A Randomized, Double‐Blind, Placebo‐ and Positive‐Controlled, Three‐Way Crossover Study in Healthy Participants to Investigate the Effect of Savolitinib on the QTc Interval

Abstract

Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, bioavailable, selective MET-tyrosine kinase inhibitor. This randomized, double-blind, 3-way, crossover phase 1 study of savolitinib versus moxifloxacin (positive control) and placeboevaluated effects on the QT interval after a single savolitinib dose. Healthy non-Japanese men were randomized to 1 of 6 treatment sequences, receiving single doses of savolitinib 600 mg, moxifloxacin 400 mg, and placebo. The primary end point was time-matched, placebo-adjusted change from baseline in the QT interval corrected for the time between corresponding points on 2 consecutive R waves on electrocardiogram (RR) by the Fridericia formula ( QTcF). Secondary end points included 12-lead electrocardiogram (ECG) variables, pharmacokinetics, and safety. All 3 treatment periods were completed by 44 of 45 participants (98%). Baseline demographics were balanced across treatment groups. After a single savolitinib 600-mg dose, the highest least-squares mean QTcF of 12 milliseconds was observed 5 hours postdose. Upper limits of the 2-sided 90% confidence interval for QTcF exceeded 10 milliseconds (the prespecified International Council for Harmonisation limit) 3-6 hours postsavolitinib but otherwise remained less than the threshold. Savolitinib showed no additional effect on PR, QRS, QT, or RR intervals. A positive QTcF signal from the moxifloxacin group confirmed study validity. Savolitinib was well tolerated, with a low incidence of adverse events. In this thorough QT/QTc study, QTcF prolongation was observed with a single savolitinib 600-mg dose. ECG monitoring will be implemented in ongoing and future studies of savolitinib to assess the clinical relevance of the observed QT changes from this study.

Clinical evaluation of the potential drug–drug interactions of savolitinib: Interaction with rifampicin, itraconazole, famotidine or midazolam

“…When midazolam was dosed in combination with savolitinib compared with midazolam alone, PK parameters ( C max , AUC and AUC [0‐ t ] ) were similar, with all 90% CIs encompassing unity. The PK exposure of savolitinib (in combination with midazolam) in the midazolam study (Table 2) was similar to the exposure of savolitinib observed in the famotidine or rifampicin studies when dosed alone; furthermore, the ranges in exposure appear to overlap compared to previous studies, even though the mean exposure is slightly lower 6,8 . Moreover, the metabolite‐to‐parent ratios for both M2 and M3 were similar across these studies, indicating that their contribution to the interaction has also been evaluated; this suggests that the exposure of savolitinib and its metabolites, M2 and M3, was sufficient to evaluate the effect on midazolam in this study.…”

“…The PK exposure of savolitinib (in combination with midazolam) in the midazolam study (Table 2 ) was similar to the exposure of savolitinib observed in the famotidine or rifampicin studies when dosed alone; furthermore, the ranges in exposure appear to overlap compared to previous studies, even though the mean exposure is slightly lower. 6 , 8 Moreover, the metabolite‐to‐parent ratios for both M2 and M3 were similar across these studies, indicating that their contribution to the interaction has also been evaluated; this suggests that the exposure of savolitinib and its metabolites, M2 and M3, was sufficient to evaluate the effect on midazolam in this study. Our results indicate that co‐administration of midazolam with savolitinib has no effect on midazolam PK and thereby, on the CYP3A4 pathway.…”

“…F I G U R E 2 Geometric mean (± gSD) savolitinib plasma concentration-time profiles for (A) savolitinib ± rifampicin, (B) savolitinib ± itraconazole (C) savolitinib ± famotidine and (D) midazolam plasma-time profile for midazolam ± savolitinib (semilogarithmic scale; pharmacokinetic analysis set) lower. 6,8 Moreover, the metabolite-to-parent ratios for both M2 and M3 were similar across these studies, indicating that their contribution to the interaction has also been evaluated; this suggests that the exposure of savolitinib and its metabolites, M2 and M3, was sufficient to evaluate the effect on midazolam in this study. Our results indicate that co-administration of midazolam with savolitinib has no effect on midazolam PK and thereby, on the CYP3A4 pathway.…”

“…lower. 6,8 Moreover, the metabolite-to-parent ratios for both M2 and M3 were similar across these studies, indicating that their contribution to the interaction has also been evaluated; this suggests that the exposure of savolitinib and its metabolites, M2 and M3, was sufficient to evaluate the effect on midazolam in this study. Our results indicate that co-administration of midazolam with savolitinib has no effect on midazolam PK and thereby, on the CYP3A4 pathway.…”

“…The apparent terminal half‐life ( t ½λ z ) is short (ranges from 3.8–6.8 h; dose ranges from 100–1000 mg QD and 300–500 mg twice daily [BD]) and, as a result, there is no accumulation of savolitinib after QD or BD dosing 6 . In previous studies, the mean plasma exposure of the pharmacologically active metabolite, M2 (N‐desmethyl savolitinib), and a non‐pharmacologically active metabolite, M3 (hydroxy savolitinib), was approximately 21–38% and 10–13% of the exposure of savolitinib, respectively (based on AUC from time 0–48 h after a single dose of savolitinib 7,8 ). The recommended Phase 2 dose of savolitinib monotherapy was established as 600 mg QD.…”