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Walbi, Ismail (2014) PHARMACOKINETICS OF THE COMBINATION OF VELIPARIB AND TEMOZOLOMIDE IN LEUKEMIA. Master's Thesis, University of Pittsburgh. (Unpublished)

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As part of a phase I clinical study, we assessed the pharmacokinetic properties of the combination of veliparib and temozolomide in patients with acute leukemias. Temozolomide is an oral alkylating agent that has activity in patients with acute leukemia. Veliparib is an oral Poly ADP Ribose Polymerase (PARP1 and PARP2) inhibitor that inhibits the base excision repair (BER) system, which results in increased temozolomide tumor toxicity and apoptosis.
Methods: Plasma samples of 22 patients were collected at the University of Maryland Greenebaum Cancer Center. Adults 18 years and older with relapsed or refractory acute myeloid leukemia (AML) or pre-B- or T-cell acute lymphocytic leukemia (ALL) were enrolled in this study. The initial starting dose of temozolomide was 150 mg/m2 administered for 7 days in combination with veliparib at 20 mg twice a day. Dose escalation followed the standard 3+3 design. The temozolomide dose would be escalated to 200 mg/m2. Subsequently, only veliparib would be escalated to 40, 80, 120, and 150 mg twice daily. Veliparib administration was continued for three additional days following the last temozolomide administration. Plasma samples were collected to evaluate the PK of temozolomide alone, veliparib alone and the combination of veliparib and temozolomide. Temozolomide was quantified by HPLC-UV and veliparib by LC-MS.
Results: Veliparib decreased temozolomide peak concentration (Cmax) by 16% (P=0.015) and increased its apparent volume of distribution (Vd/F) by 17% (P=0.017). On the other hand, temozolomide increased veliparib Cmax by 33% (P=0.0002) and decreased its Cl/F by 26% (P=0.001). Veliparib exposure appears to be mostly linear with dose. Temozolomide clearance and volume of distribution in individual patients were not well-predicted by a published population pharmacokinetics model (%RMSE=96%, 110.5%), but on average were similar (%MPE = 19%, 21.7%), respectively.
Conclusion: Veliparib has a statistically significant effect on temozolomide Cmax and Cl/F, and temozolomide has a statistically significant effect on veliparib Cmax and Cl/F. The clinical relevance of these effects is likely small.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorBeumer, Janbeumerjh@upmc.eduJHB11
Committee MemberPoloyac, Samuelpoloyac@pitt.eduPOLOYAC
Committee MemberRohan,
Committee MemberFolan, Maggiefolanm@pitt.eduFOLANM
Date: 22 April 2014
Date Type: Publication
Defense Date: 3 April 2014
Approval Date: 22 April 2014
Submission Date: 22 April 2014
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 34
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords:
Date Deposited: 22 Apr 2014 17:10
Last Modified: 19 Dec 2016 14:41


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