Determining the Risk of Elevated Digoxin Concentrations Following Loading Dose in Patients With Acute and Chronic Kidney Disease.

BACKGROUND: The optimal loading dose of digoxin in patients with reduced kidney function is unknown. Tertiary references recommend reduced loading doses; however, these recommendations are based on immunoassays that are falsely elevated by the presence of digoxin-like immunoreactive substances, a problem that is minimized in modern assays. OBJECTIVE: To determine whether chronic kidney disease (CKD) or acute kidney injury (AKI) is associated with supratherapeutic digoxin concentrations after a digoxin loading dose. METHODS: A retrospective analysis on patients who received an intravenous loading dose of digoxin with a digoxin concentration collected 6 to 24 hours after the end of the dose. Patients were stratified into 3 groups: AKI, CKD, and non-AKI/CKD (NKI) based on glomerular filtration rate and serum creatinine. The primary outcome was frequency of supratherapeutic digoxin concentrations (>2 ng/mL) and secondary outcomes included frequency of adverse events. RESULTS: A total of 146 digoxin concentrations were included (AKI = 59, CKD = 16, NKI = 71). Frequencies of supratherapeutic concentrations were similar between groups (AKI: 10.2%, CKD: 18.8%, NKI: 11.3%; P = 0.61). Pre-planned logistic regression demonstrated no significant relationship between kidney function group and the development of a supratherapeutic concentration (AKI: odds ratio [OR]: 1.3, 95% confidence interval [CI]: 0.4-4.5; CKD: OR 4.3, 95% CI: 0.7-23). CONCLUSION AND RELEVANCE: This is the first study in routine clinical practice evaluating the relationship between kidney function and digoxin peak concentrations that differentiates AKI from CKD. We did not find a relationship between kidney function and peak concentrations; however, the group with CKD was underpowered.

Acid-base effects of continuous infusion furosemide in clinically stable surgical ICU patients: an analysis based on the Stewart model.

OBJECTIVES: We sought to test the strength of correlation between predicted and observed systemic acid-base status based on the Stewart model equations during continuous infusion (CI) furosemide therapy. DESIGN, SETTING AND PARTICIPANTS: This was a prospective, single-center, observational study conducted in the Surgical ICU of a large academic medical center. Ten critically ill patients who received CI furosemide were included. MAIN OUTCOMES AND MEASURES: The primary purpose was to characterize the relationship between changes in serum electrolyte and acid-base status and the excretion of electrolytes in the urine during infusion of CI furosemide in critically ill patients. As a secondary endpoint, we sought to evaluate the predictive application of the Stewart model. Over 72-h, intake and output volumes, electrolyte content of fluids administered, plasma and urine electrolytes, urine pH, and venous blood gases were collected. Predicted and observed changes in acid-based status were compared for each day of diuretic therapy using Spearman's correlation coefficient. RESULTS: The mean (SD) strong ion difference (SID) increased from 45.2 (3.2) at baseline to 49.6 (4.0) after 72 h of continuous infusion furosemide. At Day 1, the mean SID (observed) (SD) was 47.5 (3.5) and the predicted SID was 49.5 (5.8). Day 1 observed plasma SID was positively correlated with the predicted SID (rs = 0.80, p = 0.01). By Days 2 and 3, the correlations of observed and predicted SID were no longer statistically significant. CONCLUSIONS AND RELEVANCE: Using the Stewart model, increases in SID as an indicator of metabolic alkalosis due to the chloruretic effects of furosemide were observed. Predicted and observed SID correlated well over the first 24 h of treatment.

Hydrochloric Acid Infusion for the Treatment of Metabolic Alkalosis in Surgical Intensive Care Unit Patients.

BACKGROUND: Older reports of use of hydrochloric acid (HCl) infusions for treatment of metabolic alkalosis document variable dosing strategies and risk. OBJECTIVES: This study sought to characterize use of HCl infusions in surgical intensive care unit patients for the treatment of metabolic alkalosis. METHODS: This retrospective review included patients who received a HCl infusion for >8 hours. The primary end point was to evaluate the utility of common acid-base equations for predicting HCl dose requirements. Secondary end points evaluated adverse effects, efficacy, duration of therapy, and total HCl dose needed to correct metabolic alkalosis. Data on demographics, potential causes of metabolic alkalosis, fluid volume, and duration of diuretics as well as laboratory data were collected. RESULTS: A total of 30 patients were included, and the average HCl infusion rate was 10.5 ± 3.7 mEq/h for an average of 29 ± 14.6 hours. Metabolic alkalosis was primarily diuretic-induced (n = 26). Efficacy was characterized by reduction in the median total serum CO2 from 34 to 27 mM/L ( P < 0.001). The change in chloride ion deficit and change in apparent strong ion difference (SIDa) were not correlated with total HCl administered. There were no documented serious adverse effects related to HCl infusions. CONCLUSION: HCl was effective for treating metabolic alkalosis, and no serious adverse events were seen. In this clinical setting, the baseline chloride ion deficit and SIDa were not useful for prediction of total HCl dose requirement, and serial monitoring of response is recommended.

Off-label use of gastrointestinal medications in the intensive care unit.

PURPOSE: Determine the level of evidence supporting off-label gastrointestinal (GI) medication use and identify the medication class and indication whereby off-label use was most common. MATERIALS AND METHODS: This prospective, multicentered observational study evaluated all medication orders written in 37 intensive care units (ICUs) in the United States, over a 24-hour period. All medications classified as "GI" according to a national reference were identified. The class and indication whereby off-label use was most prominent were determined and the level of evidence was described. RESULTS: There were 774 orders from 363 patients and 63% (489 of 774) were considered off-label. Proton pump inhibitors (PPIs) accounted for most of the off-label usage (55% [271 of 489]), followed by laxatives (16% [77 of 489]) and histamine-2-receptor antagonists (H2RAs; 15% [71 of 489]). When prescribed, 99% (271 of 274) of PPIs, 99% (71 of 72) of H2RAs, and 79% (30 of 38) of promotility agents were off-label. Stress ulcer prophylaxis (100% [309 of 309]), GI bleeding (100% [18 of 18]), and gastric motility (88% [30 of 34]) were the most common off-label indications. The most common strength of recommendation and level of evidence for off-label use was indeterminate (58% [282 of 489]) and none (57% [280 of 489]), respectively. CONCLUSION: The PPIs are the most widely used off-label medications in the ICU. Stress ulcer prophylaxis is the most common indication. The level of evidence supporting off-label GI medication use is poor.

New dosing strategies for an old antibiotic: pharmacodynamics of front-loaded regimens of colistin at simulated pharmacokinetics in patients with kidney or liver disease.

Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10(8) CFU/ml) of Pseudomonas aeruginosa. The pharmacokinetics were simulated for patients with hepatic (half-life [t1/2] of 3.2 h) or renal (t1/2 of 14.8 h) disease. Front-loaded regimens (n=5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve (fAUC) compared to those with traditional dosing regimens (n=14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures (fAUC of 143 mg · h/liter) obtained killing activity similar to that of traditional regimens (fAUC of 268 mg · h/liter), with an ∼97% reduction in the area under the viable count curve over 48 h. In hepatic failure simulations, front-loaded regimens yielded rapid initial killing by up to 7 log10 within 2 h, but considerable regrowth occurred for both front-loaded and traditional regimens. No regimen eradicated the high bacterial inoculum of P. aeruginosa. The current study, which utilizes an in vitro pharmacodynamic infection model, demonstrates the potential benefits of front-loading strategies for polymyxins simulating differential pharmacokinetics in patients with hepatic and renal failure at a range of doses. Our findings may have important clinical implications, as front-loading polymyxins as a part of a combination regimen may be a viable strategy for aggressive treatment of high-bacterial-burden infections.

Mathematical modeling to reduce waste of compounded sterile products in hospital pharmacies.

In recent years, many US hospitals embarked on "lean" projects to reduce waste. One advantage of the lean operational improvement methodology is that it relies on process observation by those engaged in the work and requires relatively little data. However, the thoughtful analysis of the data captured by operational systems allows the modeling of many potential process options. Such models permit the evaluation of likely waste reductions and financial savings before actual process changes are made. Thus the most promising options can be identified prospectively, change efforts targeted accordingly, and realistic targets set. This article provides one example of such a datadriven process redesign project focusing on waste reduction in an in-hospital pharmacy. A mathematical model of the medication prepared and delivered by the pharmacy is used to estimate the savings from several potential redesign options (rescheduling the start of production, scheduling multiple batches, or reordering production within a batch) as well as the impact of information system enhancements. The key finding is that mathematical modeling can indeed be a useful tool. In one hospital setting, it estimated that waste could be realistically reduced by around 50% by using several process changes and that the greatest benefit would be gained by rescheduling the start of production (for a single batch) away from the period when most order cancellations are made.

The outcomes of emergency pharmacist participation during acute myocardial infarction.

BACKGROUND: Current guidelines recommend door-to-balloon times of 90 min or less for patients presenting to the emergency department (ED) with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To determine if a clinical pharmacist for the ED (EPh) is associated with decreased door/diagnosis-to-cardiac catheterization laboratory (CCL) time and decreased door-to-balloon time. METHODS: A retrospective observational cohort study of ED patients with STEMI requiring urgent cardiac catheterization was conducted. Blinded data collection included timing of ED and CCL arrival, diagnostic electrocardiogram (ECG), and balloon angioplasty. For cases diagnosed after ED arrival, diagnosis time was substituted for door time. Diagnosis was the time ST elevations were evident on serial ECG. EPh present and not-present groups were compared. During the study period there were two EPhs and presence was determined by their scheduled time in the ED. Univariate and multivariate analyses was used to detect differences. RESULTS: Multivariate analysis of 120 patients, controlled for CCL staff presence and arrival by pre-hospital services, determined that EPh presence is associated with a mean 13.1-min (95% confidence interval [CI] 6.5-21.9) and 11.5-min (95% CI 3.9-21.5) decrease in door/diagnosis-to-CCL and door-to-balloon times, respectively. Patients were more likely to achieve a door/diagnosis-to-CCL time≤ 30 min (odds ratio [OR] 3.1, 95% CI 1.3-7.8) and≤ 45 min (OR 2.9, 95% CI-1.0, 8.5) and a door-to-balloon time≤ 90 min (OR 1.9, 95% CI 0.7-5.5) more likely when the EPh was present. CONCLUSIONS: EPh presence during STEMI presentation to the ED is independently associated with a decrease in door/diagnosis-to-CCL and door-to-balloon times.

Proposed guidance on cost-avoidance studies in pharmacy practice.

PURPOSE: Cost-avoidance studies of pharmacist interventions are common and often the first type of study conducted by investigators to quantify the economic impact of clinical pharmacy services. The purpose of this primer is to provide guidance for conducting cost-avoidance studies pertaining to clinical pharmacy practice. SUMMARY: Cost-avoidance studies represent a paradigm conceptually different from traditional pharmacoeconomic analysis. A cost-avoidance study reports on cost savings from a given intervention, where the savings is estimated based on a counterfactual scenario. Investigators need to determine what specifically would have happened to the patient if the intervention did not occur. This assessment can be fundamentally flawed, depending on underlying assumptions regarding the pharmacists' action and the patient trajectory. It requires careful identification of the potential consequence of nonaction, as well as probability and cost assessment. Given the uncertainty of assumptions, sensitivity analyses should be performed. A step-by-step methodology, formula for calculations, and best practice guidance is provided. CONCLUSIONS: Cost-avoidance studies focused on pharmacist interventions should be considered low-level evidence. These studies are acceptable to provide pilot data for the planning of future clinical trials. The guidance provided in this article should be followed to improve the quality and validity of such investigations.

Methods used to attribute costs avoided from pharmacist interventions in acute care: A scoping review.

PURPOSE: Cost-avoidance studies are common in pharmacy practice literature. This scoping review summarizes, critiques, and identifies current limitations of the methods that have been used to determine cost avoidance associated with pharmacists' interventions in acute care settings. METHODS: An Embase and MEDLINE search was conducted to identify studies that estimated cost avoidance from pharmacist interventions in acute care settings. We included studies with human participants and articles published in English from July 2010 to January 2021, with the intent of summarizing the evidence most relevant to contemporary practice. RESULTS: The database search retrieved 129 articles, of which 39 were included. Among these publications, less than half (18 of 39) mentioned whether the researchers assigned a probability for the occurrence of a harmful consequence in the absence of an intervention; thus, a 100% probability of a harmful consequence was assumed. Eleven of the 39 articles identified the specific harm that would occur in the absence of intervention. No clear methods of estimating cost avoidance could be identified for 7 studies. Among all 39 included articles, only 1 attributed both a probability to the potential harm and identified the cost specific to that harm. CONCLUSION: Cost-avoidance studies of pharmacists' interventions in acute care settings over the last decade have common flaws and provide estimates that are likely to be inflated. There is a need for guidance on consistent methodology for such investigations for reporting of results and to confirm the validity of their economic implications.

Recommendations for end-of-life care in the intensive care unit: a consensus statement by the American College [corrected] of Critical Care Medicine.

BACKGROUND: These recommendations have been developed to improve the care of intensive care unit (ICU) patients during the dying process. The recommendations build on those published in 2003 and highlight recent developments in the field from a U.S. perspective. They do not use an evidence grading system because most of the recommendations are based on ethical and legal principles that are not derived from empirically based evidence. PRINCIPAL FINDINGS: Family-centered care, which emphasizes the importance of the social structure within which patients are embedded, has emerged as a comprehensive ideal for managing end-of-life care in the ICU. ICU clinicians should be competent in all aspects of this care, including the practical and ethical aspects of withdrawing different modalities of life-sustaining treatment and the use of sedatives, analgesics, and nonpharmacologic approaches to easing the suffering of the dying process. Several key ethical concepts play a foundational role in guiding end-of-life care, including the distinctions between withholding and withdrawing treatments, between actions of killing and allowing to die, and between consequences that are intended vs. those that are merely foreseen (the doctrine of double effect). Improved communication with the family has been shown to improve patient care and family outcomes. Other knowledge unique to end-of-life care includes principles for notifying families of a patient's death and compassionate approaches to discussing options for organ donation. End-of-life care continues even after the death of the patient, and ICUs should consider developing comprehensive bereavement programs to support both families and the needs of the clinical staff. Finally, a comprehensive agenda for improving end-of-life care in the ICU has been developed to guide research, quality improvement efforts, and educational curricula. CONCLUSIONS: End-of-life care is emerging as a comprehensive area of expertise in the ICU and demands the same high level of knowledge and competence as all other areas of ICU practice.

Predictive value of sputum gram stain for the determination of appropriate antibiotic therapy in ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is diagnosed in about 30% to 50% of critically ill postsurgical and trauma patients. Early appropriate antibiotic therapy has been associated with improved survival rates. The diagnosis, however, continues to be a challenge. We routinely employ clinical pulmonary infection scores to warrant a bronchoalveolar lavage (BAL) quantitative culture to subsequently diagnose VAP. Presumptive antibiotic therapy for the first 48 to 72 hours is based on the sputum Gram stain, obtained at the time of BAL. This study was conducted to analyze the predictive value of sputum Gram stain for selecting appropriate early antibiotic therapy for VAP as confirmed by a BAL quantitative culture (>10 CFU/mL considered diagnostic). METHODS: The retrospective analysis included 124 consecutive intensive care unit patients with 186 identified episodes of presumed VAP from December 2002 to June 2006. VAP episodes were identified by a clinical pulmonary infection score > or =6, availability of a sputum Gram stain, and a corresponding quantitative culture result from a BAL sample. RESULTS: The overall correlation between Gram stain and subsequent organism identified on the BAL quantitative culture was only fair with a kappa score of 0.314. The best predictive value calculated was for the category of negative Gram stain. However, in 10 of 45 episodes where the sputum Gram stain did not identify a predominant organism, the BAL culture isolated pathogenic strains. Pseudomonas sp. was the most common bacteria isolated from the BAL samples. CONCLUSIONS: Irrespective of sputum Gram stain, presumptive triple antibiotic coverage should be instituted to provide dual antibiotic coverage for gram-negative bacilli, and vancomycin for gram-positive cocci. Additionally, identification of no organisms in the sputum Gram stain should still prompt broad-spectrum antibiotic coverage until the final results of the BAL quantitative culture are available.

Development of the Critical Care Pharmacotherapy Trials Network.

PURPOSE: The development of the Critical Care Pharmacotherapy Trials Network (CCPTN) as a model for practice-based pharmacotherapy research is described. SUMMARY: The CCPTN was formed in 2010 as a collaborative research network dedicated to scientific investigation in the field of critical care pharmacotherapy. The CCPTN organizational structure is consistent with many professional pharmacy and interdisciplinary organizations and organized into 3 primary domains: executive committee, working committees, and network membership. The network membership consists of critical care investigators dedicated to the mission and vision of the CCPTN and is open to anyone expressing an interest in contributing to high-level research. Network member sites represent the breadth of U.S. critical care practice environments. In addition, network members include individuals with demonstrated expertise in patient safety, administration, research design, grantsmanship, database management, peer review, and scientific writing. In 2015, there were more than 100 site investigators from around the United States and Canada. Projects to date have yielded numerous abstracts, platform presentations, and peer-reviewed publications in high-impact journals. The CCPTN has expanded to form collaborations with researchers in the United Kingdom, Australia, and New Zealand. The CCPTN has identified new potential partnerships and field-based areas for inquiry. Numerous opportunities for continued growth and scientific inquiry in the field of critical care pharmacotherapy research exist for the CCPTN to foster in the coming years. CONCLUSION: The CCPTN has been a successful model for practice-based pharmacotherapy research and assists its members in expanding critical care pharmacotherapy knowledge.

Evaluation of lacrimal fluid as an alternative for monitoring glucose in critically ill patients.

OBJECTIVE: This study evaluated the use of lacrimal fluid glucose concentrations as a minimally invasive, alternative sampling strategy for monitoring glucose concentrations in surgical/trauma ICU patients. DESIGN AND SETTING: Prospective, paired sample study in an adult surgical/trauma ICU. PATIENTS: Patients receiving subcutaneous or intravenous insulin requiring routine capillary blood glucose measurements. Patients receiving ocular lubricants, artificial tears, or routinely administered ophthalmic medications and patients with facial injuries were excluded. INTERVENTIONS: Lacrimal fluid was collected using glass capillary tube placed near the cul-de-sac of the eye. Capillary blood glucose was determined using a bedside glucose meter as per routine ICU care. MEASUREMENTS AND RESULTS: Lacrimal fluid glucose concentration was analyzed using high-performance liquid chromatography with pulse amperometric detection. Forty-four paired samples from five patients were analyzed. Pearson correlation between lacrimal fluid (microM) and blood glucose (mM) concentrations and the proportional change from baseline revealed no significant associations. Due to the very poor association, enrollment was discontinued after five patients. CONCLUSIONS: Lacrimal fluid and blood glucose concentrations were poorly correlated, suggesting that the former is not a reliable alternative to blood glucose monitoring in surgical/trauma ICU patients requiring insulin therapy.

Key articles and guidelines relative to intensive care unit pharmacology--2004.

Compilations of key articles and guidelines in a particular clinical practice area are useful not only to clinicians who practice in that area, but to all clinicians. We compiled pertinent articles and guidelines pertaining to drug therapy in the intensive care setting from the perspective of actively practicing critical care pharmacists. This document differs from the original 2002 version in that a broader assembly of intensive care practitioners was involved in the compilation.

Analysis of omeprazole, midazolam and hydroxy-metabolites in plasma using liquid chromatography coupled to tandem mass spectrometry.

A method has been developed and validated for the quantitation of midazolam, alphahydroxy-midazolam, omeprazole, and hydroxyomeprazole from one 250 microL sample of human plasma using high performance liquid chromatography coupled to tandem mass spectrometry. The method was validated for a daily working range of 0.400-100 ng/mL, with limits of detection between 2 and 15 pg/mL. The inter-assay variation was less than 15% for all analytes at four control concentrations and the samples were stable for three freeze-thaw cycles under the analysis conditions and 24 h in the post-preparative analysis matrix. This method was used to analyze samples in support of clinical studies probing the activity of the cytochrome P-450 enzyme system.

Relative bioavailability of orally administered fosphenytoin sodium injection compared with phenytoin sodium injection in healthy volunteers.

STUDY OBJECTIVE: To describe the pharmacokinetics of fosphenytoin (FPHT) sodium injection when administered orally, and to determine the relative oral bioavailability (FREL ) of FPHT sodium injection compared with PHT sodium injection based on pharmacokinetic modeling in healthy volunteers. DESIGN: Open-label, randomized, single-dose, two-period, two-sequence crossover study. SETTING: University-affiliated clinical research center funded by the National Center of Research Resources. SUBJECTS: Ten healthy adult volunteers. INTERVENTION: Subjects were randomized to receive a single oral dose of either PHT sodium injection or FPHT sodium injection at a dose equivalent to 400 mg PHT acid. Blood samples were collected at baseline (just prior to administration) and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after dose administration. After a 7-14-day washout period, the subjects underwent the same study procedures for administration of the other agent (PHT or FPHT). MEASUREMENTS AND MAIN RESULTS: The mean age and weight of the 10 subjects were 37 years and 72.5 kg, respectively, and the mean dose was 5.6 mg/kg based on PHT acid equivalence. The mean FREL of FPHT was 1.21 (95% confidence interval [CI] 1.07-1.35). Serum PHT concentrations were determined by fluorescence polarization immunoassay. The median (range) maximum serum concentration (Cmax ) values were significantly higher after FPHT administration compared with PHT: 10.7 (9.0-19.4) mg/L versus 5.0 (3.2-8.9) mg/L (p=0.002). The PHT concentration after oral administration of FPHT displayed faster absorption compared with PHT, with a median (range) time to reach Cmax of 1.0 (0.5-2.0) hours versus 6.0 (2.0-24.0) hours (p=0.008). All subjects completed the study without any serious adverse events reported. CONCLUSION: FPHT sodium injection given orally was absorbed more rapidly and to a significantly greater extent than PHT sodium injection given orally to healthy volunteers. Further evaluation of oral FPHT as an alternative in patients requiring enteral feedings is warranted.

Point-of-care versus laboratory monitoring of patients receiving different anticoagulant therapies.

STUDY OBJECTIVE: To compare point-of-care and standard hospital laboratory assays for monitoring patients receiving single or combination anticoagulant regimens. DESIGN: Prospective analysis. SETTING: Nursing units and clinics at a large, community hospital. PATIENTS: One hundred fifty patients receiving anticoagulants for cardiac, vascular, orthopedic, or cancer indications. Thirty patients were enrolled into each treatment group: warfarin, enoxaparin, heparin, warfarin plus enoxaparin, and warfarin plus heparin. INTERVENTION: Capillary and venous blood samples were collected once in each patient for simultaneous measurement of international normalized ratio (INR) and activated partial thromboplastin time (aPTT) by both assays. MEASUREMENTS AND MAIN RESULTS: Mean differences in paired INR and paired aPTT by point-of-care and standard assays were small, but 95% confidence intervals were wide. The INR differences were greater for the warfarin plus heparin group than for the warfarin group or warfarin plus enoxaparin group; clinical decision agreement was 47% for warfarin plus heparin, 73% for warfarin, and 93% for warfarin plus enoxaparin. The aPTT difference was greater for the warfarin plus heparin than for the heparin group; however, clinical decision agreement, 67% and 70%, respectively, was similar. CONCLUSIONS: Point-of-care methods showed limited agreement with standard hospital laboratory assays of coagulation for all treatment groups. For INR values, significantly greater disagreement was noted between the assay methods for the warfarin plus heparin group compared with the warfarin group, but the agreement was similar for the warfarin and warfarin plus enoxaparin groups. Our data indicate that the point-of-care assays should not be considered interchangeable with standard laboratory assays.

The influence of St. John's wort on the pharmacokinetics and protein binding of imatinib mesylate.

STUDY OBJECTIVE: To determine the effect of St. John's wort on the pharmacokinetics of imatinib mesylate. DESIGN: Open-label, complete crossover, fixed-sequence, pharmacokinetic study. SETTING: Clinical research center. SUBJECTS: Ten healthy adult volunteers. INTERVENTION: Single 400-mg oral doses of imatinib were administered before and after 2 weeks of treatment with St. John's wort 300 mg 3 times/day. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of imatinib were significantly altered by St. John's wort, with reductions of 32% in the median area under the concentration-time curve from time zero to infinity (p=0.0001), 29% in maximum observed concentration (p=0.005), and 21% in half-life (p=0.0001). Protein binding ranged from 97.7-90.3% (mean 94.9%), was concentration independent, and was not altered by St. John's wort. Therapeutic outcomes of imatinib have been shown to correlate with both dose and drug concentrations. CONCLUSION: Coadministration of imatinib with St. John's wort may compromise imatinib's clinical efficacy.

Effect of tenofovir disoproxil fumarate on the pharmacokinetics and pharmacodynamics of total, R-, and S-methadone.

STUDY OBJECTIVE: To evaluate the potential effect of tenofovir disoproxil fumarate (DF) on the pharmacokinetics of methadone. DESIGN: Phase I, open-label, fixed-sequence, pharmacokinetic drug-drug interaction study. SETTING: Clinical research center. SUBJECTS: Fourteen volunteers receiving stable methadone maintenance therapy who were not infected with the human immunodeficiency virus. INTERVENTION: Tenofovir DF was added to the subjects' methadone regimens. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of total, R-, and S-methadone were evaluated at baseline and after 2 weeks of daily tenofovir DF coadministration with a light meal. Steady-state tenofovir DF pharmacokinetics were evaluated at day 15. Bioequivalence testing was conducted of total, R-, and S-methadone area under the serum or plasma concentration-time curve during the 24-hour dosing interval at steady state (AUCss) and maximum concentration in serum or plasma (Cmax). Subjects were evaluated for changes in methadone pharmacodynamics by the Short Opiate Withdrawal Scale (SOWS) and pupillary diameter measurements at frequent intervals. Coadministration with tenofovir DF did not affect the pharmacokinetics of methadone. Geometric mean R-methadone systemic exposures, AUCss and Cmax, differed by 5% or less when methadone was dosed with tenofovir DF. Similar results were observed for S-methadone and for total methadone. Both AUCss and Cmax met the strict criteria for bioequivalence between the two study periods for total, R-, and S-methadone, indicating a lack of drug interaction when tenofovir DF was coadministered with methadone. No significant changes in SOWS scores or pupillary diameter measurements occurred, and no notable clinical adverse events were reported. CONCLUSION: Tenofovir DF pharmacokinetics were comparable to previously reported values of tenofovir DF in HIV-infected patients. Coadministration of methadone with tenofovir DF did not alter the pharmacokinetics or pharmacodynamics of total, R-, or S-methadone. Tenofovir DF may be given as part of a once-daily antiretroviral regimen in patients receiving methadone maintenance therapy.