4.Disscusion
Since the usage of PPI is associated with decreased TKI efficacy, prescribers are posed with a great dilemma whether or not to continue the combined treatment. To our knowledge, this is the first study to assess the PK and safety effects of omeprazole on the potent MKI famitinib as well as its major metabolite SHR116637 in healthy subjects. Our findings suggested that omeprazole did not significantly impact the PK properties of both famitinib and SHR116637, demonstrating good safety on co-administration.
Key factors in the design of a pH-dependent DDI study include study population, selection of ARAs, type of crossover design (randomized or single-sequence), and the dose/dosing regimen etc5. Previous clinical trials have demonstrated that famitinib showed linear dose-related pharmacokinetic characteristics in the dosing range of 4-27 mg. The recommended dose for phase II clinical trials is 25 mg. Hence, for the safety evaluation, the dose of famitinib was selected to be 25 mg. The main PK parameters were similar in terms of C max,AUC and t 1/2 between the patients with advanced solid cancer and healthy subjects. Food intake was unlikely to impact on the PK of famitinib9. Ideally, the DDI results obtained in this study under fasting condition can help guide cancer patients’ treatment. Furthermore, Multiple enzymes, mainly CYP3A4/5 and CYP1A1/2, are involved in famitinib metabolic clearance. And it is also a weak inhibitor of CYP3A4, in vitro study, however, it’s unlikely to affect CYP3A4 due to a single dose of famitinib at 25 mg. As a result, omeprazole was chosen for the DDI study, it gives its high affinity for CYP2C19 and moderate affinity for CYP3A, which could show little influence to the systemic exposure of famitinib and SHR116637. And a self-control study was also used to overcome the influence of enzyme differences between individuals.
Compared with famitinib single-dose administration, the geometric mean of AUC 0-∞ was slightly reduced when famitinib was co-administered with omeprazole (1417.927 vs. 1351.939 h·ng/mL, decreased by approximately 4.7%), along with theC max, T max,t 1/2, CL/F and Vz/F did not significantly differ between the two phases. The least squares GMRs ofC max, AUC 0-t andAUC 0-∞ (90% CIs) of famitinib combined with omeprazole to famitinib alone were 0.989 (0.953, 1.027), 0.956 (0.907, 1.007) and 0.953 (0.905, 1.005) respectively, indicating the absence of significant differences inAUC 0-t, AUC 0-∞ andC max of famitinib when compared with famitinib alone. The metabolite SHR116637 data was consistent with the reduced absorption famitinib, and the metabolic ratio remained similarly small for both treatment arms with 0.075 versus 0.081 for famitinib and famitinib plus omeprazole, respectively. The medianT max of famitinib metabolite SHR116637 was 5.00 h and 6.50 h, indicating that the peak time of famitinib metabolite SHR116637 was slightly prolonged after omeprazole combined with famitinib. The C max,AUC 0-t and AUC 0-∞decreased by 14.9%, 11.0% and 11.3% for famitinib and famitinib plus omeprazole, respectively. The least squares GMRs ofC max, AUC 0-t andAUC 0-∞ (90% CIs) of SHR116637 between coadministration group and alone group were 0.851 (0.786, 0.920), 0.890 (0.838, 0.946)and 0.887 (0.835, 0.943) respectively. Except the lower limit for the SHR116637 GMR of C max (90% CIs) is 78.6%, the least squares GMRs of AUC 0-t,AUC 0-∞ and C max (90% CIs) of both famitinib and SHR116637 are all in the range of 80%-125%. Compared the “no concomitant PPIs” versus “concomitant PPIs” based on their clinical characteristics, the exposure of metabolite SHR116637 is approximately equivalent to 9.47% and 8.72% of that of the parent drug, so it has little effect on the PK of famitinib. In general, there was no significant difference in the exposure, absorption, distribution or elimination of famitinib, indicating that omeprazole did not have a significant influence upon the PK parameters of famitinib.
According to one completed phase-I clinical trial, the most common AEs of famitinib included neutrocytopenia, thrombocytopenia, diarrhea, fatigue and peripheral edema. In some cases, it can also result in elevation of blood lipids and glucose9,21. In our study, we also assessed the safety profile of combination therapy in the present study, compared with the above AEs, most AEs observed in the present study was mild or moderate, such as increased gamma-glutamyl transferase, increased basophil count, increased heart rate, alanine aminotransferase, blood glucose increased, blood triglycerides elevated, the positive urine test for leukocyte-esterase and sugar. During the treatment period, a total of 6 (30.0%) subjects had 9 AEs during famitinib alone, and 1 (5.0%) subject had 1 AE during the mutiple dose of omeprazole, while 5 (25.0%) subjects had 6 AEs during famitinib combined with omeprazole. Less severe and less frequent side effects were noted after the co-administration of omeprazole and famitinib compared with the single phase of famitinib, revealing the safety and tolerability of famitinib and omeprazole coadministration in clinical settings. Co-administration of famitinib and omeprazole was associated with good safety.
In this single-center, open, single-dose and self-control study, use of a PPI may be considered a worst-case scenario in the in vivoevaluation of the pH effect. If a PPI does not result in any clinically relevant effect on the absorption of a weak base drug, further dedicated DDI studies with other classes of ARAs may not be necessary. The common dose of omeprazole is 20 mg qd, which can achieve maximum suppression of gastric acid within ~ 4 days, and the expected effect of a 40-mg dose follows a similar time-course24. Therefore, 40 mg of omeprazole was administered for 5 consecutive days in our study, and a second dose of famitinib was administered 5 days after omeprazole administration to ensure that subjects achieved maximum inhibition of gastric-acid secretion.