Monitoring C2 level predicts exposure in maintenance lung transplant patients receiving the microemulsion formulation of cyclosporine (Neoral).
BACKGROUND
Dosing of the microemulsion formulation of cyclosporine (Neoral) is conventionally based on trough levels (C(0)). However, experience in renal transplantation has shown that cyclosporine exposure during the absorption phase (AUC(0-4)) is critical for optimizing immunosuppression, and that cyclosporine (CsA) concentration at 2 hours post-dose (C(2)) shows the closest correlation with AUC(0-4). This study evaluated whether C(2) values correlate more closely with AUC(0-4) than C(0) in lung transplant patients.


METHODS
Pharmacokinetic data were collected prospectively from 20 clinically stable adult lung allograft recipients receiving CsA, mycophenolate mofetil and steroids. Indications for transplantation were emphysema (n = 15), idiopathic fibrosis (n = 2), primary pulmonary hypertension (n = 1), cystic fibrosis (n = 1) and lymphangioleiomyomatosis LAM (n = 1). Blood samples were collected at 0, 1, 2, 3 and 4 hours after administration of CsA, and then AUC(0-4) was calculated. The Correlation between cyclosporine concentration at each time-point and AUC(0-4) was also calculated.


RESULTS
C(2) showed the closest correlation with AUC(0-4) (r(2) = 0.85). C(0) had the poorest correlation of all time-points (r(2) = 0.64). Two patients with radiologic signs of gastroparesis had no peak cyclosporine levels at all and were excluded from the correlation analysis. Mean AUC(0-4) was 3,700 ng . h/ml during Year 1 post-transplant, 2,400 ng . h/ml during Years 1 to 3, and 1,500 ng . h/ml thereafter. Mean C(2) values were 1.2 microg/ml during Year 1, 0.8 microg/ml during Years 1 to 3, and 0.5 microg/ml thereafter.


CONCLUSIONS
C(2) is the single time-point that correlates most closely with AUC(0-4) in lung transplant recipients without gastroparesis. It remains to be demonstrated whether monitoring CsA based on C(2) levels results in a lower incidence of rejection without additional toxicity.
Jaksch
Peter
P
Department of Cardio-Thoracic Surgery, University Hospital, Vienna, Austria. p.jaksch@lunge.at
Kocher
A
A
Neuhauser
P
P
Sarahrudi
K
K
Seweryn
J
J
Wisser
W
W
Klepetko
W
W
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D016572:Cyclosporine / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016040:Lung Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000379:methods; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D014181:Transplantation Immunology / Q000187:drug effects / Q000502:physiology*
D015415:Biomarkers; D007166:Immunosuppressive Agents; D016572:Cyclosporine