LECTURE 18- TDM OF CYCLOSPORIN
Immunosuppressants
- Have transformed transplantations with decreased graft rejection & increased graft survival
- Narrow therapeutic window
- Exhibit PK variability (interpatient & intrapatient)  hard to get dose right
- TDM is essential to minimise risk of graft rejection & dose related adverse effects
o Once rejection begins, it is difficult to stop
- Cyclosporine (Cyclosporin A- CSA)  Neoral
- Newer agents introduced to overcome problems with absorption and toxicity profile with CsA
o Tacrolimus (Prograf)
o Sirolimus (Rapamune)
o Everolimus (Certican)
- CSA & tacrolimus inhibit calcineurin (CNI) which decreases cytokine production and thus
also inhibits T-cell proliferation
- Sirolimus & everolimus inhibit T-cell proliferation by inhibiting mTOR
CSA toxicity
- Due to immunosuppression  increased risk of infection
- Nephrotoxicity- renal vasoconstriction
o Increased risk for MDR1 3435 TT polymorphisms in the transplant donor
- Neurotoxicity- headache, tremors, seizures
- Diabetes mellitus
- Hypertension
- GIT disturbance
- Malignancies
- Serious renal impairment- VERY DANGEROUS IN RENAL TRANSPLANT PATIENTS!!
o Transient acute RF even within the therapeutic range
o Protracted acute RF
o Chronic nephropathy is irreversible and occurs when renal function is affected over
long period of time
o Doses & target concentrations lowered in patients with early signs of renal toxicity
o Reduced renal toxicity with newer agents
-
P-gp (CNI) & drug transporters (CNI-m) efflux the drug back out into the intestinal lumen
Drug transporters in the liver also efflux the drug metabolite (CNI-m) out into the intestine
CYP3A4/5 metabolise the drug into metabolites (CNI-m)
All of these contribute to drug concentration variability
Absorption
- Variable, erratic and incomplete
- F = 30% but ranges from 8-60%
- Highly lipophilic & hydrophobic which makes it difficult to formulate
o Used to be advised to be taken with a fatty meal which stimulated bile salts which
solubilised drug  however this resulted in variability
- Complex absorption: either zero order or series of first order processes
- Ethnic, gender & age differences
o Caucasians have greater F than African americans, decreased graft rejection
o Female caucasians have twice Cmax & increased F as Cl is faster in African
americans
o Caucasians have twice Vd
o African American children have reduced absorption  use neoral
Formulation
- Sandimmune (no longer available)
o Suspension in olive oil
o Emulsification by bile
o Bile drainage, cholestasis or diarrhoea reduce the amount of
bile emulsification & reduce bioavailability
- Neoral
o Microemulsion which is readily absorbed in absence of bile
o Absorbed faster (shorter Tmax) & to a greater extent
(greater AUC & higher Cmax peak)
o Absorbed more consistently with decreased variability
o Available IV in hospitals
- The 2 formulations are NOT bioequivalent & cant be interchanged
o Often need TDM during the changeover
Presystemic metabolism of CSA
- Gut, CYP3A4/5, P-gp
- Contribute to low and variable F
- Polymorphisms of CYP3A & P-gp may result in potential drug interactions & also vary F
Metabolism
- CSA extensively metabolised by CYP3A family
o Thus there is the potential for numerous drug interactions
- Half-life is 6-24 hours
Excretion
- Mainly biliary excretion
- Highly metabolised before excretion
Drug interactions
- Altering exposure changes the risk of graft rejection or nephrotoxicity
Drug-drug interactions
- CYP3A4 & P-gp inhibitors INCREASE CSA
o CCB- diltiazem, verapamil, nicordipne
o Antifungals- fluconazole, ketoconazole
 Combination of ketoconazole & diltiazem decreases CSA conc needed by 80%
o HIV protease inhibitors- indinavir, ritonavir
o Antibiotics- erythromycin
o Grapefruit juice
- CYP3A4 & P-gp inducers DECREASE CSA  graft rejection
o Antibiotics- rifampicin
o Anticonvulsants- carbamazepine, phenytoin
o St johns wort
Techniques
- Analytical technique
o Influences estimates of oral bioavailability
o Assay picks up parent AND metabolite
- HPLC assay
o Distinguishes between parent & metabolite and is the preferred method
- Lack of a single method makes it difficult to establish a TR & consistent protocols
Distribution
- Less variable than absorption
- Vd 4-6 L/kg
- Highly tissue bound- Fu normally <10%
- Temperature dependent
- TR needs to be corrected for temperature if not using whole blood as matrix
Dosage
- Typically 5-10 mg/kg/day in 2 divided doses to prevent allograft rejection
- Target blood trough conc vary according to organ transplanted, time after transplant & area
- Most clinicians accept trough levels of 150-400 ng/mL as the target range
Issues with CSA TDM
- Whole blood is the recommended matrix as:
o 20% bound to WBC, 40% to RBC & 40% to plasma lipoproteins
- Specificity of analytical method LC/MS, commercial kit & cross reactivity with metabolites
- Different TR for different methods
- Poor consensus on target concentrations- varies between countries
Optimal and convenient sampling
- Number of ways to monitor CSA
- Widely used approach
o After drug reaches steady state, measure trough concentration
o Poor correlation with clinical outcome and AUC for Sandimmune
o Slightly better correlation with Neoral
- Best method  AUC0-12
o Allows prediction of clinical outcome
o Sensitive
o Multiple blood samples required over 12 hour dosing interval
o Costly and inconvenient
- Limited sampling strategy
o Limited number of samples to estimate AUC
o Most variability in absorption for Neoral is in first 4 hours after dose
o Use AUC0-4 as most variability occurs in first 4 hours
o Sensitive predictor of acute rejection
o Neoral concentrations measured 2 hours after dose
 Most accurate marker for AUC0-4 which is correlated with clinical outcomes
- Bayesian approach individualises dose based on population PK parameters
Diltiazem usage
- CSA sparing agent  need lower immunosuppressant concentrations
- Inhibits CYP3A4 & P-gp  Decrease metabolism & efflux  increase CSA plasma conc
- Allows for dose reduction
- Cheaper for the patient
CSA concentration & CN activity
- As CSA concentration increases, CN activity decreases
- After 6 months, lower maintenance doses of CSA are used and thus CN activity is higher