Therapeutic drug monitoring of cyclosporine and area under the curve prediction using a single time point strategy: appraisal using peak concentration data

Abstract

There is an ongoing debate on the use of a single concentration time point C2 for therapeutic drug monitoring (TDM) and exposure prediction for cyclosporine. The objective of the present work was to evaluate the relationship between the peak concentration (Cmax ) versus area under the curve (AUC) for cyclosporine. Using published data from renal transplant patients from an 8-12 week study with two formulations, a simple linear regression model represented by AUC - cyclosporine = Cmax - Cyclosporine × 3.9965 + 384.5 (r = 0.9647; p < 0.001) was developed. Using the regression equation, predictions of AUC from the reported Cmax data were performed; the fold difference between observed vs predicted AUC was computed and the root mean square error for the prediction was calculated. While all but one of the predicted AUCs were contained within a 0.5-2-fold difference (99.1%), a greater proportion of the AUC values were predicted within a narrower range of 0.75 to 1.5-fold difference (78.2%), suggesting the utility of Cmax as the right surrogate for predicting the AUC for cyclosporine with a correlation coefficient of 0.8698 (n = 126; p < 0.001) and a RMSE of 26.2%. Since the time to Cmax generally varies from 1 to 2 h, although the results validate the use of C2, there may be an opportunity to explore the suitability of C1 or C1.5 in a prospective study for the purpose of TDM and AUC prediction of cyclosporine.

Correlation between Cyclosporine Blood Levels and Area under Blood Concentration Time Curve in Iraqi Bone Marrow Transplant Patients Treated with Neoral® Oral Solution

“…Therapeutic drug monitoring based on a single data point strategy was also studied to determine the best correlation between cyclosporine levels and AUC [19,20]. The measurement of AUC 0-4h was suggested as an alternative approach to AUC 0-12h and a good correlation was found between AUC 0-4h and the clinical outcome for heart transplant recipients [21], lung transplant patients [22], and other organ allografts, particularly kidney and liver transplantation, indicating the use of AUC 0-4h as a surrogate index for reflecting cyclosporine absorption and exposure [23].…”

“…Moreover, other investigations demonstrated the greatest correlation between C2, C3 and C4 cyclosporine levels and their corresponding AUC 0-12h . Among these studies which were conducted for allogeneic hematopoietic stem cell transplantation [30], allogeneic stem cell transplantation [31,32], renal transplant patients [19], for HIV infected kidney and liver transplant patients [20], for pediatric hematopoietic stem cell transplant [33], for children with idiopathic nephrotic syndrome [27], and for pediatric stem cell recipients [34].…”

Predictions of the Pharmacokinetics in Burn Injury Patients using Regression Models – Case Study with Levofloxacin

“…The prediction of pharmacokinetic data using single time point strategy using linear regression models has been previously attempted for drugs such as cyclosporine, indinavir, lopinavir, pravastatin, simvastatin, itraconazole, fexofenadine etc. using C max and/or C min data; the predicted data were in conformity of the observed data suggesting the utility of such linear regression models [28][29][30][31][32].…”

Intranasal Pharmacokinetic Data for Triptans Such as Sumatriptan and Zolmitriptan Can Render Area Under the Curve (AUC) Predictions for the Oral Route: Strategy Development and Application

“…Such an inclusion of additional data points by using the respective mean and standard deviation values has been recently reported for the analysis of cyclosporine. 53 Although the inclusion of such data points provided unambiguous prediction of AUC values for sumatriptan and zolmitriptan from higher-dose oral pharmacokinetic studies, it did not comprise the scientific rigor and integrity of the current analysis. For instance, the inclusion of high data point had a negligible influence on the slope values or intercept values for either sumatriptan or zolmitriptan as illustrated in Figure 1.…”