Cyclosporine C2 Levels Have Impact on Incidence of Rejection in De Novo Lung but Not Heart Transplant Recipients: The NOCTURNE Study Martin Iversen, MD, PhD, a Folke Nilsson, MD, PhD, b Jorma Sipponen, MD, c Hans Eiskjaer, MD, PhD, d Lena Mared, MD, e Stein Bergan, PhD, f Ulla Nyström, RN, b Hans E. Fagertun, MSc, g Dag Solbu, MSc, h and Svein Simonsen, MD, PhD i Background: Cyclosporine (CsA) absorption varies early after transplantation and can be accurately assessed by the area under the absorption curve (AUC). The 2-hour post-dose (C2) level of CsA in whole blood is reported to be a useful surrogate marker of CsA AUC in kidney and liver transplant monitoring, but should be further explored in thoracic organ recipients. Methods: In a 12-month study we included de novo lung (n = 95) and heart (n = 96) recipients. All participants received cyclosporine (Sandimmun Neoral) monitored by C0 and blood was collected for analysis of C2 retrospectively. Abbreviated AUC (AUC 0–4 ) was measured at 7 days and 3 months. Primary outcome was C2 relation to the frequency of acute cellular rejection (ACR) needing treatment and possible decline in measured glomerular filtration rate (mGFR). Recipients were divided into lower, middle and upper third C2 groups based on 2-week post-operative values (tertiles T1 to T3). Results: C2 was the most robust substitute for AUC 0–4 in the group of patients studied. For lung, but not heart, recipients there were differences in mean number of ACRs (p = 0.05), incidence of any rejections (p = 0.04), mean number of any rejections (p = 0.001) and time to first rejection (p = 0.03) between T1 and T3. C2 did not predict reduction in mGFR. Conclusions: C2 is a sensitive predictor for ACR in lung, but not heart, recipients, C2 was not predictive of a decline in mGFR. This study suggests that management of lung recipients by C2 may diminish the number of ACRs. J Heart Lung Transplant 2009;28:919 –26. Copyright © 2009 by the International Society for Heart and Lung Transplantation. Cyclosporine (CsA) has a narrow therapeutic window 1 with variable absorption characteristics 2 requiring close monitoring to ensure adequate immunosuppression for avoiding acute cellular rejection and nephrotoxicity. Even with the microemulsion formulation of CsA (Neoral) there is significant variation in absorption between and within patients. 3,4 Variability in CsA absorption is more promi- nent during the first week after transplantation. 4,5 Phar- macokinetic studies in kidney, 6 liver 7 and heart 8 trans- plant patients have demonstrated a poor correlation between traditional trough CsA level (C0) monitoring and CsA exposure measured as area under the absorption curve (AUC). This has lead to interest in finding a single time-point that better correlates with AUC than the C0 level. The first study to find a strong correlation between AUC and acute rejection identified the abbreviated AUC in the first 4 hours after oral dose AUC 0–4 in kidney trans- plant recipients as a sensitive and practical measure of AUC, 9 which was later identified as the time of greatest inter- and intra-patient CsA absorption variability. 10 Recent studies have demonstrated that the CsA level at 2 hours post-dose (C2) is the best single time-point predictor of 0- to 4-hour abbreviated AUC (AUC 0–4 ) in kidney, 5,10 liver, 11 heart 8 and lung 12 transplant recipients. In the clinical setting, several retrospective analyses a From the Department of Cardiology, Section of Heart and Lung Trans- plantation, Rigshospitalet, Copenhagen University Hospital, Copenha- gen, Denmark; b Department of Cardiothoracic Surgery and Transplant Institute, Sahlgrenska University Hospital, Göteborg, Sweden; c Depart- ment of Thoracic Surgery, Helsinki University Hospital, Helsinki, Finland; d Department of Cardiology, Århus University Hospital, Skejby, Denmark; e Department of Respiratory Medicine, University Hospital Lund, Lund, Sweden; f Department of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway; g Capturo AS (Statistics), Kjeller, Norway; h No- vartis Norge AS, Oslo, Norway; and i Department of Cardiology, Rikshos- pitalet University Hospital, Oslo, Norway. Submitted March 11, 2009; revised May 11, 2009; accepted May 13, 2009. Presented at the 29th annual meeting and scientific sessions of the International Society for Heart and Lung Transplantation, April 2009, Paris, France. This report was prepared on behalf of the Nordic Transplantation Study Group. Reprint requests: Martin Iversen, MD, Department of Cardiology, Section of Heart and Lung Transplantation Rigshospitalet, Copenha- gen University Hospital, Copenhagen, Denmark Blegdamsvej 9, 2100 Copenhagen. Telephone: +45-35-45-86-84. Fax: +45-35-45-26-48. E-mail: martin.iversen@dadlnet.dk Copyright © 2009 by the International Society for Heart and Lung Transplantation. 1053-2498/09/$–see front matter. doi:10.1016/ j.healun.2009.05.022 919