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PHARMACOKINETICS AND PHARMACODYNAMICS

A Limited Sampling Method for the Estimation of Serum Calcitriol Area under the Curve in Cancer Patients

Josephia R. Muindi, MD, PhD, John W. Wilson, PhD, Ying Peng, BS, Mary Jo Capozolli, BS, Candace S. Johnson, PhD and Donald L. Trump, MD

From the Center for Clinical Pharmacology, Department of Medicine, and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr. Muindi, Dr. Wilson, Mr. Peng, Ms. Capozolli) and the Departments of Pharmacology and Medicine, Roswell Park Cancer Institute, Buffalo, New York (Dr. Johnson, Dr. Trump).

Pharmacokinetic (PK) data from 34 cancer patients receiving 2 to 10 µg of calcitriol subcutaneously (SC) were used to develop a limited sampling method for predicting serum calcitriol area under curve (AUC) based on three samples instead of the full complement of 12 to 16 samples. Serum calcitriol levels were measured by 1, 25-dihydroxyvitamin D3-[I125] radioimmunoassay. Individual patient-corrected serum calcitriol AUC0-12 h was calculated by the trapezoidal rule after subtracting the pretreatment serum calcitriol level. PK data were split into "training" and "evaluation" sets based on calcitriol dose and chronological order of enrollment. Linear regression models of log-corrected AUC0-12 h versus individual log calcitriol serum levels in the hour 1, 2, 3, 4, 6, and 8 samples were established using the training data set of 17 patients. The fit was tested on the evaluation data set of 17 patients using mean squared error (MSE) as the fit criterion. The best single time point predictor of log AUC0-12 h was the log serum (calcitriol) at hour 6 (MSE = 0.0061). The best prediction of log AUC0-12 h using two time points was found to involve hour 6 and hour 2 (MSE = 0.0018). The prediction equation for the latter model was as follows: Log AUC = 1.125 + 0.3756 • log (calcitriol) at hour 2 + 0.5859 • log (calcitriol) at hour 6. This limited sampling method was further evaluated in 83 cancer patients treated with 4 to 38 µg of oral (PO) calcitriol; observed and predicted calcitriol AUC0-12 h were highly correlated (r >= 0.90, p = 0.0001). These results show that serum calcitriol AUC0-12 h after SC and PO calcitriol administration is accurately estimated using pretreatment and 2- and 6-hour blood samples.

Key Words: Calcitriol • cancer • antitumor activity • pharmacokinetics • limited sampling method

Address for reprints: Josephia R. Muindi, MD, PhD, 623 Scaife Hall, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15261.






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