The Hematopoietic Effect of Epotin (Recombinant Human Erythropoietin-α) on Maintenance Hemodialysis End-Stage Kidney Disease Patients

OUTCOMES

The Hematopoietic Effect of Epotin (Recombinant Human Erythropoietin-␣) on Maintenance Hemodialysis End-Stage Kidney Disease Patients S. Al-Shohaib, D.S. Shaker, B.B. Ghaedi, M. Alyarim, S. Emara, and M. Behairy ABSTRACT Recombinant human erythropoietin (rHuEpo) has revolutionized the management of renal anemia, significantly improving patient quality of life. Great attention has been paid lately on how to optimally use this potent anti-anemic agent. Aiming to overview anemic patient management with Epotin (Julphar’s rHuEpo) according to the new guidelines, we included in the study anemic (hemoglobin [Hb] ⱕ11 g/dL) end-stage kidney disease (ESKD) patients (n ⫽ 35) of ages ⱖ18 years who were of iron replete (transeferene saturation (TSAT) ⱖ20% and serum ferritin ⱖ100 ␮g/L) with no evidence of serious inflammation (c- reactive protein (CRP) ⬍30 mg/L) on thrice-weekly hemodialysis. The mean age and dialysis duration of 50.8 ⫾ 17 and 3.8 ⫾ 2.8 years, respectively, included 88.6% (n ⫽ 31) de novo patients in the corrective phase with no previous exposure to erythropoietin. Safety-efficacy parameters showed insignificant changes throughout the 4-month study period, including iron profile that was maintained according to Kidney Disease Outcome Quality Initiative guidelines. Efficacy parameters revealed a significant increase (P ⬍ .0001) of Hb levels from a baseline of 8.5 ⫾ 1.0 to 11.1 ⫾ 1.1. Targeting an absolute increase of 2.5 g/dL in Hb throughout 3 months of the study period resulted in a 90.3% success rate. There were no dropouts due to intolerance, whereas all the recorded adverse events were classified as unrelated to the test product. In conclusion, Epotin was clinically effective to correct and maintain Hb levels in ESKD anemic patients on maintenance hemodialysis within the current recommended range and with a satisfactory safety profile consistent with previous international reports.

From the College of Medicine and King Abdul Aziz University Hospital/Kingdom of Saudi Arabia (S.A.-S., M.Aly., S.E., M.Alb.), and Dubai Research Center/UAE United Arab Emirates (D.S.S., B.B.G.). The study was made possible due to the financial support © 2010 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 42, 753–759 (2010)

from Gulf Pharmaceutical Industries. None of the investigators have any financial interest in the study products. Address reprint requests to Dr. Saad Al-Shohaib, King AbdulAziz University, P.O. Box 126320, Jeddah 21352, Kingdom of Saudi Arabia. E-mail: [email protected] 0041-1345/10/$–see front matter doi:10.1016/j.transproceed.2010.02.056 753

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MAJOR challenge for nephrologists in optimizing the treatment of anemia associated with end-stage kidney disease (ESKD) is to increase the numbers of patients who reach ⬎11 g/dL as the target recommended by the European Best Practice Guidelines (EBPG) or a target range of 11–12 g/dL as per the revised National Kidney Foundation-Kidney Disease Outcome Quality Initiative (NKF/K-DOQI).1,2 In a survey by the Saudi Center for Organ Transplantation (SCOT) the current physician practice for anemia therapy across dialysis centers in the Kingdom of Saudi Arabia (KSA) was reasonable, but not optimal, compared with the K-DOQI guidelines and EBPG.3– 6 Under-dosed recombinant human erythropoietin (rHuEpo) in ESKD hemodialysis patients,7 insufficient iron stores due to improper evaluation and repletion,8 lack of awareness of the new Optimal Treatment of Renal Anemia (OPTA) guidelines,9 and economic burdens lead to our dialysis patients showing an average hemoglobin (Hb) of 8 g/dL compared with 12 g/dL in Sweden and 10.1 g/dL in Japan.10 Most of our patients were transfusion-dependent with an extremely poor quality of life.11 Limited budgets for the healthcare sector in developing countries render only 10.8% of hemodialysis patients able to take a sufficient dose of rHuEpo12 compared with 94% in Sweden and 84% in Japan.10 Thus, OPTA guidelines can only be implemented by adequately managing all factors that influence anemia in patients with chronic kidney disease without ignoring the need for a cheap, safe, and effective rHuEpo, which became possible after the key process patent for the first generation of rHuEpos had expired in Europe and other regions, opening the market for bio-similar follow-on products. Epotin manufactured by Gulf Pharmaceutical Industries (Julphar) is a Chinese Hamster Ovary (CHO) cell– derived epoetin-␣. Its safety and effectiveness to treat anemia in hemodialysis patients and correct Hb to 11–12 g/dL has been demonstrated previously13 as well as its significant impact to dramatically improve on life quality and survival as shown by other CHO cell– derived products epoetin-␣ (Epogen, Procrit, Eprex, Espo, and so on) and epoetin-␤ (Recormon, NeoRecormon, Epogin, and so on) that have been in clinical use for 20 years. Potential differences between bio-similar glycoproteins, such as rHuEpo and the originator compounds, may have implications for immunogenicity, pharmacokinetics, and purity, because the transgene, the host cell line, the culture conditions, and the purification procedure are not the same as the originator. Also, the manufacturing process cannot be exactly copied, because important details of the originator production process are not in the public domain.14 The European Medicine Agency (EMEA) has made efforts to establish guidelines15 for the development and approval of bio-similar medicinal products containing biotechnologyderived proteins, which differ from the regulations for generic chemically defined drugs.16 According to the recently published supplement referring to rHuEpo, the clinical efficacy

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AL-SHOHAIB, SHAKER, GHAEDI ET AL

and safety of bio-similar preparations must be demonstrated in at least 2 adequately powered studies.15 However, safety data for biopharmaceuticals can only be concluded from long-term clinical experiences and postmarketing surveillance. Previous studies on Epotin proved its purity, efficacy, and tolerance,13 whereas long-term safety was assessed through 3-year pharmacovigilance survey. However, recent evolutions as availability of different epoetins, occurrence of pure red blood cell aplasia (PRCA), and new OPTA guidelines have led to modifications in the management of anemia in hemodialysis patients. Consider the effectiveness of the therapy to optimize the cost-benefit ratio of anemia therapy, we have posed the real question of how intensively to administer Epotin to reach our target. METHODS The study was performed in accordance with Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by our Ethics Committee and informed consent was obtained from each patient.

Patients and Study Duration ESKD anemic patients with Hb levels ⱕ11 g/dL who were aged between 18 and 75 years and maintained with an adequate Kt/V (ⱖ1.2) on thrice-weekly dialysis had to be negative for hemoglobinopathies, chronic infection serious inflammation (C reactive protein [CRP] ⬍30 mg/L), human immunodeficiency virus (HIV), malignancy, or other terminal illness. They were asked to give informed consent to replete their iron stores (transeferene saturation [TSAT] ⱖ20% and serum ferritin ⱖ100 ␮g/L) to be qualified for inclusion into the study. At least 1 screening visit to the outpatient clinic before enrollment and 40 regular hemodialysis visits thereafter were mandatory for examination and laboratory analyses over a minimum follow-up duration of 3 months, during which we administered 2000 IU and 4000 IU Epotin.

Erythropoiesis-Stimulating Agents Patients who were maintained on other erythropoietins were shifted to Epotin at an IU:IU basis. The dose was then titrated according to the Hb response, other than that for a patient who had never received erythropoietin before, in whom we administered a dose of 150 IU/kg body weight/wk. Epotin was delivered intravenously in 3 equal doses after dialysis for a 15-week period from day 14 excluding the time needed to replenish iron stores. Titration was indicated when the increase in Hct after initiation of Epotin therapy or after a dose increase was ⬍2 percentage points over a 4-week period. The dose of Epotin was increased by 50%. Otherwise, if the absolute rate of increase of hematocrit (Hct) after initiation of Epotin therapy or after a dose increase exceeded 8 percentage points over 4 weeks or if the Hct exceeded the target of 33%–36%, the weekly dose of Epotin was reduced by 25%. All titrations were made only by the principal investigator and proper justification was written on the chronic renal failure (CRF). At the end of the study, it was optional to keep the patient on Epotin or any alternative medication.

Iron and Folic Acid After replenishing depleted iron stores as needed to achieve serum ferritin ⱖ100 ␮g/L and TSAT% ⱖ20, intravenous iron sucrose

HEMATOPOIETIC EFFECT OF EPOTIN (Ferosac, Spimaco, Riyadh, Saudi Arabia) was given throughout the study as per the NKF K/DOQI guidelines to maintain the iron profile above the recommended values. Similarly folic acid (Folicum, Julphar), 1 mg tablet, was given at each dialysis session. Intravenous iron therapy was discontinued for 1 week prior to performing iron profile measurements if the weekly dose was ⬍500 mg, or for 2 weeks if it was equal to or more than that value.

Definitions We classified the rHuEpo response after 3 months of treatment as poor if the Hb increase was ⬍2.5 g/dL, rapid if it increased by more than that in 1 month, and resistant if it failed to respond to a dose ⬎300 IU/kg/wk after full investigation and referral to a hematologist to exclude other reasons for the lack of response. PRCA was suspected if a patient treated for more than 4 weeks had a sudden rapid decrease in Hb concentration at 5–10 g/L/wk despite ongoing rHuEpo therapy or required transfusion of 1–2 U blood per week to maintain platelet and white blood cell (WBC) counts within the normal range. Confirmation by positive antierythropoietin antibodies associated with the presence of severe nonregenerative anemia, evidence of erythroid hypoplasia in a bone marrow aspirate with normal cellularity, ⬍5% erythroblast, and evidence of a red blood cell precursor maturation block.6 High blood pressure was defined as a diastolic blood pressure ⬎90 mm Hg measured with a mercury sphygmomanometer after 5 minutes in a sitting positions. A new case of hypertension was defined if it persisted for 2 weeks with no previous similar history. An absolute iron deficiency was defined as a serum ferritin level ⬍100 ng/mL and a TSAT level ⬍20%, whereas functional iron deficiency anemia was defined as a normal or elevated serum ferritin level, but TSAT ⬍20% and/or ⬎5% hypochromic red blood cells.17 While the normal blood potassium level is 3.5–5.0 mmol/L, a content between 5.1– 6.0 mmol/L reflected mild 6.1–7.0 mmol/L moderate, and ⬎7 mmol/L severe hyperkalemia.

Parameters Response influenced parameters included iron profile (transeferene saturation, total iron binding capacity (TIBC), s. iron, and serum ferritin), liver function test (aspartate aminotransferase [AST], alanine aminotransferase [ALT], albumin, bilirubin, and alkaline phosphatase), S. electrolytes (Na, Ca, K, and PO4), predialysis creatinine, cholesterol, and CRP. They were measured during screening and monthly thereafter. Kt/V was recorded weekly, whereas parathyroid hormone (PTH) and stool occult blood were performed at screening and on the last day of the study. To assess efficacy we measured Hb and Hct every 2 weeks following initiation of treatment or following dose adjustment we achieved until the target Hb of 11g/dl. Once achieved, Hb was maintained between 11 and 12 g/dL and monitored every 4 weeks. Other blood counts (RBCs, WBCs, platelets, indices, and reticulocytes) were recorded at screening and on a monthly schedule thereafter. We assessmed safety as vital signs, adverse events of thrombosis, hyperkalemia, hypertension, seizure, pruritus, and so on as well as laboratory data and medical assessments by the investigator at each scheduled visit. Adverse events were primarily classified according to the adverse reaction terminology of the World Health Organization (WHOART).

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Statistics The sample size was calculated with StatMate.18 Considering Hb as the primary efficacy parameter, the minimal response of clinical significance from day zero to the end of week 13 was 2.5 g/dL Hb (according to K-DOQI guidelines), assuming a standard deviation of 2 and considering a study power of 99% and a P value ⬍ .05. The sample size was estimated to be 35 patients. The results of the quantitative variables are expressed as mean values ⫾ standard deviation (SD) and those of qualitative variables as proportions. Statistical analysis was performed using the Graphpad instat program, by which we compared the baseline values for all parameters with values of each scheduled reading by means of a nonparametric test. A P value ⱕ .05 was considered significant.

RESULTS Demographic Data

From June to October 2007, we enrolled 35 patients including 14 males and 21 females, of age range 18 –75 years, and body mass index (BMI) range of 11.4 –35.7 kg/m2 (Table 1). Patients had been maintained on hemodialysis for varying periods prior to enrollment, ranging from 2.4 –108 months. Hypertension was the major etiology behind ESKD (68.6%; Table 2). In this study 11.4% (n ⫽ 4) of 35 patients were on erythropoietin maintenance phase with (Eprex) prior to enrollment; the others were de novo treatments in the corrective phase with no previous exposure to erythropoietin. Even though none of the patients was taking any drug that may change the response to rHuEpo, all concomitant medications were closely monitored; their doses were recorded during the study period. Overall compliance to scheduled dialysis sessions and rHuEpo doses did not fall below 98% for the study medication. The rHuEpo starting dose average of 49.8 ⫾ 6.8 IU/kg/session did not change drastically during the study to reach 50 ⫾ 6.8 IU/kg/session at the end. Efficacy Parameters

Hemogram Response to rHuEpo. There was an extremely significant increase (P ⬍ .0001) in the Hct % and Hb levels from a baseline mean of 24.5 ⫾ 3.0 and 8.5 ⫾ 1.0 to 33.4 ⫾ 3.2 and 11.1 ⫾ 1.1 at week 15, respectively. This increase started to show significance at week 5 of the study (Fig 1). RBCs and reticulocyte counts showed similar trends from 3.0 ⫾ 0.4 and 1.4 ⫾ 0.9 to 3.7 ⫾ 0.4 and 2.1 ⫾ 1.1 by week 15, respectively; otherwise, all other heme parameters remained unchanged (Table 3). All 4 maintenance-phase patients completed the study with their Hct% level within Table 1. Demographic Data M14/F21 (n ⴝ 35) Presented as Mean ⴞ SD (Range) Age (y) Height (cm) Weight (kg) BMI (kg/m2) Abbreviations: M, males; F, females.

50.8 ⫾ 17 (18–75) 160.9 ⫾ 9.8 (140–179) 63.9 ⫾ 15.8 (36–94) 24.7 ⫾ 5.4 (11.4–35.7)

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Table 2. ESKD Underlying Cause, Durations and Medical History (n ⴝ 35) ESKD underlying cause Hypertension Diabetes mellitus Undetermined Medical history Hypertension Diabetes mellitus Duration (mo) ESKD diagnosis–dialysis Dialysis–recruitment Vascular access AVF CVL SC

n (%) 24 (68.6) 8 (22.9) 3 (8.5) n (%) 30 (85.7) 14 (40) Mean ⫾ SD (range) 4.4 ⫾ 4.8 (0.3–18.4) 45.6 ⫾ 33.6 (2.4–108) n (%) 24 (68.6) 11 (31.4) 0

Abbreviations: AVF, ________; CVL, _____; SC, __________.

the target; none needed dose titration after shifting to Epotin. Success Rate and Poor Responders. Targeting an absolute increase of 2.5 g/dL in Hb throughout 3 months of the study period as per K-DOQI guidelines resulted in a 90.3% success rate after excluding the 4 maintenance patients. The 3 patients who did not achieve this target had bleeding either due to an access thrombosis-related procedure or hemorrhoidal or vaginal bleeding; none correlated with rHuEpo therapy. However, these patients were close to achieving the target. Safety-efficacy influential parameters. All safety-efficacy influencing parameters were monitored, showing insignificant changes throughout the study period, including the iron profile that was maintained according to K-DOQI guidelines (Table 4). Safety Parameters

Anaphylaxis was not reported, and there were no reports of serious adverse events that needed case withdrawal from the study.

Fig 1. Hemogram response to Epotin.

Antihypertensive medication. Upon enrollment, 85.7% (n ⫽ 30) of the study population reported hypertension for an average of 8.4 ⫾ 7.8 years (range, 0.1–25 years). Most were treated with a combination of calcium-channel blockers and ␤-adrenergic blockers with 22.8% on a single antihypertensive medication; 71.5% were on a dual regimen, and only 2 patients were on quadruple therapy. Among 30 hypertensive patients, 14 (46.7%) developed bouts of high blood pressure that were easily controllable; otherwise, we did not record new cases of hypertension. At the end of the study there was no substantial difference in antihypertensive medications or dosages. Tolerability and Adverse Events. One patient developed access thrombosis, 3 patients had mild asymptomatic hyperkalemia, and 1 patient had mild pruritis once. All recorded adverse events were WHO classification as unrelated to the test product. All other safety parameters, including vital signs and laboratory analyses, including serum electrolytes, s. creatinine, liver function test, and lipid profile, were steady throughout the study period (Table 5). DISCUSSION

The medical care of patients with renal anemia has been the focus of much attention over the past decade as nephrologists have recognized the increasing therapeutic value of erythropoiesis-stimulating agents that have transformed the lives of millions of individuals.19 A number of factors that may counteract the positive action of epoetin therapy in our region have been identified, such as inadequate dialysis dose, absolute and functional iron deficiency, or inflammation and infection. Each factor on its own could lead to a substantial decrease in the Hb or an increase in epoetin requirements of up to 100%. Still the high cost of the branded epoetin is a major problem11 that points to a real need for increased use of a cheap, safe, and effective epoetin. As first-generation patents expired for epoetin-type substances, which represent the largest market of a class of

HEMATOPOIETIC EFFECT OF EPOTIN

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Table 3. Hematological Parameters Presented as Mean (ⴞSD), n ⴝ 35 Parameter

Baseline

Wk 3

Wk 7

Wk 11

Wk 15

P

Hb g/dL Hct% RBCs ⫻106/mm3 Reticulocytes% WBCs ⫻103/mm3 Platelets/mm3 MCV FL MCH pg/cell MCHC g/dL

8.5 (1.0) 24.5 (3.0) 3.0 (0.4) 1.4 (0.9) 7.3 (3.0) 238 (83.1) 86.9 (7.5) 29.4 (2.6) 33.2 (1.4)

8.8 (0.8) 26.3 (2.4) 3.1 (0.4) 2.1 (1.2) 6.8 (2.2) 245 (85.1) 89.3 (8.5) 29.9 (2.8) 32.8 (1.2)

9.5 (0.8) 28.5 (2.5) 3.2 (0.4) 1.6 (1.3) 6.6 (2.1) 267 (85.6) 89.4 (9.5) 29.5 (3.2) 32.4 (1.5)

10.1 (1.0) 30.1 (3.2) 3.3 (0.5) 1.8 (1.3) 6.8 (2.4) 259 (94.1) 89.8 (8.8) 30.3 (2.6) 32.7 (1.2)

11.1 (1.1) 33.4 (3.2) 3.7 (0.4) 2.1 (1.1) 6.7 (2.4) 246 (76.5) 88.1 (9.0) 30.4 (2.5) 32.8 (1.2)

⬍.0001 ⬍.0001 ⬍.0001 .04 .78 .71 .61 .49 .14

Abbreviations: MCV, _______; MCH, ______; MCHC, _________.

biopharmaceuticals, namely global estimated sales of $22 billion,20 bio-industries have been motivated to develop second-generation products with prolonged half-life, allowing for less frequent application, but the questions of their dose requirements and costs have remained matters of debate.21 Similarly, this vast market opportunity did not pass without notice by the generic bio-manufacturers who have developed bio-similar follow-on products that are similar to but not the same as the already licensed or approved innovator epoetin,22,23 epoetin-␣ of Amgen or ␤ from Roche. In many countries, dozen of follow-on epoetin molecules are available, eg, Epotin, Epocim, Epokine, Epoyet, Hemax, Renogen, Vintor, Wepox, and so on. Follow-on epoetins were also entered into the European market24 in June 2007 when the Committee for Medicinal Products for Human Use (CHMP) for the European Union granted approval for 3 bio-similar versions of epoetin-␣. Clearly, the amino acid sequence of these epoetins is identical to that of endogenous Epo, but the glycans exhibit structural and biophysical differences. Epoetin-␣ is more homogenous and possesses less basic isoforms than epoetin-␤.25 As to the fine chemical structure of the glycans of the epoetins, their composition depends on the host cell, the transfected plasmid, the culture conditions, and the purification process. Accordingly, epoetin-␣ formulations (Epogen and Eprex) from established manufacturers exhibit minor differences in thermal stability, local amino acid environment, and presence of high-molecular aggregates.26 Thus, despite their identical International Nonproprietary

Name (INN), even these closely related drugs are not identical. Similarly, and due to the fact that the innovator biologics are manufactured through sequential steps, subtle variations in temperature, cell culture conditions, or even transport or storage conditions of the follow-on epoetin could result in significant difference in the clinical efficacy, biological activity, and safety with enhanced immunogenicity of the product in some cases.27 Also, variable physical characteristics of follow-on epoetin such as pH, osmolality, and isoelectric charges, have been reported.24,28 Thus, all follow-on epoetins manufactured by local biotechnology should be analyzed and tested for purity, efficacy, and safety before being licensed by the local country’s Food and Drug Administration (FDA) or equivalent drug regulatory agency. In our study we re-enforced the previous conclusion13 with Julphar’s Epotin. Efficacy and tolerability to correct anemia and to maintain Hb within the target range of 11–12 g/dL in 80% of ESKD patients on maintenance hemodialysis was achieved as per the revised NKF/K-DOQI.1,2 The most important adverse events associated with Epotin were increased blood pressure and access failure. These are, however, challenges to improve practice rather than reasons to avoid the use of the drug, their incidence did not exceed those reported internationally with other epoetins. Product immunogenicity is a major concern especially after the development of PRCA in 1998,29,30 reaching a peak in 2002,31 and even though the probability of an antibody reaction to therapeutic proteins is increased in

Table 4. Influential Factors Presented as Mean (ⴙ SD)*, n ⴝ 35 Parameter

Baseline

Wk 3

Wk 7

Wk 11

Wk 15

Epotin IU/kg/session Heparin IU/session S. ferritin ␮g/dL S. iron ␮g/dL TIBC ␮g/dL TSAT% PTH pg/mL Kt/v Occult blood

49.8 (6.8) 994 (34) 541 (378) 79.9 (30.7) 283 (51.2) 29.0 (13.3) 241 (328) 1.1 (0.1) Negative

50 (6.8) 1000 (0) 543 (396) 85.3 (38.4) 264 (59.9) 34.0 (17.2) 243 (3180) 1.2 (0.1) Negative

50 (6.8) 1000 (0) 521 (372) 77.3 (28.7) 267 (77.5) 31.5 (15.4) — 1.1 (0.1) —

50 (6.8) 1000 (0) 550 (383) 77.1 (24.5) 257 (64.6) 32.1 (12.7) — 1.1 (0.2) —

50 (6.8) 1000 (0) 493 (376) 84.9 (39.4) 267 (50.2) 33.6 (19.1) 239 (313) 1.1 (0.1) Negative

*P ⬎ .05 (not significant).

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AL-SHOHAIB, SHAKER, GHAEDI ET AL Table 5. Laboratory Safety Parameters Presented as Mean (ⴞ SD)*, n ⴝ 35 Parameter

Baseline

Wk 3

Wk 7

Wk 11

Wk 15

Cholesterol mmol/L Albumin g/dL ALT U/L AST U/L Al. phosph U/L Bilirubin ␮mol/L S. creatinine mg/dL K⫹ mmol/L Na⫹ mmol/L Ca⫹ mmol/L PO4 mmol/L

5.6 (1.2) 4.0 (0.4) 32.3 (16.7) 30.9 (17.1) 157 (124) 10.6 (2.7) 10.6 (2.7) 3.7 (0.6) 137 (2.8) 2.3 (0.2) 1.2 (0.6)

5.7 (1.3) 4.0 (0.4) 31.6 (15.8) 30.4 (16.0) 167 (134) 10.2 (2.8) 10.2 (2.8) 3.7 (0.7) 136 (2.6) 2.2 (0.2) 1.3 (0.5)

5.6 (1.2) 4.0 (0.4) 29.2 (14.0) 29.6 (12.7) 150 (129) 10.2 (2.6) 10.4 (3.0) 3.7 (0.8) 135 (2.7) 2.2 (0.2) 1.6 (0.6)

5.3 (1.2) 4.1 (0.4) 28.8 (13.4) 28.5 (12.9) 151 (128) 10.9 (2.8) 11.1 (2.9) 3.5 (0.8) 137 (2.7) 2.2 (0.2) 1.3 (0.5)

5.3 (1.2) 4.0 (0.4) 30.4 (17.7) 29.3 (16.5) 159 (144) 10.5 (2.4) 10.3 (2.7) 3.5 (0.6) 137 (2.2) 2.3 (0.2) 1.3 (0.6)

*P ⬎ .05 (not significant).

cases of structural differences when compared with endogenous prototypes (primary structure and posttranslational modification), which is not the case with Epotin. Furthermore, various laboratory analyses of Epotin have failed to show aggregation of the product or its impurities in the formulation. Still, postmarketing pharmacovigilance survey is the only practical method to show these results taking into account that preclinical studies do not provide reliable information on the immunogenicity of biopharmaceuticals. Furthermore, it is almost impossible to demonstrate an increased immunogenicity of erythropoietic recombinant drugs in clinical trials. Even during the “epidemic” phase of antibody-associated PRCA, the incidence of this immunogenic reaction was low (18 cases per 100,000 patient-years for the Eprex formulation) and the median duration of treatment before PRCA was diagnosed as long as 9 months.32 Thus, in harmony with the health regulator’s requirement for products or drugs given approval under monitored release, Julphar conducted a postmarketing safety surveillance of Epotin for a 3-year period that documented its clinical safety.33 In conclusion, clinicians will be faced with a panoply of different follow-on erythropoiesis-stimulating biopharmaceuticals. It will be important for them to be familiar with their molecular biology and clinical efficacy, taking into consideration that safety data for biopharmaceuticals can only come from clinical experience and postmarketing surveillance. In harmony with the previous clinical studies Epotin of Julphar showed efficacy to correct Hb levels in 90.3% of patients by ⱖ2.5 g/dL throughout 3 months of the study period and to maintain it within the target range of 11–12 g/dL in 80% of the patients with an acceptable tolerability profile added to its long-term safety documented in 3-year postmarketing surveillance.

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