Simultaneous modeling of biomarker and toxicity response predicted optimal regimen of guadecitabine (SGI-110) in myeloid malignancies

Cong Xu; Timothy K. Goggin; Xiang Yao Su; Pietro Taverna; Aram Oganesian; James N. Lowder; Mohammad Azab; Hagop Kantarjian

doi:10.1002/psp4.12248

Simultaneous modeling of biomarker and toxicity response predicted optimal regimen of guadecitabine (SGI-110) in myeloid malignancies

Cong Xu, Timothy K. Goggin, Xiang Yao Su, Pietro Taverna, Aram Oganesian, James N. Lowder, Mohammad Azab, Hagop Kantarjian

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Guadecitabine (SGI-110) is a novel next-generation hypomethylating agent (HMA) administered as s.c. injection with extended decitabine exposure. Dose/exposure-response analyses of longitudinal measures of long interspersed nucleotide element-1 (LINE-1) methylation and absolute neutrophil counts (ANC) pooled from 79 and 369 patients in 2 phase I/II trials, respectively, were performed to assist, through modeling and simulation, the selection of dosing regimens for phase III. Simulation of ANC predicted a decrease after a 5-day regimen of 60 mg/m² with partial recovery before the next cycle, whereas the nadir of 90 mg/m2 on the same schedule was below 100/μl. ANC following a 60 mg/m² 10-day regimen was predicted to be suppressed below 100/μl as long as treatment continued without recovery. The developed models provided useful tools to assist simultaneous evaluation of the relative dynamics of the two effects (DNA demethylation and the effect on ANC).

Original language	English (US)
Pages (from-to)	712-718
Number of pages	7
Journal	CPT: Pharmacometrics and Systems Pharmacology
Volume	6
Issue number	10
DOIs	https://doi.org/10.1002/psp4.12248
State	Published - Oct 2017
Externally published	Yes

ASJC Scopus subject areas

Modeling and Simulation
Pharmacology (medical)

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title = "Simultaneous modeling of biomarker and toxicity response predicted optimal regimen of guadecitabine (SGI-110) in myeloid malignancies",

abstract = "Guadecitabine (SGI-110) is a novel next-generation hypomethylating agent (HMA) administered as s.c. injection with extended decitabine exposure. Dose/exposure-response analyses of longitudinal measures of long interspersed nucleotide element-1 (LINE-1) methylation and absolute neutrophil counts (ANC) pooled from 79 and 369 patients in 2 phase I/II trials, respectively, were performed to assist, through modeling and simulation, the selection of dosing regimens for phase III. Simulation of ANC predicted a decrease after a 5-day regimen of 60 mg/m2 with partial recovery before the next cycle, whereas the nadir of 90 mg/m2 on the same schedule was below 100/μl. ANC following a 60 mg/m2 10-day regimen was predicted to be suppressed below 100/μl as long as treatment continued without recovery. The developed models provided useful tools to assist simultaneous evaluation of the relative dynamics of the two effects (DNA demethylation and the effect on ANC).",

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AU - Xu, Cong

AU - Goggin, Timothy K.

AU - Su, Xiang Yao

AU - Taverna, Pietro

AU - Oganesian, Aram

AU - Lowder, James N.

AU - Azab, Mohammad

AU - Kantarjian, Hagop

PY - 2017/10

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AB - Guadecitabine (SGI-110) is a novel next-generation hypomethylating agent (HMA) administered as s.c. injection with extended decitabine exposure. Dose/exposure-response analyses of longitudinal measures of long interspersed nucleotide element-1 (LINE-1) methylation and absolute neutrophil counts (ANC) pooled from 79 and 369 patients in 2 phase I/II trials, respectively, were performed to assist, through modeling and simulation, the selection of dosing regimens for phase III. Simulation of ANC predicted a decrease after a 5-day regimen of 60 mg/m2 with partial recovery before the next cycle, whereas the nadir of 90 mg/m2 on the same schedule was below 100/μl. ANC following a 60 mg/m2 10-day regimen was predicted to be suppressed below 100/μl as long as treatment continued without recovery. The developed models provided useful tools to assist simultaneous evaluation of the relative dynamics of the two effects (DNA demethylation and the effect on ANC).

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Simultaneous modeling of biomarker and toxicity response predicted optimal regimen of guadecitabine (SGI-110) in myeloid malignancies

Abstract

ASJC Scopus subject areas

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