Pharmacotherapy最新文献

Diphenhydramine overdose is a common toxicological emergency characterized by anticholinergic symptoms such as delirium, hallucinations, and cardiovascular instability. Physostigmine, a centrally acting acetylcholinesterase inhibitor, is the standard antidote but is currently unavailable within the United States due to supply limitations. We present the case of a 21-year-old female with confirmed diphenhydramine overdose (3600 mg) who demonstrated rapid clinical improvement after administration of a 9.5 mg/24-h rivastigmine transdermal patch. This case supports growing evidence suggesting that rivastigmine may serve as a safe and effective alternative when physostigmine is not accessible.

Background: Drug databases currently do not provide dosing guidance for sulbactam-durlobactam in continuous renal replacement therapy. Herein, we present the first in vivo pharmacokinetic (PK) evaluation of sulbactam-durlobactam during continuous venovenous hemofiltration (CVVH) in a patient with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) bacteremia and ventilator-associated bacterial pneumonia (VABP).

Methods: A 59-year-old critically ill patient (body mass index 60 kg/m²) required CVVH and developed CRAB bacteremia secondary to VABP. Sulbactam-durlobactam 2 g every 4 h infused over 3 h was initiated based on previous ex vivo data and the effluent rate of 6 L/h. The sulbactam-durlobactam minimum inhibitory concentration (MIC) was determined by reference broth microdilution, and whole genome sequencing (WGS) was performed. Steady-state pre-filter blood, post-filter blood, and effluent samples were collected on three different dosing intervals to characterize plasma exposure and estimate the sieving coefficient (SC).

Results: The sulbactam-durlobactam MIC was 4/4 mcg/mL (susceptible). WGS revealed penicillin-binding protein (PBP)-1b and PBP-3 mutations. The selected dose exceeded sulbactam and durlobactam PK/pharmacodynamic (PD) targets with 100% free time above MIC (fT > MIC) and the ratio of area under the unbound concentration-time curve to MIC (fAUC/MIC) = 139, respectively. The SC for sulbactam and durlobactam was 0.68 and 0.67, respectively, and protein binding was 54% and 51%, respectively. Sulbactam-durlobactam monotherapy resulted in initial microbiological clearance for CRAB bacteremia but recurred later in hospitalization 11 days after sulbactam-durlobactam treatment. The patient was ultimately transitioned to comfort care.

Conclusion: Sulbactam-durlobactam monotherapy dosed at 2 g every 4 h (3-h infusion) in CVVH achieved PD targets for this CRAB isolate with a MIC of 4/4 mcg/ml. Although sulbactam-durlobactam monotherapy resulted in initial microbiological clearance for the CRAB bacteremia, recurrence occurred, and the patient ultimately died.

Background: Oxaliplatin-induced peripheral neuropathy (OIPN) is a major clinical challenge because it leads to discontinuation of chemotherapy. Omeprazole, a proton pump inhibitor (PPI), has been shown to prevent OIPN in a rat model. Therefore, we aimed to test whether the concomitant use of a PPI reduces oxaliplatin discontinuation due to OIPN.

Methods: This retrospective study used data from 1015 patients who started treatment with oxaliplatin and evaluated two cohorts (PPI vs. non-PPI). The primary outcome measure was oxaliplatin discontinuation due to OIPN. A Kaplan-Meier curve was generated for cumulative doses and evaluated using the log-rank test and Cox proportional hazards analysis.

Results: The log-rank test showed that the number of patients who discontinued oxaliplatin due to OIPN was significantly lower in the PPI group (p = 0.0264). Cox proportional hazards analysis incorporated and analyzed factors previously reported as potentially affecting neuropathy (sex, age, use of PPIs, calcium channel antagonists, opioids and adjuvant analgesics, and the CAPOX [capecitabine + oxaliplatin] regimen). The analysis suggested that the concomitant use of PPIs was a factor in reducing oxaliplatin discontinuation (adjusted hazard ratio [HR] = 0.568, 95% confidence interval [CI], 0.344-0.937, p = 0.0269). Since there were significant differences in some patient demographics between the two groups, propensity score matching was performed to align the patient demographics and then reanalyzed. After propensity score matching, the same analysis as above showed that oxaliplatin discontinuation due to OIPN was significantly less common in the PPI group (p = 0.0081); cox proportional hazards analysis showed that PPI use was a factor that significantly reduced oxaliplatin discontinuation due to OIPN (adjusted HR = 0.478, 95% CI, 0.273-0.836, p = 0.0096).

Conclusions: These results suggest that concomitant PPI use may reduce oxaliplatin discontinuation due to OIPN in patients receiving oxaliplatin.

Background: Type 2 diabetes (T2D) is associated with an increased risk of nephrolithiasis. Emerging evidence suggests that sodium-glucose cotransporter 2 inhibitors (SGLT2i) may reduce this risk; however, data remain inconclusive.

Objective: To examine the risk of nephrolithiasis among users of SGLT2i compared to dipeptidyl peptidase-4 inhibitors (DPP4i) in a real-world population of older adults with T2D.

Methods: A retrospective cohort study was conducted using claims data from a sample of national Medicare beneficiaries. Individuals with T2D who initiated SGLT2i or DPP4i therapy between January 1, 2016, and December 31, 2018, were identified. The index date was defined as the date of the first prescription for either SGLT2i or DPP4i, with no prior use of either drug in the preceding year. Patients were followed from the index date until the earliest occurrence of a medical encounter with a primary diagnosis of nephrolithiasis, death, or December 31, 2018. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates, including sociodemographic characteristics, comorbidities, and comedication use. Cox proportional hazards regression models were applied to compare the risk of nephrolithiasis between SGLT2i and DPP4i users. Additional analyses were conducted within subgroups defined by sex, race, and baseline nephrolithiasis status.

Results: Of 116,506 included Medicare beneficiaries with T2D (mean age 72 ± 10 years, 53% women), 0.96% developed nephrolithiasis over a median follow-up of 360 days (interquartile range [IQR] 200-467 days). The incidence rate of nephrolithiasis was 9.89 (95% confidence interval [CI] 8.49-11.52) and 11.02 (95% CI 10.34-11.73) events per 1000 person-years in the SGLT2i and DPP4i groups, respectively. After applying IPTW, baseline characteristics were well balanced between the two groups. SGLT2i use was associated with a significantly lower risk of nephrolithiasis compared to DPP4i use (hazard ratio [HR], 0.81; 95% CI 0.66-0.99; p = 0.04). In subgroup analyses, SGLT2i use compared to DPP4i was associated with a significantly lower risk of nephrolithiasis among males (HR 0.75; 95% CI 0.58-0.98; p = 0.04), non-Hispanic Black (NHB) individuals (HR 0.22; 95% CI 0.07-0.64; p < 0.01), and those without baseline nephrolithiasis (HR 0.68; 95% CI 0.53-0.88; p < 0.01).

Conclusions: In older adults with T2D, SGLT2i use was associated with a lower risk of nephrolithiasis compared to DPP4i, particularly among men, NHB individuals, and those without baseline nephrolithiasis. Although causality cannot be established, these findings provide real-world evidence supporting a potential benefit of SGLT2is in reducing nephrolithiasis risk, offering valuable insights to guide the selection of glucose-lowering drugs in older adults with T2D.

Background: Model-informed precision dosing (MIPD) is a promising tool used to ensure therapeutic antimicrobial concentrations. Model selection and sampling strategy might lead to different pharmacokinetic (PK) parameter estimates. Herein, we assess the predictive performance for cefepime PK in two models implemented within the InsightRX software using differing sampling approaches.

Methods: Historic cefepime PK data and individual Bayesian estimates in predominantly critically ill patients, some of whom had extracorporeal support, served as the reference standard. Two population PK models (A; B) were evaluated using four sampling scenarios: (i) trough only, (ii) midpoint only, (iii) trough + midpoint, and (iv) peak + midpoint + trough. The median prediction error (MPE) and median absolute prediction error (MAPE) were calculated for clearance (CL) and volume of central compartment (V_c). Predicted categorical achievement of ≥70% time that the free drug concentration was greater than the minimum inhibitory concentration [fT>MIC_(8/16mg/L)] was compared.

Results: MAPE and MPE for CL and V_c resulted in variability that was dependent on model and sampling strategy. Both models' overall MPE and MAPE for CL were <±20 and <30% for all tested scenarios, respectively, with a low MPE of -2.4% to 4.4% on CL for sampling scenario 4. For V_c, MPE and MAPE were >±20 and >30% for the majority of test scenarios across both models, respectively. When excluding patients with extracorporeal support, MPE/MAPE for V_c decreased to 3.7-4.8/23.3%-34.5% and -7.9-2.5/25.2%-29.6% for model A and B, respectively. Using each model and sampling scheme, only four patients had discordant predicted achievement of ≥70% fT>MIC_(8/16mg/L).

Conclusions: These two population PK models and all sampling scenarios demonstrated acceptable prediction of cefepime PK parameters and pharmacodynamic exposures; therefore, they demonstrated suitability for utilizing MIPD for cefepime therapeutic drug monitoring.

Carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CR-PA) continue to pose a significant threat to human health. Furthermore, the prevalence of metallo-β-lactamase (MBL)-producing CRE and CR-PA is increasing, which are capable of hydrolyzing nearly all β-lactam antibiotics. Cefepime-taniborbactam (FTB) is a novel bicyclic boronate β-lactam-β-lactamase inhibitor combination with direct inhibitory activity against MBLs (Ambler Class B), in addition to Ambler Class A, C, and D serine-β-lactamases. FTB has demonstrated high in vitro activity against CRE and CR-PA, including isolates producing NDM, VIM, KPC, AmpC, OXA-48, and extended-spectrum β-lactamases (ESBLs). Furthermore, FTB has demonstrated in vitro activity against Stenotrophomonas maltophilia and Burkholderia cepacia complex. Resistance to FTB is observed in isolates producing IMP, as well as MBL variants NDM-9, NDM-30, and VIM-83. FTB remains susceptible to non-β-lactamase resistance mechanisms, including penicillin-binding protein 3 (PBP3) target mutations. The pharmacodynamic driver of taniborbactam efficacy is the ratio of the area under the curve to the minimum inhibitory concentration (AUC/MIC), and the study dose of FTB 2 g/0.5 g every 8 h infused over 2 h achieves sufficient serum and tissue exposures to maintain therapeutic efficacy. Both components are primarily renally eliminated as unchanged drug; therefore, dose adjustments for renal impairment are required. The clinical efficacy of FTB was demonstrated in the phase III Cefepime Rescue with Taniborbactam in Complicated Urinary Tract Infection (CERTAIN-1) trial, where it demonstrated both non-inferiority and superiority (prespecified analysis) to meropenem in the composite of clinical and microbiologic success at the test of cure for the treatment of complicated urinary tract infection. The safety of FTB was demonstrated throughout its clinical development. Thirteen percent of patients experienced a treatment-related adverse drug event in the phase III clinical trial, with 3% of patients requiring discontinuation of the study agent. Cefepime-taniborbactam appears to be a promising addition to the antibiotic arsenal, particularly as the prevalence of infections caused by MBL-producing organisms continues to rise.

The treatment of metastatic clear cell renal cell carcinoma (RCC) has changed significantly in the last 20 years with the advent of targeted therapies and immune checkpoint inhibitors. Belzutifan, a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, has a novel mechanism of action and was approved by the United States Food and Drug Administration (FDA) in 2023 for patients with advanced RCC. In the phase III LITESPARK-005 trial, patients receiving belzutifan had significant improvement in progression-free survival (PFS) compared with everolimus (PFS rate at 12 months: 33.4% vs. 17.1%; PFS rate at 18 months: 24.0% vs. 8.3%, respectively), as well as in objective response rate compared with everolimus (22.7% vs. 3.5%, respectively). There was no significant difference in median overall survival, with 21.4 months for belzutifan and 18.1 months for everolimus (hazard ratio [HR] 0.88; p = 0.20). In clinical practice, patients on belzutifan most often require intervention for anemia and hypoxia. This article describes the current preferred treatment options in clear cell RCC, the pharmacology of belzutifan, clinical trial data for belzutifan in clear cell RCC, our clinical experience with belzutifan and managing associated anemia and hypoxia, and future directions of belzutifan in RCC treatment.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a rare, progressive muscle disease with no available disease-modifying therapy. Creatine monohydrate (CrM) has been shown to improve muscle strength in individuals with muscular dystrophies but has not been tested in young people with FSHD. This study aimed to explore the efficacy of CrM on motor function in children with FSHD.

Methods: In a randomized placebo-controlled double-blind crossover trial, powdered CrM at a dose of 100 mg/kg/day (maximum 10 g daily) was compared with placebo in two 12-week treatment periods with a 6-week washout between crossover arms. The primary outcome measure was the Motor Function Measure for Neuromuscular Disease (MFM-32) with secondary outcomes assessing safety, endurance, strength, patient-reported outcome measures, and muscle morphology measurements as assessed by whole-body magnetic resonance imaging (MRI).

Results: Thirteen children were enrolled (mean (standard deviation, SD) 12.2 (2.67) years of age) and 11 patients completed both trial treatment periods. In an intention-to-treat analysis, no clinically meaningful difference was seen between treatment groups as measured by the mean difference in MFM-32 (0.19, 95% confidence interval (CI) -0.71 to 1.08). However, there was an improvement in 6-minute walk distance of 27.74 m (95% CI -1.41 to 56.88) and trends to improvement in the FSHD-Composite Outcome Measure for Pediatrics (FSHD-COM Peds), 10 meter walk/run, and in MRI measures. There were no serious adverse events. Serum creatinine increased by a mean 12.63 μmol/L (95% CI 1.14 to 24.12) post-CrM treatment, though this was presumed to reflect increased creatinine production. No participants discontinued CrM due to adverse events.

Conclusion: CrM is safe and well tolerated in children with FSHD. Although CrM had no effect on motor function as measured by the MFM-32 compared with placebo, there were trends toward improvement in the 6-minute walk distance and other secondary outcome measures. This study confirms the feasibility of conducting clinical trials in children with FSHD. Further assessment of the efficacy of CrM in pediatric FSHD is warranted in a larger randomized controlled clinical trial. Future studies may benefit from stratifying population cohorts according to functional ability or by MRI fat infiltration measurements.