Farmacocinética poblacional de gemcitabina aplicada a la personalización de su dosificación en pacientes oncológicos

ObjectiveTo develop and internally validate a population pharmacokinetic model for gemcitabine and its metabolite 2’,2’-difluorodeoxyuridine (dFdU); and to evaluate its predictive perfomance for personalizing the dosage used in cancer patients.MethodsGemcitabine and dFdU plasma concentrations were determined in 18 cancer patients. A 2-compartment pharmacokinetic model was implemented in the NONMEN VI program to determine the appropriate pharmacokinetic parameters. The power to identify the parameters was assessed by parametric bootstrap, and the internal model validation was performed using nonparametric bootstrap and visual and numerical predictive check methods. The final predictive performance of the model was assessed for accuracy and precision during the first (a priori) and second (a posteriori) chemotherapy cycles.ResultsThe mean and interpatient variability of gemcitabine and dFdU clearance was 2.70L/min (31.0%) and 0.0515L/min (35.8%), respectively. The estimated distribution volume at steady state was 30L for gemcitabine and 238L for dFdU. Internal validation confirmed that the population pharmacokinetic model was appropriate for describing the plasma concentrations of gemcitabine and dFdU over time, as well as its variability in the study population. The accuracy and precision of a posteriori gemcitabine plasma concentrations improved by 67% and 46%, respectively, compared to the a priori prediction.ConclusionThe population pharmacokinetic model adequately characterised the gemcitabine and dFdU plasma concentrations in the study population over time, and can be used to accurately and precisely optimise gemcitabine dosing regimens in cancer patients.     

Influencia del tiempo de perfusión de pamidronato en la función renal de pacientes con mieloma múltiple

IntroductionAdministration of biphosphonates in patients with renal failure requires a dosage adjustment.ObjectivesAnalyse renal function evolution in multiple myeloma patients after reducing infusion time for 90 mg pamidronate by 2 h.MethodsIn 2007, a retrospective study was carried out on all patients who presented multiple myeloma and bone metastasis treated with pamidronate administered every 4 h. Following a review of the literature, a protocol for administering pamidronate every 2 h was created in partnership with Haematology, and a specific dose reduction framework was established for patients with baseline renal failure. Additionally, a prospective follow-up study of those patients’ renal function was completed to analyse its evolution after the change in infusion time.ResultsA total of six patients received 90 mg pamidronate every 4 h. 33.32% of the patients (2/6) presented baseline renal insufficiency, and therefore needed to have the pamidronate dose adjusted according to the new protocol. Subsequently, all of them received the treatment every 2 h, and one patient (16.6%) experienced altered renal function after two treatment cycles.DiscussionReducing administration time for pamidronate from four to 2 h did not lead to significant variations in patients’ renal function. This therapeutic practice can improve patients' quality of life by shortening their hospital stay without aggravating their renal function.     

Revisión de la legislación sobre la investigación clínica en el Sistema Nacional Salud y los servicios de farmacia hospitalaria

The call for public funding for the Spanish Health Care System clinical research with drugs for human use projects Subprogramme highlights the need for hospital pharmacy services to include the manufacture of investigational drugs which are the subject of a clinical trial, developed by either a researcher or a group of researchers, within its activities.This article discusses the legislation concerning the manufacture of investigational drugs and the requirements that the pharmacy services must meet in order to develop, distribute, or conceal an investigational drug in a clinical trial sponsored by a professional from the SHS.     

Resistencia a la aspirina: prevalencia,mecanismos de acción y asociación con eventos tromboembólicos. Revisión narrativa

ObjectivesThe purpose of this study is to review the prevalence of aspirin resistance in patients with a high risk of cardiovascular events, and secondly, to investigate its epidemiology and mechanism of action, and the clinical consequences it can provoke.Material and methodsA search was run on PubMed, EMBASE and Reviews Database for English or Spanish articles on aspirin resistance published up to November 2008. Additional studies were obtained by searching the reference lists in the selected articles for articles relevant to our secondary objectives.ResultsAspirin resistance is described as affecting 0 to 57% of the population, and is related to a decreased protective effect against strokes and cardiovascular events. Many modifiable and unmodifiable factors can affect the efficacy of antiplatelet drugs. Possible strategies for overcoming this decreased antiaggregant effect include increasing the aspirin dosage or dual therapy with another antiplatelet agent.ConclusionsLack of response to aspirin decreases its protective effects. However, lack of a standard definition for aspirin resistance, the absence of diagnostic reference methods to identify resistant patients, and the different mechanisms of action involved in platelet aggregation call the clinical importance of this fact into question. Additional well-designed studies are needed to detect patients with real resistance in order to have more effective prevention of cardiovascular morbidity and mortality.     

Revisión de las reacciones de hipersensibilidad a antineoplásicos

ObjectiveTo review the characteristics and management of hypersensitivity reactions caused by antineoplastic agents.MethodWe conducted a search in the Pubmed and EMBASE databases for the last 10 years.ResultsAlmost all chemotherapeutic agents have the potential to cause hypersensitivity reactions, but some groups have been associated with increased risk, such as platinum compounds, taxanes, asparaginase, monoclonal antibodies and epipodophyllotoxins. The clinical manifestations of these reactions are variable and unpredictable, including symptoms affecting the skin and the pulmonary, cardiac and gastrointestinal systems. The mechanism associated with their development is not yet fully understood. Diagnosis is based on patients’ signs and symptoms and skin testing. The management of patients who suffer a hypersensitivity reaction to a chemotherapeutic agent varies with the severity of the reaction, the need to continue treatment, and the availability of alternative therapies.ConclusionsDue to a progressive increase in the use of chemotherapeutic agents an increased incidence of hypersensitivity reactions is to be expected. Desensitisation protocols are a noteworthy alternative that make it possible to re-initiate patients’ therapy with the causative agent of the hypersensitivity reaction. Their use should be assessed individually, weighing risks and benefits.     

Efectividad de la palifermina en la prevención de la mucositis oral en pacientes oncohematológicos

ObjectiveTo assess the effectiveness of palifermin for the prevention of oral mucositis in patients with haematological cancers.MethodsRetrospective observational study of cohorts of patients with haematological cancer undergoing cytotoxic therapy causing hematopoietic ablation.The main variable assessed was the duration of the oral mucositis. Secondary variables assessed were incidence of mucositis, febrile or septic neutropenia and the administration of opioids and parenteral nutrition.ResultsWe included 36 patients in this study, 11 in the group that received palifermin and 25 in the control group. The duration of oral mucositis was 4.6±3.1 days (median: 5 days) in the patients treated with palifermin in comparison with 7.4±4.0 days (median: 6 days) in patients treated with conventional prophylactic therapy (p<0.05). However, no significant differences were seen in the incidence of mucositis, febrile or septic neutropenia, opioid administration of the use of parenteral nutrition.ConclusionsProphylactic treatment with palifermin reduces the duration of oral mucosities in patients with haematological cancer. Further studies are necessary with larger samples to be able to assess palifermin and its influence on other variables, such as incidence of mucositis, sepsis, febrile neutropenia, etc.     

Análisis farmacogenético de la cinética de absorción de ciclosporina en una población española de pacientes trasplantados cardíacos

ObjectiveTo determine how single nucleotide polymorphisms located on genes MDR1, CYP3A4 and CYP3A5 affect the absorption kinetics of cyclosporine in cardiac transplant patients.MethodWe selected a sample of 30 adult patients having previously undergone a primary cardiac transplant and who had received cyclosporine as an immunosuppressant. During the first month after the transplant, we performed a pharmacokinetic study of each patient to determine values in the cyclosporine concentration area under the 12-hour curve, steady-state cyclosporine concentration, maximum cyclosporine concentration, and time to reach that concentration. Single nucleotide polymorphisms were genotyped in all patients: MDR1 3435C > T, CYP3A4-390A > G and CYP3A5 6986A > G.ResultsBeing a carrier of the T-allele for polymorphism MDR1 3435C > T is associated with higher values in the cyclosporine concentration area under the 12-hour curve (p = 0.01) and in steady-state cyclosporine concentration (p = 0.05), compared with those from patients who do not carry that allele.DiscussionOur results show that genotype differences in MDR1 3435C > T can explain part of the variability in cyclosporine absorption among individuals in the population of Spanish cardiac transplant recipients.     

Impacto presupuestario de la utilización de hormona de crecimiento de la edad pediátrica a la adulta

ObjectiveTo estimate the budget impact of somatrophin (Genotonorm^®) use in growth hormone deficiency (GHD) patients during the transition between childhood and adulthood.MethodA budget impact model was designed under the Spanish National Health System with a 5-year time horizon. Calculations of susceptible patients were based on disease prevalence (0.02%) applied to Spanish population. From total GHD cases, 60% was considered persistent and treatment candidates. An expert panel assumed that 20% of candidates would reject the treatment and 8% would withdraw therapy annually. Considered costs included: therapy costs, diagnosis (test and medical visit) and follow-up cost.ResultsThere would be 49, 93, 132, 186 and 199 patients undergoing treatment each year (2010-2014). The total impact of Genotonorm^® use during the transition phase would be €367 691, €655 430, €1044 874, €1334 059, and €1594 670 for years 1 to 5. The average annual cost per patient would be €7506, €7059, €7903, €7960, €7995.ConclusionsGHD treatment during the transition phase in Spain poses an annual average layout of €7684/patient.     

Monitorización de la vacomicina en administración intraperitoneal en pacientes sometidos a diálisis peritoneal continua ambulatoria

ObjectiveTo validate a pharmacokinetic model of the treatments with intraperitoneal vancomycin applied to patients on continuous ambulatory peritoneal dialysis with bacterial peritonitis.MethodsTo carry out a prospective study divided in 2 cohorts: the first one including ten patients of 56 ± 14 years and 65 ± 5 kg, and the second one with 10 patients (12 episodes of peritonitis) aged 52 ± 13 years and 64 ± 8 kg. The treatment consists of administering and retaining for 6 h in the peritoneal cavity a solution containing 2 g of vancomycin and 1 g of ceftazidime into 2 l of “dialysis solution”. After the antibiotic administration, blood samples were obtained at 4, 6, 8, 10, 24, 48 and 168 h in the first cohort and at 6 and 120 h (C^VAN₁₂₀) in the second. The pharmacokinetic model was developed from the parameters obtained from the first cohort and was validated by the second cohort, calculating the mean error (ME) and the mean squared prediction error (MSPE) of the C^VAN₁₂₀.ResultsVancomycin serum concentrations fell from 39.63 ± 7.62 mcg/ml at 4 h to 8.55 ± 2.87 mcg/ml at 168 h for the first cohort, and from 37.65 ± 6.84 mcg/ml at 6 h to 10.82 ± 2.66 mcg/ml at 120 h (C^VAN₁₂₀) for the second cohort. The pharmacokinetics parameters were: C1 = 0.006 1/h/kg and Vd: = 0.52 1/kg for the first cohort, and C1 = 0.006 1/h/kg and Vd: = 0.53 1/kg for the second. The predictive ME and MSPE of the C^VAN₁₂₀. were 0.59 mcg/ml ([EM*100/C^VAN₁₂₀ = 5.5%) and 10.38 mcg²/ml² ([MES*100/(C^VAN₁₂₀)²]) respectively.ConclusionThe presented model shows an adequate exactitude and precision for the monitoring of intraperitoneal vancomycin in patients submitted to continuous ambulatory peritoneal dialysis with peritonitis.