Emilie Henin

Chemotherapeutic errors in hospitalised cancer patients: attributable damage and extra costs

BackgroundIn spite of increasing efforts to enhance patient safety, medication errors in hospitalised patients are still relatively common, but with potentially severe consequences. This study aimed to assess antineoplastic medication errors in both affected patients and intercepted cases in terms of frequency, severity for patients, and costs.MethodsA 1-year prospective study was conducted in order to identify the medication errors that occurred during chemotherapy treatment of cancer patients at a French university hospital. The severity and potential consequences of intercepted errors were independently assessed by two physicians. A cost analysis was performed using a simulation of potential hospital stays, with estimations based on the costs of diagnosis-related groups.ResultsAmong the 6, 607 antineoplastic prescriptions, 341 (5.2%) contained at least one error, corresponding to a total of 449 medication errors. However, most errors (n = 436) were intercepted before medication was administered to the patients. Prescription errors represented 91% of errors, followed by pharmaceutical (8%) and administration errors (1%). According to an independent estimation, 13.4% of avoided errors would have resulted in temporary injury and 2.6% in permanent damage, while 2.6% would have compromised the vital prognosis of the patient, with four to eight deaths thus being avoided. Overall, 13 medication errors reached the patient without causing damage, although two patients required enhanced monitoring. If the intercepted errors had not been discovered, they would have resulted in 216 additional days of hospitalisation and cost an estimated annual total of 92, 907€, comprising 69, 248€ (74%) in hospital stays and 23, 658€ (26%) in additional drugs.ConclusionOur findings point to the very small number of chemotherapy errors that actually reach patients, although problems in the chemotherapy ordering process are frequent, with the potential for being dangerous and costly.

Understanding polyspecificity within the substrate‐binding cavity of the human multidrug resistance P‐glycoprotein

Human P‐glycoprotein (P‐gp) controls drugs bioavailability by pumping structurally unrelated drugs out of cells. The X‐ray structure of the mouse P‐gp ortholog has been solved, with two SSS enantiomers or one RRR enantiomer of the selenohexapeptide inhibitor QZ59, found within the putative drug‐binding pocket (Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL et al. (2009). Science 323, 1718–1722). This offered the first opportunity to localize the well‐known H and R drug‐binding sites with respect to the QZ59 inhibition mechanisms of Hoechst 33342 and daunorubicin transports, characterized here in cellulo. We found that QZ59‐SSS competes efficiently with both substrates, with KI,app values of 0.15 and 0.3 μm, which are 13 and 2 times lower, respectively, than the corresponding Km,app values. In contrast, QZ59‐RRR non‐competitively inhibited daunorubicin transport with moderate efficacy (KI,app = 1.9 μm); it also displayed a mixed‐type inhibition of the Hoechst 33342 transport, resulting from a main non‐competitive tendency (Ki2,app = 1.6 μm) and a limited competitive tendency (Ki1,app = 5 μm). These results suggest a positional overlap of QZ59 and drugs binding sites: full for the SSS enantiomer and partial for the RRR enantiomer. Crystal structure analysis suggests that the H site overlaps both QZ59‐SSS locations while the R site overlaps the most embedded location.

Solid oral forms availability in children: a cost saving investigation

AIM To assess the suitability and potential cost savings, from both the hospital and community perspective, of prescribed oral liquid medicine substitution with acceptable solid forms for children over 2 years. METHOD Oral liquid medicines dispensed from a paediatric hospital (UK) in 1 week were assessed by screening for existence of the solid form alternative and evaluating the acceptability of the available solid form, firstly related to the prescribed dose and secondly to acceptable size depending on the childs age. Costs were calculated based on providing treatment for 28 days or prescribed duration for short term treatments. RESULTS Over 90% (440/476) of liquid formulations were available as a marketed solid form. Considering dosage acceptability (maximum of 10% deviation from prescribed dosage or 0% for narrow therapeutic range drugs, maximum tablet divisions into quarters) 80% of liquids could be substituted with a solid form. The main limitation for liquid substitution would be solid form size. However, two-thirds of prescribed liquids could have been substituted with a suitable solid form for dosage and size, with estimated savings being of £5K and £8K in 1 week, respectively based on hospital and community costs, corresponding to a projected annual saving of £238K and £410K (single institution). CONCLUSION Whilst not all children over 2 years will be able to swallow tablets, drug cost savings if oral liquid formulations were substituted with suitable solid dosage forms would be considerable. Given the numerous advantages of solid forms compared with liquids, this study may provide a theoretical basis for investing in supporting children to swallow tablets/capsules.

Model-based design of rituximab dosage optimization in follicular non-Hodgkin's lymphoma

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The concentration-effect relationship of rituximab in follicular lymphoma (FL) was previously described using pharmacokinetic-pharmacodynamic (PK-PD) modelling. The influence of genetic polymorphism of FCGR3A on rituximab efficacy in FL patients was included in this PK-PD model. Previous studies suggest that increasing the dose of rituximab and/or the number of infusions may lead to a better clinical response in FL. WHAT THIS STUDY ADDS The previously validated PK-PD model can be used to design an optimized rituximab dose regimen in FL patients. Clinical trial simulation shows the potential clinical benefits of changes in rituximab dose. Optimization of the rituximab dose regimen cannot compensate for the lower response of FCGR3A-158F carriers compared with that of FCGR3A-158VV patients. AIMS Rituximab has dramatically improved the survival of patients with non-Hodgkins lymphoma (NHL). However, studies have suggested that the dose regimen currently used (i.e. 375 mg m(-2) ) could be optimized. The aims of this study were to quantify the benefits of the new dose regimen for rituximab in follicular NHL (FL) patients using a previously validated PK-PD model and to design clinical trials investigating optimization of rituximab dosage. METHODS A PK-PD model was used to predict progression-free survival (PFS) of FL patients treated by rituximab alone in asymptomatic FL, and those treated by rituximab combined with chemotherapy (R-CHOP) in relapsed/resistant FL. This model accounts for the influence of a polymorphism in FCGR3A, the gene encoding the FcγRIIIa receptor, on clinical efficacy. Several induction and maintenance dose regimens using rituximab alone or in combination with conventional chemotherapy (CHOP) were tested. The benefits of rituximab dose adjustment for F carriers were investigated. The numbers of subjects required for the design of two-armed clinical trials were calculated using model-predicted PFS at a power of 80%. RESULTS The model predicted a potential benefit of 1500 mg m(-2) maintenance doses of rituximab for both rituximab monotherapy and R-CHOP. The model shows that the PFS of FCGR3A-F carriers remains lower than that of homozygous FCGR3A-VV patients, even with markedly increased rituximab doses. CONCLUSION Our results suggest a benefit of increasing doses of rituximab in FL, both during induction and maintenance. These results need to be confirmed in controlled clinical trials.

Predictors of prescription errors involving anticancer chemotherapy agents

AIM The majority of medication errors that harm patients relate to the prescribing process. Our study aimed to identify the predictors of prescription errors involving anticancer chemotherapy agents. METHODS All consecutive antineoplastic prescriptions from June 2006 to May 2008 were analysed, with medication errors being captured. Potential risk factors for medication prescribing errors were defined in relation to the patient, chemotherapy regimen and hospital organisation. The relationship between these risk factors and observed medication errors or dose medication errors was assessed by univariate and multivariate logistic-regression analyses. RESULTS Among the 17,150 chemotherapy prescriptions, 540 contained at least one error (3.15%). The following independent predictors of risk of medication errors were identified: patients with a body surface area >2m(2) (odds ratio (OR): 1.3, 95% confidence interval (CI) 1.01-1.67, p=0.04), protocols with more than three drugs (OR: 1.91, 95%CI 1.59-2.31, p<0.001), protocols involving carboplatin (OR: 2.33, 95%CI 1.85-2.95, p<0.001), protocols requiring at least one modification by the physician (OR: 1.32, 95%CI 1.09-1.61, p=0.005), inpatient care (OR: 1.58, 95%CI 1.28-1.93, p<0.001) and prescriptions by a resident physician (OR: 1.83, 95%CI 1.50-2.22, p<0.001). The risk of medication dose prescribing errors was significantly associated with three independent factors: protocols involving carboplatin (OR: 4.47, 95%CI 3.45-5.79, p<0.001), protocols with more than three drugs (OR: 2.4, 95%CI 1.92-3.00, p<0.001) and protocols requiring at least one modification (OR: 1.33, 95%CI 1.04-1.69, p=0.02). CONCLUSION In this epidemiologic study, the independent risk factors identified should be targeted for preventive measures in order to improve anticancer agent prescriptions and reduce the risk of medication errors.

Development of a drug–disease simulation model for rituximab in follicular non‐Hodgkin's lymphoma

AIM Rituximab has dramatically improved the survival of patients with non-Hodgkins lymphomas (NHL), but the dosing regimen currently used should be optimized. However, the concentration-effect relationship of rituximab has never been described by pharmacokinetic-pharmacodynamic (PK-PD) modelling, precluding the simulation of new dosing regimens. The aim of this study was to develop a PK-PD model of rituximab in relapsed/resistant follicular NHL (FL). METHODS A model describing the relationship between rituximab concentrations and progression-free survival (PFS) was developed using data extracted from the pivotal study, which evaluated 151 relapsed/resistant FL patients. The influence of FCGR3A genetic polymorphism on the efficacy of rituximab was quantified using data from 87 relapsed/resistant FL patients. The predictive performance of the model was analysed using two independent datasets: a study that evaluated rituximab combined with chemotherapy [rituximab, cyclophosphamide, vincristine, adriamycin and prednisone (R-CHOP)] in 334 relapsed/resistant FL patients and a study that evaluated rituximab monotherapy in 47 asymptomatic FL patients with known FCGR3A genotype. RESULTS For R-CHOP, observed and model-predicted PFS (90% confidence interval) at 24 months were 0.50 and 0.48 (0.40, 0.56), respectively, for the observation arm, and 0.62 and 0.59 (0.50, 0.65), respectively, for the rituximab maintenance arm. For rituximab monotherapy, observed and predicted PFS at 24 months were 0.67 and 0.63, respectively, for FCGR3A-V/V patients, and 0.41 and 0.36 (0.25, 0.49), respectively, for FCGR3A-F carriers. CONCLUSIONS Our model provides a satisfactory prediction of PFS at 24 months. It can be used to simulate new dosing regimens of rituximab in populations of FL patients and should improve the design of future clinical trials.

Prognostic Value of Modeled PSA Clearance on Biochemical Relapse Free Survival After Radical Prostatectomy

Using population kinetic approach, we modeled PSA decline equations in patients with prostate cancer after radical prostatectomy (RP). We looked for relationships between early PSA decrease profile, characterized by PSA clearance (CLPSA) or half‐life (HLPSA), and the 2‐year biochemical relapse free survival (bRFS).

Exposure-effect population model of inolimomab, a monoclonal antibody administered in first-line treatment for acute graft-versus-host disease.

Background and objectiveInolimomab, a monoclonal antibody against interleukin (IL)-2Rα (CD25) has shown promising results in the treatment of corticosteroid-resistant acute graft-versus-host disease (GvHD). The objective of the present study was to characterise the pharmacokinetic and pharmacodynamic properties of inolimomab as first-line treatment in this condition.MethodsThe data came from 21 patients with acute GvHD (8 with an International Bone Marrow Transplant Registry [IBMTR] score of B, 11 with a score of C and 2 with a score of D) following haematopoietic stem cell transplantation after a median delay of 26 days (range 10–127 days). Inolimomab was administered at 0.1, 0.2, 0.3 or 0.4 mg/kg daily in association with methylprednisolone (2 mg/kg) for 8 or 16 days depending on the status at day 9. Then, for responder patients, administrations were continued three times weekly until day 28. Inolimomab concentrations and pharmacodynamic data (acute GvHD scores) were recorded during the study. The pharmacodynamic data were assessed in four grades according to the IBMTR and Glucksberg classification in parallel with Karnofsky scores. A population analysis was developed using a nonlinear mixedeffects model to define the pharmacokinetic model, to test covariates and, when apparent, to model the exposure-effect relationship by a proportional odds model. The modelling was finally qualified by a predictive check.ResultsThe best pharmacokinetic model was two-compartmental. For each score, the most demonstrative exposure-effect graphics linked the cumulative area under the concentration-time curve to cumulated probabilities of observing a specific score. This relationship was identified as a maximum effect model for the skin (with two patient subpopulations: sensitive/less sensitive) and a linear model for the intestinal tract and liver. No covariate was identified as influencing any of these parameters.ConclusionInolimomab exposure-effect relationships as first-line treatment for acute GvHD have been identified and modelled. The discovered dose-effect relationship allows confirmation of the treatment response, thereby establishing the first step towards optimising the inolimomab dosage in future trials.

Advantages of prostate-specific antigen (PSA) clearance model over simple PSA half-life computation to describe PSA decrease after prostate adenomectomy

OBJECTIVES A population kinetic approach based on PSA clearance (CL(PSA)) may be a more rational strategy to characterize prostate-specific antigen (PSA) decrease profile after prostate surgery than the commonly used method (half-life from mono/bi-exponential models). METHODS We used 182 post-adenomectomy PSA concentrations from 56 benign prostatic hyperplasia patients to build, with NONMEM software, a multi-exponential and a CL(PSA) model for comparison. RESULTS The best multi-exponential model was PSA(t)=4.96e(-)(0.269t)+3.10e(-)(0.16t)+0.746e(+)(0.0002t) with a stable median residual PSA at 0.64 ng/mL. The best model parametrized with clearance was CL(PSA)=0.0229()(AGE/69)(3.78). Akaike information criteria and standard errors favored the CL(PSA) model. Median peripheral zone and transitional zone productions were 0.034 ng/mL/cm(3) and 0.136 ng/mL/g. A threshold at 2 ng/mL on day 90 allowed for a diagnostic of biochemical relapse diagnostic. CONCLUSIONS The population CL(PSA) model was superior to the multi-exponential approach for investigating individual post-adenomectomy PSA decreases.

Subcutaneous trastuzumab: development of a new formulation for treatment of HER2-positive early breast cancer.

Trastuzumab is a monoclonal antibody directed against the human epidermal growth factor receptor 2 (HER2). HER2 is amplified or overexpressed in about 15% of breast cancers and is associated with aggressive disease. Clinical benefits of trastuzumab have been established in the treatment of both early and metastatic HER2-positive breast cancer. Patients with HER2-positive early breast cancer have to be treated with trastuzumab for one year in combination with and sequentially after chemotherapy. This requires that trastuzumab is intravenously infused over 30–90 minutes every 3 weeks for one year which is time-consuming for both the patient and the health care provider. Consequently, a subcutaneous formulation of trastuzumab using a recombinant human hyaluronidase has been developed. Recombinant human hyaluronidase transiently increases absorption and dispersion in the subcutaneous space of large therapeutic proteins, such as monoclonal antibodies, allowing subcutaneous administration of trastuzumab in about 5 minutes. Thus, subcutaneous trastuzumab could represent a new treatment option that could have benefit to both the patient and the health care system. This review focuses on the development of the subcutaneous trastuzumab formulation and analyzes clinical trials assessing the pharmacokinetics, efficacy, and safety of this new formulation.