Using EMR-enabled computerized decision support systems to reduce prescribing of potentially inappropriate medications: a narrative review.

Prescribing of potentially inappropriate medications (PIMs) that pose more risk than benefit in older patients is a common occurrence across all healthcare settings. Reducing such prescribing has been challenging despite multiple interventions, including educational campaigns, audits and feedback, geriatrician assessment and formulary restrictions. With the increasing uptake of electronic medical records (EMRs) across hospitals, clinics and residential aged care facilities (RACFs), integrated with computerized physician order entry (CPOE) and e-prescribing, opportunities exist for incorporating clinical decision support systems (CDSS) into EMR at the point of care. This narrative review assessed the process and outcomes of using EMR-enabled CDSS to reduce the prescribing of PIMs. We searched PubMed for relevant articles published up to January 2018 and focused on those that described EMR-enabled CDSS that assisted prescribers to make changes at the time of ordering PIMs in adults. Computerized systems offering only medication reconciliation, dose checks, monitoring for medication errors, or basic formulary information were not included. In addition to outcome measures of medication-related processes and adverse drug events, qualitative data relating to factors that influence effectiveness of EMR-enabled CDSS were also gathered from selected studies. We analysed 20 studies comprising 10 randomized trials and 10 observational studies performed in hospitals (n = 8), ambulatory care clinics (n = 9) and RACFs (n = 3). Studies varied in patient populations (although most involved older patients), type of CDSS, method of linkage with EMR, study designs and outcome measures. However, assuming little publication bias, the totality of evidence favoured EMR-enabled CDSS as being effective in reducing the prescribing of PIMs in hospitals, although results were more mixed for ambulatory care settings and RACFs. While absolute effects in most positive studies were modest, they suggest EMR-enabled CDSS are feasible and acceptable to clinicians, and if certain design features are adhered to, there is potential for even greater impact.

Self-poisoning by older Australians: a cohort study.

OBJECTIVE: To examine the epidemiology and severity of self-poisoning by older people in Australia; to compare these data with those for overdoses in younger adults. DESIGN, SETTING, PARTICIPANTS: A cohort study of people presenting to a tertiary toxicology centre after self-poisoning over 26 years (1987-2012). MAIN OUTCOME MEASURES: Hospital length of stay (LOS); types of drug ingested; intensive care unit (ICU) admissions; in-hospital deaths. RESULTS: Of 17 276 admissions, 626 patients (3.6%) were at least 65 years old. There was a steady decline in the number of overdoses with age. Most self-poisoning by older people was intentional (80% of admissions), but the proportion of unintentional poisonings increased with age (P < 0.001). Median LOS for older patients was 34 h (interquartile range [IQR], 16-75 h), longer than for younger patients (16 h; IQR, 9-25 h; P < 0.001). 133 older patients (21.2%) were admitted to an ICU, compared with 1976 younger patients (11.9%; P < 0.001). 24 older patients (3.8%) and 93 younger patients (0.6%) died; mortality among older patients declined over time. Hypotension and arrhythmias were more common in patients over 65. Benzodiazepines (24%) were the drugs most commonly ingested by older patients, but opioids the most frequently taken drugs in fatal cases. Toxic ingestion of cardiovascular drugs increased threefold over the 26 years; about one-third of poisonings were unintentional or iatrogenic. Recreational drugs were implicated in the admissions of four older patients (0.6%), but in 7.8% of those of people under 65. CONCLUSION: Older patients treated for self-poisoning differ in several important respects from patients under 65. They are more severely affected by self-poisoning: LOS is greater, and ICU admission and mortality rates are higher.

Polypharmacy among inpatients aged 70 years or older in Australia.

OBJECTIVES: To investigate medication changes for older patients admitted to hospital and to explore associations between patient characteristics and polypharmacy. DESIGN: Prospective cohort study. PARTICIPANTS AND SETTING: Patients aged 70 years or older admitted to general medical units of 11 acute care hospitals in two Australian states between July 2005 and May 2010. All patients were assessed using the interRAI assessment system for acute care. MAIN OUTCOME MEASURES: Measures of physical, cognitive and psychosocial functioning; and number of regular prescribed medications categorised into three groups: non-polypharmacy (0-4 drugs), polypharmacy (5-9 drugs) and hyperpolypharmacy (≥ 10 drugs). RESULTS: Of 1220 patients who were recruited for the study, medication records at admission were available for 1216. Mean age was 81.3 years (SD, 6.8 years), and 659 patients (54.2%) were women. For the 1187 patients with complete medication records on admission and discharge, there was a small but statistically significant increase in mean number of regular medications per day between admission and discharge (7.1 v 7.6), while the prevalence of medications such as statins (459 [38.7%] v 457 [38.5%] patients), opioid analgesics (155 [13.1%] v 166 [14.0%] patients), antipsychotics (59 [5.0%] v 65 [5.5%] patients) and benzodiazepines (122 [10.3%] v 135 [11.4%] patients) did not change significantly. Being in a higher polypharmacy category was significantly associated with increase in comorbidities (odds ratio [OR], 1.27; 95% CI, 1.20-1.34), presence of pain (OR, 1.31; 1.05-1.64), dyspnoea (OR, 1.64; 1.30-2.07) and dependence in terms of instrumental activities of daily living (OR, 1.70; 1.20-2.41). Hyperpolypharmacy was observed in 290/1216 patients (23.8%) at admission and 336/1187 patients (28.3%) on discharge, and the proportion of preventive medication in the hyperpolypharmacy category at both points in time remained high (1209/3371 [35.9%] at admission v 1508/4117 [36.6%] at discharge). CONCLUSIONS: Polypharmacy is common among older people admitted to general medical units of Australian hospitals, with no clinically meaningful change to the number or classification (symptom control, prevention or both) of drugs made by treating physicians.

Deciding when to stop: towards evidence-based deprescribing of drugs in older populations.

Minimising the harm from inappropriate prescribing in older populations is a major urgent concern for modern healthcare systems. In everyday encounters between prescribers and patients, opportunities should be taken to identify patients at high risk of harm from polypharmacy and reappraise their need for specific drugs. Attempts to reconcile life expectancy, comorbidity burden, care goals and patient preferences with the benefits and harms of medications should be made in every patient at significant risk. Drugs identified by this process of reconciliation as conferring little or no benefit and/or excessive risk of harm should be candidates for discontinuation. Evidence supporting a structured approach to drug discontinuation (or deprescribing) is emerging, and while many barriers to deprescribing exist in routine practice, various enabling strategies can help overcome them.

Therapeutic drug monitoring of tacrolimus by liquid chromatography-tandem mass spectrometry: is it truly a routine test?

Therapeutic drug monitoring of tacrolimus by high-performance liquid chromatography-tandem mass spectrometry has become standard practice. We report on the long-term (4.5 years) use of one such method. Whole blood samples (25 µL) were treated with zinc sulphate (100 µL) and acetonitrile containing ascomycin (internal standard, 250 µL). A high-performance liquid chromatography-tandem mass spectrometer operating in positive ion mode with an electrospray interface was used. Chromatography was performed on a TDM C(18) cartridge column (10 mm × 2.1 mm, 10 µm, Waters) using a switch gradient. A total of 4029 batches were analyzed for tacrolimus; this comprised of 81950 analyses of which 61027 were patient samples. Calibration curves (1.0-50 µg/L) were run on 1765 occasions (mean r(2)=0.999; range r(2)=0.988-0.999). Inter-batch accuracy and imprecision of the method (2.5, 12.5 and 30.0 µg/L), when in routine use, was 97.6-98.5% and <8.0%, respectively (n=4031). Evaluation of the method against other methods in an external quality control scheme revealed good agreement by linear regression analysis (y=0.924x+0.196, r(2)=0.985). The percentage difference between our results and that of all methods revealed a mean bias of -6.3% and a range of -33.3% to 11.1%. During the evaluation period, four batch failures occurred (0.1% failure rate) and greater than 1000 samples per analytical column was achieved. In conclusion, the described method is ideally suited as a routine test for tacrolimus in the clinical setting.

Severe acute liver injury associated with lumiracoxib.

BACKGROUND AND AIM: Significant elevations in liver transaminases were noted in some patients during pre-marketing clinical trials with lumiracoxib, a selective COX-2 inhibitor. It was withdrawn from the Australian market in August 2007, because of an association with severe liver injury. We describe in detail three cases of severe liver injury in patients taking lumiracoxib METHODS: Three patients admitted to our hospital with severe liver injury and taking lumiracoxib are described in detail, together with information on a further six cases reported to the Australian Therapeutics Goods Administration (TGA), none of whom had pre-existing liver disease or obvious risk factors for liver disease. RESULTS: Liver histology showed severe hepatic necrosis. One patient required liver transplantation and another died. Autoantibodies were detected in all three patients. As with the other six cases reported to the TGA, all were females who had been taking lumiracoxib 200-400 mg daily, typically for a few months, for osteoarthritis. CONCLUSIONS: Lumiracoxib can be associated with severe liver injury. The presence of a variety of positive auto-antibodies suggests an altered immune response may be contributory.

The current role of liquid chromatography-tandem mass spectrometry in therapeutic drug monitoring of immunosuppressant and antiretroviral drugs.

Therapeutic drug monitoring of critical dose immunosuppressant drugs is established clinical practice and there are similar good reasons to monitor antiretrovirals. The aim of this article is to review the recent literature (last five years), with particular reference to the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS offers many potential advantages. The superior selectivity of LC-MS/MS over immunoassays for immunosuppressant drugs has been widely reported. Simultaneous measurement of a number of drugs can be performed. It is currently routine practice for the four major immunosuppressants (cyclosporin, tacrolimus, sirolimus and everolimus) to be simultaneously measured in whole blood. While up to 17 antiretroviral drugs have been simultaneously measured in plasma. The exquisite sensitivity of LC-MS/MS also provides the opportunity to measure these drugs in alternative matrices, such as dried blood spots, saliva, peripheral blood mononuclear cells and tissue. However, the clinical utility of measuring these classes of drugs in alternative matrices is still to be determined.

Measurement of urinary oxypurinol by high performance liquid chromatography-tandem mass spectrometry.

Oxypurinol is the active metabolite of allopurinol which is used to treat hyperuricaemia associated with gout. Both oxypurinol and allopurinol inhibit xanthine oxidase which forms uric acid from xanthine and hypoxanthine. Plasma oxypurinol concentrations vary substantially between individuals and the source of this variability remains unclear. The aim of this study was to develop an HPLC-tandem mass spectrometry method to measure oxypurinol in urine to facilitate the study of the renal elimination of oxypurinol in patients with gout. Urine samples (50 microL) were prepared by dilution with a solution of acetonitrile/methanol/water (95/2/3, v/v; 2 mL) that contained the internal standard (8-methylxanthine; 1.5 mg/L), followed by centrifugation. An aliquot (2 microL) was injected. Chromatography was performed on an Atlantis HILIC Silica column (3 microm, 100 mm x 2.1mm, Waters) at 30 degrees C, using a mobile phase comprised of acetonitrile/methanol/50 mM ammonium acetate in 0.2% formic acid (95/2/3, v/v). Using a flow rate of 0.35 mL/min, the analysis time was 6.0 min. Mass spectrometric detection was by selected reactant monitoring (oxypurinol: m/z 150.8-->108.0; internal standard: m/z 164.9-->121.8) in negative electrospray ionization mode. Calibration curves were prepared in drug-free urine across the range 10-200 mg/L and fitted using quadratic regression with a weighting factor of 1/x (r(2) > 0.997, n=7). Quality control samples (20, 80, 150 and 300 mg/L) were used to determine intra-day (n=5) and inter-day (n=7) accuracy and imprecision. The inter-day accuracy and imprecision was 96.1-104% and <11.2%, respectively. Urinary oxypurinol samples were stable when subjected to 3 freeze-thaw cycles and when stored at room temperature for up to 6h. Samples collected from 10 patients, not receiving allopurinol therapy, were screened and showed no significant interferences. The method was suitable for the quantification of oxypurinol in the urine of patients (n=34) participating in a clinical trial to optimize therapy of gout with allopurinol.

Using N-of-1 trials to improve patient management and save costs.

BACKGROUND: N-of-1 trials test treatment effectiveness within an individual patient. OBJECTIVE: To assess (i) the impact of three different N-of-1 trials on both clinical and economic outcomes over 12 months and (ii) whether the use of N-of-1 trials to target patients' access to high-cost drugs might be cost-effective in Australia. DESIGN: Descriptive study of management change, persistence, and costs summarizing three N-of-1 trials. PARTICIPANTS: Volunteer patients with osteoarthritis, chronic neuropathic pain or ADHD whose optimal choice of treatment was uncertain. INTERVENTIONS: Double-blind cyclical alternative medications for the three conditions. MEASURES: Detailed resource use, treatment and health outcomes (response) data collected by postal and telephone surveys immediately before and after the trial and at 3, 6 and 12 months. Estimated costs to the Australian healthcare system for the pre-trial vs. 12 months post-trial. RESULTS: Participants persisting with the joint patient-doctor decision 12 months after trial completion were 32% for osteoarthritis, 45% for chronic neuropathic pain and 70% for the ADHD trials. Cost-offsets were obtained from reduced usage of non-optimal drugs, and reduced medical consultations. Drug costs increased for the chronic neuropathic pain and ADHD trials due to many patients being on either low-cost or no pharmaceuticals before the trial. CONCLUSIONS: N-of-1 trials are an effective method to identify optimal treatment in patients in whom disease management is uncertain. Using this evidence-based approach, patients and doctors tend to persist with optimal treatment resulting in cost-savings. N-of-1 trials are clinically acceptable and may be an effective way of rationally prescribing some expensive long-term medicines.

N-of-1 randomized trials to assess the efficacy of gabapentin for chronic neuropathic pain.

OBJECTIVE: The objective of this study was to compare the efficacy of gabapentin with placebo for neuropathic pain at the individual and population levels. DESIGN: This study used an n-of-1 trial methodology with three double-blind, randomized, crossover comparisons of gabapentin with placebo. SETTING: This study was carried out at specialist outpatient clinics at two Australian hospitals. Patients. The patients are adults with chronic neuropathic pain. INTERVENTIONS: Following a dose-finding period, participants underwent three comparisons of 2-week periods on gabapentin (600-1,800 mg per day) and placebo. The dose-finding period was commenced by 112 patients, of whom 39 had no response so they did not enroll, leaving 73 trial participants. Of these, 48 completed and 7 partially completed their trials, and 18 withdrew. OUTCOME MEASURES: The five outcome measures were the visual analog scale (0-10) of pain, sleep interference and functional limitation; frequency of adverse events and medication preference. The aggregate response was determined by weighting the response to each measure equally. RESULTS: Of the 55 participants who completed at least one cycle, the aggregate response to gabapentin was better than placebo in 16 (29%), of whom 15 continued gabapentin posttrial. No difference was shown in 38 (69%), and 1 (2%) showed a better response to placebo. Fifteen of these 39 continued gabapentin posttrial. Meta-analysis of the mean scores showed lower mean (standard deviation) scores for gabapentin by 0.8 (0.2) for pain, 0.6 (0.2) for sleep interference, and 0.6 (0.2) for functional limitation. CONCLUSIONS: The response rate and mean reduction in symptoms with gabapentin were small. Gabapentin prescribing posttrial was significantly influenced by the trial results.

A HPLC-mass spectrometric method suitable for the therapeutic drug monitoring of everolimus.

We report here the validation of an HPLC-electrospray-tandem mass spectrometry method for the quantification of everolimus, an immunosuppressant drug. Whole blood samples (100 microl) were extracted by protein precipitation which involved sample pre-treatment with zinc sulphate followed by acetonitrile (containing internal standard, 40-O-(3'-hydroxy)propyl-rapamycin). HPLC was performed using a step-gradient at a flow rate of 0.6 ml/min on a Waters TDM C18 column (10 mm x 2.1mm I.D.) with a resultant chromatographic analysis time of 2 min. Mass spectrometric detection by selected reaction monitoring (everolimus m/z 975.5-->908.3; internal standard m/z 989.5-->922.3). The assay was linear from 0.5 to 40 microg/l (r2>0.994, n=11). The inter- and intra-day analytical recovery and imprecision for quality control samples (1.25, 12.5 and 30 microg/l) were 93.4-98.2% and <10.7%, respectively (n=10). At the lower limit of quantification (0.5 microg/l) the inter- and intra-day analytical recovery was 94.4-95.8% with imprecision of <14.1% (n=10). The absolute recovery of everolimus (6.5 microg/l) and internal standard (12.5 microg/l) was 96.5 and 88.3%, respectively (n=3). A comparison of our method against the mean of all HPLC methods for a series of samples from an external proficiency testing scheme revealed good correlation as shown by the regression analysis: y=0.973x+0.301 (r2=0.986, n=71). In conclusion, the method described is suited to the current requirements for therapeutic drug monitoring of everolimus.

A rapid HPLC-mass spectrometry cyclosporin method suitable for current monitoring practices.

OBJECTIVES: Cyclosporin is an immunosuppressant drug with a narrow therapeutic window. Trough and 2-h post-dose blood samples are currently used for therapeutic drug monitoring in solid organ transplant recipients. The aim of the current study was to develop a rapid HPLC-tandem mass spectrometry (HPLC-MS) method for the measurement of cyclosporin in whole blood that was not only suitable for the clinical setting but also considered a reference method. METHODS: Blood samples (50 muL) were prepared by protein precipitation followed by C(18) solid-phase extraction while using d(12) cyclosporin as the internal standard. Mass spectrometric detection was by selected reaction monitoring with an electrospray interface in positive ionization mode. RESULTS: The assay was linear from 10 to 2000 microg/L (r(2)>0.996, n=9). Inter-day analytical recovery and imprecision using whole blood quality control samples at 10, 30, 400, 1500, and 2000 microg/L were 94.9--103.5% and <7.7%, respectively (n=5). The assay had a mean relative recovery of 101.6%. Ion suppression was<8.0% of the total signal (n=15). Extracted samples were stable for 6 h. Patient samples, measured by this method and compared with a validated HPLC-UV assay, revealed a strong correlation (r=0.998) and excellent agreement with a mean percentage bias of 2.1% (n=60). CONCLUSION: This high-throughput method provides accurate, precise, and specific measurement of cyclosporin in blood over a wide analytical range, thus making it suitable for current clinical monitoring strategies.

Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant.

AIMS: The pharmacokinetics of mycophenolic acid and its glucuronide are complex. This study investigated the pharmacokinetics, pharmacodynamics and protein binding of mycophenolic acid and its glucuronide metabolite, early post-transplant in renal allograft recipients. METHODS: Forty-two de novo renal transplant recipients receiving mycophenolate mofetil and concomitant cyclosporin (n = 32) or tacrolimus (n = 10) participated in the study. Blood samples were taken on day 5 post-transplant for measurement of free and total concentrations of mycophenolic acid, mycophenolic acid glucuronide and relevant biochemistry. Associations between free fraction and biochemistry were investigated. Free and total 6-h area under the concentration-time curve (AUC0-6) of mycophenolic acid was assessed relative to clinical outcomes in the first month post-transplant. RESULTS: Kinetic variability of free and total mycophenolic acid and its glucuronide was greater in patients on cyclosporin (12- to 18-fold variation) than on tacrolimus (four- to fivefold) cotherapy. Cyclosporin-treated patients also had significantly lower predose total mycophenolic acid concentrations than tacrolimus-treated patients (median 0.8 mg l(-1) and 1.6 mg l(-1), respectively, P = 0.002). Mycophenolic acid glucuronide predose concentration correlated positively with mycophenolic acid glucuronide AUC0-6 (r > 0.95). Mycophenolic acid free fraction varied 11-fold, from 1.6% to 18.3%, whilst the glucuronide free fraction varied threefold, from 17.4% to 54.1%. Urea and creatinine concentrations correlated positively (r > 0.46), whilst albumin correlated negatively (r = -0.54) with free fraction of mycophenolic acid. Similar relationships were found for the free fraction of mycophenolic acid glucuronide. Mycophenolic acid free fraction was on average 70% higher in patients with albumin concentrations below a specified albumin cut-off concentration of 31 g l(-1)[free fraction = 7 +/- 4% for lower albumin and 4 +/- 3% for higher albumin, respectively; P = 0.001; 95% confidence interval (CI) for the difference 1.9, 4.2]. Neither free nor total mycophenolic acid AUC0-6 was related to rejection (P > 0.07). Free AUC0-6 was significantly higher in those patients with thrombocytopenic, leukopenic and/or infectious outcomes than in those without (mean +/- SD 1.9 +/- 0.3 mg h(-1) l(-1) and 1.1 +/- 0.1 mg h(-1) l(-1), P = 0.0043; 95% CI for the difference 0.3, 1.4). CONCLUSIONS: The marked variability in mycophenolic acid/glucuronide pharmacokinetics occurring early post-transplant during the current study was greater in cyclosporin (12-18-fold) than in tacrolimus (four- to fivefold) treated patients. Concomitant cyclosporin was associated with total mycophenolic acid concentrations approximately half that of tacrolimus. Patients with marked renal impairment had the highest free fractions reported to date. The exposure to unbound mycophenolic acid was significantly related to infections and haematological toxicity.

The measurement of nicotine in human plasma by high-performance liquid chromatography-electrospray-tandem mass spectrometry.

The authors describe a reverse-phase high-performance liquid chromatography-electrospray-tandem mass spectrometry method for the measurement of nicotine in human plasma. Samples (500 microL) with added deuterium-labeled d3-nicotine as an internal standard (IS) were treated with a 2-step process of ether extraction (6 mL) followed by back-extraction into 0.1% formic acid (50 microL). Chromatography was performed on a phenyl Novapak column with a mobile phase consisting of 50% 10 mM ammonium formate (pH 3.3) and acetonitrile (50:50, vol/vol). A flow rate of 0.2 mL/min resulted in a total analysis time of 5 minutes per sample. Mass spectrometric detection was by selected reactant monitoring (nicotine m/z 163.2 --> 130.2; IS m/z 166.2 --> 87.2). The assay was linear from 0.5 to 100 microg/L (r > 0.993, n = 9). The accuracy and imprecision of the method for quality control samples were 87.5% to 113% and <10.2%, respectively. Interday accuracy and imprecision at the limit of quantification (0.5 microg/L) was 113% and 7.2% (n = 4). The process efficiency for nicotine in plasma was >75%. The method described has good process efficiency, stabilized nicotine, avoided concentration steps, and most importantly minimized potential contamination. Further, we have established that water-based standards and controls are interchangeable with plasma-based samples. This method was used successfully to measure the pharmacokinetic profiles of subjects involved in the development of an aerosol inhalation drug delivery system.

Severe toxicity associated with a markedly elevated mycophenolic acid free fraction in a renal transplant recipient.

A 58-year-old man with end-stage renal failure secondary to polycystic kidney disease developed a profoundly elevated mycophenolic acid (MPA) free fraction and associated severe toxicity after cadaveric renal transplantation. Initial immunosuppressive therapy was 4 mg/kg body weight bid cyclosporin (Neoral; Novartis Pharmaceutical Co Ltd, Sydney, Australia) given orally with 1 g bid mycophenolate mofetil (MMF) (CellCept; Roche Products Pty Ltd, Sydney, Australia). In the first 5 days posttransplantation, the serum creatinine concentration fell, and the patient developed profound hypoalbuminemia (serum albumin <20 g/L) and hyperbilirubinemia (serum bilirubin >150 micromol/L) that resulted from progressing biliary obstruction. On day 5 posttransplantation, the 2-hour whole-blood cyclosporin concentration and total MPA area under the curve (AUC(0-6)) were low (837 microg/L and 12.6 mg x h/L, respectively), while the total mycophenolic acid glucuronide (MPAG) AUC(0-6) was elevated (1317 mg x h/L). MMF was continued at the same dose, but tacrolimus substituted for cyclosporin. The patient subsequently experienced severe nausea, vomiting, hematemesis, and pancytopenia (nadir white cell count 1.6 x 10(9)/L, platelet count 32 x 10(9)/L, and hemoglobin 73 g/L) that were normalized after cessation of MMF. Retrospective measurement of the free MPA concentration on day 5 showed that free MPA AUC(0-6) was markedly elevated at 2.3 mg x h/L, as was the free fraction, at 18.3%. This case illustrates how altered protein binding can be associated with severe MMF toxicity caused by an increased free MPA concentration despite relatively low total MPA. These data support the monitoring of free MPA concentrations in those patients considered at risk for MMF-related toxicity.

Leflunomide-associated pancytopenia with or without methotrexate.

OBJECTIVE: To report 18 cases of pancytopenia associated with leflunomide use in Australia, 5 of which were treated at Princess Alexandra Hospital, Brisbane. case summaries: Leflunomide was used in the treatment of rheumatoid arthritis in 17 of 18 patients; the other patient was diagnosed with systemic lupus erythematosus. Median age was 65.5 years (range 18-79), and 15 of the patients were female. Fourteen patients were on combined treatment with methotrexate. Pancytopenia was typically severe, requiring hospital admission, withdrawal of the immunosuppressant(s), intensive supportive therapy, and treatment of neutropenic sepsis. Five patients died, 4 of whom were receiving concomitant methotrexate. Time to onset of pancytopenia ranged from 11 days to 4 years (median 4 mo). In one case in which the patient had been stable while receiving leflunomide, methotrexate, and hydroxychloroquine for 4 years, fatal pancytopenia was triggered by acute renal failure secondary to dehydration and use of nonsteroidal antiinflammatory drugs. The Naranjo probability scale suggested a probable causal association in 5 cases and possible association in the remainder. DISCUSSION: Leflunomide, indicated for treatment of active rheumatoid arthritis, inhibits pyrimidine synthesis in lymphocytes and other rapidly dividing cells and may rarely be associated with life-threatening pancytopenia. Combination therapy with methotrexate may increase the risk. Time to onset is variable, and clinicians should remain vigilant, particularly when there is a change in the patient's baseline health status. CONCLUSIONS: The risk of pancytopenia during leflunomide therapy appears to be increased when the drug is combined with methotrexate and in older patients. Onset may be delayed, and ongoing monitoring of blood counts is essential.

Free mycophenolic acid should be monitored in renal transplant recipients with hypoalbuminemia.

The current approach for therapeutic drug monitoring in renal transplant recipients receiving mycophenolate mofetil (MMF) is measurement of total mycophenolic acid (MPA) concentration. Because MPA is highly bound, during hypoalbuminemia the total concentration no longer reflects the free (pharmacologically active) concentration. The authors investigated what degree of hypoalbuminemia causes a significant change in protein binding and thus percentage free MPA. Forty-two renal transplant recipients were recruited for the study. Free and total concentrations of MPA (predose, and 1, 3, and 6 hours post-MMF dose samples) and plasma albumin concentrations were determined on day 5 posttransplantation. Six-hour area under the concentration-time curve (AUC(0-6)) values were calculated for free and total MPA, and percentage free MPA was determined for each patient. The authors found a significant relationship between low albumin concentrations and increased percentage free MPA (Spearman correlation = -0.54, P < 0.0001). Receiver operating characteristic (ROC) curve analysis was performed on the albumin versus percentage free MPA data. The cutoff value of albumin determined from the ROC analysis that differentiated normal from elevated percentage free MPA (defined as > or = 3%) in this patient population was 31 g/L. At this cutoff value albumin was found to be a good predictor of altered free MPA percentage, with a sensitivity and specificity of 0.75 and 0.80, respectively, and an area under the ROC curve of 0.79. To rationalize MMF dosing regimens in hypoalbuminemic patients (plasma albumin < or = 31 g/L), clinicians should consider monitoring the free MPA concentration.