164: No Clinically Relevant Effect of Moderate Hepatic Impairment on the Pharmacokinetics of Lirafugratinib

Statement of Purpose, Innovation or Hypothesis: Lirafugratinib (RLY-4008) is a potent and selective irreversible inhibitor of fibroblast growth factor receptor 2 (FGFR2). It is being developed by Relay Therapeutics for the treatment of FGFR2-driven cancers. Hepatic impairment (HI) can significantly influence drug pharmacokinetics (PK). This study was conducted to characterize the effect of moderate HI on the PK of lirafugratinib to provide dosing guidance of lirafugratinib in patients with HI.

Description of Methods & Materials: Participants with a Child-Pugh category of moderate HI and matched participants with normal hepatic function (matched control) were enrolled and evaluated. A single oral dose of 30 mg lirafugratinib was administered fasted to participants followed by PK assessments through 120 hours postdose. Plasma protein binding of lirafugratinib was also assessed at 2 and 24 h postdose. Concentrations of lirafugratinib in plasma were measured by a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay. Total and unbound PK parameters were calculated using Phoenix® WinNonlin®, and the geometric least squares mean ratios (LSGMRs) and corresponding 90% confidence intervals of C_max and AUC_0-inf (total and unbound) were estimated.

Data & Results: Sixteen participants with either moderate HI as defined by Child-Pugh (n=8) or normal hepatic function (n=8) were enrolled and completed the study. Total lirafugratinib PK was similar in participants with moderate HI and matched control (Figure 1).  The LSGMRs (90% CI) for total C_max and AUC_0-inf of lirafugratinib were 94.5% (68.2 – 131%) and 105% (81.2-135%), respectively, between participants with moderate HI and matched control. Lirafugratinib was highly bound to plasma proteins in a concentration-independent manner and the unbound fraction (f_u) was slightly higher in participants with moderate HI compared to matched controls (0.000885 versus 0.000665). As a result, the unbound PK exposures (AUC and C_max) were slightly higher for the participants with moderate HI compared to matched controls. The LSGMRs (90% CI) for C_max,u and AUC_0-inf,u of lirafugratinib were 126% (94.2 -168%) and 139% (109 – 177%), respectively, between participants with moderate HI and matched controls. This slightly higher unbound exposures are considered unlikely to be clinically relevant. There did not appear to be any notable differences in lirafugratinib PK among participants with normal, mild, moderate, and severe HI as defined by the National Cancer Institute-Organ Dysfunction Working Group (NCI-ODWG) criteria. A single 30 mg dose of lirafugratinib was safe and well tolerated in participants with HI and matched controls.

Interpretation, Conclusion or Significance: Lirafugratinib PK were similar between participants with moderate HI and matched controls. These data support that dose adjustment of lirafugratinib would not be needed in patients with moderate HI.

Disclosures: XL, RS, GS, FRa, KYJ, EK, FRi, and JS declare employment with and ownership interest in Relay Therapeutics. EL declares study support from Relay Therapeutics.

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