Teun van Gelder

Turning Off Frequently Overridden Drug Alerts: Limited Opportunities for Doing It Safely

OBJECTIVESnThis study sought to identify opportunities to safely turn off frequently overridden drug-drug interaction alerts (DDIs) in computerized physician order entry (CPOE).nnnDESIGNnQuantitative retrospective analysis of drug safety alerts overridden during 1 month and qualitative interviews with 24 respondents (18 physicians and 6 pharmacists) about turning off frequently overridden DDI alerts, based on the Dutch drug database, in a hospital setting. Screen shots and complete texts of frequently overridden DDIs were presented to physicians of internal medicine, cardiology, and surgery and to hospital pharmacists who were asked whether these could be turned off hospital-wide without impairing patient safety, and the reasons for their recommendations.nnnRESULTSnData on the frequency of alerts overridden in 1 month identified 3,089 overrides, of which 1,963 were DDIs. The category DDIs showed 86 different alerts, of which 24 frequently overridden alerts, accounting for 72% of all DDI overrides, were selected for further evaluation. The 24 respondents together made 576 assessments. Upon investigation, differences in the reasons for turning off alerts were found across medical specialties and among respondents within a specialty. Frequently mentioned reasons for turning off were alert well known, alert not serious, or alert not needing (additional) action, or that the effects of the combination were monitored or intended. For none of the alerts did all respondents agree that it could be safely turned off hospital-wide. The highest agreement was 13 of 24 respondents (54%). A positive correlation was found between the number of alerts overridden and the number of clinicians recommending to turn them off.nnnCONCLUSIONnAlthough the Dutch drug database is already a selected reduction from all DDIs mentioned in literature, the majority of respondents wanted to turn off DDI alerts to reduce alert overload. Turning off DDI alerts hospital-wide appeared to be problematic because of differences among physicians regarding drug-related knowledge and of differences across the hospital in routine drug monitoring practices. Furthermore, several reasons for suppression of alerts could be questioned from a safety perspective. Further research should investigate when each of the following might help: changes in alert texts; new differential alert triggers based on clinician knowledge or specialty; and nonintrusive alert presentation so long as serum levels and patient parameters are measured and stay within limits.

Population pharmacokinetics of mycophenolic acid in renal transplant recipients

AbstractBackground: Mycophenolate mofetil is the prodrug of mycophenolic acid (MPA) and is used as an immunosuppressant following renal, heart, lung and liver transplantation. Although MPA plasma concentrations have been shown to correlate with clinical outcome, there is considerable inter- and intrapatient pharmacokinetic variability. Consequently, it is important to study demographic and pathophysiological factors that may explain this variability in pharmacokinetics.n Objective: The aim of the study was to develop a population pharmacokinetic model for MPA following oral administration of mycophenolate mofetil, and evaluate relationships between patient factors and pharmacokinetic parameters.n Patients and methods: Pharmacokinetic data were obtained from a randomised concentration-controlled trial involving 140 renal transplant patients. Pharmacokinetic profiles were assessed on nine occasions during a 24-week period. Plasma samples for description of full 12-hour concentration-time profiles on the first three sampling days were taken predose and at 0.33, 0.66, 1.25, 2, 6, 8 and 12 hours after oral intake of mycophenolate mofetil. For the remaining six occasions, serial plasma samples were taken according to a limited sampling strategy predose and at 0.33, 0.66, 1.25 and 2 hours after mycophenolate mofetil administration. The resulting 6523 plasma concentration-time data were analysed using nonlinear mixed-effects modelling.n Results: The pharmacokinetics of MPA were best described by a two-compartment model with time-lagged first-order absorption. The following population parameters were estimated: absorption rate constant (ka) 4.1h−1, central volume of distribution (V1) 91L, peripheral volume of distribution (V2) 237L, clearance (CL) 33 L/h, intercompartment clearance (Q) 35 L/h and absorption lag time 0.21h. The interpatient variability for ka, V1, V2 and CL was 111%, 91%, 102% and 31%, respectively; estimates of the intrapatient variability for ka, V1 and CL were 116%, 53% and 20%, respectively. For MPA clearance, statistically significant correlations were found with creatinine clearance, plasma albumin concentration, sex and ciclosporin daily dose (p < 0.001). For V1, significant correlations were identified with creatinine clearance and plasma albumin concentration (p < 0.001).n Conclusion: The developed population pharmacokinetic model adequately describes the pharmacokinetics of MPA in renal transplant recipients. The identified correlations appear to explain part of the observed inter- and intrapatient pharmacokinetic variability. The clinical consequences of the observed correlations remain to be investigated.

Understanding handling of drug safety alerts: a simulation study

PURPOSEnTo study correctness of drug safety alert handling and error type in a computerized physician order entry (CPOE) system in a simulated work environment.nnnMETHODSnDisguised observation study of 18 physicians (12 from internal medicine and 6 from surgery) entering 35 orders of predefined patient cases with 13 different drug safety alerts in a CPOE. Structured interviews about how the generated drug safety alerts were handled in the simulation test and resemblance of the test to the normal work environment. Handling and reasons for this were scored for correctness and error type.nnnRESULTSnThirty percent of alerts were handled incorrectly, because the action itself and/or the reason for the handling were incorrect. Sixty-three percent of the errors were categorized as rule based and residents in surgery used incorrect justifications twice as often as residents in internal medicine. They often referred to monitoring of incorrect substances or parameters. One alert presented as a second alert in one screen was unconsciously overridden several times. One quarter of residents showed signs of alert fatigue.nnnCONCLUSIONnAlthough alerts were mainly handled correctly, underlying rules and reasoning were often incorrect, thereby threatening patient safety. This study gave an insight into the factors playing a role in incorrect drug safety alert handling that should be studied in more detail. The results suggest that better training, improved concise alert texts, and increased specificity might help. Furthermore, the safety of the predefined override reason will monitor and double alert presentation in one screen is questioned.

Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is used to prevent graft rejection in renal transplant recipients. MPA is glucuronidated to the metabolite MPAG, which exhibits enterohepatic recirculation (EHC). MPA binds for 97% and MPAG binds for 82% to plasma proteins. Low plasma albumin concentrations, impaired renal function and coadministration of cyclosporine have been reported to be associated with increased clearance of MPA. The aim of the study was to develop a population pharmacokinetic model describing the relationship between MMF dose and total MPA (tMPA), unbound MPA (fMPA), total MPAG (tMPAG) and unbound MPAG (fMPAG). In this model the correlation between pharmacokinetic parameters and renal function, plasma albumin concentrations and cotreatment with cyclosporine was quantified. tMPA, fMPA, tMPAG and fMPAG concentration–time profiles of renal transplant recipients cotreated with cyclosporine (nxa0=xa048) and tacrolimus (nxa0=xa045) were analyzed using NONMEM. A 2- and 1-compartment model were used to describe the pharmacokinetics of fMPA and fMPAG. The central compartments of fMPA and fMPAG were connected with an albumin compartment allowing competitive binding (bMPA and bMPAG). tMPA and tMPAG were modeled as the sum of the bound and unbound concentrations. EHC was modeled by transport of fMPAG to a separate gallbladder compartment. This transport was decreased in case of cyclosporine cotreatment (Pxa0<xa00.001). In the model, clearance of fMPAG decreased when creatinine clearance (CrCL) was reduced (Pxa0<xa00.001), and albumin concentration was correlated with the maximum number of binding sites available for MPA and MPAG (Pxa0<xa00.001). In patients with impaired renal function cotreated with cyclosporine the model adequately described that increasing fMPAG concentrations decreased tMPA AUC due to displacement of MPA from its binding sites. The accumulated MPAG could also be reconverted to MPA by the EHC, which caused increased tMPA AUC in patients cotreated with tacrolimus. Changes in CrCL had hardly any effect on fMPA exposure. A decrease in plasma albumin concentration from 0.6 to 0.4xa0mmol/l resulted in ca. 38% reduction of tMPA AUC, whereas no reduction in fMPA AUC was seen. In conclusion, a pharmacokinetic model has been developed which describes the relationship between dose and both total and free MPA exposure. The model adequately describes the influence of renal function, plasma albumin and cyclosporine co-medication on MPA exposure. Changes in protein binding due to altered renal function or plasma albumin concentrations influence tMPA exposure, whereas fMPA exposure is hardly affected.

Population pharmacokinetics of mycophenolic acid : a comparison between enteric-coated mycophenolate sodium and mycophenolate mofetil in renal transplant recipients.

AbstractObjective: The pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).n Methods: MPA concentration-time profiles were included from EC-MPS- (n = 208) and MMF-treated (n = 184) patients 4–257 months after renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEM®). A two-compartment model with first-order absorption and elimination was used to describe the data.n Results: No differences were detected in MPA clearance, intercompartmental clearance, or the central or peripheral volume of distribution. Respective values and interindividual variability (IIV) were 16 L/h (39%), 22 L/h (78%), 40 L (100%) and 518 L (490%). EC-MPS was absorbed more slowly than MMF with respective absorption rate constant values of 3.0 h−1 and 4.1 h−1 (p < 0.001) [IIV 187%]. A mixture model was used for the change-point parameter lag-time (tlag) in order to describe IIV in this parameter adequately for EC-MPS. Following the morning dose of EC-MPS, the tlag values were 0.95, 1.88 and 4.83 h for 51%, 32% and 17% of the population (IIV 8%), respectively. The morning tlag following EC-MPS administration was significantly different from both the tlag following MMF administration (0.30 h; p < 0.001 [IIV 11%]) and the tlag following the evening dose of EC-MPS (9.04 h; p < 0.001 [IIV 40%]). Post hoc analysis showed that the tlag was longer and more variable following EC-MPS administration (morning median 2.0 h [0.9–5.5 h], evening median 8.9 h [5.4–12.3 h]) than following MMF administration (median 0.30 h [0.26–0.34 h]; p < 0.001). The morning MPA predose concentrations were higher and more variable following EC-MPS administration than following MMF administration, with respective values of 2.6 mg/L (0.4–24.4 mg/L) and 1.6 mg/L (0.2–7.6 mg/L). The correlation between predose concentrations and the area under the plasma concentration-time curve (AUC) was lower in EC-MPS-treated patients (r2 = 0.02) than in MMF-treated patients (r2 = 0.48).n Conclusion: Absorption of MPA was delayed and also slower following EC-MPS administration than following MMF administration. Furthermore, the tlag varied more in EC-MPS-treated patients. MPA predose concentrations were poorly correlated with the MPA AUC in both MMF- and EC-MPS-treated patients.

Unjustified prescribing of CYP2D6 inhibiting SSRIs in women treated with tamoxifen

Tamoxifen is a largely inactive pro-drug, requiring metabolism into its most important metabolite endoxifen. Since the cytochrome P450 (CYP) 2D6 enzyme is primarily involved in this metabolism, genetic polymorphisms of this enzyme, but also drug-induced CYP2D6 inhibition can result in considerably reduced endoxifen formation and as a consequence may affect the efficacy of tamoxifen treatment. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) have been effectively used for the treatment of depression and hot flashes, both of which occur frequently in tamoxifen-treated women. Due to the drug–drug interaction considerably reduced endoxifen concentrations by inhibition of CYP2D6 will be the result. Evidence of a significant influence of strong CYP2D6-inhibiting drugs on the pharmacokinetics of tamoxifen has resulted in recommendations to avoid potent CYP2D6-inhibiting antidepressants (e.g., paroxetine, fluoxetine) in patients treated with tamoxifen for breast cancer. Nevertheless, dispensing data for tamoxifen and seven regularly used SSRIs/SNRIs in the period between 2005 and 2010, obtained from a large community pharmacy database in the Netherlands (3,000,000 people), show that the potent CYP2D6-inhibiting drug paroxetine remains one of the most frequently used antidepressants in tamoxifen-treated patients. Moreover, trends in the use of SSRIs/SNRIs in the population of all women were similar with trends in women using tamoxifen. Apparently, the recommendations to avoid paroxetine in tamoxifen-treated women have not been implemented into clinical practice. Several reasons may underlie continued use of this drug–drug combination. Contrary to CYP2D6 polymorphisms, drug-induced CYP2D6 inhibition can easily be avoided, since alternative drugs are available. In clinical practice, one should strive to avoid potent CYP2D6 inhibitors as much as possible in tamoxifen-treated patients to reduce the risk of compromising the efficacy of the hormonal therapy. Co-medication should be reviewed by both physicians and pharmacists and potent CYP2D6 inhibitors ought to be switched to weaker alternatives.

Individualization of tamoxifen therapy: Much more than just CYP2D6 genotyping

Clinical response to tamoxifen varies widely among women treated with this drug for hormone receptor-positive breast cancer. The principal active metabolite - endoxifen - is generated through hepatic metabolism of tamoxifen, with key roles for cytochrome P450 (CYP) CYP2D6 and CYP3A. By influencing endoxifen formation, genetic variants of CYP2D6 may affect response to tamoxifen. After a decade of research, examining the effects of CYP2D6 genetic variants on tamoxifen efficacy, there is still no agreement on the clinical utility of CYP2D6 genotype as biomarker for the prediction of breast cancer outcome, because studies revealed conflicting results. However, tamoxifen metabolism is complex and involves several other drug-metabolizing enzymes. Genetic variants of other CYP enzymes, including CYP3A4 and CYP2C9/19, as well as co-medication interfering with the metabolic activity of CYP2D6 and CYP3A4 have been shown to affect endoxifen concentrations and may also contribute to the variability in response to tamoxifen. Phenotyping strategies can predict endoxifen exposure more accurately than CYP2D6 genotype, but do not take into account all factors influencing endoxifen exposure. Therapeutic drug monitoring (TDM) is likely to be the optimal strategy for individualization of tamoxifen treatment. According to a growing amount of literature, endoxifen concentration seems to be a predictor of clinical outcome. The relationship between endoxifen levels and breast cancer outcomes has to be replicated and confirmed and the value of TDM should be evaluated in prospective clinical trials. Caution is advised regarding the concomitant use of medications which could interact with tamoxifen, including inhibitors and inducers of CYP enzymes.

Time-dependent Drug-Drug Interaction Alerts in Care Provider Order Entry: Software May Inhibit Medication Error Reductions

Time-dependent drug-drug interactions (TDDIs) are drug combinations that result in a decreased drug effect due to coadministration of a second drug. Such interactions can be prevented by separately administering the drugs. This study attempted to reduce drug administration errors due to overridden TDDIs in a care provider order entry (CPOE) system. In four periods divided over two studies, logged TDDIs were investigated by reviewing the time intervals prescribed in the CPOE and recorded on the patient chart. The first study showed significant drug administration error reduction from 56.4 to 36.2% (p<0.05), whereas the second study was not successful (46.7 and 45.2%; p>0.05). Despite interventions, drug administration errors still occurred in more than one third of cases and prescribing errors in 79-87%. Probably the low alert specificity, the unclear alert information content, and the inability of the software to support safe and efficient TDDI alert handling all diminished correct prescribing, and consequently, insufficiently reduced drug administration errors.

Within-patient variability in immunosuppressive drug exposure as a predictor for poor outcome after transplantation

Within-patient variability in immunosuppressive drug exposure is easily identified by measurement of drug concentrations at the outpatient clinic. Fluctuating levels despite a stable drug dose can be observed in a substantial proportion of patients. It has now been shown that this within-patient variability is a predictor for poor long-term outcome after transplantation. Nonadherence most likely is an important determinant of variability, and strategies to tackle nonadherence are being developed.

Unintended consequences of reducing QT-alert overload in a computerized physician order entry system

PurposeAfter complaints of too many low-specificity drug-drug interaction (DDI) alerts on QT prolongation, the rules for QT alerting in the Dutch national drug database were restricted in 2007 to obviously QT-prolonging drugs. The aim of this virtual study was to investigate whether this adjustment would improve the identification of patients at risk of developing Torsades de Pointes (TdP) due to QT-prolonging drug combinations in a computerized physician order entry system (CPOE) and whether these new rules should be implemented.MethodsDuring a half-year study period, inpatients with overridden DDI alerts regarding QT prolongation and with an electrocardiogram recorded before and within 1xa0month of the alert override were included if they did not have a ventricular pacemaker and did not use the low-risk combination cotrimoxazole and tacrolimus. QT-interval prolongation and the risk of developing TdP were calculated for all patients and related to the number of patients for whom a QT-alert would be generated in the new situation with the restricted database.ResultsForty-nine patients (13%) met the inclusion criteria. In this study population, knowledge base-adjustment would reduce the number of alerts by 53%. However, the positive predictive value of QT alerts would not change (31% before and 30% after) and only 47% of the patients at risk of developing TdP would be identified in CPOEs using the adjusted knowledge base.ConclusionThe new rules for QT alerting would result in a poorer identification of patients at risk of developing TdP than the old rules. This is caused by the many non-drug-related risk factors for QT prolongation not being incorporated in CPOE alert generation. The partial contribution of all risk factors should be studied and used to create clinical rules for QT alerting with an acceptable positive predictive value.