Effectiveness of Cipol-N(R) in Primary Living Donor Kidney Transplant Patients: Open-Label, Multi-Center Study

Park, Kiil; Kang, Chong Myung; Koh, Yong Bok; Kwak, Jin Young; Kwon, Oh Jung; Kim, Sang Joon; Kim, Soon Il; Kim, Yong Soo; Kim, Yu Seun; Moon, In Sung; Moon, Jang Il; Bang, Byung Kee; Ahn, Curie; Ha, Jongwon

Abstract

Cyclosporine (CsA) has been one of the main immunosuppressants after kidney transplantation since its introduction in Korea. There was remarkable improvement of graft survival in kidney transplantation with CsA, compared with azathioprine. Cipol-N(R)(Chong Kun Dang, Korea), microemulsion gelatin capsule formulation of CsA, is a new generic drug. This pure domestic brand of CsA was tested for bioequivalence in healthy adults compared with the reference drug of the same formulation, Sandimmun-Neoral(R)(Novartis, Switzerland) in 1997. This open-label, multi-center study is designed to evaluate the efficacy of Cipol-N(R) in primary kidney transplant recipients for 6 months after transplantation. A total of 59 patients from 4 medical centers were enrolled in the study. Maintenance immunosuppressive protocol was based on CsA and steroid dual therapy, which was induced 2 days prior to the operation. Acute rejection was diagnosed with clinical or pathological clue. Clinical criteria for the diagnosis of acute rejection were oliguria, graft swelling and tenderness, rising serum creatinine, fever, and papillary swelling and increased vascular resistant index on Doppler ultrasonography. Steroid pulse therapy was used as primary treatment. Steroid resistant acute rejection was treated with anti-lymphocyte agents such as OKT3, ATG, or ALG. The primary efficacy endpoint was onset of acute rejection or treatment failure, defined as graft loss, death, or premature termination from the study for any reason. Incidence and severity of acute rejection, actual survival rate of patient and graft, function of the graft, pharmacokinetics of the Cipol-N(R), and the primary efficacy variables were evaluated 6 months after transplantation. All enrolled patients were included in the primary analyses of efficacy on the basis of intent to treat. Mean age of the patients was 37.1 10.4 years old. Male and female ratio was 42:17. There were 38 related pairs, which included 5 HLA identical and 33 HLA haplo-identical matches, and 21 unrelated pairs. A total of 10 patients were withdrawn from the study before post- transplant 6 months. The causes for premature withdrawal were patient's request without specific reason (6), partially rescued acute rejection (3), and patient's death (1). There were 27 episodes of acute rejection in 25 patients, which were diagnosed clinically (11) and pathologically (16). Steroid pulse therapy and anti-lymphocyte agent were used in 24 and 3 cases respectively. There were 4 patients, who showed partial rescue but no graft loss due to acute rejection. Patient and graft survival was 98.3% at post-transplant 6 months. Serum creatinine concentration showed 1.3-1.7 mg/dl all through the study period, which meant relatively stable graft function. Mean daily doses of Cipol-N(R) at post-transplant 1 and 6 months were 325 and 300 mg respectively. With this short term study, we can report that Cipol-N(R) showed relatively good efficacy in primary living donor kidney transplantation. Further study is needed for the evaluation of long term efficacy and safety.