Objective The current study aimed to develop a novel milk-based formulation of docetaxel, a sparingly soluble antineoplastic agent, administered so far exclusively by the intravenous route and evaluate its oral bioavailability. Methods Pre-formulation studies included the determination of docetaxel solubility in water-alcohol mixtures as well as short-term content uniformity experiments of the final formulation. The pharmacokinetic (PK) performance of the developed milk-based formulations was further evaluated in vivo in mice using ritonavir, a potent P-glycoprotein inhibitor, as an absorption enhancer of docetaxel and the marketed intravenous docetaxel formulation, Taxotere (R), as a control. Results In vivo PK results in mice showed that all the administered oral docetaxel formulations had limited absorption in the absence of ritonavir. On the contrary, ritonavir co-administration given as pre-treatment significantly enhanced oral bioavailability of both the marketed and milk-based docetaxel formulations; an even more marked increase in drug exposure was observed when ritonavir was incorporated within the docetaxel milk-based formulation. The fixed-dose combination also showed a more prolonged absorption of the drug compared to separate administrations. Conclusions The current study provides insights for the discovery of a novel milk-based formulation that could potentially serve as an alternative, non-toxic and patient-friendly carrier for an acceptable docetaxel oral chemotherapy.

Purpose o explore the application of the parameters of the physiologically based finite time pharmacokinetic (PBFTPK) models subdivided in first-order (PBFTPK)(1) and zero-order (PBFTPK)(0) models to bioavailability and bioequivalence. To develop a methodology for the estimation of absolute bioavailability, F, from oral data exclusively. Methods Simulated concentration time data were generated from the Bateman equation and compared with data generated from the (PBFTPK)(1) and (PBFTPK)(0) models. The blood concentration C-b(tau) at the end of the absorption process tau, was compared to C-max; the utility of AUC(0)(tau) and (AUC)(t)(infinity) in bioequivalence assessment was also explored. Equations for the calculation of F from oral data were derived for the (PBFTPK)(1) and (PBFTPK)(0) models. An estimate for F was also derived from an areas proportionality using oral data exclusively. Results The simulated data of the (PBFTPK)(0) models exhibit rich dynamics encountered in complex drug absorption phenomena. Both (PBFTPK)(1) and (PBFTPK)(0) models result either in C-max = C-b(tau) or C-max > C-b(tau) for rapidly- and not rapidly-absorbed drugs, respectively; in the latter case, C-b(tau) and tau are meaningful parameters for drug's rate of exposure. For both (PBFTPK)(1) and (PBFTPK)(0) models, (AUC)(0)(tau) or portions of it cannot be used as early exposure rate indicators. (AUC)(tau)(infinity) is a useful parameter for the assessment of extent of absorption for very rapidly absorbed drugs. An estimate for F for theophylline formulations was found close to unity. Conclusion The (PBFTPK)(1) and (PBFTPK)(0) models are more akin to in vivo conditions. Estimates for F can be derived from oral data exclusively.