194

RELATIONSHIP BETWEEN CALCINEURIN ACTIVITY AND CYCLOSPORINE PHARMACOKINETICS IN STABLE LIVER TRANSPLANT PATIENTS TREATED WITH NEORAL

It has been reported that CsA 2 hr post-dose levels of 600-800 ng/ml are associated with 75.90% calcineurin inhibition. Purpose: to determine the relationship between calcineurin activity and CsA pharmacokinetics in the content of varying Neoral dose monitoring algorithms in stable liver transplant patients Methods we enrolled 35 stable patients one year or more after transplant. They were prospectively randomized into 3 groups (Gr) for Neoral dose monitoring: Gr. 1 (C0, target range 100-200 ng/ml): 7F/4M, 59±13 yr. 39±15 months posttransplant, Gr. 2 ("high" C2, target range 700-1000 ng/ml): 5F/8M, 58±11 yr.. 35217 months posttransplant, and Gr 3 ("low" 6, target range 300-600 ng/ml): 3F/8M, 56±9 y., 37±39 months posttransplant. CsA parent compound was measured in whale blood using an enzyme multiplied immunologic technique. At 6 months of follow-up, blood samples were obtained to measure CsA levels (ng/ml) for the estimation of the area-under- the-curve (ng/ml/hr) and calcineurin activity, which was reported as a percent inhibition compared to trough. Blood samples were obtained before the morning dose of Neoral trough) and at 1 hr, 2 hr and 4 hr after (AUC 0-4 hr). Results. the inhibition of calcineurin activity at 1 hr, 2 hr, and 4 hr was. 33?25%, 42±28% (p=0.055 vs. 4 hr) and 28±25%, respectively. Neoral doses (mg/kg/day) were: Gr. 1. 2.9±0.9, Gr. 2: 4±1.8 and Gr. 3. 2.6+1.3

Table 1: Inhibition of calcineurin activity (CN%) and CsA levels by groups.

	0 hr CSA*	1 hr CN %	1 hr CsA	2 hr CN %	2 hr CsA	4 hr CN %	4 hr CsA
Gr. 1	158±34**	41±30	842±370	44±17	857±226	18±16	434±92
Gr. 2	220±71	35±24	849±411	39±30	966±274	34±24	434±170
Gr. 3	120±64***	20±20	406±229****	44±35	588±274*****	31±33	400±284

*ng/ml, **p=0.02 vs Gr. 2, ***p=0.001 vs Gr. 2, ****p=0.04 vs Gr. 1 and 2, *****p=0.03 vs Gr. 1 and p=0.003 vs. Gr. 2.

There was no correlation between the inhibition of calcineurin activity at I hr. 2 hr or 4 hr, and either the CsA AUC 0-4 hr or the Neoral dose. Conclusion: in stable liver transplant patients we found a trend towards a higher inhibition of calcineurin 2 ix after the morning dose of Neoral. A similar percentage of calcineurin inhibition was observed at fixed time points analyzed between groups, in spite of different Neoral doses. Whether the degree of calcineurin activity correlates with toxicity and acute rejection remains to be determined.

M. Cantarovich, J. Barkun, L. Aspeslet(1), P Halloran(2), Z. Aalamian, J. Tchervenkov. McGill University Health Center, Montreal, Quebec, (1)Isodiagnostica Inc., and University of Alberta Hospitals, Edmonton, Alberta, Canada.