NEFROLOGÍA. Vol. XXV. Número 2. 2005 Darbepoietin alpha in the treatment of renal anemia in the patient undergoing peritoneal dialysis and previously treated with epoietin alfa C. Remón, P. Quirós, D. Fernández Marchena, M. Hernández Romero, R. del Castillo and E. Fernández Ruiz Nephrology Department. Puerto Real University Hospital. Cadiz. SUMMARY Introduction: In 2002, it was contraindicated the use of epoetin alfa by a subcutaneous way to avoid the risk of the pure red cell aplasia in chronic renal failure patients. This forced to change the prescription in the way it was supplied, which was especially problematic in predialysis and peritoneal dialysis, as treating out-patients, that is why it was necessary to change to epoetina beta o darbepoetin, where this contraindication was not established, in order to continue using this way. The darbepoetin has an average lifetime longer than the epoetin. Its efficacy and security have been well studied, especially in pre-dialysis and haemodialysis, but little less in peritoneal dialysis. Aims: To evaluate our experience about the efficacy and security of darbepoetin alfa, by a subcutaneous way, in our programme of peritoneal dialysis, after the conversion of the patients previously treated with epoetin alfa. Patients and methods: 35 patients. 7 analytical and clinical controls are evaluated, 2 before and 5 after the conversion, with an interval of 6 weeks. Statistics methods: means ± typical deviation, medians, distribution of frequencies, Wilcoxon test and Friedman test. Results: The change into darbepoetin alfa has been successful in maintaining stable haemoglobin levels in patients in peritoneal dialysis, without meaningful changes in the mean levels of haemoglobin before and after the conversion. The percentage of patients with haemoglobin in the rank 11-13 g/dl (85%) has been higher with the darbepoetin, probably due to the dose increment in the patients with previous levels of haemoglobin less than 11 g/dl. The dosages might have been widely separated (7.5 ± 3 vs 9.2 ± 3.2 days). The darbepoetin has been well tolerated, without any important adverse effects. Conclusions: The conversion of epoetin alfa into darbepoetin alfa in peritoneal dialysis was simple, effective, secure and well tolerated. Key words: Anaemia. Darbepoetin alfa. Chronic renal failure. Peritoneal dialysis Correspondence: Dr. César Remón Rodríguez Pº Marítimo, 2, 8º B 11010 Cádiz E-mail: cesarkai@telefonica.net E-mail: nefrologia.hupr.sspa@juntadeandalucia.es 170 DARBEPOIETIN ALPHA IN PERITONEAL DIALYSIS DARBEPOETINA ALFA EN EL TRATAMIENTO DE LA ANEMIA DEL PACIENTE EN DIÁLISIS PERITONEAL PREVIAMENTE TRATADO CON EPOETINA ALFA RESUMEN Introducción: En el año 2002 se contraindicó el empleo de epoetina alfa vía subcutánea para minimizar el riesgo de aplasia pura de células rojas. Esto obligó a un cambio de prescripción en su vía de administración, lo que fue especialmente problemático en prediálisis y diálisis peritoneal, por tratarse de pacientes ambulatorios, siendo necesario cambiar a epoetina beta o darbepoetina, en las que no se estableció esta contraindicación. La darbepoetina tiene una vida media superior a la epoetina. Su eficacia y seguridad han sido bien estudiadas, sobre todo en prediálisis y hemodiálisis, pero menos en diálisis peritoneal. Objetivos: Analizar nuestra experiencia en cuanto a la eficacia y seguridad del tratamiento con darbepoetina alfa por vía subcutánea para la corrección de la anemia renal en los pacientes del programa de diálisis peritoneal tratados previamente con epoetina alfa. Material y métodos: Treinta y cinco pacientes en diálisis peritoneal. Se analizan los parámetros analíticos y los acontecimientos clínicos en 7 controles, 2 antes y 5 después de la conversión a darbepoetina, con intervalos de 6 semanas. Estadística: Medias ± ds, medianas, frecuencias, tests de Wilcoxon y Friedman. Resultados: El cambio a darbepoetina alfa ha sido efectivo para mantener valores de hemoglobina estables en los pacientes en diálisis peritoneal, sin cambios significativos en los niveles medios de hemoglobina antes y después de la conversión. El porcentaje de pacientes con hemoglobina en el rango 11-13 g/dl (85%) ha sido mayor con la darbepoetina, probablemente como consecuencia del incremento de la dosis en aquellos pacientes con niveles de hemoglobina previos menores de 11 g/dl. Aunque no fue objetivo inicial, las dosis han podido ser distanciadas (7,5 ± 3 vs 9,2 ± 3,2 días). La darbepoetina ha sido bien tolerada, sin efectos adversos importantes. Conclusiones: La conversión de epoetina alfa a darbepoetina alfa en diálisis peritoneal fue sencilla, eficaz y segura. Palabras clave: Anemia. Darbepoetina alfa. Insuficiencia renal crónica. Diálisis peritoneal. INTRODUCTION Until 1998, there were very few cases described of development of anti-erythropoietin antibodies in renal failure patients treated with recombinant human erythropoietin (rHuEPO)1-3. But in December of 2002, and due to the increasing number of cases of pure red blood cells aplasia (PRBCA) associated with the development of these antibodies, especially in chronic renal failure (CRF) patients treated with subcutaneous (s.c.) epoietin alpha4,5, the Agencia Española del Medicamento (Spanish Drug Agency) and agencies in other countries decided to contraindicate the use of this administration route with this drug in CRF patients, being authorized only for use by the intravenous (i.v.) route. In order to keep on using the s.c. route, it was then necessary to switch the prescription to beta epoietin with which a much less number of cases of PRBCA have been reported7-9, or to darbepoietin alpha with which, until today, no cases have been reported. Darbepoietin alpha is an erythropoiesis-stimulating protein, developed to achieve an increase in r-HuEPO molecule biological activity by lowering its clearance from plasma. This was achieved by introducing 5 amino acids changes in its primary sequence, by increasing the carbohydrate content (5 N-glycosidation chains and 51% carbohydrate content versus 3 N-glycosidation chains and 40% carbohydrate content in r-HuEPO), and sialic acid (22 molecules versus 14 in r-HuEPO)11,12. This confers r-HuEPO a longer half-life (25.3 hours versus 8.5 h, respectively, after i.v. administration, and 48.8 h vs 24.4 h, respectively, after s.c. administration)11-13, which allows a longer frequent dosage regimen to achieve and maintain the same hemoglobin (Hb) levels, at least 171 C. REMÓN y cols. with the same efficacy than r-HuEPO and a good safety profile, as it has been shown in several studies on its use in patients with chronic renal failure in a pre-dialysis14 and dialysis status11,15-18. In the later, most of patients were on hemodialysis (HD); notwithstanding, the studies essentially or exclusively referring to patients included in peritoneal dialysis (PD) programs are seldom. The objectives of the present study were to analyze our experience after conversion from epoietin alpha to darbepoietin alpha (both s.c.) in our patients in PD program, as referred to: 1) maintenance of stable Hb levels; 2) determination of mean and partial darbepoietin doses used, as well as the resulting mean epoietin/darbepoietin conversion factor; 3) analysis of dose-frequency relationship; and 4) determination of appearance of significant adverse events. MATERIAL AND METHODS We present a study performed at the PD Unit of Puerto Real University Hospital. Of the 39 patients comprised in the program in December 2002, 35 met the flowing inclusion requisites and were included in the study: staying at the PD program for at least 4 months, not having received transfusions or presented active bleeding in the previous 4 months, having being treated for at least 3 months with epoietin alpha to correct the anemia associated to chronic renal failure, and treatment switching to darbepoietin alpha after the communiqué of the Spanish Drug Agency (both s.c.). In 32 out of the 35 patients, PD was the first technique for renal replacement therapy for CRF and although three patients were switched from HD, they had been on PD for longer than 1 year when treatment change occurred. None of them had previously received a renal transplantation. Patients with a Hb level 11-13 g/dL have not been excluded from the study since our main objective has been to study our experience in all patients after conversion, and for the same reason, besides the need for a medication change, we also had the need for correcting Hb levels in these patients in order to comply with therapeutic guidelines for renal anemia19. For treatment switching, a 1/200 epoietin alpha/darbepoietin alpha relationship was used, which is equivalent in peptide mass for both molecules, although the resulting dose was modified in those cases where Hb previous to conversion was out of the 11-13 g/dL range. Initially we did not seek for spacing the dose interval, except for those pa172 tients that received more than one dose per week, in which darbepoietin dose was administered in a single weekly injection. Eighty percent (n = 28) of patients received iron supplements at the time of conversion with the aim of maintaining ferritin levels above 100 ng/mL and a transferrin saturation level above 20%19. Of these patients, 64.3% (n = 18) were taking iron sulfate p.o. and 37.5% (n =10) were using iron i.v. because of gastric intolerance to the p.o. formulation or because they could not reach the optimal levels of iron kinetics. In order to evaluate the simplicity and safety of switching to darbepoietin within the first controls after conversion, analytical parameters and clinical events were gathered in 7 controls, in 2 prior to darbepoietin switch (performed approximately 6 weeks and immediately before switching) and in 5 they were done afterwards, at approximately 6 weeks intervals between each one of them. We analyzed: ­ Partial and total mean Hb levels in each control before and after treatment, as well as percentages of patients with stable Hb levels, within the 11-13 g/dL range. ­ The median darbepoietin used dose and the mean resulting conversion factor, as well as mean partial darbepoietin doses and partial conversion factors en each of the controls. ­ The relationship between dose and administration frequency of each molecule before and after switching. ­ The appearance of significant medication-related clinical adverse events such severe hypertension, allergic reactions or other severe ones. Statistical analysis: descriptive statistics used the mean and its standard deviation and median for quantitative variables, and frequency distribution for qualitative variables. For comparison of Hb means for each analytical check-up done before and after conversion to darbepoietin Friedman's test was used, whereas Wilcoxon's test was used for comparison of the total mean of Hb from the time period before treatment switching to the one afterwards, and for comparing each partial median darbepoietin dose and of the partial conversion factor in each analytical check-up with the corresponding ones immediately after treatment switching. For both tests, a p value < 0.05 was considered significant. RESULTS All recruited patients (n = 35) completed the follow-up period. Their characteristics at the beginning of the study are shown in Table I. DARBEPOIETIN ALPHA IN PERITONEAL DIALYSIS Table I. Demographic characteristics of patients Total number of patients Age, years Mean ± SD Range Median % older than 70 years Gender, n (%) Women Men Time on peritoneal dialysis, months Mean ± SD Range Median Renal failure etiology, n (%) Diabetes Chronic interstitial nephritis Vascular (hypertensive and arteriosclerotic) Chronic glomerulonephritis Unknown Polycystic disease Vasculitis 35 62.74 ± 15.63 [21­83] 68 41% 18 (51.43) 17 (48.57) 20 ± 19.6 [4­58] 13 8 (22.86) 7 (20) 6 (17.14) 6 (17.14) 4 (11.43) 3 (8.57) 1 (2.86) 14 13 12 11 10 9 8 Hb (g/dL) p = 0.08 11.78 ± 1.09 11.99 ± 0.95 Epoietin alpha period Darbepoietin alpha period Fig. 1.--Comparison between total Hb mean during the previous period and the one after switching treatment. Results of hematological parameters for the different analytical check-ups are shown in Table II. As it can be observed, Hb means (g/dL) in controls corresponding to treatment with darbepoietin (11.85 ± 1.38; 12.2 ± 1.03; 11.93 ± 1.39; 11.98 ± 1.35; and 12.02 ± 1.22) were very similar to the ones in controls corresponding to epoietin alpha (11.59 ± 1.35; and 11.98 ± 1.35), with no significant differences between these values (Friedman's test: p = ns Table III). In the same way, total means of Hb before and after switching did not show either significant differences (11.78 ± 1.09 vs 11.99 ± 0.95) (Wilcoxon's test: p = 0.08, Fig. 1). However, when analyzing patients that are within the 11-13 g/dL Hb range and those that are out of this range (Table II and fig. 2), we observed that the proportion of patients within that Hb range increases from 73% to 85% after conversion from epoietin alpha to darbepoietin, at the same time that the percentages of patients out of range remarkably decrease, being for Hb < 11 g/dL 22.86% (n = 8) and 17.14% (n = 6) for controls corresponding to epoietin alpha, and 11.43% (n = 4), 20% (n = 7), 8.57% (n = 3) and 5.71% (n = 2) for the five controls corresponding to darbepoietin alpha. Only one patient (2.86%) showed at some time of the follow-up period after switching to darbepoietin an Hb level < 10 g/dL as compared to 3 cases (8.57%) with epoietin alpha. There were no significant differences between serum ferritin levels or the transferrin saturation Table II. Comparison before and after conversion to darbepoietin: Hb levels, percentage of patients with Hb < 11 and 10 g/dL and of dose interval Control rEPO 1 Hb* (d/dL) mean ± SD Hb < 11g/dL [% (n)] Hb < 10 g/dL [% (n)] Mean interval beetween doses ± SD (days) * Friedman's test: p = ns Control rEPO 2 11.98 ± 1.35 17.14 (6) Control Darbe 1 11.85 ± 1.38 11.43 (4) Control Darbe 2 12.2 ± 1.03 11.43 (4) Control Darbe 3 11.93 ± 1.39 20 (7) 2.86 (1) 9.2 ± 3.2 días Control Darbe 4 11.98 ± 1.35 8.57 (3) Control Darbe 5 12.02 ± 1.22 5.71 (2) 11.59 ± 1.35 22.86 (8) 8.57 (3) 7.5 ± 3 días 173 C. REMÓN y cols. 100% 80% Hb 13 Ferritin 300 250 200 ng/nl 150 100 211 ± 29 189 ± 50 205 ± 22 213 ± 27 169 ± 05 190 ± 35 60% 73% 85% Hb 11-13 g/dL Hb 10-11 g/dL Hb < 10 g/dL 40% 20% 0% 181 ± 31 50 0 Epoietin alpha Darbepoietin alpha 40% Fig. 2.--Percentages of patients within each Hb range before and after conversion from epoietin alpha to darbepoietin alpha. 30% 29.9 ± 11 29.8 ± 10 31.1 ± 12 29.7 ± 13 35.8 ± 14 35.7 ± 19 30 ± 12 20% index (TSI) or in iron requirements after switching to darbepoietin or during the follow-up period (Fig. 3). The percentages of patients that received iron p.o. or i.v. did not vary either as compared to basal ones. In relation to the application of the 1/200 conversion factor proposed by the darbepoietin manufacturer we were able to verify that it was applicable to 78% of the cases, the remaining requiring an adjustment to correct Hb in those patients that were out of the 11-13 g/dL range, yielding a 10.5% lower average conversion factor [179.9 ± 89.6 (minimum: 66.6; maximum: 381)] for our patients, and thus, an average darbepoietin usage somewhat higher than the one expected beforehand (Table III). However, if we study the mean weekly darbepoietin dose in each analytical control (Table IV), we observe a trend towards a dose decline, reflected as a progressive increase in the conversion factor in relation to the initial one, and reaching statistical significance the comparison between median dose from the first control and the fifth control after conversion (p = 0.025) as well as for partial conversion factor in the same periods (p = 0.046). Administration frequency was longer after conversion, being 7.5 ± 3 days for epoietin alpha and 9.2 ± 3.2 days for darbepoietin (Table II), with a mean weekly dosage of 5,892 ± 4,166 IU (minimum: 666; 10% ­6 0 6 12 Weeks 24 30 TSI 36 Conversion Fig. 3.--Ferritin and TSI levels for the whole study period. maximum: 20,000) and of 33 ± 12 µg (minimum: 10; maximum: 52.5), respectively (Table III). Darbepoietin alpha treatment was well tolerated, without any relevant adverse events attributable to treatment. DISCUSSION Although CRF-associated anemia from early phases to renal replacement therapy is considered multifactorial, we know that the main etiologic factor for its development is a deficient synthesis of endogenous erythropoietin. This anemia is associated to a greater cardiovascular risk (left ventricular hyper- Table III. Mean weekly doses of epoietin and darbepoietin alpha and mean conversion factor resulting from treatment switching n Epoietin alpha (units) Darbepoietin (micrograms) Conversion factor 35 35 Mean ± SD 5,892 ± 4,166 33 ± 12 179.9 ± 89.6 V. maximum 20,000 52.5 381 V. minimum 666 10 66.6 174 DARBEPOIETIN ALPHA IN PERITONEAL DIALYSIS trophy, congestive heart failure...), to a quality of life decrement, and to an increase in the mortality rate for whatever cause. Since the beginning of rHuEPO use in the 1980s, its benefits have been widely described in relation to less transfusion requirements, an improvement in patients' quality of life and in CRF anemia-related morbidity and mortality21-23. The main rHuEPO drawback is its short half-life that imposes a dose regimen of 2-3 days per week, especially when administered i.v., with the resulting inconveniency for patients24. The s.c. route, however, allows for dose spacing a little bit longer, with the possibility of maintaining Hb levels with a single weekly rHuEPO administration in many cases. As discussed, it seems a logical inference that the s.c. route was the first modality option in CRF patients in a pre-dialysis status or in those included in a PD program since this route allows, on the one hand, an out-patient administration without the need for frequently attending a health care facility (as required for i.v. administration) and, on the other hand, it allows a single weekly administration in many cases. Although until 1998 there were isolated cases reported in the literature of PRBCA1-3 related to the development of anti-erythropoietin antibodies in rHuEPO treated patients for correction of anemia secondary to chronic renal failure, in 2002 Casadevall et al.4 reported a series of 21 cases, most of them in relation to epoietin alpha administered s.c. Due to other similar reports following that one, in December of 2002 the Spanish Drug Agency and agencies from other countries contraindicated this route for epoietin alpha administration6, and its usage has been restricted to i.v. administration and a prescription switch to epoietin beta (with which there have been much less PRBCA reported cases7-9) or to darbepoietin alpha (with which no cases have been described to date) is necessary in pre-dialysis and PD in order to continue with the s.c. route in these outpatients. Besides, because its longer half-life, darbepoietin alpha allows for spacing the doses with an adequate maintenance of Hb levels and with a good safety profile, data that been shown for both pre-dialysis and dialysis patients11-13,15,17,18,25. In most of the studies with dialysis patients, most of them were on HD, with a lower rate of PD patients. In particular, in the Spanish multicenter study on darbepoietin alpha in dialysis11, only 6% o patients were included in PD, versus 94% that where in HD. In very few other studies this distribution is somewhat more balanced --as in the study reported by Macdougall et al.26 in 2003 with 75 patients on HD and 45 on PD-- and the studies performed with patients on PD are scant. In the present study our experience is shown in relation to efficacy and safety of darbepoietin alpha treatment for correction of renal anemia, exclusively in patients with PD, belonging to a single center, after conversion from epoietin alpha to darbepoietin alpha (both s.c.). With regards to efficacy, our results confirm usefulness of darbepoietin alpha for treating the anemia of patients on PD, maintaining mean stable Hb levels without any statistically significant differences as compared to previous treatment with epoietin alpha. Although at the beginning of the conversion, and probably in relation to the intention of correcting Hb levels lower than 11 g/dL, darbepoietin dosage was higher than the one corresponding to a 1/200 factor. In the following check-ups, when the percentage of patients with optimal Hb levels was higher (Table II), used doses were already lower than the first ones after conversion. In the latest check-ups, conversion factors were near to the 1/200 reference (Table IV), and even with a darbepoietin dose reduction in relation to the estimated one by applying the 1/200 factor in the last control (conversion factor of 1/208.9). These later data in our series are in agreement with those referred in other studies, such as the multicenter study by Locatelli et al.17 and the one leaded in Spain by Martinez Castealo et al.11, both performed on dialysis patients in whom epoietin to darbepoietin switching does not induce a significant variation in Hb plasma levels. Particularly, in the later study, Hb slightly increases (0.24 g/dL) when administered s.c., even with a 4.5% darbepoietin dose reduction and a substantial increase in the administration interval, in spite of not aiming at correction in undertreated or hyporesponsive cases. Additionally, after conversion from epoietin to darbepoietin alpha, the percentage of patients that sustained stable Hb levels within the 11-13 g/dL range (85% of patients) was higher than the one achieved with epoietin alpha (73% of patients), decreasing the rate of uncontrolled patients, especially those with a Hb level lower than 10 g/dL (2.86% vs. 8.57%, respectively for darbepoietin and for epoietin). With the exception of patients that received two or more weekly doses of epoietin alpha and in whom we switched to a single weekly darbepoietin dose, initially we did not look for an increase in dose interval. However, along the study course we could confirm that the frequency of s.c. administration of darbepoietin alpha (1 dose every 9.2 ± 3.2 days) was longer than the one obtained with previous treatment with epoietin alpha (1 dose every 7.5 ± 3 days). In other studies where the objective was dose spacing it was also observed that stable Hb levels were sustained with a longer administration frequency both 175 C. REMÓN y cols. Table IV. Darbepoietin alpha doses on each analytical control after changing and its partial conversion factor in relation to previous epoietin mean doses (see table III) Mean darbepoietin weekly dose Control Control Control Control Control 1 2 3 4 5 Darbe. Darbe. Darbe. Darbe. Darbe. 36.86 35.22 34.21 30.81 28.21 ± ± ± ± ± 15.3 14.3 13 14.2 14.1 p(1) 0.230 0.138 0.065 0.025 Conversion factor 160.0 167.3 172.2 191.2 208.9 p(1) 0.583 0.455 0.141 0.046 (1) Wilcoxon's test: comparisons were control Darbe 2 versus control Darbe 1, control Darbe 3 versus control Darbe 1, control Darbe 4 versus control Darbe 1, control Darbe 5 versus control Darbe 1. in CRF patients on dialysis11,18,25 that received darbepoietin s.c. or i.v. and on pre-dialysis where it was administered s.c.14-16. In our patients, iron kinetics parameters and iron requirements were not influenced by conversion to darbepoietin, as it is also shown in the studies by Molina et al. in pre-dialysis14 and Martinez Castelao et al. in dialysis11, among others. Treatment with darbepoietin alpha was well tolerated without any adverse events attributable to it, thus the safety profile shown was adequate. 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