Dosing strategies for conversion of haemodialysis patients from short-acting erythropoiesis stimulating agents to once-monthly C.E.R.A.: experience from the MIRACEL study

International audienceAims. To analyse the impact of dosing decisions for C.E.R.A., a continuous erythropoietin receptor activator. Methods. This was a prospective, multicentre, single-arm study in haemodialysis patients receiving epoetin alfa/beta or darbepoetin alfa. After a two-month screening phase, patients were converted to monthly C.E.R.A. using pre-filled syringes during a five-month titration phase and a two-month evaluation phase. Results. 424 eligible patients were converted to C.E.R.A. Mean Hb was 11.7±0.7, 11.7±0.8 and 11.5±0.8g/dL during screening, titration and evaluation, respectively. C.E.R.A. starting dose was 125µg (n=311) or 200µg (n=106), with corresponding final doses of 129±61μg and 203±58μg. The mean number of C.E.R.A. dose decreases and increases was 0.9±1.0 and 1.1±1.0 per patient, respectively. Hb rarely exceeded 12.5g/dL after a C.E.R.A. dose increase (<8%) and remained ≥11g/dL after a dose reduction on approximately three-quarters of occasions. Among the 53 occasions where Hb decreased ≥2g/dL between two consecutive visits, the previous dose had been withheld (n=9), concomitant blood loss, coagulopathy or infection was present (n=13), or iron parameters were low (n=17). There were 104 adverse events/month during screening, and 45/month during the titration/evaluation phases. Serious adverse events occurred in 18.0 and 21.0 patients/month during the screening and titration/evaluation phases, respectively. Conclusion. Switching haemodialysis patients from shorter-acting ESA to once-monthly C.E.R.A. using pre-filled syringes is straightforward, and Hb levels remain stable. Starting doses recommendations and dose changes correlated well with the clinical setting. Collateral factors such as infection or aggravating concomitant medical conditions should be taken into account

C.E.R.A. once every 4 weeks corrects anaemia and maintains haemoglobin in patients with chronic kidney disease not on dialysis

Background. No previous randomized controlled studies have been reported examining de novo, once every 4 weeks (Q4W) administration of erythropoiesis-stimulating agents in chronic kidney disease (CKD) patients. We report results from a randomized multinational study that compared continuous erythropoietin receptor activator (C.E.R.A.) Q4W with darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) for the correction of anaemia in non-dialysis CKD patients

Development of an erythropoietin prescription simulator to improve abilities for the prescription of erythropoietin stimulating agents: Is it feasible?

BACKGROUND: The increasing use of erythropoietins with long half-lives and the tendency to lengthen the administration interval to monthly injections call for raising awareness on the pharmacokinetics and risks of new erythropoietin stimulating agents (ESA). Their pharmacodynamic complexity and individual variability limit the possibility of attaining comprehensive clinical experience. In order to help physicians acquiring prescription abilities, we have built a prescription computer model to be used both as a simulator and education tool. METHODS: The pharmacokinetic computer model was developed using Visual Basic on Excel and tested with 3 different ESA half-lives (24, 48 and 138 hours) and 2 administration intervals (weekly vs. monthly). Two groups of 25 nephrologists were exposed to the six randomised combinations of half-life and administration interval. They were asked to achieve and maintain, as precisely as possible, the haemoglobin target of 11-12 g/dL in a simulated naïve patient. Each simulation was repeated twice, with or without randomly generated bleeding episodes. RESULTS: The simulation using an ESA with a half-life of 138 hours, administered monthly, compared to the other combinations of half-lives and administration intervals, showed an overshooting tendency (percentages of Hb values &gt; 13 g/dL 15.8 ± 18.3 vs. 6.9 ± 12.2; P &lt; 0.01), which was quickly corrected with experience. The prescription ability appeared to be optimal with a 24 hour half-life and weekly administration (ability score indexing values in the target 1.52 ± 0.70 vs. 1.24 ± 0.37; P &lt; 0.05). The monthly prescription interval, as suggested in the literature, was accompanied by less therapeutic adjustments (4.9 ± 2.2 vs. 8.2 ± 4.9; P &lt; 0.001); a direct correlation between haemoglobin variability and number of therapy modifications was found (P &lt; 0.01). CONCLUSIONS: Computer-based simulations can be a useful tool for improving ESA prescription abilities among nephrologists by raising awareness about the pharmacokinetic characteristics of the various ESAs and recognizing the factors that influence haemoglobin variability

Phase II study of two dose schedules of C.E.R.A. (Continuous Erythropoietin Receptor Activator) in anemic patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy

BACKGROUND: C.E.R.A. (Continuous Erythropoietin Receptor Activator) is an innovative agent with unique erythropoietin receptor activity and prolonged half-life. This study evaluated C.E.R.A. once weekly (QW) or once every 3 weeks (Q3W) in patients with anemia and advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. METHODS: In this Phase II, randomized, open-label, multicenter, dose-finding study, patients (n = 218) with Stage IIIB or IV NSCLC and hemoglobin (Hb) ≤ 11 g/dL were randomized to one of six treatment groups of C.E.R.A. administered subcutaneously for 12 weeks: 0.7, 1.4, or 2.1 μg/kg QW or 2.1, 4.2, or 6.3 μg/kg Q3W. Primary endpoint was average Hb level between baseline and end of initial treatment (defined as last Hb measurement before dose reduction or transfusion, or the value at week 13). Hematopoietic response (Hb increase ≥ 2 g/dL or achievement of Hb ≥ 12 g/dL with no blood transfusion in the previous 28 days determined in two consecutive measurements within a 10-day interval) was also measured. RESULTS: Dose-dependent Hb increases were observed, although the magnitude of increase was moderate. Hematopoietic response rate was also dose dependent, achieved by 51% and 62% of patients in the 4.2 and 6.3 μg/kg Q3W groups, and 63% of the 2.1 μg/kg QW group. In the Q3W group, the proportion of early responders (defined as ≥ 1 g/dL increase in Hb from baseline during the first 22 days) increased with increasing C.E.R.A. dose, reaching 41% with the highest dose. In the 6.3 μg/kg Q3W group, 15% of patients received blood transfusion. There was an inclination for higher mean Hb increases and lower transfusion use in the Q3W groups than in the QW groups. C.E.R.A. was generally well tolerated. CONCLUSION: C.E.R.A. administered QW or Q3W showed clinical activity and safety in patients with NSCLC. There were dose-dependent increases in Hb responses. C.E.R.A. appeared to be more effective when the same dose over time was given Q3W than QW, with a suggestion that C.E.R.A. 6.3 μg/kg Q3W provided best efficacy in this study. However, further dose-finding studies using higher doses are required to determine the optimal C.E.R.A. dose regimen in cancer patients receiving chemotherapy

Pharmacokinetic drug interactions of antimicrobial drugs:a systematic review on oxazolidinones, rifamycines, macrolides, fluoroquinolones, and Beta-lactams

Like any other drug, antimicrobial drugs are prone to pharmacokinetic drug interactions. These drug interactions are a major concern in clinical practice as they may have an effect on efficacy and toxicity. This article provides an overview of all published pharmacokinetic studies on drug interactions of the commonly prescribed antimicrobial drugs oxazolidinones, rifamycines, macrolides, fluoroquinolones, and beta-lactams, focusing on systematic research. We describe drug-food and drug-drug interaction studies in humans, affecting antimicrobial drugs as well as concomitantly administered drugs. Since knowledge about mechanisms is of paramount importance for adequate management of drug interactions, the most plausible underlying mechanism of the drug interaction is provided when available. This overview can be used in daily practice to support the management of pharmacokinetic drug interactions of antimicrobial drugs

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Clinical Education and Postgraduate Training Opportunities in Nephrology Pharmacy

All colleges of pharmacy in the United States were surveyed to assess the availability of didactic and clinical pharmacotherapy education in the field of nephrology. Forty-four of the 54 (81.5%) colleges with PharmD programs responded to the survey. Of these programs, 64% (28/44) teach nephrology as a separate module during the PharmD curriculum. The content of the nephrology curriculum varied from 2 lecture hours to 30 lecture hours. The pharmacokinetic concepts that relate to pharmacotherapeutic management of nephrology patients are taught in a separate nephrology course in only 9% of these 28 programs. In 57% of these PharmD programs, pharmacokinetic concepts inherent to nephrology are taught as part of a separate pharmacokinetic course. There are 34% of the programs that teach these pharmacokinetic principles in both the nephrology course and as part of a separate pharmacokinetic course. Of the 44 PharmD programs that responded to the survey, 23 (52%) have elective nephrology clerkships. Ten postgraduate training opportunities in nephrology are offered by nine individuals in association with eight colleges of pharmacy. Seven programs have a primary focus in nephrology, three residencies and four fellowships, while three programs identify nephrology as a secondary focus: one residency and two fellowships. An additional eight postgraduate training opportunities with a significant nephrology component were identified. Some of these transplantation residencies and fellowships provide a focused experience in renal transplantation while others include liver, lung, heart, and/or bone marrow experiences. The newest nephrology postgraduate educational opportunity is the American Society of Hospital Pharmacists (ASHP) Clinical Pharmacy Dialysis Service Traineeship Program, which was established in 1992. Implementation of the program was directed by the ASHP Research and Education Foundation with funding from Amgen, Inc. This postgraduate training experience is designed to prepare a pharmacist practitioner to establish and maintain a specialized service for the pharmacotherapeutic management of patients undergoing dialysis. </jats:p