Gender-specific elimination of continuous-infusional 5-fluorouracil in patients with gastrointestinal malignancies: results from a prospective population pharmacokinetic study.

BACKGROUND: This study was initiated to assess the quantitative impact of patient anthropometrics and dihydropyrimidine dehydrogenase (DPYD) mutations on the pharmacokinetics (PK) of 5-fluorouracil (5FU) and to explore limited sampling strategies of 5FU. PATIENTS AND METHODS: We included 32 patients with gastrointestinal malignancies, receiving 46-h continuous-infusional 5FU and performed PK-sampling at baseline, 15, 30, 45 min, 1 and 2 h after the start of infusion and at the end of infusion, for 2 subsequent cycles. Plasma concentrations of 5FU, 5-fluorodihydrouracil (5FUH2), uracil (U) and 5,6-dihydrouracil (UH2) were determined using LC-MS/MS and submitted to population PK analysis using nonlinear mixed-effects modeling. Broad genotyping of DPYD was performed, and the potential impact of the DPYD genotype on the elimination of 5FU was assessed. Limited sampling strategies were evaluated for their accuracy to predict steady-state concentrations of 5FU (CSS(5FU)), using data simulations based on the final PK-model. RESULTS: The area-under-the concentration-time curve of 5FU (AUC(5FU)) was found to be <20 mg h/L in 33 occasions (58 %), between 20 and 30 mg h/L in 17 occasions (30 %) and >30 mg h/L in 7 occasions (12 %). Men had a 26 % higher elimination of 5FU and a 18 % higher apparent elimination of 5FUH2. Accordingly, women had a higher AUC(5FU) compared to men (22 vs. 18 mg h/L, p = 0.04). No DPYD risk variants were found, and the DPYD variants detected (c.496A>G, c.1601G>A, c.1627A>G) were not significantly associated with the elimination of 5FU. Individual baseline UH(2)/U ratio was significantly associated with AUC(5FU) (R = -0.49, p < 0.001). Limited sampling strategies with time-points <3 h after the start of infusion were not adequate to predict CSS(5FU). Female gender was the only predictor of nausea/emesis in the multivariate model. CONCLUSIONS: Gender-specific elimination of 5FU is supported by the present data and may partly explain the gender-specific association between DPYD risk variants and 5FU-specific toxicity.

[Hospital drug safety: medication errors and adverse drug reactions]. / Arzneimittelsicherheit im Spital: Medikationsfehler und unerwünschte Arzneimittelwirkungen.

BACKGROUND: Drug related problems (medication errors and adverse drug reactions) are frequent and cause increased costs. AIMS: Evaluation of the original articles published between 1991-2001 reporting frequencies of medication errors and/or METHODS: Medline search with the expressions "medication error", "adverse drug reaction", "adverse drug event", "hospital" and completion of the retrieved articles by evaluating the references and by checking review articles about this subject. RESULTS: Medication errors occur with a frequency of 5-10% of all applications, studies retrieved. This variability can be explained by the way the frequencies are expressed (per application, per patient days or per hospitalization), the reporting system (systematic acquisition vs. spontaneous reports) and the wards investigated, but not by the distribution system. Application errors are more frequent than prescription errors. Risk factors are insufficient education in pharmacology, overworked nursing personnel, non-computerized transmission of the prescriptions and lacking pharmaceutical support on the wards. Adverse drug reactions appear in about 8% of the hospitalized patients, also with a high variability among the 20 studies retrieved. This variability can be explained by differences between the wards studied and by the detection systems used. Risk factors are medication errors, female sex, age > 65 years, polypharmacy, impaired drug elimination and deviance of risk factors (e.g. previous allergic reactions). CONCLUSIONS: Computerizing the whole medication process and improving the pharmacological education of physicians and nurses could help to reduce medication errors. In addition, the adoption of clinical pharmacists on critical wards could also lower the medication error rate. For lowering the frequency of adverse drug reactions, medication errors should be avoided and the dosage of the drugs should be adapted strictly to the function of the eliminating organs. Risk factors such as drug allergies and familiar diseases should be screened for and drug therapies adapted accordingly. Severe and/or novel adverse drug reactions have to be reported to the regional pharmacovigilance centers.

[Toxic liver injuries]. / Toxische Leberschäden.

Drug induced hepatotoxicity is clinically important for several reasons. These forms of liver injury can mimic almost all other liver diseases, making it necessary to include them into the differential diagnosis in patients with unclear liver damage. The diagnosis must be made indirectly, by judging the temporal relationship with therapy and by exclusion of other liver diseases. Re-exposure is dangerous should be avoided. Knowledge of the most important risk factors is important for avoiding drug-induced liver injury. Since there is no specific therapy for most drug-induced liver injuries, early stopping of the administration of suspected drugs is very important.