Preliminary population pharmacokinetic (popPK) co-variates and exposure response (ER) assessment of QT for RP-3500, a highly potent and specific inhibitor of ataxia telangiectasia and Rad3-related (ATR) protein kinase
Lee, E Yap, T Fontana, E. Rosen, E Spigel, D Lheureux, S Mettu, N Carter, Louise Plummer, R Patel, S
Lee, E
Yap, T
Fontana, E.
Rosen, E
Spigel, D
Lheureux, S
Mettu, N
Carter, Louise
Plummer, R
Patel, S
Citations
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Abstract
"Background: RP-3500 is an oral inhibitor of ATR (ATRi) in development for the
treatment of patients (pts) with advanced solid tumors carrying alterations in ATRi sensitizing genes. We report popPK co-variates and effect on QT prolongation in 120
pts treated with RP-3500 in the phase 1 TRESR study (NCT04497116).
Methods: PK samples were collected from 120 pts on multiple days across doses and
schedules during the dose-finding portion of the study. Pt demographics and baseline
characteristics were collected at study enrollment. Triplicate electrocardiograms
(ECGs) were collected prior to any drug administration and in conjunction with PK
sampling at time points up to 4 hr post-RP-3500 dose. A popPK model was developed
using Phoenix WinNonLin. PK co-variates were analyzed to assess the effect of age sex, body weight (BW), body surface area (BSA), and renal/hepatic function on
RP-3500 PK. Changes in ECG parameters were evaluated in an ER assessment.
Results: Plasma PK samples (N¼2627) from 120 pts were analyzed; 85 pts were
sampled on at least 3 different days. The PK data set encompassed an RP-3500 dose
range of 5e200 mg QD and BID across 2 different weekly regimens: 5 days on/2 days
off, 3 days on/4 days off. RP-3500 PK was well described using a 2-compartment
model with a lag-time incorporated to accurately describe drug absorption. Pre liminary co-variate analysis suggested some variation in RP-3500 PK according to BW
and BSA. There was no significant impact on PK values in patients with mild renal or
hepatic impairment. Among patients with moderate renal impairment, a small
reduction in clearance was observed with limited impact on other compartmental PK
values. Results of the initial ER assessment showed no RP-3500-related changes in QT
intervals.
Conclusions: These popPK results from TRESR confirm a predictable RP-3500 PK
profile with low variability. Importantly, the data indicate that RP-3500-induced
changes in QT are unlikely, and strongly support further clinical development of
RP-3500 with limited ECG evaluation. Further investigation into the potential need for
moderate renal impairment-, BW- or BSA-adjusted RP-3500 dosing is ongoing."
Description
Date
2022
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Lee, E, Yap, T. A, Fontana, E, Rosen, E, Spigel, D, Lheureux, S, Mettu, N B, Carter, Louise, Plummer, R Patel, S, McDougall, R, Papp, R, May, SPreliminary population pharmacokinetic (popPK) co-variates and exposure response (ER) assessment of QT for RP-3500, a highly potent and specific inhibitor of ataxia telangiectasia and Rad3-related (ATR) protein kinase. Annals of Oncology. 2022 , Nejad, P, Ulanet, D, Wainszelbaum, M, Manley, P., Koehler, M, Fretland, A J, Hojgaard, M.