Clinical Pharmacology and Therapeutics

394 ANAEMIA AND OTHER HAEMATOLOGICAL DISORDERS
Adverse effects
These include the following:
• hypertension which can be severe;
• thrombosis, for example of shunts, or causing a
cardiovascular/cerebrovascular accident;
• influenza-like symptoms;
• iron deficiency may be unmasked;
• pure red cell aplasia associated with antibodies to
erythropoietin has been reported during treatment with
epoetin alfa.
HUMAN GRANULOCYTE COLONY-STIMULATING
FACTOR (FILGRASTIM, LENOGRASTIM,
PEG-FILGRASTIM).
Granulocyte colony-stimulating factor (G-CSF) is a 174 amino
acid glycoprotein. Filgrastim is unglycosylated rhG-CSF and
lenograstim is glycosylated rhG-CSF. Pegylated G-CSF (PEGfilgrastim)
has a protracted half-life and can be given much
less frequently.
Uses
Indications for G-CSF include:
• to prevent and treat the neutropenia induced by cytotoxic
cancer chemotherapy (main use);
• congenital neutropenia;
• human immunodeficiency virus (HIV)-related
AZT-induced neutropenia (chronic therapy);
• aplastic anaemia;
• mobilization of peripheral blood-cell progenitors and
subsequent harvesting for transplant;
• following bone marrow transplantation.
G-CSF is usually administered by subcutaneous injection.
Therapy is monitored by regular neutrophil counts. After
stopping treatment, neutrophil counts return to baseline after
four to seven days.
Mechanism of action
G-CSF stimulates the proliferation and differentiation of progenitor
cells of the myelogranulocyte lineage. It binds to the G-CSF
receptor on myelogranulocyte precursors, enhancing cell replication
and differentation. Once bound to its receptor, G-CSF is
internalized and signal transduction involves a number of tyrosine
kinase proteins which induce the synthesis of proteins that
upregulate cell-cycle and differentiation processes.
Adverse effects
These include the following:
• bone pain;
• injection site reactions;
• myalgia and fevers;
• splenomegaly;
• thrombocytopenia;
• abnormal liver enzymes.
Contraindications
G-CSF should not be given to patients with myeloid or
myelomonocytic leukaemia, because it increases proliferation
of the malignant clone.
Pharmacokinetics
The bioavailability of subcutaneously administered G-CSF is
54%. The G-CSF plasma t 1/2 ranges from two to six hours.
Clearance of G-CSF is complex and it increases as the granulocyte
count rises. In addition, G-CSF is metabolized in the kidney
and liver to its component amino acids, with little or no
G-CSF found in the urine.
INTERLEUKIN-11 AND THROMBOPOIETIN
Interleukin-11 is a recombinant protein which enhances
megakaryocyte maturation and is used to prevent thrombocytopenia
in patients who developed platelet counts 20 000/μL
with prior cycles of cytotoxic chemotherapy. Interleukin-11
(oprelvekin, not yet available in the UK) is given daily via subcutaneous
injection until the platelet count 10 000/μL. Major
side effects include fluid retention and associated cardiac symptoms,
injection site reactions, paraesthesias and blurred vision.
Thrombopoietin is a recombinant protein which binds to
the mpl-proto-oncogene, stimulates megakaryocyte proliferation
and differentiation in humans. It synergizes with stem cell
factor and G-CSF in promoting bone marrow production of
granulocytes. Thrombopoietin may be useful in drug-induced
thrombocytopenia and in bone marrow transplantation.
Key points
Haematopoietic growth factors
• The clinically used haematopoietic growth factors are
recombinant DNA products of the endogenous
glycoprotein.
• Erythropoietin (Epo)/darbepoetin:
– stimulate proliferation of erythroid (red cell)
precursors;
– are used in the treatment of the anaemia of renal
failure (myelodysplasia);
– are given parenterally; its toxicities include
hypertension and thrombotic episodes.
• Granulocyte colony-stimulating factor (G-CSF):
– stimulates proliferation of myeloid precursors;
– is used to treat neutropenia of chemotherapy,
aplastic anaemia and bone marrow transplant;
– is given parenterally and its toxicities include myalgias,
bone pain, fever, thrombocytopenia and hepatitis.
COAGULATION FACTORS AND
HAEMOPHILIAS A AND B
Pathophysiology
In haemophilia A there is a deficiency of factor VIII. In
haemophilia B there is a deficiency of factor IX. Both types
present with excessive bleeding in response to trauma, e.g.
muscle haematoma, haemarthrosis, haemorrhage after minor
(e.g. dental) or major surgery, and intracranial bleeding following
minor head injury.