piperidines and posaconazole

The efficacy and safety of alectinib, a central nervous system-active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time-dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed-sequence studies evaluating drug-drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates.

Topics: Adult; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Midazolam; Middle Aged; Piperidines; Receptor Protein-Tyrosine Kinases; Rifampin; Treatment Outcome; Triazoles; Young Adult

The purpose of this study was to evaluate the effects of solubilizing excipients on Caco-2 transport parameters of poorly water-soluble NCEs (new chemical entities), and determine their permeability class under the BCS guidance (Biopharmaceutics Classification System). The effect of solubilizing excipients on soluble donor concentration of Sch 56592, Sch-X and Sch-Y was estimated. The transport of reference compounds and NCEs was studied across Caco-2 monolayers in absence or presence of solubilizing agents. The Caco-2 permeability of reference compounds showed good correlation with their extent of human oral absorption data. Sch 56592, Sch-X and Sch-Y exhibited high baseline Caco-2 permeability (>10(-5) cm/s). Povidone (1%) improved soluble donor concentration and flux of Sch 56592 by 40%. Other solubilizing excipients predominantly improved Sch 56592 soluble donor concentration, with either no change or a decrease in flux. With Sch-X, 1% povidone, pluronic F68, gelucir 44/14, and 3:2 propylene glycol/Tween-80 markedly improved soluble donor concentration, while increasing Sch-X flux by 40-65%. The soluble donor concentration of Sch-Y was also enhanced by excipients; however, only 1% pluronic F68 and PEG 300 increased Sch-Y flux by 35-50%. Sch 56592, Sch-X and Sch-Y are low solubility-high permeability compounds under the BCS guidance. For such poorly water-soluble NCEs, solubilizing excipients should be carefully screened based on their effects on solubility profiles and membrane transport.

Topics: Alkaloids; Biological Transport; Caco-2 Cells; Cell Membrane Permeability; Cimetidine; Diltiazem; Excipients; Furans; Humans; Hydrogen-Ion Concentration; Imidazoles; Intestinal Absorption; Naphthalenes; Phenytoin; Piperidines; Poloxamer; Polyethylene Glycols; Povidone; Propranolol; Solubility; Triazoles