This document discusses maintenance immunosuppressive therapy for kidney transplant recipients. It provides details on tacrolimus and cyclosporine, including their mechanisms of action, dosing, therapeutic drug monitoring, and conversion between formulations. Adverse effects and contraindications are also summarized. Monitoring drug levels is important for efficacy and toxicity, with target trough ranges outlined for different time periods post-transplant.

1. Presenter – Dr Prem Mohan Jha
DNB Nephrology Resident
Max Super Speciality Hospital, Vaishali.

2.  Maintenance immunosuppressive therapy is administered to
almost all kidney transplant recipients to help prevent acute
rejection and the loss of the renal allograft.
 Although an adequate level of immunosuppression is
required to dampen the immune response to the allograft,
the level of chronic immunosuppression is decreased over
time to help lower the overall risk of infection and
malignancy.

3. Tacrolimus
Cyclosporine

4.  Also known as Fujimycin or FK506.
 First discovered in 1987.
 From bacterium Streptomyces tsukubaensis.
 First approved by the FDA in 1994 for use in liver
transplantation; this has been extended to include kidney,
heart, small bowel, pancreas, lung, trachea, skin, cornea,
bone marrow, and limb transplants.

5.  Small cyclic polypeptide of fungal origin.
 Consists of 11 amino acids and has a molecular weight of
1203.
 Neutral and insoluble in water but soluble in organic solvents
and lipids.
 The amino acids at positions 11, 1, 2, and 3 form the active
immunosuppressive site, and the cyclic structure of the drug
is necessary for its immunosuppressive effect.

6. 1. TCR recognition of the alloantigen.
2. Increase in the intracellular calcium concentration of T cells.
3. Activation of CnB.
4. CnB unleashes the phosphatase activity of CnA.
5. Activated CnA dephosphorylates cytoplasmic NFATc.
6. A transcription factor, allowing for its translocation with
activated calcineurin into the nucleus.
7. Upregulates the expression of multiple cytokines and
costimulatory molecules necessary for full activation of T
cells.
8. Generated IL-2 binds to the IL-2 receptors and induces cell
activation and proliferation.

11.  Cyclosporine
◦ Consistent time of the day.
◦ Consistent relation to meals.
 Cyclosporine
◦ Nonmodified oral solution
 Should be mixed with milk, chocolate milk, or orange
juice at room temperature.
◦ Cyclosporine modified oral solution
 Should be mixed with water, orange juice, or apple juice.

12.  Tacrolimus
◦ Consistent time of the day.
◦ Preferably on an empty stomach.
◦ Patients should not chew, divide, or crush the
tablets.
◦ If dose is missed, patients should take it as soon
as possible, ideally within four hours.

13.  Cyclosporine
◦ Cyclosporine modified is initially dosed at 4 to
10 mg/kg/day orally in two divided doses.
◦ The first dose may be administered within 24 hours of
transplantation.
◦ In newly transplanted patients, the initial dose of
cyclosporine modified is the same as the initial dose of
cyclosporine non-modified, although cyclosporine modified
is preferred.

14.  Tacrolimus –
◦ Typically dosed at 0.1 to 0.2 mg/kg/day orally in two
divided doses.
◦ The product information recommends the following for
tacrolimus initiation :
 At 0.1 mg/kg/day in kidney transplant recipients who
also receive MMF plus an interleukin (IL)-2 receptor
antagonist.
 At 0.2 mg/kg/day in kidney transplant recipients treated
with azathioprine rather than MMF.

15.  Tacrolimus (Extended Release) –
◦ In patients receiving MMF, steroids, and basiliximab induction,
extended-release tacrolimus capsules (Astagraf XL) should be
given at a dose of 0.15 to 0.2 mg/kg/day prior to reperfusion
or within 48 hours of the completion of the transplant
procedure.
◦ In patients treated with MMF and steroids without basiliximab
induction, extended-release tacrolimus capsules should be
given as a single dose of 0.1 mg/kg within 12 hours prior to
reperfusion, then 0.2 mg/kg at least 4 hours after the
preoperative dose, and within 12 hours after reperfusion, then
0.2 mg/kg daily.

16.  Therapeutic monitoring of cyclosporine and tacrolimus is
complicated by the narrow margin between adequate
immuno- suppression and toxicity.
 Whole blood should be used as a sample for both drugs.
 A variety of assays are available, and clinicians should
become familiar with the one used in their local laboratory.

17.  Should be monitored using 12-hour trough (C0), two-hour
post-dose (C2), or abbreviated area under the time
concentration curve (AUC).
 Although monitoring of C0 is common practice, there is a
poor correlation with safety, efficacy, and drug exposure
using this strategy.
 C2 monitoring may correlate more closely with exposure, and
higher C2 concentrations have been associated with
decreased acute rejection rates in the first year.

18.  C2 monitoring may be more accurate but is often
more difficult and less convenient for the patient.
 Most centers monitor either C0 or C2
concentrations but not both.
 In rare circumstances, assessing both may be
beneficial in a patient with absorption issues.

19.  Should be monitored using 12- and 24-hour trough (C0)
concentrations for the immediate-release and extended-
release preparations, respectively.
 Blood concentrations should be checked two to three days
after starting and after any dose change.
 Typically, after transplant, concentrations are measured every
one or two days while hospitalized.
 After discharge, levels should be measured once or twice
weekly for the first month, then weekly until three months
posttransplantation, then every two weeks until six months
posttransplant, and then monthly.

20.  Tacrolimus-
◦ In patients who receive ATG for induction therapy:
 7 to 10 ng/mL for the first month after transplantation
 3 to 7 ng/mL for subsequent months
◦ In patients who do not receive antilymphocyte-depleting
agents for induction therapy:
 8 to 10 ng/mL for months 1 to 3 after transplantation
 3 to 7 ng/mL for subsequent months

21.  Cyclosporine -
◦ Monitor whole-blood 12-hour trough (C0) concentrations.
◦ 200 to 300 ng/mL in months 1 to 3 after transplantation
◦ 50 to 150 ng/mL for subsequent months
 C2 level may correlate more closely with exposure, with
higher C2 concentrations being associated with decreased
acute rejection rates in the first year post transplant.

22.  However, C2 monitoring is often more difficult and
less convenient for the patient. Our C2 target levels
are the following:
◦ 800 to 1000 ng/mL in months 1 to 3 after
transplantation
◦ 400 to 600 ng/mL for subsequent months

23.  If a cyclosporine concentration is high, then the dose of
cyclosporine may be lowered by 25 to 50 mg per dose.
 For tacrolimus, dose adjustments are typically 0.5 to 1 mg
per dose.
 If a drug concentration is supratherapeutic (>400 ng/mL for
cyclosporine or >30 ng/mL for tacrolimus), then the dose
may be held until the concentration returns to the therapeutic
range.

24.  Testing for polymorphisms of the multidrug resistance-1 (P-
glycoprotein) and CYP3A5 genes may aid in the dosing of
calcineurin inhibitors
 But large, well-designed trials are needed to determine if
testing improves outcomes and is cost effective.

25.  When switching formulations of products, drug conc. should
be closely monitored for several weeks.
 The frequency of monitoring should depend upon several
factors.
 In a stable patient who is more than six months post
transplant, we monitor drug conc. weekly for 2-3 weeks.
 The dose should subsequently be adjusted to attain the
preconversion blood concentration.
 In addition, safety and efficacy should be monitored after
conversion.

26.  ORAL TO INTRAVENOUS ADMINISTRATION –
◦ For patients unable to take oral cyclosporine, the
intravenous dose should be equal to one-third of the oral
dose.
◦ Intravenous administration should occur over at least two
to six hours twice daily in a well-hydrated patient to avoid
nephrotoxicity.

27.  NONMODIFIED TO MODIFIED FORMULATION –
◦ In general, modified formulations of cyclosporine lead to
higher area under the time concentration curve (AUC) than
nonmodified preparations.
◦ Thus, patients stabilized on either form should generally
not be switched from one to the other.
◦ If patients are switched, a 1:1 ratio is recommended when
converting from the nonmodified to the modified
formulation.

28.  CYCLOSPORINE TO TACROLIMUS
◦ Clinicians use a 40:1 ratio when converting from
cyclosporine to tacrolimus.
◦ As an example, if a patient takes 125 mg of
modified cyclosporine twice daily
(250 mg/day), then a tacrolimus dose of 3 mg twice
daily (6 mg/day) would be appropriate.

29.  Tacrolimus
◦ Oral to intravenous administration –
 For patients unable to take oral tacrolimus, the
intravenous dose should be equal to one-third to one-
fifth of the oral daily dose and should be given as a
continuous 24-hour infusion.

30.  Immediate-release to extended release capsules
◦ A 1:1 conversion from immediate-release tacrolimus to
extended-release tacrolimus capsules (Astagraf XL) has
been proven equivalent.
◦ The ratio of exposure (AUC0-24) of extended-release
tacrolimus capsules to immediate-release tacrolimus twice
daily is approximately 90 percent across various conversion
studies in kidney, liver, and heart transplant recipients.

31.  Immediate-release to extended-release tablets
◦ Eighty percent of the total daily dose of immediate-
release tacrolimus should be used when converting to
extended-release tablets (Envarsus XR).
 Oral immediate-release to sublingual immediate-
release tacrolimus –
◦ To convert from oral tacrolimus to sublingual tacrolimus,
the oral tacrolimus dose should be decreased by 50
percent.

43.  Hypersensitivity to cyclosporine, tacrolimus, or polyoxyl
castor oil products (used as solvents for injection preparation
of both drugs) is a contraindication to their use.
 The following conditions are generally accepted
contraindications to the use of cyclosporine or tacrolimus:
◦ Concurrent malignancy (except for nonmelanoma skin
carcinoma)
◦ Uncontrolled hypertension
◦ Uncontrolled infections
◦ Hypersensitivity

45.  High dose
 Older age of donated kidney
 Concomitant use of nephrotoxic drugs, particularly
nonsteroidal antiinflammatory drugs (NSAIDs)
 Salt depletion and diuretic use
 Drugs that inhibit cytochrome P-
450 3A4/5 (CYP3A4/5), thereby increasing exposure to CNI
metabolites.
 Drugs that inhibit P-glycoprotein-mediated efflux of CNIs
from tubular epithelial cells, thereby increasing local renal
exposure to CNIs
 Genetic polymorphisms in the genes
encoding CYP3A4/5 (CYP3A4/5) and P-glycoprotein (ABCB1).

50.  The primary commercial assays-
◦ Mass spectrometry
◦ Immunoassays
 Cyclosporine is measured with-
◦ High performance liquid chromatography (HPLC),
◦ Fluorescence polarization immunoassay (FPIA),
◦ Enzyme-multiplied-immunoassay techniques (EMIT),
◦ Liquid chromatography-tandem mass spectrometry (LC-
MS/MS).
 Tacrolimus can be monitored with-
◦ LC-MS/MS,
◦ Enzyme-linked immunosorbent assay (ELISA),
◦ Microparticle enzyme immunoassay (MEIA).