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    Pharmacokinetic (PK) profile and food effect of RP-3500, a highly potent and specific inhibitor of ataxia telangiectasia and Rad3-related (ATR) protein kinase in patients (pts) with cancer

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    Authors
    Lheureux, S
    Rosen, E
    Lee, E
    Spigel, D
    Hojgaard, M
    Fontana, E.
    Mettu, N B
    Carter, Louise
    Patel, S
    Papp, R
    May, S
    Nejad, P
    Ulanet, D
    Wainszelbaum, M
    Manley, P
    Koehler, M
    Fretland, A J
    Plummer, R
    Yap, T A
    Show allShow less
    Affiliation
    Repare Therapeutics, Cambridge, MA, USA
    Issue Date
    2022
    
    Metadata
    Show full item record
    Abstract
    "Background: RP-3500 is an oral ATR inhibitor (ATRi) in development for the treatment of patients (pts) with advanced solid tumors carrying alterations in ATRi-sensitizing genes. The dose-escalation portion of the TRESR study (NCT04497116) evaluated RP-3500 5e200 mg once daily (QD) or twice daily at defined intermittent schedules in 120 pts. Methods: RP-3500 plasma levels were assessed and PK parameters were determined by non-compartmental analysis (Phoenix WinNonLin) in pts with evaluable plasma concentration-time points. To determine the effect of food on RP-3500 PK, 12 pts received a single dose of RP-3500 following a standard high-fat meal on Day -3 and after a 24-hr fast on Day 1. Serial blood samples were collected for PK analysis at baseline and after RP-3500 administration. Results: 120 pts had sufficient data on day 1, cycle 1, to report PK parameters. Overall, 323 plasma concentration-time profiles were collected. Plasma exposure was dose-linear with low within-pt variability and a T½ of w6 hr. No accumulation of RP-3500 was observed after multiple doses were given. At therapeutic doses of 120 mg and 160 mg QD on day 1, cycle 1, mean AUC0-24 was 33.6 and 48.2 mg٠hr/mL, respectively, and mean Cmax was 5.74 and 7.64 mg/mL, respectively. Within the therapeutic dose range, median Tmax was 2 hr (range 0.5e6). When administered with a high fat meal, RP-3500 median Tmax was delayed by 3 hrs and mean Cmax was reduced by 45% compared with fasting values within this cohort. Mean AUC0-24 was 16% lower compared with AUC0-24 in the fasted state. Importantly, the plasma levels required for the pharmacological activity of RP-3500 did not substantially differ between the fed and fasted states. Conclusions: The PK profile of RP-3500 is predictable with low observed variability. RP-3500 given orally to pts at recommended doses of 120-160 mg QD on 3 days/ week, with or without food, reaches or exceeds preclinically defined target exposure requirements (Roulston et al., Mol Cancer Ther. 2021). RP-3500 can be administered with or without food without affecting PK parameters relevant to tolerability and therapeutic window."
    Citation
    Lheureux, S, Rosen, E, Lee, E, Spigel, D, Hojgaard, M, Fontana, E, Mettu, N B, Carter, Louise, Patel, S, Papp, R, May, S, Nejad, P, Ulanet, D, Wainszelbaum, M, Manley, P, Koehler, M, Fretland, A. J, Plummer, R Yap, T A. Pharmacokinetic (PK) profile and food effect of RP-3500, a highly potent and specific inhibitor of ataxia telangiectasia and Rad3-related (ATR) protein kinase in patients (pts) with cancer . Annals of Oncology . 2022
    Journal
    Annals of Oncology
    URI
    http://hdl.handle.net/10541/625197
    DOI
    10.1016/j.annonc.2022.01.071
    Additional Links
    https://dx.doi.org/10.1016/j.annonc.2022.01.071
    Type
    Meetings and Proceedings
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.annonc.2022.01.071
    Scopus Count
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