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Eur J Cancer. 2013 Sep;49(13):2791-7. doi: 10.1016/j.ejca.2013.05.009. Epub 2013 Jun 18.

Pharmacokinetic/pharmacodynamic modelling-based optimisation of administration schedule for the histone deacetylase inhibitor abexinostat (S78454/PCI-24781) in phase I.

Author information

1
Institut de Recherches Internationales Servier, Clinical Pharmacokinetics, Suresnes, France.

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.

KEYWORDS:

Decision support techniques; Drug administration schedule Drug toxicity; Mechanism of action; Pharmacodynamics; Pharmacokinetics

PMID:
23790467
DOI:
10.1016/j.ejca.2013.05.009
[Indexed for MEDLINE]

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