Immunosuppression
Monitoring C2 Level Predicts Exposure in Maintenance Lung Transplant Patients Receiving the Microemulsion Formulation of Cyclosporine (Neoral)

https://doi.org/10.1016/j.healun.2003.05.002Get rights and content

Background

Dosing of the microemulsion formulation of cyclosporine (Neoral) is conventionally based on trough levels (C0). However, experience in renal transplantation has shown that cyclosporine exposure during the absorption phase (AUC0–4) is critical for optimizing immunosuppression, and that cyclosporine (CsA) concentration at 2 hours post-dose (C2) shows the closest correlation with AUC0–4. This study evaluated whether C2 values correlate more closely with AUC0–4 than C0 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 AUC0–4 was calculated. The Correlation between cyclosporine concentration at each time-point and AUC0–4 was also calculated.

Results

C2 showed the closest correlation with AUC0–4 (r2 = 0.85). C0 had the poorest correlation of all time-points (r2 = 0.64). Two patients with radiologic signs of gastroparesis had no peak cyclosporine levels at all and were excluded from the correlation analysis. Mean AUC0–4 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 C2 values were 1.2 μg/ml during Year 1, 0.8 μg/ml during Years 1 to 3, and 0.5 μg/ml thereafter.

Conclusions

C2 is the single time-point that correlates most closely with AUC0–4 in lung transplant recipients without gastroparesis. It remains to be demonstrated whether monitoring CsA based on C2 levels results in a lower incidence of rejection without additional toxicity.

Section snippets

Study Design

The study was conducted in a prospective way at a single center. All patients enrolled were adult recipients of a single- or double-lung graft, and were at least 3 months post-transplant.

Inclusion Criteria

To be included in the study, all patients were required to have no infections or episodes of graft rejection within the preceding month, with stable lung, bronchiolitis obliterans syndrome (BOS) Stage 0 and stable kidney and liver function during the preceding 3 months.

Immunosuppression

All patients were receiving a triple

Patient Population

Twenty patients with stable graft function and in a stable clinical condition were enrolled. Patient demographics and baseline characteristics are shown in Table 1 The mean time since transplantation was 740 days. Ten patients were <1 year post-transplant, 8 were 1 to 3 years post-transplant, and 2 were transplanted >3 years previously.

CsA Pharmacokinetics

Pharmacokinetic data are shown in Table 2

Effect of Gastroparesis

Two patients with radiologic signs of gastroparesis demonstrated no peak CsA level and were excluded from all

Discussion

Individualizing CsA therapy can be achieved by application of therapeutic drug-monitoring principles. Evidence suggests that CsA exposure in the first 4 hours post-dose (AUC0–4) is critical for optimal outcome,12 but data reported here confirm that, as in other types of solid organ transplantation,11, 13, 14, 15, 16 conventional measurement of C0 does not provide the most accurate marker for AUC0–4 after lung transplantation. This study is the first to evaluate alternative single time-point

References (27)

  • B.W. McKane et al.

    Lung transplantation and bronchiolitis obliteransan evolution in understanding

    Immunol Res

    (2001)
  • D.W. Holt et al.

    Methodological and clinical aspects of cyclosporin monitoringreport of the Association of Clinical Biochemists task force

    Ann Clin Biochem

    (1994)
  • D.L. DeMeo et al.

    Clinical status of lung transplantation

    Transplantation

    (2001)
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