Growth factors - Pharmaceutical Biotechnology: Concepts and Aapplications - page 274

Box 10.1

Product case study: Neupogen

Neupogen (tradename, also known as fi lgrastim) is a recombinant G-CSF fi rst approved for
medical use in the USA in 1991. It is indicated for the treatment of neutropenia associated with
various medical conditions, often in cancer patients undergoing chemotherapy. The 175 amino
acid, 18.8 kDa protein is produced in engineered E. coli and is identical to native human G-CSF
except for (a) the presence of an additional methionine residue at the molecule's N terminal
end and (b) the absence of glycosylation. Both differences are a consequence of expression
in E. coli . Production entails cell growth and harvest, followed by product extraction and
purifi cation using several chromatographic and ultrafi ltration procedures. It is presented as
a sterile solution in either single-use vials or pre-fi lled syringes and contains acetate buffer,
sorbitol and Tween 80 as excipients.
Details of administration vary according to exact indication, but it is administered by s.c.
or i.v. infusion daily, usually for several days at dosage levels of 5-10 g kg 1 day 1 . Peak

plasma concentrations are usually observed within 2-8 h after s.c. administration and the
drug's elimination half-life ranges between 2 and 5 h. The product is used in conjunction
with cancer chemotherapy in one of two ways: prophylactically, to prevent neutropenia onset,
or therapeutically, to reverse established neutropenia. Numerous clinical trials have been
undertaken with various cancer patient types, and the product has generally been shown to be
safe and effective in accelerating neutrophil count recovery following various chemotherapeutic
regimes. The product was found to reduce the median number of days of severe neutropenia
observed in patients with severe chronic neutropenia, acute myeloid leukaemia and non-myeloid
malignancies who receive myeloblative chemotherapy followed by bone marrow transplant.
Commonly reported side effects include bone and muscle pain. Serious (sometimes life
threatening) but rare side effects have included splenic rupture and adult respiratory distress
syndrome. Neupogen is manufactured and marketed by Amgen Inc.

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G-CSF and GM-CSF have also found application after allogenic or autologous bone marrow
transplantation, to accelerate neutrophil recovery. (Allogenic means that donor and recipient are
different individuals, and autologous means that donor and recipient are the same.)

10.2.6 Erythropoietin

EPO is an additional haemopoietic growth factor. It is primarily responsible for stimulating and
regulating erythropoiesis (i.e. erythrogenesis, the production of red blood cells) in mammals.
The erythron is a collective term given to mature erythrocytes, along with all stem-cell-derived
progeny that have committed to developing into erythrocytes. It can thus be viewed as a disperse
organ whose primary function relates to transport of oxygen and carbon dioxide (haemoglobin
constitutes up to one-third of the erythrocyte cytoplasm), as well as maintaining blood pH. An
average adult contains in the region of 2.3 10 13 erythrocytes (weighing up to 3 kg). They are