Maximum a posteriori Bayesian estimation of epirubicin clearance by limited sampling.
OBJECTIVE
To develop a limited sampling strategy for estimation of epirubicin clearance.


METHODS
The data set comprised 1051 concentrations measured in 105 patients with advanced or metastatic breast cancer treated with epirubicin alone. Ten limited sampling designs comprising two or three blood samples were proposed, taken at times identified by D-optimality from population pharmacokinetic parameter estimates. The data set was then truncated to include the sampling times for each of the designs. MAP Bayesian estimates of clearance were generated for each design and compared with clearance estimates obtained using all the data. The limited sampling designs were also validated using a separate data set obtained from 18 patients with either breast cancer or hepatocellular carcinoma. The sensitivity of the best limited sampling designs to sample time recording errors of 0-10% or 10-20% was then assessed using a simulated data set including 200 patients.


RESULTS
The optimum sampling times were: end of the injection and 18 min, 40 min, 3 h, 10 h and 48 h after the start of the injection. The best three-sample design included samples at 40 min, 3 h and 48 h and gave unbiased estimates of clearance with an imprecision of 9.1% (95% CI 7.3, 10.5). The best two sample design included samples at 3 and 48 h and gave unbiased estimates of clearance with an imprecision of 12.4% (95% CI 9.6, 14.6). Using the validation data set, these two and three sample designs gave unbiased estimates of clearance with an imprecision of 5.6% (95% CI 3.7, 7.0) and 4.2% (95% CI 2.6, 5.3), respectively. Simulations that included 0-10% or 10-20% errors in the recording of the blood sampling times had negligible effects on the bias and imprecision of clearance estimates.


CONCLUSIONS
Limited sampling designs have been identified and validated that estimate epirubicin clearance with adequate precision and without bias from two or three blood samples. These designs also allow flexibility in blood sample collection and are robust with regard to sample time recording errors.
Ralph
Lorraine D
LD
Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, UK. lorraine.ralph@quintiles.com
Thomson
Alison H
AH
Dobbs
Nicola A
NA
Twelves
Chris
C
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D001499:Bayes Theorem; D002851:Chromatography, High Pressure Liquid; D015251:Epirubicin / Q000493:pharmacokinetics*; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000903:Antibiotics, Antineoplastic; D015251:Epirubicin