Therapeutic drug monitoring of neoadjuvant mFOLFIRINOX in resected pancreatic ductal adenocarcinoma.

BACKGROUND: Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer. METHODS: Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated. RESULTS: By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg·h/mL or CPT-11 AUC values below 10 mcg·h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC ≥28 mcg·h/mL [HR = 0.251, 95% CI 0.096-0.656; p = 0.005] and CPT-11 AUC <10 mcg·h/mL [HR = 0.189, 95% CI 0.073-0.486, p = 0.001]. CONCLUSIONS: Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma.

A pharmacometrics model to define docetaxel target in early breast cancer.

AIMS: We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure. METHODS: A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75-100 mg/m2 infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose-intensified docetaxel (300-350 mg/m2 ). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence. RESULTS: Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum and Cmax in patients showing docetaxel-associated adverse events were significantly higher than in patients free of toxicity (P < .05). Fatigue and decrease in haemoglobin and haematocrit levels were related to docetaxel AUC and Cmax and pain to AUC. AUC and Cmax >4.5 mg*h/L and 3.5 mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5 mg*h/L was associated with tumour recurrence. CONCLUSION: We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients.

Impact of the Acceptance of the Recommendations Made by a Meropenem Stewardship Program in a University Hospital: A Pilot Study.

Antimicrobial stewardship programs (ASP) promote appropriate antimicrobial use. We present a 4-year retrospective study that evaluated the clinical impact of the acceptance of the recommendations made by a meropenem-focused ASP. A total of 318 meropenem audits were performed. The ASP team (comprising infectious disease physicians, pharmacists and microbiologists) considered meropenem use in 96 audits (30.2%) to be inappropriate. The reasons to consider these uses inappropriate were the possibility of de-escalating to a narrower-spectrum antibiotic, in 66 (68.7%) audits, and unnecessary meropenem use, in 30 (31.3%) audits. The ASP team recommended de-escalation in 66 audits (68.7%) and discontinuation of meropenem in 30 audits (31.3%). ASP interventions were stratified according to whether or not recommendations were followed. The group in which recommendations were accepted and followed (i.e., accepted audit, AA) included 66 audits (68.7%) and the group in which recommendations were not followed (i.e., rejected audit, RA) included 30 (31.3%) audits. The comorbidity of the AA group (Charlson score) was higher than in the RA group (7.0 (5.0-9.0) vs. 6.0 (4.0-7.0), p = 0.02). Discontinuation of meropenem was recommended in 83.3% of audits in the AA group vs. 62.2% in the RA group (OR 3.05 (1.03-8.99), p = 0.04). Ertapenem de-escalation resulted in a 100% greater rate of follow-up compared with the non-carbapenem option (100% vs. 51.9%, OR 1.50 (1.21-1.860), p = 0.001). Significant differences were observed in the AA group when cultures were taken before antibiotic prescription-98.5% vs. 83.3% (p = 0.01, OR 13.0 (1.45-116.86))-or when screening cultures were taken-45.5% vs. 19.2% (p = 0.03, OR 3.5 (1.06-11.52)). There were no differences between the groups in terms of overall mortality and 30-day mortality, length of stay, Clostridiodes difficile infection, 30-day readmission or hospitalization costs. In conclusion, meropenem ASP recommendations contributed to a decrease in meropenem prescription without worsening clinical and economic outcomes.

Effects of dexmedetomidine on subthalamic local field potentials in Parkinson's disease.

BACKGROUND: Dexmedetomidine is frequently used for sedation during deep brain stimulator implantation in patients with Parkinson's disease, but its effect on subthalamic nucleus activity is not well known. The aim of this study was to quantify the effect of increasing doses of dexmedetomidine in this population. METHODS: Controlled clinical trial assessing changes in subthalamic activity with increasing doses of dexmedetomidine (from 0.2 to 0.6 µg kg-1 h-1) in a non-operating theatre setting. We recorded local field potentials in 12 patients with Parkinson's disease with bilateral deep brain stimulators (24 nuclei) and compared basal activity in the nuclei of each patient and activity recorded with different doses. Plasma levels of dexmedetomidine were obtained and correlated with the dose administered. RESULTS: With dexmedetomidine infusion, patients became clinically sedated, and at higher doses (0.5-0.6 µg kg-1 h-1) a significant decrease in the characteristic Parkinsonian subthalamic activity was observed (P<0.05 in beta activity). All subjects awoke to external stimulus over a median of 1 (range: 0-9) min, showing full restoration of subthalamic activity. Dexmedetomidine dose administered and plasma levels showed a positive correlation (repeated measures correlation coefficient=0.504; P<0.001). CONCLUSIONS: Patients needing some degree of sedation throughout subthalamic deep brain stimulator implantation for Parkinson's disease can probably receive dexmedetomidine up to 0.6 µg kg-1 h-1 without significant alteration of their characteristic subthalamic activity. If patients achieve a 'sedated' state, subthalamic activity decreases, but they can be easily awakened with a non-pharmacological external stimulus and recover baseline subthalamic activity patterns in less than 10 min. CLINICAL TRIAL REGISTRATION: EudraCT 2016-002680-34; NCT-02982512.

Using pharmacokinetics and pharmacogenetics to optimize psychiatric treatments: A systematic review.

OBJECTIVE: Neuropsychiatrists often resort to drugs with broad interindividual pharmacokinetic variability metabolized by highly polymorphic enzymes such as CYP2D6 and CYP2C19. Pharmacokinetics and  pharmacogenetics offer considerable promise as techniques capable to allow individualized adjustments in treatments with psychoactive drugs. The  purpose of this study was to review the existing evidence for the application of  pharmacokinetics and pharmacodynamics to the dosing of drugs used in  neuropsychiatry. METHOD: A literature search was conducted in PubMed and Embase to find  prospective studies published between January 2000 and April 2021 that used  determination of psychotropic drug plasma levels or genotyping to improve  response to treatment or minimize adverse events in adult patients with  psychiatric conditions. MeSH terms and free search terms were used. Each  article was reviewed by two independent reviewers to ensure that they met the  inclusion criteria. A quantitative method was established to assess the  quality of the articles selected. Results: A total of 27 articles met the inclusion  criteria of which 16  used pharmacokinetic and 11 pharmacogenetic techniques.  Fifty percent of pharmacokinetic studies met the five predefined quality criteria. Eight of the 16  papers were on antidepressants; the remainder were on antipsychotics. Two of the latter did not find an association with efficacy or safety. None of the  pharmacogenetic studies met the five quality criteria. Only one of the two  studies on antipsychotics found fewer adverse events with genetics-guided  dosing in patients on CYP2D6 substrate antipsychotics. Six of the nine studies  on antidepressants found that pharmacogeneticsbased dosing improved  efficacy. CONCLUSIONS: The evidence available on pharmacokinetics and  harmacodynamics- based personalization of treatment with psychoactive drugs  is scarce. Many existing studies analyze associations between genotypes and response or toxicity but provide few data on the efficacy of  treatment individualization. The results obtained suggest the existence of  significant differences in pharmacokinetic parameters between responding and  nonresponding patients, particularly in the treatment of depression. Given that  the availability of pharmacogenetic information may be useful at the beginning  of treatment, combining both techniques could help optimize pharmacotherapy.  However, clinical trials are needed to establish  their benefits with greater accuracy.

OBJETIVO: Dentro de la neuropsiquiatría es habitual el empleo de fármacos con  amplia variabilidad farmacocinética interindividual y  etabolizados por enzimas altamente polimórficas como CYP2D6 y CYP2C19. La  farmacocinética y la farmacogenética se vislumbran como herramientas de  ayuda para conseguir un ajuste personalizado en el tratamiento con psicofármacos. El objetivo de este trabajo es revisar la evidencia existente sobre la aplicación de farmacocinética y farmacogenética en la  selección de dosis de los medicamentos empleados en neuropsicofarmacología.Método: Se realizó una búsqueda en PubMed y Embase para localizar estudios  prospectivos, publicados entre enero de 2000 y abril de  021, que utilizasen la determinación de niveles plasmáticos de psicofármacos o  genotipado para mejorar la respuesta o minimizar efectos adversos en  pacientes adultos con trastornos psiquiátricos. Se emplearon términos MeSH y  texto libre. Cada artículo fue revisado por dos revisores independientes para  asegurar que cumplían los criterios de inclusión. Se estableció un método  cuantitativo para valorar la calidad de los artículos incluidos. Resultados: Se incluyeron 27 artículos, 16 utilizaban farmacocinética y 11  farmacogenética. El 50% de los estudios de farmacocinética cumplieron los  cinco criterios de calidad predefinidos. Ocho de los 16 trabajos analizaron  antidepresivos y los estudios restantes antipsicóticos. Dos de estos 8, no  encontraron asociación con eficacia o seguridad. Ninguno de los estudios de  farmacogenética cumplía los cinco criterios de calidad. Sólo 1 de los 2 estudios  de antipsicóticos encuentra reducción de efectos adversos con dosis guiadas  por genética en pacientes con antipsicóticos sustratos del CYP2D6. Seis de los  9 estudios con antidepresivos encuentran mayor eficacia al dosificar utilizando  farmacogenética. CONCLUSIONES: La evidencia disponible sobre farmacocinética y  farmacogénetica en individualización del tratamiento con psicofármacos es escasa. Gran parte de los estudios analizan asociaciones entre genotipos y  respuesta o toxicidad, proporcionando pocos datos sobre la eficacia en la  individualización del tratamiento. Los resultados obtenidos apuntan a la  existencia de diferencias significativas en parámetros farmacocinéticos entre  pacientes respondedores y no respondedores, especialmente en el tratamiento  de la depresión. Disponer de información farmacogenética puede ser de  utilidad al inicio del tratamiento, por lo que combinar ambas técnicas podría  ayudar a optimizar la farmacoterapia, pero hacen falta ensayos clínicos para  establecer claramente su beneficio.

Effectiveness of Pharmacokinetic/Pharmacodynamic-Guided Meropenem Treatment in Critically Ill Patients: A Comparative Cohort Study.

BACKGROUND: The proper dosage of antibiotics is a key element in the effective treatment of infection, especially in critically ill patients. This study aimed to evaluate the efficacy of optimized meropenem regimens based on pharmacokinetic/pharmacodynamic criteria in patients admitted to the intensive care unit. METHODS: This observational, naturalistic, retrospective, unicentric cohort study was performed between May 2011 and December 2017. The clinical and bacteriologic responses of 77 control intensive care unit patients receiving meropenem were compared with those of 77 propensity score-balanced patients who received meropenem dose adjusted by therapeutic drug monitoring. The primary end point of clinical response was a reduction at the end of treatment of at least 80% of the maximum procalcitonin (PCT) value recorded during the meropenem treatment. RESULTS: The primary end point was met by 55 patients (71.4%) in the adjusted group compared with 41 (53.3%) patients in the control group (mean difference 18.1%, P = 0.02). Fifty-one patients (66.2%) in the adjusted group required a meropenem dose adjustment, being necessary in 46 of them (90.2%) to decrease the dose. The reduction of PCT was the greatest in the adjusted group compared with the unadjusted group (93% versus 85%, P = 0.004); a greater percentage of patients reached a PCT level < 0.5 ng/mL (63.6% versus 41.6%, P = 0.006), and there was a trend toward an improved bacteriologic response (relative risk = 1.27; 95% confidence interval: 0.92-1.56). There were no differences in early mortality or safety between groups. CONCLUSIONS: Adjustment of meropenem therapy by monitoring is a useful strategy for improving meropenem effectiveness in the treatment of infection in critically ill patients, with no impact on safety.

Farmacocinética y farmacogenética en la optimización de los tratamientos en psiquiatría: Revisión sistemática / Using pharmacokinetics and pharmacogenetics to optimize psychiatric treatments: A systematic review

Objetivo: Dentro de la neuropsiquiatría es habitual el empleo de fármacos con amplia variabilidad farmacocinética interindividual y metabolizados por enzimas altamente polimórficas como CYP2D6 y CYP2C19. Lafarmacocinética y la farmacogenética se vislumbran como herramientasde ayuda para conseguir un ajuste personalizado en el tratamiento conpsicofármacos. El objetivo de este trabajo es revisar la evidencia existentesobre la aplicación de farmacocinética y farmacogenética en la selecciónde dosis de los medicamentos empleados en neuropsicofarmacología.Método: Se realizó una búsqueda en PubMed y Embase para localizarestudios prospectivos, publicados entre enero de 2000 y abril de 2021, queutilizasen la determinación de niveles plasmáticos de psicofármacos o genotipado para mejorar la respuesta o minimizar efectos adversos en pacientesadultos con trastornos psiquiátricos. Se emplearon términos MeSH y textolibre. Cada artículo fue revisado por dos revisores independientes para asegurar que cumplían los criterios de inclusión. Se estableció un método cuantitativo para valorar la calidad de los artículos incluidos.Resultados: Se incluyeron 27 artículos, 16 utilizaban farmacocinéticay 11 farmacogenética. El 50% de los estudios de farmacocinética cumplieron los cinco criterios de calidad predefinidos. Ocho de los 16 trabajos analizaron antidepresivos y los estudios restantes antipsicóticos. Dosde estos 8, no encontraron asociación con eficacia o seguridad. guno de los estudios de farmacogenética cumplía los cinco criterios decalidad. Sólo 1 de los 2 estudios de antipsicóticos encuentra reducciónde efectos adversos con dosis guiadas por genética en pacientes conantipsicóticos sustratos del CYP2D6. Seis de los 9 estudios con antidepresivos encuentran mayor eficacia al dosificar utilizando farmacogenética. (AU)

Objective: Neuropsychiatrists often resort to drugs with broad interindividual pharmacokinetic variability metabolized by highly polymorphicenzymes such as CYP2D6 and CYP2C19. Pharmacokinetics and pharmacogenetics offer considerable promise as techniques capable to allowindividualized adjustments in treatments with psychoactive drugs. The purpose of this study was to review the existing evidence for the applicationof pharmacokinetics and pharmacodynamics to the dosing of drugs usedin neuropsychiatry.Method: A literature search was conducted in PubMed and Embase tofind prospective studies published between January 2000 and April 2021that used determination of psychotropic drug plasma levels or genotyping to improve response to treatment or minimize adverse events in adultpatients with psychiatric conditions. MeSH terms and free search termswere used. Each article was reviewed by two independent reviewersto ensure that they met the inclusion criteria. A quantitative method wasestablished to assess the quality of the articles selected.Results: A total of 27 articles met the inclusion criteria of which 16 usedpharmacokinetic and 11 pharmacogenetic techniques. Fifty percent of pharmacokinetic studies met the five predefined quality criteria. Eight of the16 papers were on antidepressants; the remainder were on antipsychotics. Two of the latter did not find an association with efficacy or safety. None of the pharmacogenetic studies met the five quality criteria. Onlyone of the two studies on antipsychotics found fewer adverse events withgenetics-guided dosing in patients on CYP2D6 substrate antipsychotics.Six of the nine studies on antidepressants found that pharmacogeneticsbased dosing improved efficacy. (AU)

Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats.

Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90 mg/kg), higher dose (110-140 mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean Cmax 86.2 ng/ml vs. 26.2 ng/ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.

Clinical and economic impact of clinical pharmacist interventions regarding antimicrobials on critically ill patients.

BACKGROUND: Incorporating in the Intensive Care Unit (ICU) a clinical pharmacist who performs interventions on antimicrobials may be cost-effective. OBJECTIVES: To evaluate the clinical and economic impact of clinical pharmacist interventions on antimicrobials in an ICU. To identify drug related problems and medication errors detected by the pharmacist. METHODS: A retrospective observational study was performed to analyze drug related problems, medication errors and clinical pharmacist interventions related to antimicrobials in adults admitted to an ICU in a 5-month period. The economic impact of pharmacist interventions was estimated considering difference in cost derived from antimicrobial treatment, adverse drug events and clinical pharmacist time. RESULTS: A total of 212 drug related problems were detected in 114 patients, 18 being medication errors. Clinical pharmacist developed one intervention for each problem identified. 204 interventions (96.2%) were considered important with improved patient care and 7 (3.3%) very important. No negative impact of any intervention was identified. Physicians accepted 97.6% of the interventions. A potential saving of 10,905 € was estimated as a result of pharmacist interventions and 4.8 € were avoided per euro invested in a clinical pharmacist. CONCLUSIONS: A clinical pharmacist performing interventions on antimicrobials in the ICU has a positive impact on patient care and decreases costs.

Effectiveness of adjunctive nebulized antibiotics in critically ill patients with respiratory tract infections.

The purpose of the study was to analyze the effectiveness of adding nebulized antibiotics to systemic antimicrobials in critically ill patients with respiratory tract infections (pneumonia or tracheobronchitis) and the effect on renal function. A retrospective observational cohort study including critically ill patients with respiratory tract infections during a 2-year period was conducted. Intervention group included patients that received nebulized and systemic antimicrobials. Patients in the control group received only systemic antimicrobials. Clinical resolution was the primary endpoint. Secondary outcomes included change in fever, inflammatory parameters, and creatinine clearance; length of hospital stay, systemic therapy, and mechanical ventilation; hospital readmission; and mortality. Regression models were performed to estimate the effect of nebulized antibiotics on outcome variables adjusted by potential confounders. A total of 136 patients were included (93 in control group and 43 in intervention group). The intervention group had higher odds of clinical resolution (adjusted odds ratio (OR): 7.1; 95% confidence interval (95% CI): 1.2, 43.3). Nebulized antibiotic therapy was independently associated with reduction in procalcitonin (adjusted OR: 12.4; 95% CI: 1.4, 109.7). There were no significant differences in the rest of the secondary outcomes or in creatinine clearance reduction. Adding nebulized antibiotics for the management of respiratory tract infections has a positive impact on clinical resolution without increasing the risk of renal toxicity.

Prediction of irinotecan toxicity in metastatic colorectal cancer patients based on machine learning models with pharmacokinetic parameters.

Irinotecan (CPT-11) is a drug used against a wide variety of tumors, which can cause severe toxicity, possibly leading to the delay or suspension of the cycle, with the consequent impact on the prognosis of survival. The main goal of this work is to predict the toxicities derived from CPT-11 using artificial intelligence methods. The data for this study is conformed of 53 cycles of FOLFIRINOX, corresponding to patients with metastatic colorectal cancer. Supported by several demographic data, blood markers and pharmacokinetic parameters resulting from a non-compartmental pharmacokinetic study of CPT-11 and its metabolites (SN-38 and SN-38-G), we use machine learning techniques to predict high degrees of different toxicities (leukopenia, neutropenia and diarrhea) in new patients. We predict high degree of leukopenia with an accuracy of 76%, neutropenia with 75% and diarrhea with 91%. Among other variables, this study shows that the areas under the curve of CPT-11, SN-38 and SN-38-G play a relevant role in the prediction of the studied toxicities. The presented models allow to predict the degree of toxicity for each cycle of treatment according to the particularities of each patient.

Mining Small Routine Clinical Data: A Population Pharmacokinetic Model and Optimal Sampling Times of Capecitabine and its Metabolites.

PURPOSE: The present study was performed to demonstrate that small amounts of routine clinical data allow to generate valuable knowledge. Concretely, the aims of this research were to build a joint population pharmacokinetic model for capecitabine and three of its metabolites (5-DFUR, 5-FU and 5-FUH2) and to determine optimal sampling times for therapeutic drug monitoring. METHODS: We used data of 7 treatment cycles of capecitabine in patients with metastatic colorectal cancer. The population pharmacokinetic model was built as a multicompartmental model using NONMEM and was internally validated by visual predictive check. Optimal sampling times were estimated using PFIM 4.0 following D-optimality criterion. RESULTS: The final model was a multicompartmental model which represented the sequential transformations from capecitabine to its metabolites 5-DFUR, 5-FU and 5-FUH2 and was correctly validated. The optimal sampling times were 0.546, 0.892, 1.562, 4.736 and 8 hours after the administration of the drug. For its correct implementation in clinical practice, the values were rounded to 0.5, 1, 1.5, 5 and 8 hours after the administration of the drug. CONCLUSIONS: Capecitabine, 5-DFUR, 5-FU and 5-FUH2 can be correctly described by the joint multicompartmental model presented in this work. The aforementioned times are optimal to maximize the information of samples. Useful knowledge can be obtained for clinical practice from small databases.

Population pharmacokinetic model of irinotecan and its metabolites in patients with metastatic colorectal cancer.

PURPOSE: Irinotecan (CPT-11) is a drug used against a wide range of tumor types. The individualized dosing of CPT-11 is essential to ensure optimal pharmacotherapy in cancer patients, given the wide interindividual pharmacokinetic variability of this drug and its active metabolite SN-38. Moreover, the reabsorption from SN-38-G to SN-38, by enterohepatic recirculation, is critical due to its influence in the treatment tolerance. The aim of this research was to build a joint population pharmacokinetic model for CPT-11 and its metabolites (SN-38, and its glucuronide, SN-38-G) that enabled an individualized posology adjustment. METHODS: We used data of 53 treatment cycles of FOLFIRINOX scheme corresponding to 20 patients with metastatic colorectal cancer. In order to build the population pharmacokinetic model, we implemented parametric and non-parametric methods using the Pmetrics library package for R. We also built multivariate regression models to predict the area under the curve and the maximum concentration using basal covariates. RESULTS: The final model was a multicompartmental model which represented the transformations from CPT-11 to its active metabolite SN-38 and from SN-38 to inactive SN-38-G. Besides, the model also represented the extensive elimination of SN-38-G and the reconversion of the remaining SN-38-G to SN-38 by enterohepatic recirculation. We carried out internal validation with 1000 simulations. The regression models predicted the PK parameters with R squared adjusted up to 0.9499. CONCLUSION: CPT-11, SN-38, and SN-38-G can be correctly described by the multicompartmental model presented in this work. As far as we know, it is the first time that a joint model for CPT-11, SN-38, and SN-38-G that includes the process of reconversion from SN-38-G to SN-38 is characterized.

Propuesta para la creación de una Estrategia Nacional sobre Medicina de Precisión en Cáncer: posicionamiento de la SEOM, SEAP y SEFH / Proposal of the SEOM, SEAP and SEFH for the creation of a National Strategy for Precision Medicine in Cancer

La medicina de precisión es un enfoque emergente para el tratamiento y prevención de las enfermedades que tiene en cuenta la variabilidad individual en los genes, el medio ambiente y el estilo de vida de cada persona. La medicina de precisión está transformando la investigación clínica y biomédica así como la asistencia sanitaria, tanto desde un punto de vista conceptual como metodológico, ofertando oportunidades extraordinarias para mejorar la salud pública y reducir los costes del sistema sanitario. Sin embargo, la implementación de la medicina de precisión supone un reto a nivel ético-legal, regulatorio, organizativo y de conocimiento. Sin una estrategia nacional, la medicina de precisión, que se implantará en cualquier caso, lo podría hacer sin la adecuada planificación que permita garantizar la calidad técnica, la equidad de los ciudadanos en el acceso a las mejores prácticas, vulnerando los derechos de pacientes y profesionales y arriesgando la solvencia del sistema de salud. Con este artículo de las sociedades españolas de Oncología Médica (SEOM), Anatomía Patológica (SEAP) y Farmacia Hospitalaria (SEFH), señalamos la necesidad de establecer una estrategia nacional consensuada para el desarrollo de la medicina de precisión en nuestro país, revisamos el contexto nacional e internacional, comentamos las oportunidades y los retos para la implementación de la medicina de precisión, y delineamos los objetivos de una estrategia nacional sobre medicina de precisión en cáncer

Precision medicine is an emerging approach to the prevention and treatment of disease that takes into account variability in genes, environment and lifestyle for each individual. Precision medicine is transforming clinical and biomedical research, as well as health care itself, from a conceptual, as well as a methodological viewpoint, providing extraordinary opportunities to improve public health and lower the costs of the healthcare system. However, the implementation of precision medicine poses ethical-legal, regulatory, organizational and knowledge-related challenges. Without a national strategy, precision medicine -which eventually will be implemented one way or another- could take place without the appropriate planning to guarantee technical quality and equal access to the best practices for all citizens, thus violating the rights of patients and professionals as well as jeopardizing the solvency of the healthcare system. This paper from the Spanish Societies of Medical Oncology (SEOM), Pathology (SEAP) and Hospital Pharmacy (SEFH), highlights the need to institute a consensual national strategy for the development of precision medicine in our country, reviews the national and international context, comments on the opportunities and challenges for implementing precision medicine and outlines the objectives of a national strategy on precision medicine in cancer

Nanomedicines for Pediatric Cancers.

Chemotherapy protocols for childhood cancers are still problematic due to the high toxicity associated with chemotherapeutic agents and incorrect dosing regimens extrapolated from adults. Nanotechnology has demonstrated significant ability to reduce toxicity of anticancer compounds. Improvement in the therapeutic index of cytostatic drugs makes this strategy an alternative to common chemotherapy in adults. However, the lack of nanomedicines specifically for pediatric cancer care raises a medical conundrum. This review highlights the current state and progress of nanomedicine in pediatric cancer and discusses the real clinical challenges and opportunities.

Influence of Sex, Age, and Weight on Levetiracetam Pharmacokinetics.

BACKGROUND: Levetiracetam (LEV) is a second-generation antiepileptic drug extensively used in therapeutics. The aim of this study was to evaluate the influence that sex, age, and weight exert on LEV pharmacokinetics in clinical practice. METHODS: We conducted a 6-year retrospective observational study. Patients were classified in subgroups according to sex, weight (normal range, overweight, and obese), and age (young adult: 16-30 years old, middle-aged adult: 31-50 years old, advanced adult: 51-64 years old, and elderly adult: ≥65 years old). We compared LEV apparent oral clearance (LEV CL/F) between the subgroups. RESULTS: A total of 238 LEV basal serum concentrations (LEV C0) corresponding to 156 patients were identified. Significant differences were observed in LEV CL/F between males and females when LEV CL/F was expressed as L/h [mean (SD): 4.79 (1.84) L/h in males versus 4.13 (1.64) L/h in females; P < 0.001]. These differences were not significant when LEV CL/F was normalized by weight [mean (SD): 60.64 (24.90) mL/h/kg in males versus 64.10 (28.87) mL/h/kg in females; n.s.]. Weight in females was 17% lower compared with males. A progressive reduction in LEV CL/F was observed with increasing age, in a proportion that was similar to the decline in renal function. The elderly patients presented 30% lower LEV CL/F (mL/h/kg) and 43% lower creatinine clearance (CCr) in comparison with adults. No statistically significant differences were observed in LEV CL/F calculated in L/h between weight subgroups. However, when LEV CL/F was expressed in mL/h/kg, a progressive reduction was observed [normal weight: 72.21 (28.97); overweight: 57.84 (25.38); obese: 49.45 (14.50); P < 0.001]. A significant and positive correlation between CCr and LEV CL/F was observed, confirming the important role of the renal function in LEV CL/F. The CCr increased in each sex group when weight increased; however, LEV CL/F (L/h) remained constant. CONCLUSIONS: Sex, age, and weight affect LEV pharmacokinetics, having an impact on the individual dosage regimen needed to achieve the therapeutic objective. Sex is a conditioning factor of LEV CL/F, although its influence is principally due to the weight. LEV CL/F decreases with advancing age, proportionally to the decline in renal function. It is confirmed that LEV dosage per body weight is not required, and prescribing higher doses of LEV in obese patients is not justified. These data suggest that routine LEV therapeutic drug monitoring in the elderly patients, patients with renal dysfunction, and obese patients is indicated.

[Proposal of the SEOM, SEAP and SEFH for the creation of a National Strategy for Precision Medicine in Cancer]. / Propuesta para la creación de una Estrategia Nacional sobre Medicina de Precisión en Cáncer: posicionamiento de la SEOM, SEAP y SEFH.

Precision medicine is an emerging approach to the prevention and treatment of disease that takes into account variability in genes, environment and lifestyle for each individual. Precision medicine is transforming clinical and biomedical research, as well as health care itself, from a conceptual, as well as a methodological viewpoint, providing extraordinary opportunities to improve public health and lower the costs of the healthcare system. However, the implementation of precision medicine poses ethical-legal, regulatory, organizational and knowledge-related challenges. Without a national strategy, precision medicine -which eventually will be implemented one way or another- could take place without the appropriate planning to guarantee technical quality and equal access to the best practices for all citizens, thus violating the rights of patients and professionals as well as jeopardizing the solvency of the healthcare system. This paper from the Spanish Societies of Medical Oncology (SEOM), Pathology (SEAP) and Hospital Pharmacy (SEFH), highlights the need to institute a consensual national strategy for the development of precision medicine in our country, reviews the national and international context, comments on the opportunities and challenges for implementing precision medicine and outlines the objectives of a national strategy on precision medicine in cancer.

Targeting cattle for malaria elimination: marked reduction of Anopheles arabiensis survival for over six months using a slow-release ivermectin implant formulation.

BACKGROUND: Mosquitoes that feed on animals can survive and mediate residual transmission of malaria even after most humans have been protected with insecticidal bednets or indoor residual sprays. Ivermectin is a widely-used drug for treating parasites of humans and animals that is also insecticidal, killing mosquitoes that feed on treated subjects. Mass administration of ivermectin to livestock could be particularly useful for tackling residual malaria transmission by zoophagic vectors that evade human-centred approaches. Ivermectin comes from a different chemical class to active ingredients currently used to treat bednets or spray houses, so it also has potential for mitigating against emergence of insecticide resistance. However, the duration of insecticidal activity obtained with ivermectin is critical to its effectiveness and affordability. RESULTS: A slow-release formulation for ivermectin was implanted into cattle, causing 40 weeks of increased mortality among Anopheles arabiensis that fed on them. For this zoophagic vector of residual malaria transmission across much of Africa, the proportion surviving three days after feeding (typical mean duration of a gonotrophic cycle in field populations) was approximately halved for 25 weeks. CONCLUSIONS: This implantable ivermectin formulation delivers stable and sustained insecticidal activity for approximately 6 months. Residual malaria transmission by zoophagic vectors could be suppressed by targeting livestock with this long-lasting formulation, which would be impractical or unacceptable for mass treatment of human populations.

Influence of Comedication on Levetiracetam Pharmacokinetics.

BACKGROUND: To evaluate the effect of concomitant antiepileptic therapy on levetiracetam (LEV) pharmacokinetics. METHODS: A 6-year retrospective observational study. Patients were grouped according to the antiepileptic drug used as concomitant medication: group A, LEV in monotherapy; group B, LEV + enzyme-inducing antiepileptic drugs (EIAEDs); and group C, LEV + non-enzyme-inducing antiepileptic drugs (NEIAEDs). Apparent oral levetiracetam clearance (LEV CL/F) and basal serum levetiracetam concentrations (LEV C0) were compared among the different groups by analysis of variance. RESULTS: A total of 330 LEV C0 corresponding to 205 patients (56% men) were identified. The mean (±SD) of LEV CL/F in group A (n = 180), B (n = 92), and C (n = 58) was 4.41 ± 2.06 L/h, 7.23 ± 3.72 L/h, and 4.87 ± 1.65 L/h, respectively. EIAEDs increased LEV CL/F (L/h) by 64% compared with the monotherapy group and by 48% compared with the NEIAEDs group. The greatest induction in LEV CL/F, compared with the LEV monotherapy group, was observed with carbamazepine, followed by oxcarbazepine and phenobarbital, and was increased by 81%, 64%, and 44%, respectively. LEV C0 values were significantly lower in the EIAEDs group than in the monotherapy group (17.30 ± 7.77 versus 20.08 ± 9.69 mcg/mL; P = 0.038) or indeed the NEIAEDs group (17.30 ± 7.77 versus 20.49 ± 9.46 mcg/mL; P = 0.027). CONCLUSIONS: Comedication with EIAEDs increased LEV CL/F by more than 40%, whereas carbamazepine had the greatest inducing potency with LEV CL/F being 81% higher than that of the monotherapy group. These data suggest that monitoring LEV serum concentration during polytherapy with EIAEDs is indicated.

Propuesta para la creación de una Estrategia Nacional sobre Medicina de Precisión en Cáncer: posicionamiento de la SEOM, SEAP y SEFH / Proposal for the Creation of a National Strategy for Precision Medicine in Cancer: a position statement of SEOM, SEAP and SEFH

La medicina de precisión es un enfoque emergente para el tratamiento y prevención de las enfermedades que tiene en cuenta la variabilidad individual en los genes, el medio ambiente y el estilo de vida de cada persona. La medicina de precisión está transformando la investigación clínica y biomédica así como la asistencia sanitaria, tanto desde un punto de vista conceptual como metodológico, ofertando oportunidades extraordinarias para mejorar la salud pública y reducir los costes del sistema sanitario. Sin embargo, la implementación de la medicina de precisión supone un reto a nivel ético-legal, regulatorio, organizativo y de conocimiento. Sin una estrategia nacional, la medicina de precisión, que se implantará en cualquier caso, lo podría hacer sin la adecuada planificación que permita garantizar la calidad técnica, la equidad de los ciudadanos en el acceso a las mejores prácticas, vulnerando los derechos de pacientes y profesionales y arriesgando la solvencia del sistema de salud. Con este artículo de las sociedades españolas de Oncología Médica (SEOM), Anatomía Patológica (SEAP) y Farmacia Hospitalaria (SEFH) señalamos la necesidad de establecer una estrategia nacional consensuada para el desarrollo de la medicina de precisión en nuestro país, revisamos el contexto nacional e internacional, comentamos las oportunidades y los retos para la implementación de la medicina de precisión, y delineamos los objetivos de una estrategia nacional sobre medicina de precisión en el cáncer (AU)

Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. Precision medicine is transforming clinical and biomedical research, as well as health care itself from a conceptual, as well as a methodological viewpoint, providing extraordinary opportunities to improve public health and lower the costs of the healthcare system. However, the implementation of precision medicine poses ethical-legal, regulatory, organizational and knowledge-related challenges. Without a national strategy, precision medicine, which will be implemented one way or another, could take place without the appropriate planning that can guarantee technical quality, equal access of all citizens to the best practices, violating the rights of patients and professionals and jeopardizing the solvency of the healthcare system. With this paper from the Spanish Societies of Medical Oncology (SEOM), Pathology (SEAP), and Hospital Pharmacy (SEFH) we highlight the need to institute a consensual national strategy for the development of precision medicine in our country, review the national and international context, comment on the opportunities and challenges for implementing precision medicine, and outline the objectives of a national strategy on precision medicine in cáncer (AU)