Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101)

Steele, N.L., Plumb, J.A., Vidal, L., Tjørnelund, J., Knoblauch, P., Buhl-Jensen, P., Molife, R., Brown, R., de Bono, J. S. and Evans, T.R.J. (2011) Pharmacokinetic and pharmacodynamic properties of an oral formulation of the histone deacetylase inhibitor Belinostat (PXD101). Cancer Chemotherapy and Pharmacology, 67(6), pp. 1273-1279. (doi: 10.1007/s00280-010-1419-5)

Abstract

The primary objective of this sub-study, undertaken as an extension to the previously reported phase-I study, was to explore the feasibility, tolerability and pharmacokinetics (PK) of belinostat when administered by the oral route. Preliminary pharmacodynamic (PD) studies were also performed to enable comparison of the biological effects of the oral and intravenous formulations. Oral belinostat was administered in a range of doses and schedules (once, twice or thrice daily), on either day 1 or days 1-5, of the second or a subsequent treatment cycle in 15 patients who were included in the phase-I trial of intravenous belinostat. Serial blood samples were collected for PK and PD (histone acetylation) analyses, and the results compared with corresponding analyses following intravenous administration. A total mean daily AUC of 2,767 +/- A 1,453 ng h/ml (8.7 +/- A 4.6 mu M h) resulted from a dose of 1,000 mg/m(2) once daily (qd). There was no clear evidence of drug accumulation on twice daily dosing (bid); however, a trend towards accumulation was apparent when belinostat was given three times daily (tid). Mean half-life (TA1/2) of a single dose of 1,000 mg/m(2) was 1.5 h (+/- 0.3 h) and peak levels were reached in an average of 1.9 h (+/- 0.3 h). The half-life was found to be independent of dose, but a trend towards increasing half-life following multiple dosing was observed. Histone H4 hyperacetylation in PBMCs estimated after oral dosing was comparable to that achieved after intravenous administration. High doses of oral belinostat, up to 1,000 mg/m(2) bid for 5 consecutive days, have been tolerated in this small study. An oral formulation could lead to enhanced drug exposure and, more importantly, prolonged effects on the intended drug target. Future trials are required to establish the optimal dose and schedule of oral administration of belinostat

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Plumb, Dr Jane and Evans, Professor Jeff and Brown, Prof Robert
• Authors: Steele, N.L., Plumb, J.A., Vidal, L., Tjørnelund, J., Knoblauch, P., Buhl-Jensen, P., Molife, R., Brown, R., de Bono, J. S., and Evans, T.R.J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Chemotherapy and Pharmacology
• ISSN: 0344-5704