The influence of hepatic function on the pharmacokinetics and dose requirements of epirubicin
The aims of this thesis were to develop new dosage guidelines for epirubicin. In this thesis, a population analysis performed using a UK data set, including 109 patients with breast cancer treated with single-agent epirubicin, identified aspartate aminotransferase (AST) as the only covariate that had a clinically significant influence on epirubicin CL. The population model for epirubicin CL was as follows: CL (L/h) = 72.9 x (1- (0.135 x (In AST)). Inclusion of AST reduced the inter-individual variability in CL from 49 to 39 %. Using the population model, new dosage guidelines were proposed to achieve a target AUC of 4000 ng.h/ml, as identified from the literature. The following doses were predicted to achieve this exposure with the greatest precision: ASK150 U/L = 125 mg; AST 150-250 U/L = 90 mg; AST 250-500 U/L = 60 mg; AST> 500 U/L = 30 mg. In the UK data set, the new guidelines achieved the target with greater precision (root mean squared error (rmse) = 39.0 %) than the current UK guidelines, current USA guidelines or an earlier equation based on AST (raise = 63 %, 62 % and 59 %, respectively). Furthermore, as the proposed dosing guidelines do not require adjustment according to BSA, they could reduce dosage preparation time and minimise the potential for prescribing and dispensing errors. The predictive performance of the model was evaluated using two external data sets. In 18 patients with either breast cancer or hepatocellular carcinoma, the population model estimated CL values with poor precision (rmse = 82 %). Similarly, in a Swedish data set including 79 patients with breast cancer, the population model also estimated CL values with poor precision (rmse = 43 %). A comparison of CL values in patients with normal liver function showed that the median CL in patients from the Swedish data set was nearly twice that in the UK data set The Swedish and UK data sets were combined and a new population model using all the data was developed. Despite the increase in patient numbers, AST was still the only clinical factor that was identified as influencing epirubicin PK.