Population pharmacokinetics and exposure–response assessment of veliparib co-administered with temozolomide in patients with myeloid leukemias

on behalf of the ETCTN-6745 study team

Research output: Contribution to journalArticle

Abstract

Purpose: Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design. Methods: Population pharmacokinetic analysis was performed using Phoenix® NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CLCR), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival. Results: A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CLCR and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure. Conclusions: Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure–safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure–efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit–risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.

Original languageEnglish (US)
JournalCancer Chemotherapy and Pharmacology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

temozolomide
Myeloid Leukemia
Pharmacokinetics
Population
Mucositis
Acute Myeloid Leukemia
veliparib
Survival Rate

Keywords

  • Exposure-response
  • Pharmacometrics
  • Temozolomide
  • Veliparib

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

@article{d5f13eacca074feca427f54c35d7d35a,
title = "Population pharmacokinetics and exposure–response assessment of veliparib co-administered with temozolomide in patients with myeloid leukemias",
abstract = "Purpose: Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design. Methods: Population pharmacokinetic analysis was performed using Phoenix{\circledR} NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CLCR), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival. Results: A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CLCR and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure. Conclusions: Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure–safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure–efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit–risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.",
keywords = "Exposure-response, Pharmacometrics, Temozolomide, Veliparib",
author = "{on behalf of the ETCTN-6745 study team} and Renu Singh and Shailly Mehrotra and Mathangi Gopalakrishnan and Ivana Gojo and Judith Karp and Greer, {Jacqueline M.} and Alice Chen and Richard Piekarz and Kiesel, {Brian F.} and Jogarao Gobburu and Michelle Rudek-Renaut and Beumer, {Jan H.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1007/s00280-018-3731-4",
language = "English (US)",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",

}

TY - JOUR

T1 - Population pharmacokinetics and exposure–response assessment of veliparib co-administered with temozolomide in patients with myeloid leukemias

AU - on behalf of the ETCTN-6745 study team

AU - Singh, Renu

AU - Mehrotra, Shailly

AU - Gopalakrishnan, Mathangi

AU - Gojo, Ivana

AU - Karp, Judith

AU - Greer, Jacqueline M.

AU - Chen, Alice

AU - Piekarz, Richard

AU - Kiesel, Brian F.

AU - Gobburu, Jogarao

AU - Rudek-Renaut, Michelle

AU - Beumer, Jan H.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Purpose: Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design. Methods: Population pharmacokinetic analysis was performed using Phoenix® NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CLCR), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival. Results: A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CLCR and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure. Conclusions: Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure–safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure–efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit–risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.

AB - Purpose: Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design. Methods: Population pharmacokinetic analysis was performed using Phoenix® NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CLCR), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival. Results: A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CLCR and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure. Conclusions: Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure–safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure–efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit–risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.

KW - Exposure-response

KW - Pharmacometrics

KW - Temozolomide

KW - Veliparib

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U2 - 10.1007/s00280-018-3731-4

DO - 10.1007/s00280-018-3731-4

M3 - Article

C2 - 30456480

AN - SCOPUS:85056868514

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

ER -