Early non-steady-state population pharmacokinetics of oral cyclosporine in renal transplant recipients

Hyunjeong Baek,1,* Seunghoon Han,2,3,* Dong-Seok Yim,2,3 Sung Joo Kim,4 Soo-Youn Lee,5 Hye Ryoun Jang,6 Jung Eun Lee,6 Dae Joong Kim,6 Yoon-Goo Kim,6 Ha Young Oh,6 Wooseong Huh6 1Department of Medicine, Kangwon National University School of Medicine, Chuncheon, Republic of Korea; 2Department of Pharmacology, College of Medicine, the Catholic University of Korea, Seoul, Republic of Korea; 3PIPET (Pharmacometrics Institute for Practical Education and Training), Seoul, Republic of Korea; 4Department of Surgery, 5Department of Laboratory Medicine and Genetics, 6Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea *These authors equally contributed tothis work Abstract: This study aimed to evaluate the change in the pharmacokinetics (PK) of cyclosporine in the non-steady-state period in the first week after renal transplantation; the factors influencing this change, including genetic variability; and the time point concentration that correlated best with drug exposure. Data were obtained from 69 patients, and PK studies were conducted on postoperative days (PODs) 2, 3, and 7. Samples were taken pre-dose and at 1, 2, 3, 4, 6, 8, and 12 hours after drug administration. MDR1, CYP3A4, and CYP3A5 were genotyped. A population PK analysis and correlational analysis between the concentration at each time point and the area under the time–concentration curve were performed. A two-compartment model with first-order absorption was chosen. The rate and extent of drug absorption showed a significant increase on POD3, followed by a slight decrease on POD7. Until POD3, 8 hours post-dose was the single time point concentration that correlated best with drug exposure and 3 hours was the best time point on POD7. In both analyses, the MDR1 genotype showed potential as a factor influencing PK change. We conclude that oral administration of cyclosporine and dose adjustment based on a single concentration measurement might result in unexpected drug exposure during this early posttransplantation period. Keywords: renal transplantation, multidrug resistance 1 (MDR1) gene, cytochrome P450