Transcript Therapeutic Drug Monitoring of Cyclosporine

Therapeutic Drug Monitoring of Cyclosporine
Therapeutic Drug Monitoring
Quantification of drug concentration in a biological fluid to
assess therapeutic compliance, efficacy, and/or to prevent
drug-induced toxicity.
Cyclosporine
11-amino acid cyclic peptide, discovered in soil fungus in 1970.
It has tremendously improved graft survival in all areas of
transplantation, through inhibition of T lymphocytes activity.
Tolypocladium inflatum
Why cyclosporine needs to be monitored?
1. Narrow therapeutic index.
Desirable pharmacological effect only within narrow ranges of concentration in
the blood.
Too much  nephrotoxicity; Too little  graft rejection.
2. Poor dose response relationship.
Soluble only in organic solvents or lipids, it is insoluble in water.
Highly variable absorption between and within patients.
3. The clinical effect is difficult to measure.
Graft rejection may be the first indication of therapeutic ineffectiveness.
The major adverse effect of the drug is hard to distinguish from a lack of
therapeutic effects.
Measuring cyclosporine blood concentration
Whole blood
Cyclosporine is 90% protein bound and concentrated in erythrocytes. The
degree of concentration in erythrocytes is temperature dependent in vitro.
Immunoassay
cross-reactivity to the metabolites
HPLC
HPLC-MS/MS
When cyclosporine should be monitored?
1. Trough, C0 monitoring
Trough level is the lowest level that a medicine is present in the body. In a
medicine that is administered periodically, the trough level should be measured
just before the administration.
Titrate the dose of cyclosporine to get the predose blood concentration of the
drug into a range that is considered both nontoxic and effective.
2. Average concentration (CAV) and area under the concentration-time curve
(AUCt) monitoring
Mutiple blood samples are taken over a dosing interval and the conentrationtime curve is drawn.
CAV= AUCt/T
AUC0-4: Area under the concentration-time curve in the first 4 hours.
3. C2 monitoring
The concentration 2 hours after dosing
Trough, C0 monitoring
Benefits:
simple, practical
Challenges:
inaccurate indicator of total drug exposure
not a sensitive predictor of clinical outcomes
The method of choice for most transplant units until recently.
Overlap in the predose concentrations seen in patients with
rejection and those exhibiting nephrotoxicity
Relationship between C0 level and either rejection or
nephrotoxicity could not be always established in different
studies.
AUC monitoring
AUC monitoring
Benefits:
Challenges:
more precise indicator of total drug exposure
more sensitive predictor of clinical outcomes
able to characterize abnormal absorption patterns
impractical, extra blood sampling required
higher cost
AUC was better correlated with dose and was a better predictor of
acute and chronic rejection, graft survival rate, nephrotoxicity, and
efficacy of treatment in psoriatic patients.
AUC monitoring
Sparse sample algorithms
Keown et al.Transplant Proc 1998;30:1645–9.
AUC monitoring
Sparse sample algorithms
AUC = Constant + M1 × Ct1 + M2 × Ct2 + M3 × Ct3 . . .+ Mi ×
Cti
AUC monitoring
Sparse sample algorithms
AUC monitoring
Sparse sample algorithms
AUC monitoring
Sparse sample algorithms
Ther Drug Monit 2001; 23(2):100-114.
AUC monitoring
Sparse sample algorithms
Benefits:
more practical, 2-3 point-sampling is adequate
accurate estimators of Neoral® AUC value
Challenges:
be careful when choose which algorithm to
follow.
AUC(0-4) monitoring
The study population comprised 98
consecutive primary kidney transplant
recipients transplanted between August
1998 and December 1999 at the Queen
Elizabeth II Health Sciences Centre in
Halifax. All patients were followed for
a minimum of 6months.
The diagnosis of AR was confirmed
by percutaneous core needle biopsy,
and classified according to the Banff
criteria.
American Journal of Transplantation 2002; 2: 789–795.
C2 monitoring
Benefits:
more practical
accurate estimators of Neoral® AUC value
Challenges:
under validation in various graft transplantation
C2 monitoring
Transplantation 2001; 72(6):1024-1032.
C2 monitoring
American Journal of Transplantation 2002;2:148-156.
Patients receiving transplants between February 2002 and September 2003 (n89) were prospectively
managed by daily C2 monitoring of CsA-MEF. CsA-MEF was administered orally, mostly in
capsule formulation, at 5 AM and 5 PM under the supervision of a nurse. Blood was collected daily
by a study nurse at 2 hours after the morning dose, and C2 concentrations of CsA were determined
by fluorescence-polarization immunoassay (FPIA). Target C2 levels were1,500±200 ng/mL.
Patients managed by C2 monitoring (C2 group) were retrospectively compared with the kidneytransplant recipients receiving transplants throughout 2001 (n88) who fulfilled the same criteria
for inclusion in the study but who had been managed by trough level monitoring of CsA-MEF
(C0group). In the C0 group, target levels for CsA were 250 ± 50 ng/mL (FPIA).
The study was conducted in 21 centers in eight
countries using a prospective, multicenter,
randomized, parallel cohort open-label design which
was approved by the ethics committee at each
participating center.
All patients received immunoprophylaxis with
basiliximab 20mg i.v. on the day of transplant and
20mg i.v. on day 4, and maintenance double-drug
immunosuppression consisting of cyclosporine
emulsion and prednisone.
Treatment with cyclosporine emulsion was
commenced at a dose of 4±6mg/kg given orally twice
daily, starting within the first 12h following
transplantation. CsA levels were measured at each
site by a monoclonal antibody assay specific for the
parent molecule, and the daily dose was adjusted to
maintain the selected target ranges within each
Daily Dose
American Journal of Transplantation 2002;2:157-166.
American Journal of Transplantation 2002;2:157-166.
Thirty-one patients (27 men and 4 women, 52±10 years, 74% Caucasian) who
underwent routine surveillance endomyocardial biopsy following OHT at the
Hospital of the University of Pennsylvania were enrolled.
Ther Drug Monit 2005; 27(4):417-421.
Ther Drug Monit 2005; 27(4):417-421.
N should be 83(C0) and 21(C2) in each group to get a power of 80% to detect if P<0.05
Ther Drug Monit 2005; 27(4):417-421.
Opposite to expected
Ther Drug Monit 2005; 27(4):417-421.