Study design
This was a single-center, single-oral dose, randomized, open-label, three-step, 2 x 2 crossover phase 1 study conducted in 20 healthy adults between February and May 2017 in Japan (Figure 2). The study protocol and the informed consent form were approved by the institutional review board of Hakata Clinic. All participants gave written informed consent before initiation of any study-specific procedures. The study was conducted in accordance with the ethical principles originating in or derived from the Declaration of Helsinki, and Good Clinical Practice guidelines.
Twenty subjects were randomized at the study site using medication numbers in permutated blocks and treatment-sequence assignments, with half the subjects assigned to each treatment sequence (sequence A and sequence B). Subjects were admitted to the study center on day -1. Subjects in sequence A received a single oral dose of carotegrast methyl 960 mg in combination with oral rifampicin 600 mg on the morning of day 1 after overnight fasting (period I). After being discharged on day 2, they were again admitted to the study center on day 7, and on the morning of day 8, received a single oral dose of carotegrast methyl 960 mg after overnight fasting (period II). Subjects were discharged on day 9. Follow-up observation was conducted on day 14. The subjects in the other group (sequence B) received the same treatments but in the opposite order.
Because of inexperience in terms of systemic exposure and safety when 960 mg of carotegrast methyl is administered in combination with rifampicin, we decided to adopt sentinel dosing administration. This began with a small number of patients (two subjects) as Step 1, and sequentially moving to Step 2 (four subjects) and Step 3 (remaining 14 subjects) while confirming safety and evaluating PK at each step. Transition from Step 1 to Step 2, and Step 2 to Step 3 was determined based on the absence of the following safety criteria; (1) the same moderate or severe AEs in more than 50% of the subjects, (2) a serious AE (SAE), or (3) neurological symptoms suggestive of PML that could not be ruled out as having a causal relationship with the study drug during the period between the first dose of Period I (day 1) and two days after Period II (day 9) in each step. The medical advisor assessed the validity of the investigator’s decision of moving to the next step, taking into consideration the PK results. The safety committee provided advice to the clinical trial sponsor from a third-party perspective, based on professional expertise, in order to ensure safety regarding the potential for PML to occur.
The Pharmaceuticals and Medical Devices Agency Guideline on drug interaction for drug development and appropriate provision of information recommends that rifampicin or cyclosporine should be considered for evaluating drug-drug interactions in humans if the study drug is a substrate of OATP1B1 and OATP1B3.15Rifampicin was selected as a potent inhibitor of OATP1B1 and OATP1B3 in this study since cyclosporine has been reported to inhibit P-glycoprotein in the gastrointestinal tract16 and carotegrast methyl was shown to be a substrate for P-glycoprotein (data not shown). The guideline recommends15 that the dose of inhibitors used in clinical drug interaction studies should be a dose that maximizes the likelihood of a drug interaction being exhibited; therefore, the dose of rifampicin was set at 600 mg. The dose of carotegrast methyl was set at 960 mg, which was the maximum dose used in healthy adults and patients with moderately active ulcerative colitis in previous studies, and this dose was safe and well tolerated.3,8,9,17
Two treatment periods were separated by a 7-day washout period based on more than five times the terminal elimination half-life (t1/2) of carotegrast methyl and carotegrast, which were approximately 8.0 – 20.2 h and 10.0 – 15.6 h, respectively, when 960 mg of carotegrast methyl was orally administered in healthy adults. The t1/2 of rifampicin 450 mg was 2.3 h.18Following this washout period, subjects returned to the study center for the next treatment.