Evaluation of Oral Bioavailability and Intestinal Availability from Pharmacokinetic Changes Associated with Drug-Drug Interaction

[Background] In general, oral bioavailability (F) and intestinal availability (F_G, a ratio of drug escaping from intestinal metabolism during absorption) are calculated by comparing the clearances evaluated after intravenous and oral doses.  Thus, an intravenous-dose study is necessary for their evaluations, and moreover, inter-individual and inter-study differences in the clearance may produce serious errors.  In the previous study, we demonstrated that F_G is evaluable from changes in the AUC and plasma half life (t_1/2) associated with drug-drug interaction (DDI) for relatively well-absorbed substrate drugs of CYP3A4 when its inhibitor is co-administered¹⁾.  In this study, the application of this method (DDI method) is extended to less absorbed drugs, and furthermore, to the evaluation of F. [Method] Basic equations of the DDI method (Scheme) were derived from the clearance theory.  To evaluate F_G and F in the DDI method, the absorption ratio (F_A) needs to be approximated, but unnecessary to be very precise, hence it is named tentative F_A in the scheme.  Tentative F_A was fixed previously¹⁾, but in this study, approximated statistically or by the membrane permeability determined in vitro experiments.  It was assumed that F_G becomes 1.0 when strong inhibitors are co-administered (F_G^*).  Extensive Monte-Carlo simulations were conducted to check preciseness of the DDI method.  Furthermore, F_G and F of approximately 60 drugs (mainly substrates of CYP3A4) were evaluated based on literature information, and compared with the observed values if available.  [Results and Discussion] The simulation study indicated that the modified DDI method provides reasonable estimation of F_G using tentative F_A approximated statistically even for poorly absorbed drugs (i.e. F_A < 0.3).  For evaluation of F, tentative F_A needs to be more precise; accordingly approximated by in vitro information such as the permeability determined in the Caco-2 system.  Overall, F and F_G obtained by the DDI method were in excellent accord with those evaluated by other methods using the systematic clearance after intravenous dose (Figure).  Since evaluation of a DDI is frequently carried out within a single study using the same subjects, it seemed that the DDI method provides more stable evaluation compared with the conventional methods in many situations.  [Conclusion] The DDI method was proposed as a robust technique for evaluation of F_G, and in addition, it may become an alternative method for evaluation of F when an intravenous-dose study is unavailable.  Reference: ¹⁾ Tsukihashi et al., A new calculation method of intestinal availability from pharmacokinetic changes by drug-drug interaction, 25th JSSX Annual Meeting, 2010, Tokyo, Japan.