Darbepoetin Alfa

Manufacturer Amgen Inc., Thousand Oaks, CA Indications Treatment of anemia associated with chronic renal failure, including patients on dialysis or not on dialysis Type of submission Biologics license application A. General description Darbepoetin alfa is an erythropoiesis-stimulating protein, closely related to erythropoietin, that is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Darbepoetin is a 165 amino-acid protein that differs from recombinant human...

Therapeutic Use of Coagulation Factors

Hemostasis is the process of blood clot formation at the site of vessel injury. When a blood vessel wall breaks, the hemostatic response must be rapid, localized, and carefully regulated. Abnormal bleeding or a propensity to nonphysiologic thrombosis (i.e., thrombosis not required for hemostatic regulation) may occur when specific elements of these processes are missing or dysfunctional. The elements responsible for normal hemostasis have received extensive review. Hemostasis begins with the...

Transforming New Molecular Entities Into Drugs

To gain FDA approval or license for marketing, a pharmaceutical product must be shown to be safe and effective for its proposed or intended use. The drug company or sponsor must also provide evidence to show that the processes and control procedures used for synthesis, manufacture, and packaging are independently validated to ensure that the pharmaceutical product meets established standards of quality. The overall effort from the inception of a new molecular entity and the establishment of...

Filgrastim

Manufacturer Amgen Inc., Thousand Oaks, CA Indications Treatment of patients with nonmyeloid malignancies receiving myelo- suppressive anticancer drugs to decrease the incidence of infection. Treatment of adults with acute myeloid leukemia, following induction or consolidation chemotherapy, to reduce the time to neu-trophil recovery and the duration of fever. Treatment of patients with nonmyeloid malignancies undergoing myeloablative chemotherapy, followed by marrow transplantation to reduce...

Administration

Dosage forms All human insulin products contain 100 units ml. Humulin is available in six formulations Regular (R), NPH (N), Lente (L), Ultralente (U), Humulin 50 50, and Humulin 70 30. Humulin 50 50 is a sterile suspension containing a mixture of 50 Human Insulin Isophane Suspension and 50 Human Insulin (rDNA origin). It is an intermediate-acting insulin combined with the more rapid onset of action of regular insulin.The duration of activity may last up to 24 hours following injection. Humulin...

Insulin Lispro

Manufacturer Eli Lilly, Indianapolis, IN Indications Treatment of diabetes mellitus Type of submission New drug application A. General description Humalog (insulin lispro, rDNA origin) is a rapid-acting human insulin analog. Chemically it is Lys(B28), Pro(B29) human insulin analogue (molecular weight 5.8 kDa), created when the amino acids at positions 28 and 29 on the insulin B-chain are reversed. Humalog is synthesized in a laboratory strain of Escherichia coli bacteria that has been...

Pharmacology and pharmaceutics

Clinical pharmacology Avonex is indicated for the treatment of relapsing-remitting forms of MS. MS is a chronic inflammatory disorder of the central nervous system (CNS) that results in injury to the myelin and to myelin-producing cells. Two-thirds to three-quarters of affected individuals are women. Clinical onset is usually between the ages of 20 and 40 years. Four different clinical forms of MS have been recognized. The first, relapsing-remitting type of MS (RRMS), accounts for approximately...

Insulin Glargine

Manufacturer Hoechst Marion Roussel, Frankfurt am Main, Germany Distributed by Aventis Pharmaceuticals Inc., Kansas City, MO Indications Treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mel- litus who require basal (long-acting) insulin for the control of hyperglycemia Type of submission New drug application A. General description Insulin glargine is a recombinant human insulin analogue with a long duration of action (up to 24...

Clinical pharmacology Filgrastim and

Pegfilgrastim are colony-stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors. They stimulate proliferation, differentiation, commitment, and end cell function activation. They both have the same mechanism of action. Pegfilgrastim has reduced renal clearance and prolonged persistence in the body as compared with filgrastim. Pharmacokinetics The pharmacoki-netics of pegfilgrastim were studied in 379 patients with cancer. The pegylated version of...

Optimization of Molecular Characteristics

Not only must we optimize the expression and yield of purified recombinant proteins, we must ensure that the protein is stable, has a high degree of potency and a low degree of toxicity, and has suitable pharmaceutical properties. Pharmaceutical properties encompass distribution and residence time in target tissues, and frequency of dosing, and may have an impact on efficacy and safety. Starting with a purified recombinant protein, biochemical and biophysical tools are used to elucidate...

Physical and Chemical Stability

Proteins, peptides, and other polymeric macromolecules display varying degrees of chemical and physical stability. The degree of stability of these macromolecules influence the way they are manufactured, distributed, and administered. Chemical stability refers to how readily the molecule can undergo chemical reactions that modify specific amino-acid residues, the building blocks of the proteins and pep-tides. Chemical instability mechanisms of proteins and peptides include hydrolysis,...

BOX 46 Current Good Manufacturing Practice cGMP

The FDA through the establishment of the Good Manufacturing Practice (GMP) regulation ensures that drugs produced by pharmaceutical companies consistently meet quality specification. Since it was first introduced in 1963 as a part of the Kefauver-Harris Drug Amendment of 1962, it has been updated periodically. The latest version is called current GMP (cGMP) regulation. Information is posted on the FDA's Web site (http www.fda.gov cder dmpq cgmpregs.htm). The cGMP regulations encompass the...

Interferonp In The Treatment Of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS), affecting 250,000 to 350,000 people in the United States. MS derives its name from the multiple scarred areas or lesions in brain tissues visible on macroscopic examination 1,2 . These demyelinated lesions or plaques vary in size from 1 or 2mm to several cen- TABLE 7.5. Multiple sclerosis disease presentation and the location of CNS lesions Cerebrum and cerebellum Balance problems,...

Insulin Aspart

Manufacturer Novo Nordisk, Princeton, NJ Indications Treatment of adult patients with diabetes mellitus, for the control of hyperglycemia Type of submission New drug application A. General description Insulin aspart (rDNA origin) is a rapid-acting human insulin analogue. It is homologous with regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology utilizing Saccharomyces...

Interferon Treatment of Chronic Hepatitis B

Hepatitis B virus (HBV) is a DNA virus that causes one of the most common infec tious diseases in the world, affecting about two billion people at some time during their lives 13 .About 15 of infected individuals develop chronic infection, characterized by persistence of hepatitis B surface antigen (HBsAg) in serum and some degree of HBV replication. Infected patients with active liver disease usually have detectable hepatitis B e antigen (HBeAg) and high levels of serum HBV DNA, while those...

Therapeutics Based On Biotechnology

This part of the book is concerned with biopharmaceuticals that have received the approval of the FDA and are currently available in the United States by prescription (except for insulin, which is available without prescription). All but one agent, a DNA-based therapy, are proteins. The chapters are organized by molecular function rather than therapeutic indication. We believe this novel approach is useful when dealing with the products of biotechnology because these drugs relate to one another...

Oprelvekin

Manufacturer Genetics Institute, Inc., Andover, MA Indications Prevention of severe thrombo-cytopenia and the reduction of the need for platelet transfusions following myelosup-pressive chemotherapy in patients with nonmyeloid malignancies who are at high risk of severe thrombocytopenia Type of submission Biologics license application A. General description Interleukin-11 is a thrombopoietic growth factor that stimulates the production of hematopoietic stem cells and megakaryocyte progenitor...

Historical Perspective Of Pharmaceutical Biotechnology

The application of biological processes to develop useful products is as old as Mendel's pea experiment, which he con ducted in 1866 (Figure 1.1). As a result of his avocation, Mendel developed the principles of heredity, and thereby laid the basis of modern genetics. While the listing of biotechnology in the dictionary did not occur until 1979, the fermentation technology we use today to produce recombinant proteins was first used in World War I to ferment corn starch (with the help of...

Route of administration Novo Log

Should be administered by subcutaneous injection in the abdominal wall, the thigh, or the upper arm. Injection sites should be rotated within the same region. As with all insulins, the duration of action will vary according to the dose, injection site, blood flow, temperature, and level of physical activity. Recommended dosage and monitoring requirements The dosage of NovoLog should be individualized and determined in accordance with the needs of the patient. The total daily individual insulin...

Somatrem

Manufacturer Genentech Inc., South San Francisco, CA Indications Treatment of growth hormone deficiency in children Type of submission Product license application A. General description Somatrem is a polypeptide hormone produced by DNA technology. It has 192 amino-acid residues and a molecular weight of 22kDa. Soma-trem contains the sequence of 191 amino acids constituting pituitary-derived human growth hormone plus an additional amino acid, methionine, on the N-terminus of the molecule....

Dosage Form And Routes Of Administration

Without exception, biotechnology-based pharmaceuticals must be formulated into dosage forms suitable for human administration in a safe and effective manner. These formulations must be stable under defined storage conditions for a defined period of time and be uniformly reconstitutable during that time. Hence biopharmaceuticals must be in compliance with stringent manufacturing guidelines and pass quality control and quality assurance standards for all bulk materials used to formulate the...

Route of administration Bene Fix

Should be injected intravenously over several minutes, within 3 hours of reconstitution. Recommended dosage and monitoring requirements Dosage and duration of treatment for all factor IX products depend on the severity of the factor IX deficiency, the location and extent of bleeding, the patient's clinical condition and age, and recovery of factor IX. Dose should be titrated to the patient's clinical response. Patients should be monitored for normalization of coagulation parameters and the...

References

Frasier, S.D., The not-so-good old days working with pituitary growth hormone in North America, 1956 to 1985. J Pediatr, 1997.131(1 Pt 2) S1-4. 2. Goeddel, D.V., H.L. Heyneker, T. Hozumi, R. Arentzen, K. Itakura, D.G. Yansura, M.J. Ross, G. Miozzari, R. Crea, and P.H. Seeburg, Direct expression in Escherichia coli of a DNA sequence coding for human growth hormone. Nature, 1979. 281(5732) 544-8. 3. Goeddel, D.V., D.G. Kleid, F. Bolivar, H.L. Heyneker, D.G. Yansura, R. Crea,T. Hirose, A....

Interferon Beta1b

Manufacturer Chiron Corporation, Emeryville, CA Distributed by Berlex Laboratories, Richmond, CA Indications Treatment of ambulatory patients with relapsing-remitting multiple sclerosis to reduce the frequency of clinical exacerbations Type of submission Product license application A. General description Interferon beta-1b is a protein product produced by recombinant DNA techniques. It is manufactured by bacterial fermentation of a strain of Escherichia coli that bears a genetically engineered...

Somatropin Recombinant

Trade names Humatrope, Genotropin, Norditropin, Nutropin, Saizen, Serostim Manufacturer Eli Lilly, Indianapolis, IN Humatrope Pharmacia, Stockholm, Sweden Genotropin Novo Nordisk A S, Denmark Norditropin Genentech, Inc., South San Francisco, CA Nutropin Serono Laboratories, Inc., Randolph, MA Saizen, Serostim Indications Long-term treatment of pedi-atric patients who have growth failure due to an inadequate secretion of endogenous growth hormone Genotropin, Humatrope, Norditropin, Nutropin,...