring serum CFZ concentration.

Assessing Clinical Outcomes of Vancomycin Treatment in Adult Patients with Vancomycin-Susceptible Enterococcus faecium Bacteremia.

PURPOSE: Enterococcal bacteremia is associated with high mortality and long-term hospitalization. Here, we aimed to investigate the clinical outcomes and evaluate the risk factors for mortality in adult patients treated with vancomycin (VCM) for vancomycin-susceptible Enterococcus faecium (E. faecium) bacteremia. METHODS: This is a retrospective, record-based study. The data were collected from inpatients at a single university hospital between January 2009 and December 2020. The area under the curve (AUC) of VCM was calculated using the Bayesian approach. The primary outcome was a 30-day in-hospital mortality. RESULTS: A univariate analysis showed significant differences in the concomitant use of vasopressors, history of the use of no clinically relevant activity antimicrobial agents against E. faecium, VCM plasma trough concentration, and renal dysfunction during VCM administration between the 30-day in-hospital mortality and survival groups. However, the groups' AUC/minimum inhibitory concentration (MIC) were not significantly different. A multivariate analysis suggested that concomitant vasopressors may be an independent risk factor for 30-day in-hospital mortality (odds ratio, 7.81; 95% confidence interval, 1.16-52.9; p = 0.035). The VCM plasma trough concentrations and the AUC/MIC in the mortality group were higher than those in the surviving group. No association between the AUC/MIC and the treatment effect in E. faecium bacteremia was assumed, because the known, target AUC/MIC were sufficiently achieved in the mortality group. CONCLUSIONS: There may be no association between the AUC/MIC and the treatment effect in E. faecium bacteremia. When an immunocompromised host develops E. faecium bacteremia with septic shock, especially when a vasopressor is used in a patient with unstable hemodynamics, it may be difficult to treat it, despite efforts to ensure the appropriate AUC/MIC and therapeutic vancomycin concentration levels.

Physiologically based pharmacokinetic modeling of ponatinib to describe drug-drug interactions in patients with cancer.

PURPOSE: This study aimed to investigate the drug-drug interactions of ponatinib with strong, moderate, or weak CYP3A4 inhibitors/inducers by developing physiologically based pharmacokinetic (PBPK) models. METHODS: Simcyp® Ver 20.1 (Certara Inc., Sheffield, UK) was used to construct a PBPK model for ponatinib and to predict its interaction with strong, moderate, or weak CYP3A4 inhibitors/inducers. The constructed model was validated by comparing predicted values with actual observed values. Inhibitors or inducers that increased or decreased the area under the plasma concentration curve of ponatinib by more than two-fold when used in combination were considered significant. RESULTS: The PBPK model of ponatinib accurately represented its oral pharmacokinetics. It also reasonably predicted its pharmacokinetics when combined with ketoconazole and rifampicin. No weak to strong CYP3A4 inhibitor combinations significantly increased the AUC of ponatinib. However, the strong CYP3A4 inducers rifampicin (oral, 600 mg QD) and phenytoin (oral, 100 mg TID) decreased AUC by 60-70% and 50%, respectively. CONCLUSIONS: The PBPK model predicted a significant drug interaction when ponatinib was combined with a strong CYP3A4 inducer. Conversely, the combination with weak-to-strong CYP3A4 inhibitors did not suggest a drug interaction with ponatinib.

Population kinetic-pharmacodynamic analysis of serum potassium in patients receiving sulfamethoxazole/trimethoprim.

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 concentration-response 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.

Genome-wide analysis identify novel germline genetic variations in ADCY1 influencing platinum-based chemotherapy response in non-small cell lung cancer.

To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P < 1 × 10-3 in cohort 1 discovery stage, of which 3 SNPs were verified in 262 independent samples. A total of 541 SNPs were significant at P < 1 × 10-4 in cohort 2 discovery stage, of which 8 SNPs were verified in 347 independent samples. Comparing the validated SNPs in two GWAS, ADCY1 gene was verified in both independent studies. The results of fine-mapping showed that the G allele carriers of ADCY1 rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy. In conclusion, our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.

Involvement of the effect of renal hypoperfusion medications on vancomycin trough concentration: A secondary analysis using a retrospective observational data.

This study examined the association between vancomycin (VCM) trough concentration and confounding factors including renal hypoperfusion medications which include angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, loop/thiazide diuretics, or non-steroidal anti-inflammatory drugs. This secondary analysis included patients aged >15 years who were administered VCM intravenously between June 2015 and August 2017 at the Tokyo Women's Medical University Medical Center East. We investigated predictors for three (initial, mean, and final) dose-normalized VCM trough concentration (dose-normalized VCMtrough ) as outcome using a multiple linear regression analysis. In total, 208 patients were analysed (use of loop/thiazide diuretics: 48 [23%]). Multiple linear regression analysis revealed that the initial dose-normalized VCMtrough was negatively correlated with estimated glomerular filtration rate (eGFR) (p = 0.028) and positively correlated with the use of loop/thiazide diuretics (p = 0.003). Meanwhile, there was a positive correlation between the mean dose-normalized VCMtrough and age (p = 0.023). The mean dose-normalized VCMtrough was negatively correlated with eGFR (p < 0.001) and serum albumin (p < 0.001). The final dose-normalized VCMtrough was positively associated with age (p = 0.034) and negatively associated with eGFR (p = 0.032) and serum albumin (p = 0.007). Clinicians should closely monitor VCM trough concentration while receiving VCM and loop/thiazide diuretics.

Impact of concomitant medication on clinical outcomes in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors: A retrospective study.

BACKGROUND: It has recently been suggested that concomitant medication may affect the clinical outcome of patients treated with immune checkpoint inhibitors (ICIs). However, only a few studies on the impact of concomitant medication on immune-related adverse events (irAEs) have previously been reported. Here, we aimed to determine the impact of concomitant medication on the efficacy and safety of ICIs. METHODS: We retrospectively analyzed the data of 300 patients treated with nivolumab or pembrolizumab for advanced non-small cell lung cancer (NSCLC) between January 2016 and July 2018. Multivariate logistic regression analysis was used to assess the effect of concomitant medication on treatment response or irAEs. A multivariate Cox proportional hazards model was used to evaluate concomitant medication-related factors associated with time-to-treatment failure or overall survival (OS). RESULTS: A total of 70 patients responded to treatment and 137 experienced irAEs. The response rate and incidence of irAEs in patients treated with ICIs were not significantly associated with concomitant medication. Multivariate analysis showed that the use of opioids was an independent factor (time-to-treatment failure: hazard ratio 1.39, p = 0.021, OS: hazard ratio 1.54, p = 0.007). CONCLUSIONS: The efficacy and safety of nivolumab or pembrolizumab in the treatment of patients with advanced NSCLC were not significantly influenced by concomitant medication. However, opioid usage might be associated with shorter OS in patients treated with these ICIs. Further mechanistic investigations should explore whether these associations are purely prognostic or contribute to ICI resistance.