Bioavailability of controlled release carbamazepine estimated by mixed effect modelling

Summary

The absorption properties of a conventional tablet of carbamazepine (T) and a controlled release form of carbamazepine (TCR) have been compared using a nonlinear mixed effect model (NONMEM). Plasma carbamazepine concentration data were obtained from an open, steady-state, crossover bioavailability study in which 494 measurements were obtained from 13 patients, with an equal number of samples per patient for each dosage form. The pharmacokinetic model used was a one-compartment open model with first-order absorption and elimination. The objective function was used as a measure of the goodness of fit of the model to the data.

Body weight was an important determinant of carbamazepine clearance (CL) but not volume of distribution (V). Accounting for the interindividual variability in volume of distribution did not significantly influence the objective function. Including different rates of absorption (ka) for the two dosage forms resulted in a significant improvement in the objective function, as well as reducing the interindividual variability in the rate of absorption. Adding a parameter for relative bioavailability (f) of TCR improved the objective function statistically, but an unrealistic value for V was obtained, and the absorption and elimination rates appeared to be transposed in the classical “flip-flop” manner. Fixing V to the value obtained before introducing f did not change the objective function and permitted estimation of f without the confounding influence of excessive parameters.

The final population parameter estimates (standard error of estimate) were: CL, 0.0522 (0.0019) l·h⁻¹·kg⁻¹; V, 63.7 (FIXED)l; kaT, 0.312 (0.064) h⁻¹; kaTCR, 0.149 (0.016) h⁻¹; f, 1.01 (0.0326); variance (additive) in CL, 0.291 (0.083) (l·h⁻¹·kg⁻¹)²; residual intrasubject error variance (additive), 0.572 (0.082) (mg·l⁻¹)². The 95% confidence interval of the extent of absorption (f) of 93.6%–107.4% was well within the generally accepted range of ±20%, while the rate of absorption of Tegretol CR was significantly slower than that of Tegretol, as expected for a controlled release product.