DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

capsules and a 100-mg/mL oral solution. Because the original and
microemulsion formulations are not bioequivalent, they cannot be
used interchangeably without supervision by a physician and monitoring
of drug concentrations in plasma. Generic preparations of
both NEORAL and SANDIMMUNE, now widely available, are bioequivalent
by FDA criteria. When switching between formulations,
increased surveillance is recommended to ensure that drug levels
remain in the therapeutic range. This need for increased monitoring
is based on anecdotal experience rather than validated differences.
Because SANDIMMUNE and NEORAL differ in terms of their pharmacokinetics
and definitely are not bioequivalent, their generic versions
cannot be used interchangeably. This has been a source of
confusion to pharmacists and patients. Transplant units need to educate
patients that SANDIMMUNE and its generics are not the same as
NEORAL and its generics, such that one preparation cannot be substituted
for another without risk of inadequate immunosuppression or
increased toxicity.
Blood is most conveniently sampled before the next dose
(a C 0
or trough level). Although convenient to obtain, C 0
concentrations
do not reflect the area under the drug concentration curve (AUC)
as a measure of cyclosporine exposure in individual patients. As
a practical solution to this problem and to better measure the overall
exposure of a patient to the drug, it has been proposed that levels
be taken 2 hours after a dose administration (so-called C 2
levels)
(Cole et al., 2003). Some studies have shown a better correlation of
C 2
with the AUC, but no single time point can simulate the exposure
as measured by more frequent drug sampling. In complex patients
with delayed absorption, such as diabetics, the C 2
level may underestimate
the peak cyclosporine level obtained, and in others who are
rapid absorbers, the C 2
level may have peaked before the blood sample
is drawn. In practice, if a patient has clinical signs or symptoms
of toxicity, or if there is unexplained rejection or renal dysfunction,
a pharmacokinetic profile can be used to estimate that person’s exposure
to the drug. Many clinicians, particularly those caring for transplant
patients some time after the transplant, monitor cyclosporine
blood levels only when a clinical event (e.g., renal dysfunction or
rejection) occurs. In that setting, either a C 0
or C 2
level helps to ascertain
whether inadequate immunosuppression or drug toxicity is present.
As described above, cyclosporine absorption is incomplete
following oral administration and varies with the individual patient
and the formulation used. The elimination of cyclosporine from the
blood generally is biphasic, with a terminal t 1/2
of 5-18 hours (Noble
and Markham, 1995). After intravenous infusion, clearance is ~5-7
mL/min/kg in adult recipients of renal transplants, but results differ
by age and patient populations. For example, clearance is slower in
cardiac transplant patients and more rapid in children. Thus, the intersubject
variability is so large that individual monitoring is required.
After oral administration of cyclosporine (as NEORAL), the
time to peak blood concentrations is 1.5-2 hours (Noble and
Markham, 1995). Administration with food delays and decreases
absorption. High- and low-fat meals consumed within 30 minutes
of administration decrease the AUC by ~13% and the maximum concentration
by 33%. This makes it imperative to individualize dosage
regimens for outpatients.
Cyclosporine is distributed extensively outside the vascular
compartment. After intravenous dosing, the steady-state volume of
distribution reportedly is as high as 3-5 L/kg in solid-organ transplant
recipients.
Only 0.1% of cyclosporine is excreted unchanged in urine.
Cyclosporine is extensively metabolized in the liver by CYP3A and to
a lesser degree by the GI tract and kidneys. At least 25 metabolites
have been identified in human bile, feces, blood, and urine. All of the
metabolites have reduced biological activity and toxicity compared to
the parent drug. Cyclosporine and its metabolites are excreted principally
through the bile into the feces, with ~6% being excreted in the
urine. Cyclosporine also is excreted in human milk. In the presence of
hepatic dysfunction, dosage adjustments are required. No adjustments
generally are necessary for dialysis or renal failure patients.
Therapeutic Uses. Clinical indications for cyclosporine
are kidney, liver, heart, and other organ transplantation;
rheumatoid arthritis; and psoriasis. Its use in dermatology
is discussed in Chapter 65. Cyclosporine generally
is recognized as the agent that ushered in the modern
era of organ transplantation, increasing the rates of
early engraftment, extending kidney graft survival, and
making cardiac and liver transplantation possible.
Cyclosporine usually is combined with other agents,
especially glucocorticoids and either azathioprine or
mycophenolate and, most recently, sirolimus.
The dose of cyclosporine varies, depending on the organ
transplanted and the other drugs used in the specific treatment
protocol(s). The initial dose generally is not given before the transplant
because of the concern about nephrotoxicity. Especially for
renal transplant patients, therapeutic algorithms have been developed
to delay cyclosporine or tacrolimus introduction until a threshold
renal function has been attained. The amount of the initial dose
and reduction to maintenance dosing is sufficiently variable that no
specific recommendation is provided here. Dosing is guided by signs
of rejection (too low a dose), renal or other toxicity (too high a dose),
and close monitoring of blood levels. Great care must be taken to
differentiate renal toxicity from rejection in kidney transplant
patients. Ultrasound-guided allograft biopsy is the best way to assess
the reason for renal dysfunction. Because adverse reactions have
been ascribed more frequently to the intravenous formulation, this
route of administration is discontinued as soon as the patient can
take the drug orally.
In rheumatoid arthritis, cyclosporine is used in severe cases
that have not responded to methotrexate. Cyclosporine can be combined
with methotrexate, but the levels of both drugs must be monitored
closely. In psoriasis, cyclosporine is indicated for treatment of
adult immunocompetent patients with severe and disabling disease
for whom other systemic therapies have failed. Because of its mechanism
of action, there is a theoretical basis for the use of cyclosporine
in a variety of other T cell–mediated diseases. Cyclosporine reportedly
is effective in Behçet’s acute ocular syndrome, endogenous
uveitis, atopic dermatitis, inflammatory bowel disease, and nephrotic
syndrome, even when standard therapies have failed.
Toxicity. The principal adverse reactions to cyclosporine therapy are
renal dysfunction and hypertension; tremor, hirsutism, hyperlipidemia,
and gum hyperplasia also are frequently encountered.
Hypertension occurs in ~50% of renal transplant and almost all cardiac
transplant patients. Hyperuricemia may lead to worsening of
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CHAPTER 35
IMMUNOSUPPRESSANTS, TOLEROGENS, AND IMMUNOSTIMULANTS