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Drug-drug interaction study to assess the effects of administration of clarithromycin or rifampicin on the pharmacokinetics of K-237 in healthy adult volunteers

Drug-drug interaction study of K-237 (clarithromycin, rifampicin)

30

The clarithromycin concomitant administration group (Group A) (n=10) [Age, Mean (SD)] 31.0 (7.3) years [Weight, Mean (SD)] 66.60(8.73)kg [Height, Mean(SD)] 172.77(4.86)cm [Body Mass Index, Mean(SD)] 22.26(2.26)kg/m2 The post-rifampicin group (Group B) (n=10) [Age, Mean (SD)] 31.5 (8.5) years [Weight, Mean (SD)] 61.42(9.88)kg [Height, Mean(SD)] 168.40(5.27)cm [Body Mass Index, Mean(SD)] 21.58(2.60)kg/m2

Informed Consent Obtained: 30 subjects Enrollment in Treatment Period: 20 subjects (Group A: 10, Group B: 10) Treatment Period 1 completed: 20 subjects (Group A: 10, Group B: 10) Treatment Period 2 completed: 19 subjects (Group A: 9, Group B: 10) Safety Analysis Set: 20 (Group A: 10, Group B: 10) Pharmacokinetic Analysis Set: 20 (Group A: 10, Group B: 10)

Adverse events and adverse drug reactions were not reported in Treatment Period 1 but reported in both groups during Treatment Period 2, i.e., 1 subject (3 events) during Treatment Period 2 (pre-dosing period) and 6 subjects (10 events) during Treatment Period 2 (K-237 tablet period) in Group A, and 1 subject (1 event) and 3 subjects (3 events) during Treatment Period 2 (K-237 tablet period) in Group B. The adverse events reported in at least 2 subjects in the same group were an increase of alanine aminotransferase in 3 subjects (3 events) and COVID-19 in 2 subjects (2 events) in Group A, while no event was reported in Group B. The increased alanine aminotransferase was found to be temporally related to study drug administration, and, accordingly, all these three events were considered ""related"" to the study drug, but they were mild and resolved. COVID-19 was considered unrelated to the study drug, and the events were moderate and alleviated.

For the PK parameters of unchanged Ivermectin B1a (IVM B1a) in Group A, the geometric means of Cmax and AUC0-72h were16.041 ng/mL and 225.932 ng*h/mL in Treatment Period 1 and 40.391 ng/mL and 1059.887 ng*h/mL in Treatment Period 2, respectively. For the PK parameters of unchanged IVM B1a in Group B, the geometric means of Cmax and AUC0-72h were 94.394 ng/mL and 1416.596 ng*h/mL in Treatment Period 1 and 23.008 ng/mL and 114.470 ng*h/mL in Treatment Period 2, respectively. The geometric mean ratios (90% CI) of Cmax and AUC0-72h for unchanged IVM B1a during Treatment Period 2 to those during Treatment Period 1 were 2.518 (2.222 to 2.853) and 4.691 (4.158 to 5.293) in Group A, respectively, and 0.244 (0.158 to 0.376) and 0.081 (0.049 to 0.134) in Group B, respectively.

Cmax and AUC0-72h of K-237 increased when K-237 was co-administered with clarithromycin, while these parameters decreased when K-237 was administered following repeated dosing of rifampicin, suggesting that K-237 may be affected by drug interactions with clarithromycin or rifampicin. Finally, no safety issues were identified in the treatment periods.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2051210203

Tanigawa Ryohei

Kowa Company, Ltd.

4-14, Nihonbashi-honcho 3-chome, Chuo-ku, Tokyo

ctrdinfo@kowa.co.jp

Contact for clinical trial information -

Kowa Company, Ltd.

4-14, Nihonbashi-honcho 3-chome, Chuo-ku, Tokyo

+81-3-3279-7454

ctrdinfo@kowa.co.jp

Complete

May. 01, 2022

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

crossover assignment

treatment purpose

(1) Subject is a healthy adult male volunteer.
(2) Subject is between the ages of 18 and 45 years at the time of signing informed consent.
(3) Subject has a body mass index of 17.6 to 26.4 kg/m2 at Screening.

(1) Subject has used a drug (including over-the-counter drug, vaccination) within 14 days before the administration of the study drug in the first treatment period, or those who need to use it during the study period.
(2) Subject has received products containing St John's wort within 4 weeks before the administration of the study drug in the first treatment period. Subject has received supplements and products containing grapefruit within 14 days before the administration of the study drug in the first treatment period.
(3) Subject has a current malabsorption, and those who had an operation on the gastrointestinal tract that may affect absorption (excluding appendectomy).

Male

COVID-19

- Clarithromycin administration group:
K-237 3 mg single dose administration under fasting
Clarithromycin 400 mg twice daily before breakfast and supper
- Rifampicin administration group:
K-237 0.3-0.4 mg / kg single dose administration under fasting
Rifampicin 600 mg once daily before breakfast

Plasma pharmacokinetic parameters

+81-6-6395-9000

Mar. 18, 2022

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