Pharmacotherapy [JOURNAL]
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200 papers
The Effect of Multiple Doses of Itraconazole on the Pharmacokinetics of a Single Oral Dose of Zongertinib in Healthy Male Volunteers.
Scudamore O, Wind S, Grempler R … +2 more , Esmaeili H, Müller F
Pharmacotherapy · 2026 Jul · PMID 42324472 · Publisher ↗
INTRODUCTION: Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing wild-type epidermal growth factor receptor (EGFR), thereby mi...
INTRODUCTION: Zongertinib is an irreversible tyrosine kinase inhibitor that selectively inhibits human epidermal growth factor receptor 2 (HER2) while sparing wild-type epidermal growth factor receptor (EGFR), thereby minimizing associated toxicities. Oxidative hepatic metabolism of zongertinib in vitro is principally driven by cytochrome P450 (CYP) 3A. It is necessary, therefore, to assess the effect of a strong CYP3A inhibitor on the pharmacokinetics of zongertinib in humans. OBJECTIVE: This study investigated the effect of multiple oral doses of the strong CYP3A inhibitor and regulatory-recommended probe inhibitor of P-glycoprotein (P-gp), itraconazole, on the pharmacokinetics of a single dose of zongertinib in healthy male participants. METHODS: This open-label, two-period, fixed-sequence, clinical drug-drug interaction study assessed the pharmacokinetics of a 15 mg oral dose of zongertinib in the absence and presence of multiple oral doses of itraconazole. The extent of drug-drug interaction was estimated using the adjusted geometric mean (gMean) ratios (90% confidence intervals [CIs]) for the test (T) treatment (zongertinib and itraconazole) vs. the reference (R) treatment (zongertinib alone). Primary endpoints were the area under the plasma concentration-time curve from time 0 to infinity (AUC) and the maximum measured plasma concentration (C) of zongertinib. The secondary pharmacokinetic endpoint was AUC for zongertinib from time 0 to the last quantifiable time point (AUC). RESULTS: Sixteen participants received zongertinib alone (Period 1, R), followed by co-administration with itraconazole (Period 2, T). In terms of zongertinib exposure, the gMean ratio of T to R was 141.2% (90% CI: 126.3-157.7%) for AUC, 142.8% (90% CI: 126.0-161.9%) for AUC, and 126.9% (90% CI: 106.6-151.0%) for C. CONCLUSION: Co-administration with itraconazole resulted in a mild increase in total exposure to zongertinib that was not considered clinically relevant given its wide therapeutic window. These data indicate that the approved 120 mg dose of zongertinib can be administered without dose adjustment in combination with CYP3A/P-gp inhibitors.
Menopausal Hormone Therapy: A Narrative Review of Contemporary Evidence.
Finks SW, Cieri-Hutcherson NE, Vernon V … +1 more , McBane SE
Pharmacotherapy · 2026 Jul · PMID 42304170 · Publisher ↗
Menopausal hormone therapy (MHT) remains the most effective treatment for vasomotor and genitourinary symptoms of menopause; however, its use declined sharply following the publication of the Women's Health Initiative (W...
Menopausal hormone therapy (MHT) remains the most effective treatment for vasomotor and genitourinary symptoms of menopause; however, its use declined sharply following the publication of the Women's Health Initiative (WHI). Misinterpretation and limitations of WHI findings have led to persistent misconceptions and underutilization of MHT. This expert opinion aims to clarify evidence-based approaches to MHT selection, safety, and individualized management. This article was informed by a structured narrative review of the literature with the aim to contextualize evolving pharmacotherapeutic evidence and inform clinical decision-making. PubMed/MEDLINE, Embase, and the Cochrane Library were searched for studies published from 2002 to 2025. Key opinion statements were developed through expert consensus and paired with a synthesis of contemporary evidence to form recommendations. A critical appraisal of the WHI and subsequent analyses demonstrates that age at initiation, timing since menopause, and hormone formulation utilized significantly influence outcomes. Contemporary data support the preferential use of transdermal estradiol due to its lower risk of venous thromboembolism and favor oral micronized progesterone (MP) over synthetic progestogens when endometrial protection is required. Individualization of therapy-including formulation, route, and dosing-is emphasized as central to optimizing the benefit-risk profile. Current evidence supports the safety of low-dose vaginal estrogen for genitourinary syndrome of menopause including in cancer survivors. Further evidence highlights potential cardiovascular and cognitive benefits when MHT is initiated within 10 years of menopause. Clinicians caring for menopausal women should promote individualized, evidence-based MHT through education, therapeutic selection, shared decision making, and ongoing monitoring. Continued research is needed to refine dosing targets, evaluate long-term preventive outcomes, and expand evidence for modern formulations beyond WHI-era therapies. Ultimately, MHT should be viewed not as a one-size-fits-all therapy, but as a personalized, evidence-informed strategy that supports the health and quality of life of menopausal women.
Getting It Right the Second Time: How Can we Optimize First-Generation Cephalosporin Dosing for Skin and Soft Tissue Infections in the 21st Century?
Ryder JH, Sunagawa SW, Rhodes NJ … +4 more , Van Schooneveld TC, Tigh JE, Avedissian SN, Cortes-Penfield N
Pharmacotherapy · 2026 Jul · PMID 42272168 · Full text
Optimal cephalexin and cefadroxil dosing for skin and soft tissue infections (SSTIs) is unclear. We summarize clinical and pharmacokinetic/pharmacodynamic (PK/PD) data that compare dosing strategies for SSTIs. Additional...
Optimal cephalexin and cefadroxil dosing for skin and soft tissue infections (SSTIs) is unclear. We summarize clinical and pharmacokinetic/pharmacodynamic (PK/PD) data that compare dosing strategies for SSTIs. Additionally, we conduct population PK target attainment simulations for varying doses of cephalexin and cefadroxil for Staphylococcus aureus and Group A Streptococcus. Although some clinical data support lower doses in mild SSTIs, higher doses optimize PK/PD parameters in moderate-severe SSTIs, especially due to Staphylococcus aureus. Further prospective clinical and PK/PD studies, especially in obese adults, would be beneficial.
Buprenorphine Initiation During Extracorporeal Membrane Oxygenation Decreases Sedative and Opioid Exposure: A Retrospective Matched Case-Control Study.
Carroll DK, Woodcock EA, King A … +13 more , Isaacson AR, Yakey B, Dolcourt BA, Wein R, Cochrane J, Darling A, Fares AM, Hoover J, Terasaki Y, Coyle BE, Chittenden E, Chacko R, Greenwald MK
Pharmacotherapy · 2026 Jul · PMID 42272072 · Publisher ↗
INTRODUCTION: Patients supported with extracorporeal membrane oxygenation (ECMO) frequently require prolonged, high-intensity analgosedation because of neuromuscular blockade, pain related to procedures, and pharmacokine...
INTRODUCTION: Patients supported with extracorporeal membrane oxygenation (ECMO) frequently require prolonged, high-intensity analgosedation because of neuromuscular blockade, pain related to procedures, and pharmacokinetic alterations. These exposures increase the risk of iatrogenic medication toxicity and withdrawal. OBJECTIVES: We evaluated whether buprenorphine (BUP) use during ECMO reduced full agonist opioid exposure and improved sedation compared with matched comparators. METHODS: Using a retrospective matched case-control cohort design among ECMO patients in a cardiovascular intensive care unit, we contrasted 30 patients treated with BUP versus 30 comparator patients not treated with BUP (NO-BUP) matched using an a priori deterministic hierarchy. Comparisons were anchored to two matched time points: (i) the day before BUP exposure and (ii) the day after attaining the full therapeutic BUP dose; NO-BUP comparators were assessed on the analogous ECMO days. The primary outcome was the between-group difference in change in daily intravenous morphine milligram equivalents (MME) across this time period. RESULTS: Each cohort included 27 venovenous and three venoarterial ECMO patients. Demographics and illness severity did not differ between groups. Groups significantly differed in MME change scores (p < 0.001) with the BUP cohort decreasing significantly (p < 0.001) from 184.1 (interquartile range [IQR] 70.2-367.2) to 0.0 (IQR 0.0-11.6) median MME whereas NO-BUP comparators nonsignificantly decreased (p = 0.517) from 230.8 (IQR 153.3-567.0) to 177.2 (IQR 85.3-663.1). Groups also differed (p = 0.031) in time in target RASS range (-2 to 0); the BUP cohort significantly improved from 53.9% to 91.2% (p < 0.001) whereas NO-BUP comparators nominally improved from 37.8% to 46.1% (p = 0.275). In the BUP cohort, there was no precipitated withdrawal, opioid-induced constipation, or respiratory depression. Rates of tracheostomy, mortality, and extubation before decannulation did not differ significantly. CONCLUSION: BUP initiation among ECMO patients was feasible and associated with a marked reduction in full agonist opioid exposure and improved light-sedation target attainment. These findings are hypothesis-generating given the retrospective design and potential residual confounding.
Voriconazole Dosing and Therapeutic Drug Monitoring in Patients Before and After Liver Transplantation.
Hoffmann WJ, Tsai S, Succar L … +6 more , Sanghvi A, Jones SL, Connor AA, Mobley CM, Ghobrial RM, Nigo M
Pharmacotherapy · 2026 Jul · PMID 42272052 · Publisher ↗
BACKGROUND: Voriconazole is a triazole antifungal, primarily metabolized by the liver, and poses a dosing challenge in patients with liver impairment. Although the manufacturer recommends a maintenance dose reduction for...
BACKGROUND: Voriconazole is a triazole antifungal, primarily metabolized by the liver, and poses a dosing challenge in patients with liver impairment. Although the manufacturer recommends a maintenance dose reduction for mild-to-moderate hepatic dysfunction, no standardized recommendations exist for severe liver impairment. Prior evidence suggests a need for significant dose reduction in the setting of severe liver failure; however, there is limited data on empirical dosing in patients undergoing orthotopic liver transplant (OLT) evaluation and surgery. METHODS: This is a single-center, retrospective cohort study assessing voriconazole dosing and therapeutic drug monitoring (TDM) in patients with advanced cirrhosis who received voriconazole during urgent OLT evaluation and/or surgery. Patients were included if voriconazole trough concentrations were collected at least 7 days after therapy initiation pre-OLT or at least 5 days post-OLT. The target therapeutic range was defined as 1-4 mcg/mL. The primary outcome was the distribution of voriconazole trough concentrations in the pre- and post-transplant cohorts. RESULTS: The pre-OLT cohort comprised 76 patients with 124 concentrations, and the post-OLT cohort comprised 36 patients with 71 concentrations. As anticipated, the pre-OLT group exhibited more abnormal liver enzymes and a high median Model for End-Stage Liver Disease (MELD) score of 35 (Interquartile Range (IQR) 29.5-40). In the pre-OLT setting, doses less than 2 mg/kg/dose were more likely associated with therapeutic voriconazole concentrations. Supratherapeutic concentrations were observed in 41 patients (average dose of 2.4 mg/kg/dose), of which five patients required therapy interruption. In the post-OLT group, only 23 of 71 concentrations fell within the therapeutic range, with an average dose of 2.8 mg/kg/dose. CONCLUSION: We found that empiric voriconazole dosing in patients with advanced cirrhosis undergoing OLT evaluation should not exceed 2 mg/kg/dose initially to mitigate the risk of drug accumulation and potential toxicity. In post-OLT patients, it is reasonable to consider reverting to standard manufacturer-recommended dosing. Given the pharmacokinetic variability observed, TDM is essential for effective and safe management in this high-risk patient population.
Quantifying the Serum Magnesium Response and Predictors of Response Following Intravenous Magnesium Replacement in Critically Ill Patients.
Said N, Angelotti G, Awad W … +3 more , Al-Kharabsheh A, Wong AI, Nazer L
Pharmacotherapy · 2026 Jul · PMID 42266166 · Full text
BACKGROUND AND OBJECTIVE: Intravenous magnesium is commonly used in critically ill patients; however, data on the serum level response following its administration are limited. This study aimed to evaluate serum magnesiu...
BACKGROUND AND OBJECTIVE: Intravenous magnesium is commonly used in critically ill patients; however, data on the serum level response following its administration are limited. This study aimed to evaluate serum magnesium changes after administration of intravenous magnesium sulfate (IV-MgSO) and identify predictors of a greater response among critically ill patients. METHODOLOGY: This retrospective multicenter study included adult critically ill patients from the Medical Information Mart for Intensive Care IV and eICU databases. Patients were included if they received IV-MgSO and had serum magnesium measured within 36 h before and after administration. Patients receiving renal replacement therapy, total parenteral nutrition, magnesium-containing intravenous fluids, or oral magnesium supplementation were excluded. Linear regression analyses were performed to identify predictors of greater magnesium response. RESULTS: The study included 25,637 patients who received 54,556 doses of IV-MgSO. The mean age was 62.8 ± 16.5 Standard deviation years, and 13,180 (51.4%) were females. The most common intensive care unit admission diagnoses were cardiovascular (n = 7399; 28.9%) and respiratory (n = 4245; 16.6%). Baseline magnesium levels were normal in 39,149 (71.8%) episodes, mild-to-moderate hypomagnesemia in 13,588 (24.9%), and severe hypomagnesemia in 1819 (3.3%). Median serum magnesium increased by 0.15 mg/dL (interquartile range (IQR) 0.05-0.25) per 1 g of IV-MgSO administered, and the greatest increase was observed in patients with severe hypomagnesemia (median [IQR]: 0.25 mg/dL [0.10-0.50]), followed by mild-to-moderate hypomagnesemia (median [IQR]: 0.22 mg/dL [0.10-0.40]). Predictors of greater response to IV-MgSO were lower initial magnesium (β = 0.2035; 95% confidence interval (CI): 0.193 to 0.214; p < 0.001) and reduced renal function (β = 0.2557; 95% CI: 0.212 to 0.300; p < 0.001). CONCLUSION: Among a large cohort of critically ill patients, 1 g of IV-MgSO was associated with a median serum magnesium increase of 0.15 mg/dL. Lower initial magnesium and reduced renal function were predictors of greater serum magnesium increase with intravenous replacement.
Correction to "Bayesian Dosing Simulator (BDS): A Pharmacokinetic Modeling Tool for Optimized Antibiotic Therapy".
Pharmacotherapy · 2026 Jul · PMID 42266165 · Publisher ↗
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Cost-Effectiveness Analysis of Patient Self-Management of Warfarin Among Patients With Non-Valvular Atrial Fibrillation.
Kategeaw W, Witt DM, King JB … +2 more , Malone DC, Chaiyakunapruk N
Pharmacotherapy · 2026 Jun · PMID 42136139 · Full text
BACKGROUND: Patient self-management (PSM) is a warfarin management strategy that allows patients to independently adjust their doses. PSM significantly reduces thrombosis events and has been widely implemented internatio...
BACKGROUND: Patient self-management (PSM) is a warfarin management strategy that allows patients to independently adjust their doses. PSM significantly reduces thrombosis events and has been widely implemented internationally. However, adoption of PSM is limited in the United States. This study estimated the cost-effectiveness of PSM compared with available strategies, including anticoagulation management services (AMS) and usual care (UC) for patients with non-valvular atrial fibrillation (NVAF) aged 70 years and older in the United States. METHODS: A cost-effectiveness analysis was performed to estimate lifetime costs and outcomes of PSM compared with AMS and UC employing a Markov model. The model simulated a 70-year-old with NVAF over the patient's lifetime from modified societal and payer perspectives. Transition probabilities were derived from annual event rates reported in the ARISTOTLE trial. Comparative efficacy and safety among the interventions were obtained from a network meta-analysis. Costs, presented in 2024 US dollars (USD), and utility data were obtained from data sources in the United States. A discount rate of 3% was applied for future costs and outcomes. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the findings. RESULTS: The lifetime costs from the modified societal perspective were $137,509 USD for UC, $129,216 USD for AMS, and $76,515 USD for PSM. Discounted quality-adjusted life years (QALYs) were estimated to be 8.27 for UC, 8.30 for AMS, and 8.47 for PSM. Additionally, PSM substantially reduced stroke incidence compared with AMS and UC, contributing to lower costs and greater QALYs. Probabilistic sensitivity analysis showed that PSM appeared to be the most cost-effective at any willingness-to-pay threshold. CONCLUSIONS: PSM is the most cost-effective strategy for managing warfarin in the target population at any willingness-to-pay threshold. Implementation of PSM in the US health care setting should be considered.
Factors That Influence Blood Pressure Changes With the Use of Sodium-Glucose Cotransporter 2 Inhibitors in People With Type 2 Diabetes.
Salama S, Bolch C, Landup D … +2 more , Van Dril E, Schumacher C
Pharmacotherapy · 2026 Jun · PMID 42130462 · Publisher ↗
STUDY OBJECTIVE: Multiple clinical trials have reported variable reductions in blood pressure with sodium-glucose cotransporter 2 (SGLT2) inhibitors. Given the variability in the magnitude of blood pressure reduction obs...
STUDY OBJECTIVE: Multiple clinical trials have reported variable reductions in blood pressure with sodium-glucose cotransporter 2 (SGLT2) inhibitors. Given the variability in the magnitude of blood pressure reduction observed across studies, there is interest in understanding how patient-specific factors influence the blood pressure-lowering effects of SGLT2 inhibitors. The primary objective of this study was to evaluate factors that influence blood pressure changes in people with type 2 diabetes when an SGLT2 inhibitor is initiated. DESIGN: Multicenter retrospective cohort chart review. DATA SOURCE: Patients were selected through an electronic medical record-generated report between January 1, 2013, and September 30, 2019. PATIENTS: Adults (≥ 18 years) receiving care within Advocate Medical Group were included if they had a documented diagnosis of type 2 diabetes and had been prescribed one of four SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin) for at least 7 days. RESULTS: In 1,422 patients, mean systolic blood pressure (SBP) decreased by 4.1 mmHg (range -58.7 to 58.0), and mean diastolic blood pressure (DBP) decreased by 2.1 mmHg (range -44.7 to 29.0) after SGLT2 inhibitor initiation. Significant blood pressure reductions occurred only in patients with elevated baseline blood pressure, with greater declines at higher baseline pressures (p < 0.001). Patients with baseline SBP > 160 mmHg showed a mean reduction of 26.7 mmHg, whereas those with SBP < 120 mmHg had a mean increase of 6.1 mmHg. DBP followed a similar pattern: Individuals with baseline DBP > 100 mmHg had a mean reduction of 16.0 mmHg, whereas those with DBP < 60 mmHg experienced a mean increase of 10.7 mmHg. CONCLUSION: Blood pressure responses to SGLT2 inhibitors were driven by baseline blood pressure, with the greatest reductions observed in patients with elevated blood pressure at initiation. Individuals with lower starting pressures showed minimal change or slight increases, indicating a normalizing effect rather than uniform blood pressure lowering with initiation of SGLT2 inhibitors. These findings support incorporating baseline blood pressure into treatment selection to optimize cardiovascular risk management in patients with type 2 diabetes.
Pharmacokinetic Analysis of Intravenous Push Cefepime in Critically Ill Patients With Sepsis.
Smith SE, Bagodiya R, Luong P … +6 more , Shinde S, Bland CM, Barry C, Bartlett MG, Fox NR, Branan TN
Pharmacotherapy · 2026 Jun · PMID 42121318 · Full text
BACKGROUND: Intravenous push (IVP) administration of cefepime increases ease of preparation and limits the need for small volume parenterals. The data on IVP pharmacokinetic/pharmacodynamic (PK/PD) parameters are limited...
BACKGROUND: Intravenous push (IVP) administration of cefepime increases ease of preparation and limits the need for small volume parenterals. The data on IVP pharmacokinetic/pharmacodynamic (PK/PD) parameters are limited, but may be especially relevant in critically ill patients with altered PK/PD for time-dependent antibiotics like cefepime. The objective of this study was to characterize the PK profile and PD target attainment of IVP cefepime in critically ill patients with sepsis. METHODS: In this institutional review board-approved, prospective, noninterventional PK study, hospitalized adult patients receiving IVP cefepime were included if they had a central/midline catheter, intensive care unit (ICU) length of stay ≥ 48 h, creatinine clearance > 30 mL/min without renal replacement therapy, and diagnosis of sepsis. Blood samples were obtained at cefepime steady state immediately before and at 5, 15, 30, 60, 120, and 240 min after a dose. Serum concentrations of cefepime were measured using high-performance liquid chromatography with ultraviolet detection. Patient characteristics and outcomes were collected retrospectively from the electronic health record. The primary outcome was the PK profile of cefepime following IVP administration. RESULTS: Patients (n = 17) had a median age of 69 years, body mass index (BMI) of 29.9 kg/m, creatinine clearance of 94 mL/min, and sequential organ failure assessment (SOFA) score of 9. Following IVP administration, PK analysis demonstrated a maximum concentration (C) of 158 μg/mL, time to maximum concentration (T) of 5 min, area under the curve (AUC) of 286.95 μg × h/mL, and elimination rate constant (K) of 0.31 h. Additionally, the analysis showed a volume of distribution of 43.91 L, elimination half-life (t) of 3.76 h, clearance (CL) of 7.86 L/h, and time above minimum inhibitory concentration (T > MIC) of 86%. CONCLUSIONS: Intravenous push cefepime in critically ill patients achieved systemic exposure comparable to traditional intermittent infusion but demonstrated substantial interpatient PK variability. These findings highlight the impact of critical illness on cefepime disposition and support further evaluation of personalized cefepime dosing for the ICU population.
Continuous Subcutaneous Ketamine Infusion May Induce Tacrolimus and Sirolimus Clearance: A Case Report.
Stojanova J, Murnion B, Burrows F … +7 more , Carlos L, Mizuno T, Nadai T, Irie K, Helsby N, Muthiah K, Day R
Pharmacotherapy · 2026 Jun · PMID 42115000 · Full text
BACKGROUND: Drug interactions involving immunosuppressants can compromise transplant outcomes. Although repeated ketamine administration induces hepatic enzymes in experimental models, clinical reports of induced clearan...
BACKGROUND: Drug interactions involving immunosuppressants can compromise transplant outcomes. Although repeated ketamine administration induces hepatic enzymes in experimental models, clinical reports of induced clearance of cytochrome P450 (CYP) substrates are lacking. Continuous subcutaneous ketamine infusions are increasingly used for acute pain management. We present a case of difficult-to-maintain tacrolimus and sirolimus concentrations in the context of subcutaneous ketamine infusion for acute pain management. METHODS: A 55-year-old male heart transplant recipient received continuous subcutaneous ketamine (5.2-10.4 mg/h) for pain management following lower limb thrombectomy. Tacrolimus and sirolimus concentrations were monitored throughout hospitalization and rehabilitation. Population pharmacokinetic modeling with Bayesian estimation characterized temporal clearance changes, incorporating inter-occasion variability across six periods (pre-, during-, and weekly post-ketamine administration for 4 weeks). RESULTS: Following ketamine initiation, tacrolimus and sirolimus concentrations remained subtherapeutic despite dose escalations of 1.8-fold and 5-fold, respectively. Pharmacokinetic modeling revealed approximately 2-fold clearance increases during ketamine administration, peaking 1 week after initiation. Following ketamine discontinuation, tacrolimus and sirolimus concentrations progressively increased over 3 weeks, consistent with enzyme induction and recovery. Drug Interaction Probability Scale assessment indicated probable interaction (score + 5). Brief concomitant flucloxacillin use may have contributed to the observed changes. CONCLUSIONS: This case provides preliminary evidence of potential interaction between ketamine and CYP3A4-metabolized immunosuppressants. Clinicians should consider increased therapeutic drug monitoring when using ketamine with narrow therapeutic range medications, continuing approximately 3 weeks post-discontinuation.
Hyperfiltration in Critically Ill Older Adults: Incidence, Risk Factors, Time Course, and Predictive Performance of Kidney Function Estimation.
Mikami R, Imai S, Hayakawa M … +7 more , Izumi G, Kashiwagi H, Sato Y, Nashimoto S, Wada T, Sugawara M, Takekuma Y
Pharmacotherapy · 2026 Jun · PMID 42114995 · Publisher ↗
STUDY OBJECTIVE: This study aimed to evaluate the incidence, associated risk factors, time course, and predictive performance of kidney function estimation equations for hyperfiltration in critically ill older adults. ME...
STUDY OBJECTIVE: This study aimed to evaluate the incidence, associated risk factors, time course, and predictive performance of kidney function estimation equations for hyperfiltration in critically ill older adults. METHODS: This retrospective observational study evaluated 325 patients (median age, 76 years) admitted to the intensive care unit (ICU) of a tertiary-care university hospital, for a total of 2934 patient-days. The hyperfiltration threshold was defined using measured creatinine clearance (Clcr) > -0.883 × age + 167.398. Independent factors associated with hyperfiltration were identified via a multivariable logistic regression model, and time to onset and duration were evaluated using Kaplan-Meier curves. Additionally, the predictive performance of the measured Clcr was assessed using the Cockcroft-Gault equation. Bias was analyzed using the Bland-Altman analysis, and accuracy was evaluated using the percentage within 30% of the measured Clcr (P30). RESULTS: Hyperfiltration occurred in 56% of the patients. Risk factors included male sex, high body mass index, trauma-related admission, vasopressor use, and low serum creatinine levels. The median time from ICU admission to hyperfiltration onset was 5 days, and the median duration of hyperfiltration episodes was 8 days. The Cockcroft-Gault equation substantially underestimated measured Clcr in patients with hyperfiltration. Even among those whose measured Clcr did not meet the conventional augmented renal clearance (ARC) threshold (> 130 mL/min), the equation exhibited a clinically significant negative bias (-35 mL/min) with limited accuracy (P30: 39%). This underestimation was even more pronounced in patients meeting the ARC criteria (bias: -62 mL/min; P30: 27%). CONCLUSIONS: Hyperfiltration is highly prevalent in critically ill older adults. The Cockcroft-Gault equation substantially underestimated actual kidney function, even without meeting the ARC criteria. Continuous monitoring of the measured Clcr is recommended to avoid inappropriate medication dose reductions due to underestimation.
Cancer Treatment Modalities and Female Fertility Preservation.
Song S, Davenport L, Paone S … +1 more , Chin-Hon J
Pharmacotherapy · 2026 Jun · PMID 42114985 · Publisher ↗
Oncofertility is the practice of joining oncology clinicians with reproductive endocrinologists to assess patients' tumor biology, tumor stage, and mutation analysis to discuss the infertility risks from tumor-directed t...
Oncofertility is the practice of joining oncology clinicians with reproductive endocrinologists to assess patients' tumor biology, tumor stage, and mutation analysis to discuss the infertility risks from tumor-directed treatments and provide fertility preservation opportunities to patients who will undergo or have received tumor-directed therapy since cancer treatments can affect fertility. Tumor-directed therapies, such as radiation and antineoplastic agents, have greatly expanded beyond traditional deoxyribonucleic acid (DNA)-damaging agents to encompass pharmacologic agents, such as targeted monoclonal antibodies, kinase inhibitors, and immune activating therapies that may have varying effects on women's fertility. Here, we review the current literature to provide a comprehensive summary on the effect of cancer treatment modalities on female fertility, fertility preservation options in female patients, and the role of pharmacists in oncofertility practice.
Predictors and Clinical Outcomes of Long-Term Opioid Therapy in Older Adults: A Systematic Review.
Ahmed I, Teo NE, Keshk N … +1 more , Foster DR
Pharmacotherapy · 2026 Jun · PMID 42112570 · Full text
INTRODUCTION: Older adults have a higher prevalence of pain and are more likely to receive long-term opioid therapy (LTOT) compared to other age groups. They are also at elevated risk of opioid-related adverse events due...
INTRODUCTION: Older adults have a higher prevalence of pain and are more likely to receive long-term opioid therapy (LTOT) compared to other age groups. They are also at elevated risk of opioid-related adverse events due to physiological changes and polypharmacy. This systematic review aimed to identify predictors and clinical outcomes associated with LTOT in older adults. METHODS: We searched PubMed, Embase, and Cochrane Library to identify randomized clinical trials (RCT) and observational studies published from inception until July 31, 2025. We included studies that examined opioid use for ≥ 90 days and included participants aged ≥ 60 years. Data were synthesized using harvest plots and narrative synthesis. The Newcastle-Ottawa Scale was used for risk of bias assessment. RESULTS: Forty-one observational studies were included; no RCTs met the inclusion criteria. Patient-related factors associated with LTOT across most studies were low income/wealth (n = 6/6 studies), depressive disorders (n = 6/9 studies), and dual insurance eligibility/enrollment (n = 4/6 studies). Prescription/dispensation-related factors associated with LTOT across most studies were opioid use before surgery/trauma (n = 6/6 studies), prior/concurrent use of benzodiazepines (n = 6/6 studies), anxiolytics/sedatives/hypnotics (n = 3/4 studies), anticonvulsants (n = 3/4 studies), opioid use after surgery/trauma (n = 3/3 studies), long-acting opioids (n = 3/3 studies), and longer duration of initial opioid (n = 2/2 studies). Regarding outcomes of LTOT, most studies reported positive associations between LTOT and hospital readmission/emergency department visit (n = 3/4 studies), revision surgery (n = 2/2 studies), health care costs (n = 2/2 studies), opioid overdose (n = 1/1 study), and falls (n = 1/1 study). Evidence on the association of LTOT with mortality and fractures was inconclusive. CONCLUSIONS: This systematic review identified several predictors and adverse outcomes associated with LTOT in older adults. However, no evidence exists regarding the effectiveness of LTOT for pain management in this population. Prospective studies with long-term follow-up are needed to address this gap and inform benefit-harm assessment of LTOT in clinical practice.
Bayesian Dosing Simulator (BDS): A Pharmacokinetic Modeling Tool for Optimized Antibiotic Therapy.
Valadez A, Scheetz MH, Neely MN … +4 more , Donnelly HK, Korth E, Wunderink RG, Rhodes NJ
Pharmacotherapy · 2026 May · PMID 42057443 · Full text
BACKGROUND: Meropenem is widely used to treat hospital-acquired pneumonia in critically ill patients, with efficacy dependent on the time that free concentrations exceed the minimum inhibitory concentration (fT > MIC). I...
BACKGROUND: Meropenem is widely used to treat hospital-acquired pneumonia in critically ill patients, with efficacy dependent on the time that free concentrations exceed the minimum inhibitory concentration (fT > MIC). In practice, single-sample therapeutic drug monitoring (TDM) may not ensure target attainment, particularly in patients requiring continuous renal replacement (CRRT). Model-informed precision dosing (MIPD) enables individualized, real-time adjustments, but implementation is limited. Herein, we developed a Shiny application for Bayesian meropenem dose optimization. METHODS: A previously published nonparametric model was translated into a parametric Bayesian framework with maximum a posteriori (MAP) updating implemented through a Shiny interface. Plasma pharmacokinetic (PK) data from critically ill patients served for external validation. Posterior predictions were benchmarked against population and individual (MAP) outputs from Pmetrics 3.09 and population median profiles from 1000 Monte Carlo simulations per patient. Predictive performance was assessed using relative median prediction error (rMPE) and relative median absolute prediction error (rMAPE), for the combined cohort overall and stratified by CRRT status. Sparse sampling scenarios (one, two, and three observations per patient) were also evaluated. RESULTS: Eighteen patients were evaluated (non-CRRT n = 13; CRRT n = 5). In Pmetrics, rMPE ranged from -7.7% to 9.4% and rMAPE from 18.5% to 25.5% across renal replacement strata and prediction types. Simulation-based population predictions yielded greater error, with rMPE/rMAPE of -25%/34% in CRRT patients and -21%/30% in non-CRRT patients. Across Bayesian Dosing Simulator (BDS) sampling scenarios, prediction error remained within prespecified limits (rMPE ±20%, rMAPE ≤ 30%), with F20 ranging from 80% to 94% and F30 from 87% to 94%. CONCLUSION: A validated nonparametric meropenem model was successfully implemented within an open-source Bayesian framework yielding predictive accuracy comparable to the reference model with robust performance under sparse sampling, supporting its feasibility for individualized meropenem dosing. Prospective evaluation of its clinical safety and effectiveness is needed.
Impact of Dosing Interval Adherence on Pharmacokinetic Outcomes of Recombinant Erwinia Asparaginase in Pediatric Leukemia or Lymphoma.
Matherne MM, Panetta JC, Hopp J … +5 more , Inaba H, Pui CH, Karol SE, Bernhardt MB, Swanson HD
Pharmacotherapy · 2026 May · PMID 42011546 · Publisher ↗
INTRODUCTION: Treatment for pediatric acute lymphoblastic leukemia includes asparaginase as an integral component of therapy. Hypersensitivity reactions or silent inactivation to Escherichia coli (E. coli) formulations m...
INTRODUCTION: Treatment for pediatric acute lymphoblastic leukemia includes asparaginase as an integral component of therapy. Hypersensitivity reactions or silent inactivation to Escherichia coli (E. coli) formulations may necessitate switching to Erwinia-based asparaginase (asparaginase Erwinia chrysanthemi [E-ASP] or recombinant asparaginase Erwinia chrysanthemi [R-ASP]). However, pharmacokinetic data for R-ASP in pediatrics remain limited, and recommended dosing schedules present logistical challenges. We investigated if adherence to approved dosing regimens for R-ASP is necessary to achieve optimal pharmacokinetic exposure in pediatric patients with leukemia or lymphoma. METHODS: We performed a single institution, retrospective review of pharmacokinetic data in patients who received R-ASP between October 1, 2021 and September 30, 2024. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to evaluate asparaginase pharmacokinetic activity. The pharmacokinetic model was used to determine if the labeled dosing window for R-ASP is required to achieve effective asparagine depletion. RESULTS: Twenty-six patients with 115 measurements of serum asparaginase activity (SAA) were included in the analysis. Based on model simulations from our pediatric patient data, maintaining SAA ≥ 0.1 IU/mL in 90% of patients throughout the dosing interval with R-ASP 25/25/50 mg/m administered intramuscularly on Monday, Wednesday, and Friday requires precise timing. Specifically, the Friday 50 mg/m dose must be administered within 58 h of the Wednesday morning dose to sustain therapeutic activity. Additionally, only 62.5% of patients maintained SAA ≥ 0.1 IU/mL at 72 h after the last dose with R-ASP 25 mg/m administered intramuscularly on a Monday, Wednesday, and Friday dosing schedule. CONCLUSION: Overall, our findings support the importance of adhering closely to the United States Food and Drug Administration approved dosing schedule for R-ASP to ensure adequate asparaginase activity in pediatric patients with leukemia or lymphoma.
Thrombosis Across Female-Specific Malignancies: From Chemotherapy-Driven Risk to Prophylaxis and Drug Interactions.
Aghakouchakzadeh M, Kakavand H, Goldberg AJ … +4 more , Accordino M, Trivedi M, Raikhelkar JK, Talasaz AH
Pharmacotherapy · 2026 May · PMID 41998827 · Publisher ↗
Cancer-associated thrombosis (CAT) remains a leading cause of morbidity and mortality among patients with cancer. Female-specific malignancies such as breast, ovarian, endometrial, and cervical cancers exhibit distinct t...
Cancer-associated thrombosis (CAT) remains a leading cause of morbidity and mortality among patients with cancer. Female-specific malignancies such as breast, ovarian, endometrial, and cervical cancers exhibit distinct thrombotic profiles driven by hormonal, anatomical, and treatment-related factors. This review summarizes current evidence on CAT in these malignancies, emphasizing chemotherapy- and hormone-related risk, thromboprophylactic strategies, and pharmacologic considerations in anticoagulant selection. Ovarian cancer carries the highest incidence of venous thromboembolism (VTE), ranging from 5% to 14%, largely due to advanced disease, ascites, and platinum-based chemotherapy. Breast cancer accounts for approximately 15% of all CAT cases, with increased risk observed among patients treated with selective estrogen receptor modulators or cyclin-dependent kinase 4/6 inhibitors. Endometrial cancer presents a moderate to high risk for CAT, especially in obese patients and those receiving hormonal therapy or radiation. Prophylaxis with low-molecular-weight heparins (LMWHs) or direct oral anticoagulants (DOACs) effectively reduces VTE incidence in high-risk patients. In the API-CAT trial, reduced-dose apixaban (2.5 mg twice daily) was non-inferior to full-dose therapy for extended anticoagulation after 6 months of treatment (2.1% vs. 2.8%; adjusted subhazard ratio, 0.76; 95% Confidence Interval (CI), 0.58-0.97; p = 0.001). Drug-drug interactions with anticoagulants and agents such as doxorubicin, ribociclib, and tamoxifen warrant individualized anticoagulant selection and close monitoring. A patient-centered pharmacotherapeutic approach, supported by multidisciplinary collaboration, is essential to optimize thrombosis prevention and minimize bleeding risk in women with cancer.
Incidence of Acute Kidney Injury With the Use of Nafcillin Versus Oxacillin.
Perez AD, Brenner AL, Pieta E … +4 more , Harrison R, Sultan S, Ponder MG, Daniels L
Pharmacotherapy · 2026 May · PMID 41998805 · Publisher ↗
BACKGROUND: Antistaphylococcal penicillins (ASPs) are highly effective against infections caused by methicillin-susceptible Staphylococcus aureus (MSSA). Nafcillin and oxacillin are ASPs with similar spectra of activity,...
BACKGROUND: Antistaphylococcal penicillins (ASPs) are highly effective against infections caused by methicillin-susceptible Staphylococcus aureus (MSSA). Nafcillin and oxacillin are ASPs with similar spectra of activity, rates of efficacy, pharmacokinetic profiles, and cost. However, there is a growing body of evidence suggesting key distinctions between the safety profiles of nafcillin and oxacillin, including a higher rate of acute kidney injury (AKI) with nafcillin. This retrospective study aims to compare the rate of AKI with nafcillin versus oxacillin at a large academic medical center. METHODS: A retrospective cohort study was conducted including adult inpatients who were treated with at least six doses of oxacillin or nafcillin. The primary outcome was the incidence of AKI during treatment. Secondary outcomes included change in serum creatinine from baseline, AKI stage, duration of therapy, duration of hospitalization, and in-hospital mortality. Exploratory outcomes included the incidence of moderate hypokalemia, severe hypokalemia, and hepatotoxicity. RESULTS: Among 638 patients (171 on nafcillin, 467 on oxacillin), AKI occurred in 33.3% of patients in the nafcillin group compared to 19.5% in the oxacillin group (adjusted risk ratio 1.55, 95% confidence interval 1.16-2.06; p < 0.01). Nafcillin was associated with a greater incidence of AKI at each stage, longer duration of hospitalization, higher in-hospital mortality rate, and increased rates of moderate and severe hypokalemia compared to oxacillin. CONCLUSION: In this study, nafcillin was associated with a significantly higher incidence of AKI than oxacillin.
Contemporary Immunosuppression in Simultaneous Heart-Kidney Transplantation: A United Network for Organ-Sharing Database Analysis.
Huang X, Baker WL, Colombo PC … +2 more , Yuzefpolskaya M, Jennings DL
Pharmacotherapy · 2026 May · PMID 41947674 · Publisher ↗
BACKGROUND: Simultaneous heart-kidney transplantation (SHKT) has become increasingly common over the past decade, accompanied by evolving recipient characteristics and outcomes introduced by the 2018 United Network for O...
BACKGROUND: Simultaneous heart-kidney transplantation (SHKT) has become increasingly common over the past decade, accompanied by evolving recipient characteristics and outcomes introduced by the 2018 United Network for Organ Sharing (UNOS) heart allocation policy change. However, contemporary data on immunosuppression practices in SHKT recipients remain limited. To address these knowledge gaps, this study characterizes contemporary immunosuppression practices in SHKT recipients and evaluates their association with post-transplant outcomes. METHODS AND RESULTS: This UNOS registry analysis included adult SHKT recipients from January 2013 to June 2025. We evaluated induction and maintenance immunosuppression strategies and 1-year outcomes including treated rejection, graft failure, infection, and mortality. Among 2634 recipients, T-cell depleting agents remained the most used induction strategy (41.3%), followed by basiliximab (36.8%) and no induction (21.9%). Basiliximab use increased post-2018, while anti-thymocyte globulin use declined. mTOR inhibitor use at 1 year was highest among patients receiving T-cell depleting agents. Despite these shifts, adjusted analyses showed no significant differences in 1-year rejection, graft failure, or mortality across induction groups. CONCLUSION: Contemporary SHKT recipients experience similar 1-year outcomes across induction strategies. Basiliximab may be sufficient for standard-risk SHKT recipients.
Association of Human Leucocyte Antigen with Tacrolimus Pharmacokinetics in Renal Transplant Patients.
Hemani RJ, Joreja AS, Shete NB … +9 more , Srivastava R, Soni SM, Gang SD, Konnur AM, Hegde UN, Patel HB, Mukhopadhyay BN, Raval MA, Pandey SN
Pharmacotherapy · 2026 May · PMID 41947660 · Publisher ↗
INTRODUCTION: Tacrolimus (Tac or FK-506) is an immunosuppressive agent that inhibits T-cell activation and proliferation. It has a narrow therapeutic index and shows inter-patient variabilities in its plasma concentratio...
INTRODUCTION: Tacrolimus (Tac or FK-506) is an immunosuppressive agent that inhibits T-cell activation and proliferation. It has a narrow therapeutic index and shows inter-patient variabilities in its plasma concentration. Human Leucocyte Antigen (HLA) plays a major role in immune regulation and function. Tac inhibits the T-cells, and HLA antigens are expressed in T-cells. The objective of this study was to determine the role of the HLA Class I (HLA-A, HLA-B, and HLA-C) and Class II (HLA-DRB1, HLA-DQB1, and HLA-DQA1) in influencing Tac PK among renal transplant patients. MATERIAL AND METHODS: This study included HLA genotyping data of 462 renal transplant patients. Tacrolimus blood trough concentration/dose (Co/D) was calculated on day 7 and months 1, 3, 6, and 12 post-transplantation, and the association with HLA alleles was studied. Furthermore, biopsy-proven toxicity, rejection, and pathological events were evaluated for their association with HLA alleles. RESULT: One-way ANOVA analysis showed that HLA-B*51:01 and HLA-C*16:02 were significantly associated with Tac Co/D at multiple time points, with a significance level of p < 0.05. In addition, HLA-DRB1*04:03 was associated with post-renal transplant toxicity [Hazard Ratio (HR) = 8.500, 95% Confidential Interval (CI) (1.517-47.619)] and pathological events [HR = 2.310, 95% CI (1.149-4.642)]. HLA-A*02:11 [HR = 3.530, 95% CI (1.074-11.601)], and HLA-DQB*03:01 [HR = 5.055, 95% CI (1.544-16.551)] were associated with high risk of transplant rejection. CONCLUSION: Our data suggest that HLA alleles influence the PK of Tac and affect graft survival in renal transplant patients.
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