Biomedical Engineering Reference
In-Depth Information
Box 14.3
Product case study: Vitravene
In August 1998, Vitravene (tradename) became the fi rst (and thus far the only) antisense prod-
uct to be approved for general medical use by the FDA. It gained approval within the EU the
following year, although it has since been withdrawn from the EU market due to commercial
rather than technical reasons. The product is a 21-nucleotide phosphorothioate based product
of the following base sequence:
5´- G - C- G -T-T-T- G - C-T- C-T-T- C-T-T- C-T-T- G - C- G -3´
Developed by the US company, Isis, Vitravene is used to treat cytomegalovirus (CMV) retin-
itis in AIDS patients. It is synthesized chemically and formulated as a sterile solution (6.6 mg
active drug/ml) in WFI using a bicarbonate buffer to maintain a fi nal product pH of 8.7.
The product inhibits replication of human CMV (HCMV) via an antisense mechanism. Its
nucleotide sequence is complementary to a sequence in mRNA transcripts of the major im-
mediate early region (IE2 region) of HCMV. These mRNAs code for several essential viral
proteins and blocking their synthesis effectively inhibits viral replication.
Administration is by direct injection of 0.05 ml product into the eye (intravitreal injection),
initially once every 2 weeks and subsequently once every 4 weeks. Animal studies (rabbits) in-
dicated that the product is cleared from the eye over the course of 7-10 days, with direct nucle-
ase-mediated metabolism representing the primary route of elimination. The most commonly
observed side effect is ocular infl ammation, which typically occurs in one in every four patients.
14.8 Oligonucleotide pharmacokinetics and delivery
Oligo administration during many clinical trials entails direct i.v. infusion, often over a course of
several hours. S.c. and, in particular, intradermal administration is usually also associated with
high bioavailability.
Oligos bind various serum proteins, including serum albumin (as well as a range of heparin-
binding and other proteins that commonly occur on many cell surfaces). Targeting of naked oligos
to specifi c cell types, therefore, is not possible. Following administration, these oligos tend to
distribute rapidly to many tissues, with the highest proportion accumulating in the liver, kidney,
bone marrow, skeletal muscle and skin. They do not appear to cross the blood-brain barrier. Bind-
ing to serum proteins provides a repository for these drugs and prevents rapid renal excretion.
The precise mechanism(s) by which oligos enter cells is not fully understood. Most are charged
molecules, sometimes displaying a molecular mass of up to 10-12 kDa. Receptor-mediated
endocytosis appears to be the most common mechanism by which charged oligos, such as
phosphorothioates, enter most cells. One putative phosphorothioate receptor appears to consist
of an 80 kDa surface protein, associated with a smaller 34 kDa membrane protein. However, this
in itself seems to be an ineffi cient process, with only a small proportion of the administered drug
eventually being transferred across the plasma membrane.
Uncha rge d ol igos app ea r to ent er t he cel l by pa ssive d i f f usion, a s wel l a s possibly by endocy tosis.
However, elimination of the charges renders the resultant oligos relatively hydrophobic,
thus generating additional diffi culties with their synthesis and delivery.
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