Oral bioavailability of docetaxel in combination with OC144-093 (ONT-093)

Objective Docetaxel given orally as monotherapy results in low bioavailability of <10%. Previous studies have indicated that the intestinal efflux pump P-glycoprotein (P-gp) prevents uptake from the gut resulting in low systemic exposure to docetaxel. The purpose of this study was to determine the degree of enhancement of the oral uptake of docetaxel on combination with orally administered OC144-093, a potent P-gp inhibitor. Furthermore, the safety of combined treatment was determined and whether known functional genetic polymorphisms of the MDR1 gene could be associated with variability in docetaxel pharmacokinetics was also investigated.Patients and methods A proof of concept study was carried out in 12 patients with advanced solid tumors. Patients were randomized to receive one course of 100 mg oral docetaxel combined with 500 mg OC144-093 followed 2 weeks later by a second i.v. course of docetaxel at a flat dose of 100 mg, without OC144-093, or vice versa. This was followed by standard i.v. docetaxel treatment if indicated.Results The apparent relative oral bioavailability of docetaxel was 26±8%. Orally administered docetaxel combined with oral OC144-093 resulted in a C_max of 415±255 ng ml^–1, an AUC_0– of 844±753 ng h ml^–1 and k_el of 0.810±0.296 h^–1. These values differed significantly from those following i.v. administration of docetaxel, with a C_max of 2124±1054 ng ml^–1, an AUC_0– of 2571±1598 ng h ml^–1 and a k_el of 1.318±0.785 h^–1 (P=0.003, P=0.006, P=0.016). The study medication was well tolerated and most of the adverse events possibly or probably related to OC144-093 and docetaxel were of CTC grade 1 and 2. One patient had a homozygous 3435T/T mutation, which is associated with low intestinal P-gp expression, and two other patients had a homozygous mutation on exon 21.Conclusion The relative apparent bioavailability of 26% was most likely caused by a significant effect of OC144-093 on the oral uptake of docetaxel. Large intrapatient and interpatient (pharmacokinetic) variation was found after oral as well as after i.v. administration of docetaxel. Higher plasma levels were observed after 100 mg i.v. docetaxel than after 100 mg oral docetaxel plus 500 mg oral OC144-093. The safety of the oral combination was good. More patients should be evaluated to determine the effect of P-gp single nucleotide polymorphisms on oral pharmacokinetic values of docetaxel.