11/20/2022

Therapeutic Drug Monitoring:

selected examples

CYCLOSPORINE
• Cyclosporine is a cyclic polypeptide with
immunosuppressant properties that is used for the
prevention of graft rejection in solid organ
transplantpatients, and for the treatment of
psoriasis, rheumatoid arthritis and a variety of
other autoimmune diseases.

• For patients receiving cyclosporine after a

transplantation, the goal of therapy is to prevent
graft rejection while avoiding adverse effects of
immunosuppressant therapy.
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• Because of the vital role that cyclosporine plays

as an immunosuppressant in transplant patients,
as well as the severity of its concentration- and
dose-dependent side effects, cyclosporine
concentrations should be monitored in every
patient receiving the drug.
• Often, desired cyclosporine concentrations differ
between the various types of organ transplants,
change with time during the post-transplantation
phase, and are determined by protocols specific
to the transplantation service and institution

Basic pharmacokinetics of cyclosporine

• Cyclosporine is almost completely eliminated by
hepatic metabolism (>99%). Hepatic metabolism is
mainly via the CYP3A4 enzyme system.
• There are more than 25 identified cyclosporine
metabolites. None of these metabolites appear to have
significant immunosuppressive effects in humans.
• Most of the metabolites are eliminated in the bile. Less
than 1% of a cyclosporine dose is recovered as
unchanged drug in the urine. Within the therapeutic
range, cyclosporine follows linear pharmacokinetics

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• There is a large amount of intra-subject

variability in cyclosporine concentrations
obtained on a day-to-day basis, even when the
patient should be at steady state.

• There are many reasons for this variability

among which is that cyclosporine has low water
solubility, and its gastrointestinal absorption can
be influenced by many variables.
• Food containing a large amount of fat enhances
the absorption of cyclosporine.

• Cyclosporine is a low-to-moderate hepatic extraction

ratio drug with an average liver extraction ratio of
~30%.

• Because of this, its hepatic clearance is influenced by

unbound fraction in the blood (fB), intrinsic clearance
(Cl′int), and liver blood flow (LBF).

• Cyclosporine binds primarily to erythrocytes and

lipoproteins, yielding unbound fractions in the blood
that are highly variable (1.4–12%).

• Transplantation type does not appear to have a

substantial effect on cyclosporine pharmacokinetics.
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INITIAL DOSAGE DETERMINATION METHODS

• Several methods to initiate cyclosporine therapy are

available. The pharmacokinetic dosing method is the most
flexible of the techniques. It allows individualized target
serum concentrations to be chosen for a patient, and each
pharmacokinetic parameter can be customized to reflect
specific disease states and conditions present in the
patient.

• Literature-based recommended dosing is a very commonly

used method to prescribe initial doses of cyclosporine.

Pharmacokinetic Dosing Method

The goal of initial dosing of cyclosporine is to compute the

best dose possible for the patient in order to prevent graft
rejection.

CLEARANCE ESTIMATE
Cyclosporine is almost completely metabolized by the liver.
Unfortunately, there is no good way to estimate the elimination
characteristics of liver metabolized drugs using an
endogenous marker of liver function in the same fashion that
serum creatinine is estimated.

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• Because of this, a patient is categorized

according to the disease states and conditions
that are known to change cyclosporine clearance,
and the clearance previously measured in these
studies is used as an estimate of the current
patient’s clearance rate.

• For example, an adult transplant patient with

normal liver function would be assigned a
cyclosporine clearance rate equal to 6 mL/min/kg,
while a pediatric transplant patient with the same
profile would be assumed to have a cyclosporine
clearance of 10 mL/min/kg.
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• a very simple pharmacokinetic equation that calculates

the average cyclosporine steady-state serum
concentration is widely used and allows maintenance
dose computation: Css = [F(D/τ)]

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Example 1:
HO is a 50-year-old, 75-kg (5 ft 10 in) male
renal transplant patient 2 days post
transplant surgery. The patient’s liver
function tests are normal. Suggest an
initial oral cyclosporine dose designed to
achieve a steady-state cyclosporine trough
blood concentration equal to 250 ng/mL.
(F = 0.3)

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1. Estimate clearance according to disease

states and conditions present in the patient.

The mean cyclosporine clearance for adult patients

is 6 mL/min/kg. The cyclosporine clearance for this
patient is expected to be 27 L/h: Cl = 6 mL/min/kg ⋅
75 kg ⋅(60 min/h / 1000 mL/L) = 27 L/h.

2. Compute dosage regimen.

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A 12-hour dosage interval will be used for this

patient. (Note: ng/mL = μg/L and this
D = (Css ⋅ Cl ⋅ τ) / F =
= (250 μg/L ⋅ 27 L/h ⋅ 12 h) / (0.3 ⋅ 1000 μg/mg) =
270 mg,
rounded to 300 mg every 12 hours.
• Cyclosporine serum concentrations would be
obtained on a daily basis with steady state
expected to occur in about 2 days (5 half-lives =
5 ⋅ 10 h = 50 h, or ~2 days).

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Example 2: Same patient as in example 1,

except compute an initial dose using intravenous
cyclosporine.
1. Estimate clearance according to disease
states and conditions present in the patient.
• The mean cyclosporine clearance for adult
patients is 6 mL/min/kg. The cyclosporine
clearance for this patient is expected to be
27 L/h: Cl = 6 mL/min/kg ⋅ 75 kg ⋅
• (60 min/h / 1000 mL/L) = 27 L/h.

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2. Compute dosage regimen.

A 12-hour dosage interval will be used for this
patient. (Note: ng/mL= μg/L)
The dosage equation for intravenous cyclosporine
is D = Css ⋅ Cl ⋅ τ =
• (250 μg/L ⋅ 27 L/h ⋅ 12 h) / (1000 μg/mg) = 81
mg, rounded to 75 mg every 12 hours.

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