Abstract CT123: Population pharmacokinetics of ripretinib in patients with advanced malignancies
Authors: George Suzanne , Janku Filip , Chi Ping , von Mehren Margaret , Somaiah Neeta , Gelderblom Hans , Jones Robin L. , Allard Martine , Taylor Adekemi , Li Xiaoyan , Meade Julie , Reichert Vienna , Ruiz-Soto Rodrigo , Wang Jing , Heinrich Michael C. 
Published: July 2021

Ripretinib is a tyrosine kinase inhibitor (TKI) indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib. In a phase 1 study (NCT02571036), the maximum tolerated dose was not reached at doses up to 200 mg twice daily (BID). Ripretinib 150 mg BID intrapatient dose escalation regimen was offered to patients in the phase 1 and 3 trials (INVICTUS, NCT03353753) after radiologic progression at 150 mg once daily (QD). The BID dose was well tolerated with a similar safety profile to the 150 mg QD (approved dose regimen). In this analysis, the population pharmacokinetics (popPK) of ripretinib and DP-5439, a metabolite TKI with in vitro activity and exposure similar to ripretinib, were characterized and potential covariates influencing exposure were evaluated. The popPK models were developed for ripretinib and DP-5439 using 5284 and 5160 quantifiable concentrations, respectively, from 350 patients pooled from the phase 1 and INVICTUS phase 3 studies. Models were estimated using first-order conditional estimation with interaction method in NONMEM® (version 7.3; ICON, Hanover, MD, USA) and evaluated based on standard goodness-of-fit metrics. A covariate analysis was conducted to assess the sources of variability in ripretinib pharmacokinetics (PK) using a full model approach with backward elimination (significance level = 0.005). Tested covariates included age, body weight, sex, race, tumor type, prior gastrectomy, and mild hepatic impairment and mild to moderate renal impairment. Ripretinib oral PK was well described by a 2-compartment model with zero-order drug release at the absorption site followed by first-order absorption with a modest, linear dose-dependent decrease in relative bioavailability and linear elimination. A high-fat meal was predicted to increase the ripretinib AUC by 36% at 150 mg QD relative to the fasted state. The only covariate effect retained in the final popPK model for ripretinib was 29% lower apparent clearance in females compared with males, resulting in a 40% higher AUC in females. No other covariates were identified for ripretinib. The resulting effect on DP-5439 was similar. PK exposure in patients with mild hepatic impairment or mild to moderate renal impairment was similar to that in patients with normal organ function. There were no clinically meaningful differences in the PK of ripretinib based on age, race, body weight, or tumor type. Based on the safety profile of ripretinib observed in patients with advanced GIST and PK variability, the effects of sex, fasted state, and prior gastrectomy on ripretinib PK were not considered clinically significant. Therefore, ripretinib can be taken with or without food by all patients and no dose adjustment is recommended for patients with mild hepatic impairment or patients with mild to moderate renal impairment.

Citation Format: Suzanne George, Filip Janku, Ping Chi, Margaret von Mehren, Neeta Somaiah, Hans Gelderblom, Robin L. Jones, Martine Allard, Adekemi Taylor, Xiaoyan Li, Julie Meade, Vienna Reichert, Rodrigo Ruiz-Soto, Jing Wang, Michael C. Heinrich. Population pharmacokinetics of ripretinib in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT123.