PMID- 31667735 OWN - NLM STAT- MEDLINE DCOM- 20210322 LR - 20210322 IS - 1179-187X (Electronic) IS - 1175-3277 (Print) IS - 1175-3277 (Linking) VI - 20 IP - 3 DP - 2020 Jun TI - Bioequivalence of a Newly Developed Dabigatran Etexilate Tablet Versus the Commercial Capsule and Impact of Rabeprazole-Induced Elevated Gastric pH on Exposure in Healthy Subjects. PG - 249-258 LID - 10.1007/s40256-019-00377-x [doi] AB - BACKGROUND AND OBJECTIVE: Dabigatran etexilate (DE) is an anticoagulant with proven efficacy and tolerability for stroke prevention in patients with non-valvular atrial fibrillation. For the commercial capsule, a complex formulation is used to maintain the acidic microenvironment required for maximal absorption. Consequently, its efficacy and safety are similar with or without concomitant intake of proton-pump inhibitors (PPIs). A simplified DE tablet formulation was developed and tested in two studies. One investigated bioequivalence (BE) of the novel DE tablet versus the commercial DE capsule. The other investigated DE bioavailability (BA) under pretreatment with the PPI rabeprazole and assessed the effect of elevated pH on exposure to dabigatran. METHODS: BE of the novel DE tablet versus the DE capsule was assessed in a randomized two-treatment, four-period, two-sequence crossover study (NCT03070171). The effect of rabeprazole on the BA of the DE tablet was assessed in an open-label, single-arm study (NCT03143166). Both studies were conducted at sites in Japan. Participants were healthy male volunteers, aged >/= 20-40 years. In the BE study, participants received the DE tablet or capsule (single oral dose, 110 mg); primary endpoints were area under the concentration-time curve from baseline to the last quantifiable data point (AUC(0-tz)) and maximum plasma concentration (C(max)) of unconjugated dabigatran. In the relative BA study, participants received the DE tablet (single oral dose, 110 mg) with or without rabeprazole pretreatment (once daily for 5 days, 20 mg); primary endpoints were AUC(0-tz) and C(max) of total dabigatran. RESULTS: In total, 160 participants were randomized in the BE study; 36 participants were enrolled in the BA study. The 90% confidence intervals of geometric mean (gMean) ratios for AUC(0-tz) (101.4-116.0%) and C(max) (101.8-116.6%) of unconjugated dabigatran were within pre-defined acceptance criteria for BE. In the relative BA study, the gMeans of AUC(0-tz) (667 to 192 ng h/mL) and C(max) (83.1 to 21.8 ng/mL) were decreased by approximately 70% when the tablet was administered under rabeprazole pretreatment. The reduction in BA was observed at a mean gastric pH of 5.3. Treatment was well tolerated; no deaths, serious adverse events (AEs) or significant AEs were reported in either study. CONCLUSION: The DE tablet demonstrated BE to the capsule; however, at high gastric pH, BA of the tablet was reduced by approximately 70%, which may lead to reduced efficacy. Data indicate the importance of examining not only BE under standard conditions, but relative BA at elevated gastric pH. Such investigations may avoid the reduced BA at elevated pH that is quite common in the target population (the elderly and/or patients treated with gastric-acid modifying co-medications), and therefore reduce treatment failure with DE. Registration: ClinicalTrials.gov identifier numbers: NCT03070171, and NCT03143166. FAU - Harada, Akiko AU - Harada A AUID- ORCID: 0000-0003-3311-8817 AD - Clinical PK/PD Department, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. akiko.harada@boehringer-ingelheim.com. FAU - Ikushima, Ippei AU - Ikushima I AD - SOUSEIKAI Sumida Hospital, 1-29-1 Honjo, Sumida-ku, Tokyo, 130-0004, Japan. FAU - Haranaka, Miwa AU - Haranaka M AD - SOUSEIKAI Hakata Clinic, 6-18 Tenyamachi, Hakata-ku, Fukuoka, 812-0025, Japan. FAU - Yanagihara, Aki AU - Yanagihara A AD - Medicine Division, Nippon Boehringer Ingelheim Co., Ltd., 2-1-1 Osaki, Shinagawa-ku, Tokyo, 141-6017, Japan. FAU - Nakayama, Daisuke AU - Nakayama D AD - Medicine Division, Nippon Boehringer Ingelheim Co., Ltd., 2-1-1 Osaki, Shinagawa-ku, Tokyo, 141-6017, Japan. LA - eng SI - ClinicalTrials.gov/NCT03070171 SI - ClinicalTrials.gov/NCT03143166 GR - Not applicable/Nippon Boehringer Ingelheim/ PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PL - New Zealand TA - Am J Cardiovasc Drugs JT - American journal of cardiovascular drugs : drugs, devices, and other interventions JID - 100967755 RN - 0 (Antithrombins) RN - 0 (Proton Pump Inhibitors) RN - 32828355LL (Rabeprazole) RN - I0VM4M70GC (Dabigatran) SB - IM MH - Administration, Oral MH - Antithrombins/administration & dosage/pharmacokinetics MH - Biological Availability MH - Cross-Over Studies MH - *Dabigatran/administration & dosage/pharmacokinetics MH - Drug Compounding/methods MH - Female MH - Gastric Juice/chemistry MH - Healthy Volunteers MH - Humans MH - Hydrogen-Ion Concentration/*drug effects MH - Male MH - Middle Aged MH - *Proton Pump Inhibitors/administration & dosage/pharmacokinetics MH - *Rabeprazole/administration & dosage/pharmacokinetics MH - Risk Adjustment MH - Stroke/prevention & control MH - Therapeutic Equivalency PMC - PMC7266796 COIS- Akiko Harada: employee of Nippon Boehringer Ingelheim Co., Ltd. Ippei Ikushima: no conflicts of interest to disclose. Miwa Haranaka: no conflicts of interest to disclose. Aki Yanagihara: employee of Nippon Boehringer Ingelheim Co., Ltd. Daisuke Nakayama: employee of Nippon Boehringer Ingelheim Co., Ltd. EDAT- 2019/11/02 06:00 MHDA- 2021/03/23 06:00 PMCR- 2019/10/30 CRDT- 2019/11/01 06:00 PHST- 2019/11/02 06:00 [pubmed] PHST- 2021/03/23 06:00 [medline] PHST- 2019/11/01 06:00 [entrez] PHST- 2019/10/30 00:00 [pmc-release] AID - 10.1007/s40256-019-00377-x [pii] AID - 377 [pii] AID - 10.1007/s40256-019-00377-x [doi] PST - ppublish SO - Am J Cardiovasc Drugs. 2020 Jun;20(3):249-258. doi: 10.1007/s40256-019-00377-x.