Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-03-16
2001-12-25
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S021800, C514S814000, C530S380000, C530S397000
Reexamination Certificate
active
06333306
ABSTRACT:
The present invention relates to pharmaceutical combination preparations containing erythropoietin and iron preparations. In particular, these preparations are used in the treatment of anemia or hemodialysis patients.
The present invention is directed to a pharmaceutical combination preparation comprising 2,000-7,000 U of recombinant human erythropoietin (rhEPO) and 1-20 mg of an equivalent amount of iron ions of a physiologically tolerable iron preparation, wherein said rhEPO and said iron preparation may be present in separate administration forms or in an integrated administration form.
The use of recombinant erythropoietin in the therapy of hemodialysis patients suffering from anemia, particularly transfusion-induced anemia is well-known. Anemia in chronic diseases is the second-most frequent anemia form worldwide.
In anemias caused by a reduced erythropoiesis in the bone marrow or by disorders in the iron reutilization, the reduced regeneration of erythrocytes is the prominent feature. With a daily decline in erythrocyte regeneration around 1%, the anemia can be detected clinically only after 1-3 weeks. The daily iron requirement in normal erythropoiesis is 25 mg. Only about 1 mg thereof is from dietary sources, the manor requirement normally being met by reutilization of the hemoglobin iron after degradation of aged erythrocytes. In chronic diseases, the iron release from the reticular cells is massively reduced. The iron is held in the reticulo-endothelial system and is no longer available for erythropoiesis. Therefore, this is also referred to as “interior iron deficiency” where triggering of normal compensation mechanisms is incomplete. Reticulocytopenia and lacking hyperplasia of the erythropoiesis, which is necessary to compensate the anemia, are typical. Reduced erythropoietin secretion or activity may be an additional pathogenic factor. For example, a significant change in iron metabolism would be a compensatorily increased formation of transferrin. Thus, the basic disorder lies in the lacking release of iron from the iron depots (in the reticulo-endothelial cells) into the plasma (and thus, into the erythron as well), whereby normal compensation mechanisms are not triggered. The administration of recombinant erythropoietin is used in therapy to effect a significant increase in the number of erythrocytes.
In clinical chemistry, the serum ferritin concentration is determined for the diagnosis of anemia and disorders in iron metabolism. In case a real on deficiency is present in addition to the anemia of the chronic diseases, ferritin does not increase (in most of the cases it remains below 90-95 ng/ml). When clinical signs of infection, inflammation or a malignant disease are also present, this value indicates a combination of iron deficiency and anemia accompanied by a chronic disease. Since serum ferritin in such diseases may also react in the, sense of an acute phase protein, the diagnostic utilization of erythrocyte ferritin can be improved.
The total body iron is about 3.5 g in males and 2.5 g in females. The iron is found in the active metabolism and in storage compartments. In the active pool of a male, an average of 2100 mg is found in hemoglobin, 200 mg in myoglobin, 150 mg in tissue enzymes (hem and non-hem), and 3 mg in the iron transport compartment. In the tissue, iron is stored intracellularly as ferritin (700 mg) and hemosiderin (300 mg).
There may be a pathophysiological disorder in the bioavailability of iron, so that the iron absorption in the body is reduced. Of those approximately 10 mg being available daily by way of food, only about 1 mg is resorbed by an adult. In case of iron deficiency, the resorption increase, but rarely more than 5-6 mg unless additional iron is supplied. The precise mechanism of resorption for iron is not clear. Regulation is effected crucially by the intestinal mucosa calls. The crucial signal for the mucosa seems to be the total iron content of the body. It was demonstrated that the serum ferritin concentration is in inverse correlation to the amount of absorbed iron.
The iron is transferred to transferrin by the intestinal mucosa cells. This iron transport protein has two iron binding sites. It is synthesized in the liver. Thus, there is a mechanism by which iron is taken over by cells (e.g., intestinal mucosa, macrophages) and delivered to specific membrane receptors of erythroblasts, placenta cells or liver cells. By way of endocytosis, the transferrin/iron receptor complex enters the erythrocyte precursor cells where the iron is passed on to the mitochondria. There, hem is formed from iron and protoporphyrin.
The iron which is not needed for erythropoiesis is conveyed to two types of storage pools by transferrin. The most important depot is ferritin. This is a heterogeneous class of proteins enclosing an iron core. It is soluble and represents the active storage form in the liver (hepatocytes), bone marrow, spleen (macrophages), erythrocytes and the serum (about 100 ng/ml). The tissue ferritin pool is highly labile and quickly available in case iron is required. The circulating serum ferritin comes from the reticulo-endothelial system, and its circulating concentration goes parallel to that of total body iron (each ng/ml corresponding to 8 mg of iron reserve).
In the case of hemodialysis patients, the iron requirement of patients treated with rhEPO was found to be quite considerable. As a rule, an additional iron therapy is conducted with these patients because the EPO can develop its optimum effect only in case the corresponding iron depots in the body are filled as much as possible. To date, it has been common to administer high doses of iron preparations in order to fill the iron depots as much as possible, However, excessive doses of iron preparations may also give rise to undesirable side effects in patients. In particular, the intravenous application of iron preparations is not safe in physiological terms due to the extreme toxicity of iron ions. In patients where the situation of allergic reactions is well-known, e.g., asthmatics, the use of certain iron preparations is even discouraged, as a rule. Estimating the filling level of the iron depots is possible by determining the ferritin protein and by determining the transferrin saturation (M. Wick, W. Pingerra, P. Lehmann, “Eisenstoffwechsel, Diagnose und Therapie der Anämien”, pp. 5-14, 38-55, 65-80, 94-98, third advanced edition, September 1996, Springer Verlag, Vienna, N.Y.), wherein said transferrin saturation represents the iron flow from the depots to the marrow, while the serum ferritin value is a measure of stored iron.
The iron depots are regarded as “filled” when the serum ferritin is >150 &mgr;g/l and a transferrin saturation of >20% is present. P. Grützmacher et al., in Clinical Nephrology, Vol. 38, No. 1, 1992, pp. 92-97, describe that maximum response to the EPO therapy can be assumed under these conditions.
At present, one speaks of a “correction phase” and a “maintenance phase” in the iron therapy of EPO-treated dialysis patients. During the correction phase, iron preparations are administered at dosages as high as possible in order to refill the iron depots as rapidly as possible. Conveniently, the application of suitable iron preparations is then effected by way of intravenous bolus injection. The iron depots are then “maintained filled” during the maintenance phase using lower iron dosages. The application of suitable iron preparations in this phase is not effected as a rapid bolus injection but in the form of common infusion preparations or by oral administration.
The iron requirement of rhEPO-treated hemodialysis patients may be quite considerable in both the correction and maintenance phases. In order to synthesize 1 g/dl hemoglobin during the correction phase, 150 mg of iron is required which either is delivered from endogenic iron depots or must be supplied exogenously. Similarly, there is an increased iron requirement during the maintenance phase because each treatment of hemodialysis patients gives rise to a minor loss of bloo
Arent Fox Kintner & Plotkin & Kahn, PLLC
Carlson Karen Cochrane
Roche Diagnostics GmbH
Schnizer Holly
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