title: Pharmacokinetic/pharmacodynamic modelling-based optimisation of administration schedule for the histone deacetylase inhibitor abexinostat (S78454/PCI-24781) in phase I.
abstract: Abexinostat, an oral pan-histone deacetylase inhibitor (HDACi), was evaluated in patients with advanced solid tumours in two single agent phase I studies (PCYC-402 and CL1-78454-002). In PCYC-402 study testing four different administration schedules, the maximum tolerated dose (MTD) was established at 75 mg/m(2) BID (twice daily) and the recommended dose at 60 mg/m(2) BID regardless of the schedule tested. The dose limiting toxicity (DLT), consistently observed across all these schedules, was reversible thrombocytopenia. The CL1-78454-002 study was initially investigating an additional schedule of 14 days on/7 days off. While testing two first cohorts, thrombocytopenia was observed without reaching DLT. To address this issue, a pharmacokinetic/pharmacodynamic (PK/PD) model was used to predict the optimal schedule allowing higher doses with minimal thrombocytopenia. Several administration schedules were simulated using this model. A 4 days on/3 days off schedule was associated with the smallest platelet decrease. Accordingly, the CL1-78454-002 study was amended. After reaching MTD1 (75 mg/m(2) BID) with the initial schedule, subsequent cohorts received abexinostat on a revised schedule of 4 days on/3 days off, starting at one dose level below MTD1 (60 mg/m(2) BID). As expected, the dose-escalation continued for two more dose levels beyond MTD1. The MTD2 reached for this optimised schedule was 105 mg/m(2) BID and the recommended dose 90 mg/m(2) BID. In conclusion, early understanding of toxicities and PK determination allowed us to build a PK/PD model of thrombocytopenia, which predicted the optimal administration schedule. This optimised schedule is currently used in the trials in solid tumours with abexinostat.
authors.affiliation: Institut de Recherches Internationales Servier, Clinical Pharmacokinetics, Suresnes, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Fouliard
authors.forename: Renata
authors.initials: R
authors.lastname: Robert
authors.forename: Anne
authors.initials: A
authors.lastname: Jacquet-Bescond
authors.forename: Quentin Chalret
authors.initials: QC
authors.lastname: du Rieu
authors.forename: Sriram
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: David
authors.initials: D
authors.lastname: Loury
authors.forename: Yohann
authors.initials: Y
authors.lastname: Loriot
authors.forename: Antoine
authors.initials: A
authors.lastname: Hollebecque
authors.forename: Ioana
authors.initials: I
authors.lastname: Kloos
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Marylore
authors.initials: M
authors.lastname: Chenel
authors.forename: Stéphane
authors.initials: S
authors.lastname: Depil
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D001572:Benzofurans / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005602:France; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D020714:Maximum Tolerated Dose; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010976:Platelet Count; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced
chemical_list: D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C512352:abexinostat
keywords: Decision support techniques; Drug administration schedule Drug toxicity; Mechanism of action; Pharmacodynamics; Pharmacokinetics