Effect of repeated intranasal cobalamin (Vitamin B12) administration on cobalamin deficiency in elderly

Among elderly the prevalence of cobalamin (Vitamin B12) deficiency is estimated
to be between 10 and 50%, with the highest rates in the geriatric population.
Cobalamin is a cobalt containing vitamin that serves as a coenzyme for several
important biochemical reactions in the formation of blood and the functioning
of the brain and nervous system. Consequently, cobalamin deficiency causes
anaemia and irreversible neurological damage.
In the acidic environment in the stomach, cobalamin is extracted from food
proteins by pepsin. Subsequently, cobalamin is bound to the intrinsic factor in
the duodenum and actively absorbed in the intestines. Hence, lack of intrinsic
factor and changes in gastric physiology due to aging or use of certain drugs
(i.e. proton pump inhibitors, metformin) impair cobalamin absorption and cause
cobalamin deficiency.
The standard treatment for cobalamin deficiency is administration of cobalamin
by way of intramuscular injection. These injections, however, have several
disadvantages. Injections are painful, injection related adverse events such as
infections and bruises may occur and these injections cannot be
self-administered by the patients. Safer and more convenient ways of
administration such as oral and intranasal administration are therefore being
explored. Oral treatment, however, is not an option in patients that are unable
or unwilling to take oral medication. Intranasal administration of cobalamin
seems a suitable alternative for both cobalamin injections and oral
administration in elderly.
Reproducible intranasal cobalamin absorption has been demonstrated in healthy
elderly volunteers en patients with ileal resections. These studies, however
did not provide insight in the pharmacokinetics of intranasal administered
cobalamin compared to intramuscular administered cobalamin in elderly.
Therefore we previously we explored the pharmacokinetics of intranasal
administered cobalamin compared to intramuscular administered cobalamin in
cobalamin deficient elderly. This study demonstrated significant differences in
the pharmacokinetics between cobalamin administered by intramuscular injection
and cobalamin administered by intranasal spray. Despite these differences,
intranasal administration of a single dose of 1000 microgram cobalamin led to a
cobalamin serum level well within the therapeutic cobalamin range (preliminary
data). The maximum cobalamin serum level of 1000 pmol/l found is this study is
comparable to the maximum cobalamin serum level after an oral dose of 1000
microgram cobalamin. As mentioned above, daily oral cobalamin administration
has been shown effective in treating cobalamin deficiency. Hence, the
absorption of intranasal administered cobalamin seems sufficient to effectively
treat cobalamin deficiency. Although this study provided insight in the
pharmacokinetics of intranasally administered cobalamin it, however, did not
provide insight in the optimum intranasal dosage regimen for treating cobalamin
deficiency.
In order to establish an optimum dosage regimen for intranasal cobalamin
administration in cobalamin deficient elderly the effects of two intranasal
cobalamin 1000 microgram dosage regimens i.e. once every three days and once
every day, followed by once every week are evaluated in this study.

The objective of this study is to establish the optimal intranasal cobalamin
dosing regimen in elderly.

A randomized, open, comparative intervention study.

Randomisation; patients will be randomised over two intranasal dosage regimens.

Arm A:
1000 microgam every day for two weeks, followed by 1000 microgram once every
week for three months (90 days).

Arm B:
1000 microgram every three days for three months (90 days)

Per subject a total of 6 blood samples are collected to assess cobalamin,
methylmalonicacic and homocystein serum levels over time.
Subjects have to come to the hospital twice; at the beginning and at the end of
the sudy. The first and last blood samples will be taken at the geriatric
departmen.
Both dosageregimens will raise cobalamin serum levels. Cobalamin serum levels
in the once every 3 days administration group might not be raised to the same
extent as in the once every day administration group. Normalization of serum
cobalamin levels might therefore, take longer in subjects in the once every 3
days administration group.
A cobalamin dose of 1000 µg was chosen because this corresponds with the
registered cobalamin intramuscular injection dose.
After participating in this study subjects are transferred to standard care and
treatment for cobalamin deficiency or if maintenance therapy is nescessary.