High Plasma Levels and Effective Lymphatic Uptake of Docetaxel in an Orally Available Nanotransporter Formulation

Abstract

Docetaxel, an efficient chemotherapeutic drug, exhibits low and variable oral bioavailability due to the active efflux by P-glycoprotein (P-gp) and more so to CYP3A4 gut metabolism. Using a spray-drying technique, docetaxel was incorporated in PLGA [poly(lactic-co-glycolic acid)] nanocapsules (NC) which were embedded in entero-coated microparticles. An oral administration of the NC formulation elicited a higher absolute bioavailability than both a docetaxel solution (276%) and a free docetaxel NC formulation (400%) injected intravenously, a 5-mg/kg dose. The batches (B) I and II NC formulations elicited C max values that were 1,735% and 2,254%, respectively; higher than the C max value of the oral docetaxel solution combined with blank microparticles, a 10-mg/kg dose. No significant difference in AUC (area under curve) was observed between the batches. These unexpected results can be explained only if the pharmacokinetics of docetaxel had been modified. It was shown that NCs released from the microparticles penetrated the enterocytes, bypassing P-gp; apparently circumventing gut metabolism and accumulating within the lymphatic system from where both intact or biodegraded NCs and free docetaxel were progressively released into the circulation as plausibly supported by the fluorescent imaging results. Furthermore, the circulating docetaxel in plasma was unencapsulated and circulated either in free form or bound to albumin. Both free docetaxel NCs and microparticles exhibited in vitro efficacy on WRC 256 cells suggesting that the activity of docetaxel was not altered. This delivery concept has potential for clinical translation, perhaps allowing docetaxel chemotherapy to be switched from intravenous to oral delivery. Cancer Res; 71(8); 3018-28. Ó2011 AACR.

Oral delivery system prolongs blood circulation of docetaxel nanocapsules via lymphatic absorption

“…S3 and S4) and markedly in favor of the docetaxel NC formulation (C max and AUC of NCs vs. solution, P < 0.03). Consequently, the clearance (CL) values were decreased significantly (CL of docetaxel NCs vs. docetaxel solution, P < 0.03) as previously reported (9). It can also be deduced that the formulation is in fact gastro-resistant, because C max is delayed compared with the rat study, in which the formulation was diluted into an aqueous dispersion, whereas in the minipigs, the formulation was packed in a conventional solid-capsule dosage form (Fig.…”

“…In contrast, our approach where docetaxel is dissolved in the oil core of PLGA NCs, which are embedded in MPs consisting of a blend of polymers (Eudragit L and hydroxypropylmethylcellulose (HPMC)), not only significantly improved oral bioavailability of docetaxel without affecting the physiological activity of the P-gp and CYP3A4, but also elicited much higher C max and AUC values than the respective values yielded by Taxotere injected i.v. at an equivalent dose (9). The results of the physicochemical characterization indicate that the experimental conditions for the preparation of the NC-loaded MP formulations were well controlled, as good reproducibility, in terms of particle size distribution, zeta potential, and drug content, was achieved.…”

“…The batch with 4% docetaxel in NCs was tested and reported in extensive previous rat studies (9). For the purpose of confirming the enhanced docetaxel oral absorption in large animals, in this study, the same batch was tested in minipigs, in addition to the efficacy evaluation in the metastatic SCID-bg mice model.…”

“…Recently, we reported that the oral delivery of docetaxel NCs to rats elicited a higher bioavailability compared with the i.v. or oral administration of Taxotere (9). These unexpected results could only be explained if the pharmacokinetics of docetaxel had been modified (9).…”

“…or oral administration of Taxotere (9). These unexpected results could only be explained if the pharmacokinetics of docetaxel had been modified (9). In this study, the drug absorption of the selected poly(DL-lactide-coglycolide) (PLGA) formulation was also investigated following oral administration to minipigs to verify if animal size might affect the oral bioavailability improvement observed in rats.…”