TOPIC:

CYCLOSPORINE
SUBMITTED TO: MA’AM AMNA
SAEED
:SUBMITTED BY
SARAH ASHFAQ BPD02171025
BISMAH NASIR BPD02171034
BUSHRA NAEEM BPD02171028
ADEEL SULTAN BPD02171117
AMNA ASLAM BPD02171012
MEHVISH MAQSOOD BPD02171041
ALEESHA IQBAL BPD02171083
MAHALQA AMAN BPD02171071
AMMARA JABEEN BPD02171118
HANNAN WARIS BPD02171119
 INTRODUCTION

■ CsA is a small cyclic polypeptide

(molecular weight of 1204)
■ It is originally isolated from fungal
cultures of Tolypocladium inflatum
Gams in 1970.
■ Currently approved in the USA as an
immunosuppressive drug to prolong
organ and patient survival in kidney,
liver, heart and bone marrow transplants.
INTRODUCTION

■ CsA is available for both oral and intravenous administration

(Sandimmune).
■ A micro emulsion formulation of CsA, called Neoral, exhibiting more
reproducible absorption characteristics is also available for oral
administration
■ Several generic micro emulsion formulations are now available and are
often referred to as CsA modified.
■ It reduces the activity of immune system by interfering with activity and
growth of T-cells.
 Dosage Forms & Strengths
 usually (5–30%) oral absorption of sandimmune is variable. It is ranging from 4 to 89% in
renal and liver transplant patients. Neoral has consistent absorption approximately 40 %
 Bioavailability: Neoral >Sandimmune
 Capsule
 25mg (Gengraf, Neoral, Sandimmune)
■ 50mg (Gengraf, Sandimmune)
■ 100mg (Gengraf, Neoral, Sandimmune)
 oral solution
■ 100mg/mL (Gengraf, Neoral, Sandimmune)
 Injection
■ 50mg/mL
 :FDA approved indications include
■ Cyclosporine is an immunosuppressive agent used to treat organ rejection
post-transplant. It also has uses in certain other autoimmune diseases.

 In solid organ transplantation:

■ it has clinical use for the treatment of organ rejection in kidney, liver, and
heart allogeneic transplants.
 In patients with rheumatoid arthritis:
■ it is indicated when the disease has not adequately responded to
methotrexate.
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 For psoriasis:
■ indications include the treatment of adult, non immunocompromised patients
with severe, recalcitrant, plaque psoriasis who have not responded to at least
one systemic therapy.
 In individuals with graft vs. host disease (GVHD):
■ it prevents and treats the disease.
 In the case of uveitis:
■ cyclosporin is indicated for refractory posterior uveitis and Behcet disease.
continue

 In patients with amyotrophic lateral sclerosis (ALS or Lou Gehrig

disease)
■ cyclosporin is approved to treat amyotrophic lateral sclerosis and its variants.
 In nephrotic syndrome:
■ it is indicated to treat focal segmental glomerulosclerosis not responding to
corticosteroids.
 Dosage
Dosing for Organ Transplant in Adults

 Oral:
■ Four to 12 hours pre-transplant: 14 to 18 mg/kg by mouth for one dose
■ One to two weeks post-transplant: 5 to 15 mg/kg per day by mouth divided
twice a day
■ Reduce the dose by 5% per week until 5 to 10 mg/kg per day by mouth
divided twice per day
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 Intravenous (IV):
■ (Maximum concentration 2.5 mg/dL)
■ Four to 12 hours pre-transplant IV:
5 to 6 mg/kg IV for one dose over 2
to 6 hours
■ Post-transplant, until the patient can
tolerate oral therapy: 2 to 10 mg/kg
IV once per day
 ..Continue
 Focal Segmental Glomerulosclerosis:
■ Oral 3 mg/kg/day every 12 hours
 Rheumatoid Arthritis:
■ Oral (modified): Initially: 2.5 mg/kg per day every 12 hrs, increase 0.5 to 0.75
mg/kg per day after eight weeks if the response has not been effective.
Maximum dose: 4 mg/kg per day
 Psoriasis:
■ Oral (modified): Initially: 2.5 mg/kg per day every 12 hours, increase 0.5 mg/kg
per day after four weeks if the response has not been effective. Maximum dose:
4 mg/kg per day
■ Adjust dosage according to trough levels
 Ideal therapeutic range in whole blood

 Kidney transplant:
■ 200 to 400 ng/ml in the first week after transplantation; 125 to 275 ng/ml
in the second week to the sixth-month post-transplantation; 100 to 150
ng/ml in the seventh to the twelfth-month post-transplantation; and 75 to
160 ng/ml one year after transplantation (residual concentration Predose).
 Heart transplant:
■ 250 to 350 ng/mL in the first six months; 100 to 200 ng/mL six months to
one year after transplantation (residual concentration predose)
 Ideal therapeutic range in whole blood

 Liver transplant:
■ 250 to 350 ng/mL for the first six months; 100-
200 ng/mL six months to one year after
transplantation (residual concentration Predose)
■ The range between effective cyclosporine
concentrations and the concentrations
associated with serious toxicity is fairly narrow.
Sub-optimal doses or concentrations can lead to
therapeutic failure or severe toxicity.
■ Cyclosporine is subject to therapeutic
monitoring based on pharmacokinetics
measures.
Pharmacokinetics

■ Half-Life: 8.4 to 27 hours
■ Clearance: 5 to 7 mL/min/kg in patients who are recipients of renal or liver
allografts while appearing to be somewhat slower in cardiac transplant
patients.
■ Peak blood concentrations typically occur between 1–3 and 2–6 h following
oral administration of Neoral and Sandimmune, respectively.
■ Factors that are known to influence absorption: time post-transplant, bile flow,
dietary composition, gastrointestinal state, liver function, small bowel length,
and vehicle.
..Continue

■ Drugs that can decrease CsA levels include rifampicin, rifabutin, isoniazid, barbiturates,
phenytoin, carbamazepine, intravenous trimethoprim, intravenous sulfadimidine,
imipenem, cephalosporins, terbinafine, ciprofloxacin, ticlopidine, octreotide, and
nefazodone.
■ Drugs that can increase CsA levels include verapamil, diltiazem, amlodipine,
nicardipine, ketoconazole, fluconazole, itraconazole, erythromycin, clarithromycin,
azithromycin, saquinavir, indinavir, nelfinavir, ritonavir, methylprednisolone.
• CsA is highly bound to plasma proteins (>90% to lipoproteins), with
the majority of CsA localizing in erythrocytes.
• CsA is lipophilic, so highly bounds with plasma proteins, therefore
its concentration changes in changes with hematocrit.
• EDTA - anticoagulated whole blood is used to measure the conc. of
CsA.
• CsA is highly metabolized by cytochrome P450, which is located in
small intestine and liver.
• P-glycoproteins are immunosuppressive drugs, which highly effects
the metabolism of CsA by pumping it into the lumen of gut.
• CYP3A and P-glycoprotien genetic polymorphism can
affect the bioavailability of CsA by causing its delayed
absorption.
• CsA is oxidized or N-demethylated to more than 30
metabolites which are not clinically significant. Therefore
CsA contribute to CsA toxicity.
• Major route of CsA elimination is biliary excretion into
faeces but only a small fraction is excreted in urine.
• Dose adjustment is necessary in patients with hepatic
dysfunction but not in renal insufficiency.
:SIDE EFFECTS OF CYCLOSPORINE

SIDE EFFECTS RELATED TO CYCLOSPORINE TREATMENT

.ARE CONCENTRATION DEPENDENT
:THEY INCLUDE
Infection
Headache
Nausea
Hyperlipidemia
Hirsutism
Female reproductive disorder
Yellowing of the eyes/skin 
Severe abdominal pain
Easy bruising/bleeding
Unusual tiredness and muscle weakness
 Mental/mood changes
 Night sweats
 Hypertrichosis
 Gingival hypertrophy
Hypertrichosis and Hirsutism
 Glucose intolerance
 Hypertension
 Hypomagnesemia
 Hypokalemia

Gingival hypertrophy
LAB TESTS WHICH SHOULD BE MONITORED ARE:
■ KIDNEY/LIVER FUNCTION
■ BLOOD PRESSURE
■ BLOOD MINERAL LEVELS
■ CYCLOSPORINE BLOOD LEVELS
■ COMPLETE BLOOD COUNT,
■ URIC ACID LEVELS
■ LIPID LEVELS
■ CREATININE LEVEL
OVER SUPPRESSION
In general, over suppression of the immune system leads to an increased risk for both
■ VIRAL INFECTIONS
■ LYMPHOPROLIFERATIVE DISEASE- ESPECIALLY IN CHILDREN
 :TOXICITY
■ Considering the widespread application of this drug, accidental overdoses and
subsequent toxicities are highly probable.
■ Repeated therapeutic ingestion may produce toxicity when trough serum levels
exceed 300 ng/ml.
■ Toxic effects include:
■ Nephrotoxicity
■ Tremors
■ Neurotoxicity
■ Hepatotoxicity,
■ Hypertension
■ Venous thrombosis,
■ Paresthesia, gout, etc.
WHY CYCLOSPORINE NEEDS TO BE MONITORED?

Few features that makes the pharmacotherapy monitoring important

are following:
• Narrow therapeutic index. Desirable pharmacological effect occurs
only within narrow ranges of concentration in the blood.

• Extremely high pharmacokinetic variability

• Differences in bioavailability between different pharmaceutical

products on the market

• High risk of interactions CYP3A4 and CYP3A5 dependent with

direct and immediate consequences(over/under dosing)

• Nephrotoxicity dose-dependent
SAMPLING
Because cyclosporine binds significantly to figurative elements
especially to red blood cells, whole blood is a better biological matrix
for assessing cyclosporine concentration than plasma.

The purpose of monitoring is to prevent rejection (graft survival) and

improved tolerance (avoidance of adverse reactions, particularly
nephrotoxicity and too high immunosuppression). Trough residual
concentration is directly correlated with nephrotoxicity, but it is not a
useful marker for prediction of acute rejection.

Instead, both nephrotoxicity and acute rejection are better correlated

with the area under the concentration-time curve measured between 0-
4h.
 TIME OF SAMPLING:
■ But typically trough level is monitored.
■ A trough level is the lowest concentration reached by a drug before the next
dose is administered.
■ Timing of specimen collection has always been right before administration
of next dose.
■ For standardization timing should be within ONE hour before the next dose.
■ But majority of laboratories use whole blood samples for cyclosporine
testing instead of serum or plasma and will collect samples 12 hours after
the last dose.
METHODS OF ANALYSIS:

 There are many methods currently available to measure CsA.

 Factors that need to be considered when selecting a CsA assay include:

 Metabolite
 Cross reactivity,
 Cost of instrumentation and reagents,
 Ease of operation,
 Level of technical expertise required to perform testing,
 Test volume
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CsA can be measured by:

1. radioimmunoassay (RIA),
2. semi-automated and automated non-isotopic immunoassays,
3. High-performance liquid chromatography (HPLC) with UV (HPLC-UV) or
4. Mass spectrometry detection systems (HPLC-MS).

 HPLC methods to measure CsA are specific for parent compound and,
because of this, are considered the “gold standard” for CsA quantitation
Currently Used Methods to Measure Cyclosporine (CsA)

Method Assay Manufacturer Laboratories Using

)%( Assay
Radioimmunoassay Cyclo-Trac SP DiaSorin 1
Immunoassay
Semi-automated Polyclonal FPIA Abbott 2
Monoclonal FPIA Abbott 71
CEDIA PLUS Microgenics 8
5
Syva EMIT 2000 Dade-Behring
Automated Dimension ACMIA Dade-Behring 5
HPLC-UV 2
HPLC-MS 6
• FPIA, fluorescence polarization immunoassay;
• CEDIA, cloned enzyme donor immunoassay;
• EMIT, enzyme-multiplied immunoassay technique;
• ACMIA, antibody-conjugated magnetic immunoassay;

All the immunoassays, with the exception of the

• Dimension antibody conjugated magnetic immunoassay are semi
automated because they require a whole blood pre-treatment step.
:Metabolite Cross-Reactivity

The Abbott polyclonal antibody-based FPIA is non-specific and has extensive cross reactivity with
CsA metabolites.

The use of this assay has been declining over the years, and only about 2% of all laboratories
currently use this assay.

CsA results using the Abbott polyclonal FPIA are approximately four times higher than
those obtained using HPLC methods.

Because of the magnitude of metabolite cross-reactivity and the poor correlation with clinical
outcomes and toxicity, the use of this polyclonal assay should be discouraged .
C2 MONITORING
■ it is important to consider metabolite cross-reactivity and the degree of CsA
overestimation when selecting the “right” CsA immunoassay to support a solid organ
transplant program.
■ Therapeutic ranges for CsA are often organ-specific and can vary widely between
transplant centers. They also differ based on various immunosuppressive drug
combinations, the time after transplant, and during periods of toxicity and organ rejection.
Trough whole blood CsA levels following kidney transplants are typically between 150–
250micro g/L shortly after transplant and are tapered down to <150micro g/L during
maintenance therapy. Recommended levels after liver and heart transplants are 250–
350micro g/L shortly after transplant and <150micro g/L during maintenance therapy.
■ These target ranges were determined using HPLC and will vary considerably when
measured using immunoassay, depending on the amount of metabolite cross reactivity.
reference

.Handbook of therapeutic drug monitoring methods, chapter 9.1

cyclosporine, Medscape, data retrieved 27 April 2021.2
https://reference.medscape.com/drug/neoral-sandimmune-cyclosporine -343196 : url
cyclosporin ,ncbi. Data retreived on 27 april 2021 .3
Tapia C, Nessel TA, Zito PM. Cyclosporine. [Updated 2020 Dec
1]. In: StatPearls [Internet]. Treasure Island (FL):
:StatPearls Publishing; 2021 Jan-. Available from
/https://www.ncbi.nlm.nih.gov/books/NBK482450
reference

Midtvedt K. Therapeutic drug monitoring of cyclosporine. Transplant Proc. 2004 .4 ■

Mar;36(2 Suppl):430S-433S. doi: 10.1016/j.transproceed.2004.01.025.
PMID:15041380
Jorga A, Holt DW, Johnston A. Therapeutic drug monitoring of cyclosporine..5 ■
Transplant Proc. 2004 Mar;36(2 Suppl):396S-403S. doi:
10.1016/j.transproceed.2004.01.013. PMID: 15041374