Bioequivalence and Bioavailability Forum

Dear all!

I have some questions relating to a zero-order absorption model with first order elimination. I found that concentrations after extra-vascular administration can be adequately described by the following model:

C = (k₀ x F) / (V x k_e) x (1-exp(-k_e x t_abs)) x exp(-k_e x time).

The parameters k₀, V and F refers to the zero order absorption rate, volume of distribution (I suppose during the elimination phase) and the bioavailability. The parameter t_abs denotes the time of absorption fitted using an indicator variable and the parameter k_e refer to the elimination rate. The estimated model parameters were therefore t_abs, k_e and k₀xF/V. The reason for k₀xF/V is simply due to the inability to determine k₀, F and V separately. I have also data from an IV bolus administration for a different group of subjects enabling to calculate F via the ratio of dose-normalized AUCs.

Additionally, I want to calculate CLs, Vz, Vss and k₀ for the extra-vascular administration. Here are my questions:

1. I have some doubts that (dose x F) / AUC_0-infinity gives an accurate estimate of CLs in the case of zero order absorption. What do you think?
   
   
2. I would be happy to receive some ideas how to calculate/extract the zero order absorption rate and V from the value k₀xF/V. Mathematically the following equation should be correct: k₀ x F = (dose/t_abs) x F. Where the dose is known, t_abs is an estimated model parameter available for each subject and a common F is obtained from the IV data. This equation and the corresponding estimates should enable to calculate k₀ and V for each subject on the assumption of an identical F. Am I correct? Is there any other method available to calculate k₀ for each subject separately without the assumption of a common F for all subjects?

Any suggestions are highly appreciated!

Martin