Limited sampling strategy to predict AUC of the CYP3A phenotyping probe midazolam in adults: application to various assay techniques.
Midazolam clearance is used to phenotype hepatic CYP3A activity but requires multiple plasma samples following a single intravenous dose. The authors evaluated the use of a limited sampling scheme, using different assay techniques to determine the reproducibility of such a strategy in estimating midazolam AUC. Seventy-three healthy adults received midazolam as a single intravenous bolus dose. At least eight plasma samples were collected from each subject and were assayed using either LC/MS/MS or electron capture gas chromatography. Eleven subjects were randomly selected for the training set using stepwise linear regression to determine relationships between midazolam plasma concentrations and AUC. Validation of the predictive equations was done using the remaining 62 subjects. Mean percent error (MPE), mean absolute error (MAE), and root mean square error (RMSE) were calculated to determine bias and precision. Based on the training set, five models were generated with coefficients of determination ranging from 0.87 to 0.95. Validation showed that MPE, MAE, and RMSE values were acceptable for three of the models. Intrasubject reproducibility was good. In addition, training set datafrom one institution were able to predict data from the other two institutions using other assay techniques. Minimized plasma sampling mayprovide a simpler method for estimating midazolam AUC for CYP3A phenotyping. A limited sampling strategy is more convenient and cost-effective than standard sampling strategies and is applicable to more than one assay technique.
Kim
Jooran S
JS
Clinical Pharmacology Research Center, Bassett Healthcare, Cooperstown, New York 13326-1394, USA.
Nafziger
Anne N
AN
Tsunoda
Shirley M
SM
Choo
Edna E
EE
Streetman
Daniel S
DS
Kashuba
Angela D M
AD
Kulawy
Robert W
RW
Beck
Debra J
DJ
Rocci
Mario L
ML
Wilkinson
Grant R
GR
Greenblatt
David J
DJ
Bertino
Joseph S
JS
D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D002849:Chromatography, Gas / Q000706:statistics & numerical data; D002853:Chromatography, Liquid / Q000706:statistics & numerical data; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000097:blood* / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry / Q000706:statistics & numerical data; D008874:Midazolam / Q000097:blood*; D010089:Oxidoreductases, N-Demethylating / Q000097:blood* / Q000235:genetics*; D010641:Phenotype; D011237:Predictive Value of Tests
D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam