(Z)-Endoxifen and Early Recurrence of Breast Cancer: An Explorative Analysis in a Prospective Brazilian Study.

Adherence to treatment and use of co-medication, but also molecular factors such as CYP2D6 genotype, affect tamoxifen metabolism, with consequences for early breast cancer prognosis. In a prospective study of 149 tamoxifen-treated early-stage breast cancer patients from Brazil followed up for 5 years, we investigated the association between the active tamoxifen metabolite (Z)-endoxifen at 3 months and event-free survival (EFS) adjusted for clinico-pathological factors. Twenty-five patients (16.8%) had recurred or died at a median follow-up of 52.3 months. When we applied a putative 15 nM threshold used in previous independent studies, (Z)-endoxifen levels below the threshold showed an association with shorter EFS in univariate analysis (p = 0.045) and after adjustment for stage (HR 2.52; 95% CI 1.13-5.65; p = 0.024). However, modeling of plasma concentrations with splines instead of dichotomization did not verify a significant association with EFS (univariate analysis: p = 0.158; adjusted for stage: p = 0.117). Hence, in our small exploratory study, the link between impaired tamoxifen metabolism and early breast cancer recurrence could not be unanimously demonstrated. This inconsistency justifies larger modeling studies backed up by mechanistic pharmacodynamic analyses to shed new light on this suspected association and the stipulation of an appropriate predictive (Z)-endoxifen threshold.

The Influences of Adherence to Tamoxifen and CYP2D6 Pharmacogenetics on Plasma Concentrations of the Active Metabolite (Z)-Endoxifen in Breast Cancer.

Tamoxifen efficacy in breast cancer is suspected to depend on adherence and intact drug metabolism. We evaluated the role of adherence behavior and pharmacogenetics on the formation rate of (Z)-endoxifen. In 192 Brazilian patients, we assessed plasma levels of tamoxifen and its metabolites at 3, 6, and 12 months of treatment (liquid-chromatography tandem mass spectrometry), adherence behavior (Morisky, Green, and Levine medication adherence scale), and cytochrome P450 2D6 (CYP2D6) and other pharmacogene polymorphisms (matrix-assisted laser-desorption-ionization time of flight) mass spectrometry, real-time polymerase chain reaction). Adherence explained 47% of the variability of tamoxifen plasma concentrations (P < 0.001). Although CYP2D6 alone explained 26.4%, the combination with adherence explained 40% of (Z)-endoxifen variability at 12 months (P < 0.001). The influence of low adherence to not achieving relevant (Z)-endoxifen levels was highest in patients with noncompromised CYP2D6 function (relative risk 3.65; 95% confidence interval 1.48-8.99). As a proof-of-concept, we demonstrated that (Z)-endoxifen levels are influenced both by patient adherence to tamoxifen and CYP2D6, which is particularly relevant for patients with full CYP2D6 function.

Patient safety and the value of pharmaceutical intervention in a cancer hospital.

Objective To demonstrate economic impact of pharmaceutical evaluation in detection and prevention of errors in antineoplastic prescriptions. Methods This was an observational and retrospective study performed in a cancer hospital. From July to August 2016 pharmacists checked prescriptions of antineoplastic and adjuvant drugs. Drug-related problems observed were classified and analyzed concerning drug, pharmaceutical intervention, acceptability and characteristic of the error. In case of problem related to dose, we calculated a deviation percentage related with correct dose and value spent or saved. Data were analyzed using descriptive statistics with frequency and percentage. Results A total of 6,104 prescriptions and 12,128 medications were evaluated. Drug-related problems were identified in 274 (4.5%) prescriptions. Most of them was due to lack of information (n=117; 36.1%). Problems associated with dose accounted for 32.1% (n=98) of the total. In 13 cases (13.3%) ranging of prescribed dose was 50% greater than the correct dose. Intercepted drug-related problems provided savings of R$54.081,01 and expenses of R$20.863,36, therefore resulting in a positive balance of R$33.217,65. Each intervention promoted saving of R$126,78 with an acceptance rate of 98%. Main pharmaceutical interventions were information inclusion (n=117; 36.1%) and dose change (n=97; 29.9%). All errors were classified as error with no harm. Conclusion Simple actions such as prescription checking are able to identify and prevent drug-related problems, avoid financial losses and add immeasurable value to patient safety.

Patient safety and the value of pharmaceutical intervention in a cancer hospital / Segurança do paciente e o valor da intervenção farmacêutica em um hospital oncológico

ABSTRACT Objective To demonstrate economic impact of pharmaceutical evaluation in detection and prevention of errors in antineoplastic prescriptions. Methods This was an observational and retrospective study performed in a cancer hospital. From July to August 2016 pharmacists checked prescriptions of antineoplastic and adjuvant drugs. Drug-related problems observed were classified and analyzed concerning drug, pharmaceutical intervention, acceptability and characteristic of the error. In case of problem related to dose, we calculated a deviation percentage related with correct dose and value spent or saved. Data were analyzed using descriptive statistics with frequency and percentage. Results A total of 6,104 prescriptions and 12,128 medications were evaluated. Drug-related problems were identified in 274 (4.5%) prescriptions. Most of them was due to lack of information (n=117; 36.1%). Problems associated with dose accounted for 32.1% (n=98) of the total. In 13 cases (13.3%) ranging of prescribed dose was 50% greater than the correct dose. Intercepted drug-related problems provided savings of R$54.081,01 and expenses of R$20.863,36, therefore resulting in a positive balance of R$33.217,65. Each intervention promoted saving of R$126,78 with an acceptance rate of 98%. Main pharmaceutical interventions were information inclusion (n=117; 36.1%) and dose change (n=97; 29.9%). All errors were classified as error with no harm. Conclusion Simple actions such as prescription checking are able to identify and prevent drug-related problems, avoid financial losses and add immeasurable value to patient safety.

RESUMO Objetivo Demonstrar o impacto econômico da avaliação farmacêutica na detecção e na prevenção de erros em prescrições de antineoplásicos. Métodos Estudo observacional e retrospectivo realizado em um hospital oncológico. De julho a agosto de 2016, prescrições contendo antineoplásicos e fármacos adjuvantes ao tratamento foram avaliadas por farmacêuticos. Os problemas detectados relacionados a medicamentos foram classificados e analisados quanto ao medicamento, à intervenção farmacêutica, à aceitabilidade e à caracterização do erro. Quando o problema envolveu dose, calcularam-se a percentagem de desvio em relação à dose correta e o valor gasto ou economizado. Os dados foram analisados por estatística descritiva com aplicação de frequência e percentual. Resultados Foram avaliadas 6.104 prescrições e 12.128 medicamentos. Identificaram-se problemas relacionados a medicamentos em 274 (4,5%) prescrições, sendo a maioria causado por falta de informações (n=117; 36,1%). Quando reunidos, os problemas envolvendo dose representaram 32,1% (n=98) do total. Em 13 casos (13,3%), a variação da dose prescrita em relação à correta foi maior do que 50%. Os problemas relacionados a medicamentos interceptados representaram economia de R$54.081,01 e gastos de R$20.863,36, resultando em saldo positivo de R$33.217,65. Cada intervenção promoveu economia de R$126,78 com aceitabilidade de 98%. As principais intervenções foram inclusão de informações (n=117; 36,1%) e alteração de dose (n=97; 29,9%). Todos os erros foram considerados sem dano. Conclusão Ações simples de serem implantadas, como análise de prescrições, são capazes de identificar e prevenir problemas relacionados a medicamentos, evitar perdas financeiras e agregar imensurável valor na segurança do paciente.