A drug interaction study between dextromethorphan and panobinostat (LBH589), an orally active deacetylase inhibitor, in patients with advanced cancer.

Abstract

e13089 Background: Panobinostat (PAN; LBH589) has been found to inhibit CYP2D6 in vitro. It was hypothesized that PAN may inhibit the metabolic clearance of comedications metabolized by CYP2D6 in patients (pts). A crossover study was designed to assess the inhibitory effect of PAN on the disposition of dextromethorphan (DM, a sensitive CYP2D6 substrate) in pts with advanced cancer. Methods: Pts with advanced solid tumors with adequate organ function and ECOG PS ≤2 received single-agent DM 60 mg po on Day (D) 1 and PAN at 20 mg/day po on Days 3, 5, and 8. On D 8, the second DM dose was administered 1 hr after PAN dose. Prior to drug administration, genotyping analysis of CYP2D6 gene was performed using AmpliChipCYP450 in consenting pts. Serial plasma samples were collected for DM pharmacokinetic (PK) evaluations on D 1 and 8. Plasma concentrations of DM and its metabolite dextromethorphan (DX) were measured by LC-MS-MS. PK parameters were estimated by using non-compartmental analysis. Results: 17 pts were enrolled with median age 67 years (range 47–74). 14 pts were evaluable for DM PK on D 1 and 8, of whom 13 pts were classified as extensive or intermediate metabolizers (EM or IM) of CYP2D6 by genotyping method, and 1 pt was classified as EM by metabolic ratio DM/DX. DM PK parameters are expressed as either mean (CV%), median (range) or ratio (see Table). Coadministration of PAN and DM increased DM Cmax and AUC by 1.8- and 1.6-fold, respectively, but with no change in Tmax. Conclusions: The observed increase in DM AUC upon coadministration with PAN in nonpoor CYP2D6 metabolizers is most probably a result of CYP2D6 inhibition by PAN. However, the less than 2-fold increase in DM exposure suggests PAN has a weak CYP2D6 inhibition potential on a sensitive CYP2D6 substrate. It is concluded that clinically relevant interactions between PAN and CYP2D6 substrates may occur only in medications that are sensitive CYP2D6 substrates, which also have a narrow therapeutic index. D 1 DM alone D 8 PAN + DM N 14 14 Tmax (hr) 1 (0.5–4) 1 (0.5–6) Cmax (ng/mL) 13 (151%) 17 (121%) AUC0-inf (ng*hr/mL) 188 (170%) 157 (138%) Comparison geometric mean ratio with (90% CI) - Combo/PAN Cmax ratio - 1.8 (1.4–2.3) AUC ratio 1.6 (1.2–2.3) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis