Population modelling and simulations of binimetinib pharmacokinetics in subjects with hepatic impairment to explore optimal dosing regimen using total and unbound binimetinib exposures
Del Frari L. (1), Gosselin N. (2), Claudia Jomphe (2), JF Marier (2), Wollenberg L. (3), Reddy M. (3), Litwiler K. (3), Didier E. (1)
(1) Institut de Recherche Pierre Fabre (2) Certara Strategic Consulting (3) Array BioPharma
Objectives: Binimetinib is a potent and selective inhibitor of MEK 1 and MEK 2. Binimetinib is indicated for use in combination with encorafenib for the treatment of adult patients with unresectable or metastatic melanoma, with BRAF V600 mutation. Binimetinib is mainly eliminated through hepatic metabolism mediated by multiple enzymes. A population pharmacokinetic (popPK) modelling approach was used to identify optimal binimetinib dose and/or dosing regimens in patients with hepatic impairment (HI) based on the objective of exposure matching to non-impaired subjects. Data from a phase 1 clinical study with subjects with hepatic impairment (Study CMEK162A2104) were used.
Methods: The clinical study was a Phase 1, multicenter, open-label, single-dose study to assess the PK of binimetinib in healthy subjects with mild, moderate, and severe HI, with a normal hepatic function control group. 27 subjects were enrolled in four groups (5-6 subjects per HI group, based on Child-Pugh (CP) scores). PK samples were collected from pre-dose to 120 hours after dosing. An additional blood sample for the determination of unbound plasma concentration was collected at 1 hour after dosing. A popPK model previously developed for binimetinib [1] was used as a starting point to assess the PK of binimetinib in healthy subjects with HI. Since subjects with normal hepatic function were matched to subjects with HI with respect to their age, gender and body weight, the covariate analysis focused on the impact of HI severity. Monte Carlo simulations were performed for each HI group (250 virtual subjects per group) to explore total and unbound binimetinib exposures for the following regimens: 15 mg, 30 mg, and 45 mg twice a day (BID) as well as 15 mg three times a day (TID). Normal distribution for unbound fraction within each HI group were used to generate 250 values. Descriptive steady state statistics and box plots of simulated maximum concentration (Cmax), minimum concentration (Cmin), average concentration (Cave) and area under the concentration-time curve during 24 hours (AUC) are provided for total and unbound binimetinib.
Results: The effect of hepatic impairment on binimetinib apparent oral plasma clearance (CL/F) was evaluated based on National Cancer Institute Organ Dysfunction Working Group (NCIODWG) and CP classifications:
- Healthy subjects and subjects with mild hepatic impairment had comparable CL/F using either NCIODWG or CP classifications.
- Subjects with moderate and severe hepatic impairment had comparable CL/F. Their typical values were about half the value estimated in subjects with normal hepatic function using either NCIODWG or CP classifications.
Based upon the distribution of total binimetinib concentrations following administration of 15 mg TID or 30 mg BID, subjects with moderate and severe HI based were predicted to have similar exposures (i.e., AUC, Cmin, Cave and Cmax) relative to healthy subjects and subjects with mild HI receiving 45 mg BID. Exposure unbound metrics were also predicted to compare impaired groups with non impaired subjects. Similar results were obtained using both NCIODWG and CP classifications of hepatic impairment.
Conclusions: The proposed popPK modelling and simulations predict optimal binimetinib dose and dosing regimen in patients with various degrees of HI based upon both total and unbound binimetinib exposures. This approach can be used to support dose selection in the patient population with unresectable or metastatic melanoma, with BRAF V600 mutation.
References:
[1] Wollenberg L. et al Abstracts for the Ninth American Conference on Pharmacometrics (ACoP9) J Pharmacokinet Pharmacodyn (2018) 45(Suppl 1): 3.Abstract T051(https://doi.org/10.1007/s10928-018-9606-9)