Clinical Pharmacology and Therapeutics

408 CLINICAL IMMUNOPHARMACOLOGY
hypogammaglobulinaemia and IgG subclass deficiency
(e.g. Bruton’s agammaglobulinaemia, Wiskott–Aldrich syndrome),
idiopathic thrombocytopenic purpura and for
prophylaxis of infection in bone marrow transplant patients.
Adverse effects
The most common adverse effects occur during the first infusion
and are dependent on the antigenic load (dose) given.
They include the following:
• fever, chills and rarely anaphylaxis – most commonly seen
with the first dose, and reduced by slow administration
and premedication with antihistamines and
glucocorticosteroids;
• increased plasma viscosity – caution is needed in patients
with ischaemic heart disease;
• aseptic meningitis (high dose).
Contraindications
Normal immunoglobulin is contraindicated in patients with
known class-specific antibody to IgA.
Interactions
Live virus vaccinations may be rendered less effective.
SPECIFIC IMMUNOGLOBULINS
These antibodies are prepared by pooling the plasma of
selected donors with high levels of the specific antibody
required. The following are currently available and effective:
rabies immunoglobulin, tetanus immunoglobulin (human
origin-HTIG), varicella zoster immunoglobulin (VZIG) (limited
supply); anti-CMV immunoglobulin (on a named patient
basis).
ANTI-D (RHO) IMMUNOGLOBULIN
This immunoglobulin is used to prevent a rhesus-negative
mother from forming antibodies to fetal rhesus-positive cells
that enter the maternal circulation during childbirth or abortion.
An intramuscular injection is given to rhesus-negative mothers
up to 72 hours after the birth/abortion. This prevents a subsequent
child from developing haemolytic disease of the newborn.
Case history
A 35-year-old woman had a cadaveric renal transplant for
polycystic kidneys two years previously and was stable on her
immunosuppressive regimen of ciclosporin, 300 mg twice a
day, and mycophenolate mofetil, 1 g twice a day. Her usual
trough ciclosporin concentrations were 200–250 μg/L and her
hepatic and liver function was normal. She went on holiday
to southern California for ten days, where she was well, but
drank plenty of fluids (but no alcohol) as she was warned
about the dangers of dehydration. By the end of her visit,
she noted some nausea and a mild tremor. Following a long
return flight, she went to her local hospital and sustained a
brief spontaneously remitting epileptic fit in the outpatient
department where she was having her blood ciclosporin
concentration checked. The fit lasted about one minute and
she was taken to the Accident and Emergency Department.
Examination revealed no abnormalities apart from slight
tremor which she said she had noted for the last 48 hours.
Her ciclosporin concentration was 650 μg/L. All other medical
biochemistry tests were normal. She was not taking any
other prescribed medications or over-the-counter drugs.
Questions
What caused this patient’s seizures?
How can you explain the markedly elevated trough
ciclosporin concentration?
Answer
In this patient, the development of an acute epileptic seizure
in the context of a very high ciclosporin trough concentration
indicates ciclosporin toxicity; epilepsy is a well-recognized
toxic effect of high ciclosporin concentrations. The difficult
issue in the case is why she developed high ciclosporin blood
concentrations (in the face of normal renal and hepatic function)
when she was adamant that there had been no alteration
in the daily dose of ciclosporin she was taking, nor had
she started any other drugs (prescribed or over-the-counter
agents). Further questioning defined that she was drinking
about 1 L/day of grapefruit juice – a taste she had acquired
while on holiday in California. Grapefruit juice contains psoralens
and flavonoids which inhibit CYP3A (gastrointestinal
and hepatic) and flavonoids which inhibit P-gp in the gut wall,
increasing the bioavailability of ciclosporin by 19–60%, the
combined effect leading to higher concentrations without a
change in dose. The patient had her ciclosporin dosing
stopped until the concentration was 300 μg/L. She had no
further fits, her nausea and tremor subsided, and she was
then restarted on her normal dose with clear instructions not
to drink grapefruit juice.
Examples of other drugs whose oral bioavailability is
increased in humans with co-ingestion of grapefruit juice
include midazolam, oestrogens, atorvastatin (and most
statins except pravastatin), testosterone, felodipine, nifedipine
(but not diltiazem), some anti-HIV protease inhibitors,
other calcinerin inhibitors. Patients who are taking these
agents or other drugs metabolized by CYP3A/P-gp should be
warned not to ingest even single cupfuls of grapefruit juice,
as this may precipitate toxic drug concentrations.
FURTHER READING
Golightly LK, Greos LS. Second-generation antihistamines: actions
and efficacy in the management of allergic disorders. Drugs 2005;
65: 341–84.
Lindenfeld J, Miller GG, Shakar SF et al. Drug therapy in the heart
transplant recipient: part II: immunosuppressive drugs. Circulation
2004; 110: 3858–65.
Lipsky JJ. Drug profile. Mycophenolate mofetil. Lancet 1996; 348:
1357–9.
Plaut M, Valentine MD. Clinical practice. Allergic rhinitis. New
England Journal of Medicine 2005; 353: 1934–44.
Simons ERF, Simons KJ. Drug therapy:the pharmacology and use of
H 1 -receptor antagonist drugs. New England Journal of Medicine
1994; 330: 1663–70.
Waldman TA. Immunotherapy: past, present and future. Nature Medicine
2003; 9: 269–77.