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• W2023410004 abstract "Cyclosporine (CsA) exhibits a tight relationship between efficacy and toxicity with total drug exposure (1). Although therapeutic pharmacokinetic (PK) monitoring of CsA with area under the concentration time curve (AUC) plays an important role in the optimal care of renal transplant patients, it is expensive and inconvenient. Several single time points as well as two- or three-point methods were tested for assessing CsA exposure, and 2 hr (C2) and 3 hr (C3) after dose measurements were reported to be highly correlated with AUC (2). To identify surrogate measures that best estimate the AUC in the least costly strategy, we retrospectively analyzed the CsA PK (8 hr) profiles of 83 renal transplant recipients (38 female, 45 male; mean age 40±14 years) who were receiving CsA modified (microemulsion) capsules (b.i.d.). PK profile included blood samples obtained before (C0; trough) and then at 0.5, 1, 2 (C2), 4 (C4), 6 (C6), and 8 (C8) hours after CsA administration. Samples were measured using monoclonal fluorescence polarization immunoassay (FPIA). A trapezoidal mathematical construct was used to evaluate which data points individually, and in combination, provided statistically significant and substantive estimates of AUC, which was corrected to the average concentration (Cav) by dosing interval adjustment (Cav=AUC/τ). Target levels of CsA exposure expressed as Cav were 550 ng/ml (first 3 months), 450 ng/ml (3–6 months), and 350 ng/ml thereafter (4). We have chosen the five time points (C0, C2, C4, C6, and C8) that spanned the largest total duration and were complete for all patients. Data were analyzed using the SPSS statistical package (SPSS Inc., Cary, NC). Linear regression methods were chosen a priori to test the following: (1) the contribution of all five PK data points to the overall prediction of AUC; (2) the effect of including only two PK data points as predictors; and (3) the individual effect of each of these PK data points as predictors (5). With this methodology, the linear regression assumption was not violated, which is a potential limitation of some earlier reports. Each of the five PK data points exhibited statistically significant (P <0.001) bivariate correlation coefficients in relation to AUC (C0, r =0.73; C2, r =0.73; C4, r =0.81; C6, r =0.83; and C8, r =0.80). When the five predictors were analyzed simultaneously, C0, C2, and C8 each contributed significantly to the overall prediction of AUC (all P <0.01). The elimination of C4 and C6 from the model did not have a statistically significant impact on overall prediction. This three-point predictor model was statistically significant (R=0.94, R2=0.88, P <0.001), and the standardized regression coefficients demonstrated that the order of importance of the individual predictors was C2 (β=0.52, P <0.001), C8 (β=0.40, P <0.001), and C0 (β=0.26, P =0.003) (Table 1). Table 1: Multiple regression statisticsThe elimination of C4, C6, and C8 from the complete model resulted in a statistically significant reduction in model R2 (from 0.88 to 0.84, P <0.001) that was due solely to the elimination of C8. However, although the consequence of eliminating the C8 data point was statistically significant, the overall reduction in the proportion of covariance accounted for by the two-point model (in comparison to the five-point model) was only 4 percentage points (i.e., 0.88–0.84). In the context of this two-point predictor model (R=0.92, R2=0.84, P <0.001), C0 and C2 were comparably important (both β=0.58 and P <0.001). Although both C0 and C2 were each individually correlated with AUC (both r =0.73 and P <0.001), their percentage of variance shared with AUC was only 53% and 52%, respectively. Because of the different methods used for CsA blood level determination (FPIA versus high-performance liquid chromatography) as well as the form of CsA used (conventional versus modified) and administration of the drug (once versus twice daily), there are discrepancies in the literature regarding the use of abbreviated AUC. Our study included a uniform group of patients who were on modified CsA formulation administered twice daily, and the FPIA method was used for blood level measurements. Keown et al. (3) demonstrated that trough (C0) blood levels, when used alone, did not correlate closely with drug exposure and the combination of C0 and C2 provided the closest association with AUC (R2=0.945). In another study, Mahalati and colleagues (1) utilized a five-point (C0, C1, C2, C3, and C4) PK study that was more closely associated with acute rejection and CsA nephrotoxicity than C0 alone. We demonstrated that although the three-point model (C0, C2, C8) statistically best predicts the AUC drug exposure for modified CsA, the two-point model (C0, C2) is as closely related and clinically feasible. But, the 95% confidence intervals around the individual regression parameters are not sufficiently narrow to warrant recommendation of a specific formula for clinical application at this time. Replication of these analyses in a large, prospective study considering the different absorptive characteristics of different patient groups (i.e., children, diabetics with gastroparesis, patients with malabsorption syndromes) would be necessary to generate more precise predictive equations." @default.
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• W2023410004 title "A SYSTEMATIC EXAMINATION OF ESTIMATES OF CYCLOSPORINE AREA UNDER THE CURVE IN RENAL TRANSPLANT RECIPIENTS1" @default.
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