Bioavailability of everolimus administered as a single 5 mg tablet versus five 1 mg tablets: a randomized, open-label, two-way crossover study of healthy volunteers

Abstract

BackgroundThe mammalian target of rapamycin (mTOR) inhibitor everolimus has a well-established pharmacokinetics profile. We conducted a randomized, single-center, open-label, two-sequence, two-period crossover study of healthy volunteers to assess the relative bioavailability of everolimus administered as one 5 mg tablet or five 1 mg tablets.MethodsSubjects were randomized 1:1 to receive everolimus dosed as one 5 mg tablet or as five 1 mg tablets on day 1, followed by a washout period on days 8–14 and then the opposite formulation on day 15. Blood sampling for pharmacokinetic evaluation was performed at prespecified time points, with 17 samples taken for each treatment period. Primary variables for evaluation of relative bioavailability were area under the concentration–time curve from time zero to infinity (AUCinf) and maximum blood concentration (Cmax). Safety was assessed by reporting the incidence of adverse events (AEs).ResultsTwenty-two participants received everolimus as one 5 mg tablet followed by five 1 mg tablets (n=11) or the opposite sequence (n=11). The Cmax of five 1 mg tablets was 48% higher than that of one 5 mg tablet (geometric mean ratio, 1.48; 90% confidence interval [CI], 1.35–1.62). AUCinf was similar (geometric mean ratio, 1.08; 90% CI, 1.02–1.16), as were the extent of absorption and the distribution and elimination kinetics. AEs, all grade 1 or 2, were observed in 54.5% of subjects.ConclusionAlthough the extent of absorption was similar, the Cmax of five 1 mg tablets was higher than that of one 5 mg tablet, suggesting these formulations lead to different peak blood concentrations and are not interchangeable at the dose tested.

Anti-proliferative and anti-secretory effects of everolimus on human pancreatic neuroendocrine tumors primary cultures: is there any benefit from combination with somatostatin analogs?

“…We then tested the effect of 1nM everolimus during 72h, in the primary cultures from 22 pNETs. This concentration is approximately the blood concentration of everolimus (range 2.7-95 nM) measured after 24h treatment of patients with 5-10mg per day [ 23 , 24 ]. Everolimus decreased viable cell number from 14 % to 77 % of control value in 20 primary cultures (Figure 1B ) with a median value of 59.3% (Figure 1C ).…”