Biomedical Engineering Reference
In-Depth Information
could have unintended infl uences upon pharmacokinetic and/or pharmacodynamic characteristics
of the drug. Preclinical and, in particular, clinical evaluations undertaken upon the analogues thus
far approved, however, have confi rmed their safety and effi cacy. The sequence changes introduced
are relatively minor and do not seem to elicit an immunological response. Fortuitously, neither
have the alterations made affected the ability of the insulin molecule to interact with the insulin
receptor, and trigger the resultant characteristic biological responses.
11.2.8 Additional means of insulin administration
Issues surrounding protein delivery via means alternative to parenteral routes have been outlined
in Chapter 4. One such product (inhalable insulin, tradename Exubera) has gained marketing ap-
proval (Box 11.2). An additional approach that may mimic more closely the normal changes in
blood insulin levels entails the use of infusion systems that constantly deliver insulin to the patient.
The simplest design in this regard is termed an 'open-loop system'. This consists of an infusion
pump that automatically infuses soluble insulin subcutaneously, via a catheter. Blood glucose lev-
els are monitored manually and the infusion rate is programmed accordingly.
Although the potential of such systems is obvious, they have not as yet become popular in prac-
tice, mainly due to complications that can potentially arise, including:
Box 11.2
Product case study: Exubera
Exubera (tradename) is a recombinant human insulin fi rst approved for medical use in the USA in
2006. It is indicated for the treatment of diabetes mellitus for the control of hyperglycaemia and is
particularly noteworthy in that it is the fi rst such product delivered by inhalation technology. The
recombinant insulin is produced in E. coli and, after purifi cation, is formulated as a powder also
containing citrate buffer components, mannitol and glycine as excipients. It is sold as blisters con-
taining 1 mg or 3 mg unit doses that are administered using a specially designed inhaler. A frac-
tion of the total dose is emitted as fi ne particles capable of reaching the deep lung, from where the
insulin is absorbed. Pharmacokinetic studies (in both healthy and diabetic subjects) show that the
insulin is absorbed as quickly as s.c. administered rapid-acting insulin analogues and, therefore,
should be administered within 10 min of mealtime. Glucose-lowering activity usually commences
within 10-20 min of administration, with a maximum effect observed after approximately 2 h
and an activity duration of approximately 6 h. Actual serum insulin concentrations typically peak
50 min post administration, compared with 100 min or so for s.c. administered regular insulin.
Pre-approval safety and effi cacy clinical studies involved product administration to 2500 adults
with either type-1 or -2 diabetes. The primary effi cacy parameter measured was glycaemic control
(as measured by the reduction from baseline in haemoglobin A1c). Hypoglycaemia was the most
commonly reported adverse effect. Trials also showed a greater decline in pulmonary function in
the Exubera group, and product should not be administered to patients with underlying lung disease,
or to smokers. Exubera was developed by Nektar Inc. and is marketed under licence by Pfi zer.
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