Bayesian pharmacokinetic-guided prophylaxis with recombinant factor VIII in severe or moderate haemophilia A.

INTRODUCTION: Personalised pharmacokinetics (PK) using Bayesian analysis with limited sampling is assumed to help to optimise prophylaxis in haemophilia A (HA) patients. MATERIALS AND METHODS: Our prospective, observational study analysed the influence of PK parameters on clinical variables (bleeding rates, joint status, adherence, and consumption) using myPKFiT® in a cohort of twenty-one severe and moderate HA patients on prophylaxis with recombinant FVIII (Advate®) in two periods of one year, the first before PK-based tailoring and the second after PK-guided prophylaxis. Intra-individual and inter-individual coefficients of variation (CV) of half-life (t1/2) were calculated. RESULTS: A total of 73 PK estimations were performed in both periods, resulting in 17.2% inter-individual CV in mean t1/2, and 4.9% intra-individual CV. Before PK-based tailoring a significant association between joint bleeds and t1/2 was found (P = 0.010), especially in patients with short t1/2. This finding was reproduced (P = 0.013) after withdrawal of two patients with bleeding phenotype related to their advanced arthropathy but normal t1/2 and trough levels. Patients with joint bleeds weighed less (P = 0.039) and required higher doses (P = 0.032) than patients with zero joint bleeds. These associations were not observed in the second period after the adoption of PK-guided prophylaxis. There were no differences between the two periods, although a tendency to fewer spontaneous bleeds was suggested after PK-based tailoring. CONCLUSIONS: PK-guided prophylaxis facilitates an adequate level of bleeding control in patients with HA, maintaining clinical variables and patient convenience in an integrative manner, without increasing FVIII consumption.

Pilot evaluation of home delivery programme in haemophilia.

WHAT IS KNOWN AND OBJECTIVES: Most of the clotting factor (CF) dispensations to haemophiliac patients are centralized in a few haemophilia treatment centres, necessitating frequent visits and long travel distances. The aim was to evaluate the home delivery programme developed by the Outpatient Pharmaceutical Care Unit (OPCU) through the association of patients (ASHECOVA). METHODS: A specific software programme was designed to communicate the individual CF requirements. Dispensations were prepared in advance, and an ASHECOVA member collected and delivered to patients' homes in optimal conditions. Data regarding the programme were analysed from December 2011 to December 2017. An electronic satisfaction survey with 34 questions was conducted, asking about organizational aspects, education and communication, use of apps and satisfaction level. RESULTS AND DISCUSSION: Forty-nine patients were included and 2464 home deliveries were made, without any reported incident related to dispensation errors, drug preservation, communication or confidentiality problems. This system avoids 11.4 annual dispensation visits per patient to OCPU, and a mean travel distance, time and cost of 1189.1 km, 945.3 minutes and 373.5 euros, respectively. Overall satisfaction with home delivery was 9.7, without any change suggested in the current system. Ninety-five per cent of individuals believed that the programme improves adherence and all patients would recommend it to other patients. The most common benefits reported were less frequent visits to hospital, reducing time and cost spent on transportation. WHAT IS NEW AND CONCLUSION: The home delivery programme guarantees a proper follow-up of treatments with full patient satisfaction. This programme allows OPCU to achieve better pharmaceutical care, traceability of the process and optimization of working times and CF stock management.

Impact of NADPH oxidase functional polymorphisms in acute myeloid leukemia induction chemotherapy.

Efficacy and toxicity of anthracycline treatment in acute myeloid leukemia (AML) is mediated by reactive oxygen species (ROS). NADPH oxidase is the major endogenous source of ROS and a key mediator of oxidative cardiac damage. The impact of NADPH oxidase polymorphisms (CYBA:rs4673, NCF4:rs1883112, RAC2:rs13058338) was evaluated in 225 adult de novo AML patients. Variant alleles of NCF4 and RAC2 were related to higher complete remission (P=0.035, P=0.016), and CYBA homozygous variant showed lower overall survival with recessive model (P=0.045). Anthracycline-induced cardiotoxicity was associated to NCF4 homozygous variant (P=0.012) and CYBA heterozygous genotype (P=0.027). Novel associations were found between variant allele of CYBA and lower lung and gastrointestinal toxicities, and a protective effect in nephrotoxicity and RAC2 homozygous variant. Moreover, RAC2 homozygous variant was related to delayed thrombocytopenia recovery. This study supports the interest of NADPH oxidase polymorphisms regarding efficacy and toxicity of AML induction therapy, in a coherent integrated manner.

A systematic review and meta-analysis of the impact of WT1 polymorphism rs16754 in the effectiveness of standard chemotherapy in patients with acute myeloid leukemia.

The polymorphism rs16754 of the WT1 gene has been described as a possible prognostic marker in different acute myeloid leukemia (AML) cohorts; however, it is not supported by all the studies. We performed the first meta-analysis evaluating the effect of this polymorphism upon the effectiveness of standard AML therapy. Fourteen cohort studies were included (3618 patients). Patients with the variant allele showed a significant higher overall survival (OS) at 5 years (OR:1.24, 95% CI: 1.06-1.45, P=0.007, with dominant model). WT1 did not influence complete remission, but a higher disease-free survival was observed with the variant allele. In the subgroup analysis, Caucasians, pediatric and patients treated with idarubicin and etoposide carrying the variant allele showed consistent results in OS, whereas patients with cytogenetically normal AML did not show differences. To verify the effect of this polymorphism upon other outcomes, studies in larger and multiracial populations are needed.

Trans-arterial chemoembolization with doxorubicin-eluting particles versus conventional trans-arterial chemoembolization in unresectable hepatocellular carcinoma: A study of effectiveness, safety and costs.

OBJECTIVES: To compare the effectiveness, survival and cost in patients with unresectable hepatic cell carcinoma (HCC) treated with trans-arterial chemoembolization using doxorubicin-eluting beads (DEB-TACE) versus conventional TACE (cTACE) in clinical practice. MATERIAL AND METHODS: This single-centered retrospective observational study compared 60 consecutive HCC unresectable patients: 30 were treated with DEB-TACE and 30 used cTACE. Comparisons were with χ(2) test, Student t-test, and Kaplan Meier method. RESULTS: Of the 60 patients with HCC in non-curative stage, baseline characteristics were similar for both groups of treatment, and of these we observed lower survival in male patients and those who had hepatitis C virus (p=0.014 and p=0.003, respectively). No statistically significant differences were observed as a function of treatment employed with respect to overall survival (OS) at 5 years (29.99 months; 95%CI: 21.38-38.60 versus 30.67 months; 95%CI:22.65-38.70; p=0.626) and progression free survival (PFS) median of 11.57 months (95%CI: 0.97-22.18) versus 12.80 months (95%CI:0.00-32.37; p=0.618). The median length of hospital admission were 2.6 and 5.4 days (p<0.001) for DEB(-)TACE and cTACE, respectively. Toxicities grade 2-4 were higher in cTACE group (54 versus 31; p<0.001). The cost of the treatment was 1581 € for DEB(-)TACE and 514.63 € for cTACE. The overall mean cost of intervention was 3134 € and 3694.35 €, respectively (p=0.173). CONCLUSIONS: Chemoembolization in patients with unresectable HCC achieved OS close to 30 months at 5 years, independent of the technique employed. Similar overall costs but better tolerance of the DEB-TACE justified the higher costs of the procedure.

Influence of ABCB1 polymorphisms upon the effectiveness of standard treatment for acute myeloid leukemia: a systematic review and meta-analysis of observational studies.

The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07-2.01), 2677G>T/A at years 4-5 (OR: 1.37, 95% CI: 1.01-1.86) and 3435C>T at years 3 (OR: 1.41, 95% CI: 1.03-1.94) and 4-5 (OR: 1.42, 95% CI: 1.05-1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on larger populations and multiethnic groups should help clarify the effect of P-gp polymorphisms upon other outcomes.

[Evaluation of the written informed consent form in clinical trials]. / Evaluación de la hoja de información al paciente y del consentimiento informado en ensayos clínicos.

PURPOSE: To assess the quality of the written informed consent form (WICF) in clinical trials. MATERIAL AND METHODS: Retrospective observational study was performed on 50 WICF of clinical trials started between 2010 and 2011. The quality of the content of the WICF was assessed using the "Guideline for Good Clinical Practice" contained in the CPMP/ICH/135/95 of the European Medicines Agency. Legibility indexes were applied to the WICF. RESULTS: The WICF was correct in all aspects in 10% of the clinical trial; five sections were correct in all WICF: "trial involves research", "trials goals", "participation is voluntary and the subject may withdraw at any time without penalty", "study personnel with access to medical records" and "documents that identify the patient are confidential". Aspects less present were "the subject's responsibilities" and "available alternatives". All WICF required clarification by the Ethics Committee (EC), with a mean of 4.24 (SD=1.87) changes per WICF. The WICF showed good results in the indices of readability. Almost all (98%) of WICF were considered with an acceptable readability. CONCLUSIONS: Compliance with different aspects that must appear in the WICF is high. Aspects to improve are the subject's responsibilities and available alternatives to the clinical trial. The complexity of reading the WICF is suitable for the average population. The review of the WICF by the EC guarantees the access to comprehensive and appropriate information.