Safety, tolerability and pharmacokinetics of higher‐dose mizoribine in healthy male volunteers

British Journal of Clinical Pharmacology - Tập 63 Số 4 - Trang 459-468 - 2007
Daria Stypinski1, Mohammad Obaidi1, Michelle D. Combs1, Meg Weber1, Adrian Stewart1, Hiroaki Ishikawa2
1MDS Pharma Services, Lincoln, NE, USA, MDS Pharma Services, Belfast, Northern Ireland, UK and
2Clinical Development Centre, Asahi Kasei Pharma Corporation, Tokyo, Japan

Tóm tắt

AimsMizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at ≥0.5 but <3 µg ml−1. It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2–5 mg kg−1 day−1. The safety, tolerability and pharmacokinetics from two clinical trials of higher‐dose mizoribine treatments in healthy male volunteers are presented.MethodsForty‐eight healthy White male nonsmokers participated in two randomized, double‐blind, placebo‐controlled trials: 32 in a single‐dose study (3, 6, 9 and 12 mg kg−1) and 16 in a multiple‐dose study [6 mg kg−1 day−1 once daily for 5 days or twice daily (12 mg kg−1 day−1) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed.ResultsThe safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg−1 day−1) in the multiple‐dose study. Orally administered mizoribine reached peak concentrations within 2–3 h and was eliminated mostly via the kidney (65–100% of dose) with a 3‐h half‐life. Only the 12 mg kg−1 day−1 group achieved trough concentrations that were within the therapeutic window.ConclusionsBased on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6–12 mg kg−1 day−1 range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.

Từ khóa


Tài liệu tham khảo

Hardy M, 1999, Message from the Directors of Renal Transplantation Program.

Parker S., 1997, Renal Transplantation.

10.1056/NEJMra033540

10.7164/antibiotics.27.775

10.1016/0006-2952(83)90301-5

Matsumoto K, 1982, A comparative, subacute toxicity study of mizoribine and azathioprine in dogs – with particular reference to hepatotoxicity, nephrotoxicity and hematotoxicity, Japan J Transplant, 17, 603

10.1111/j.1432-2277.2004.00042.x

10.1007/BF00609886

Akiyama T, 1982, Clinical experience in the use of and a pharmacokinetic study of Bredinin in renal transplantation, Japan J Transplant, 17, 753

Micromedex Inc.Mizoribine 2003.Available athttp://csi.micromedex.com/DKS/DATA/DE/DE2064.HTM?Top=Yes(last accessed: 21 April 2005).

10.1172/JCI115101

10.1016/j.transproceed.2004.12.288

10.1016/S0378-4347(00)80663-5

10.1177/009286159502900324

Thông tin
Thông tin xuất bản

British Journal of Clinical Pharmacology

Tập 63 Số 4

459-468

Thông tin tác giả