THE INFLUENCE OF GENDER ON THE PHARMACOKINETICS AND DYNAMIC RESPONSE OF GLUCOCORTICOIDS IN RENAL TRANSPLANT RECIPIENTS

Abstract

790 Glucocorticoids have been an integral component of combination immunosuppressive therapy in renal transplant recipients (RTR). No data has described the influence of gender on the pharmacokinetics or cortisol response of these agents. The purpose of this study was to evaluate the pharmacokinetics and cortisol response of methylprednisolone (MEPN) in female RTR with stable creatinine clearances (CrCl) compared to previously evaluated male RTR. Thirteen premenopausal (PRE) [ages 30-49; CrCl: 52 ± 21 ml/min} and 8 post-menopausal (POST) RTR [ages 40-68; CrCl:55 ± 22 ml/min] receiving chronic MEPN (mean dose; 7 mg) were evaluated over 24-hours. Serial blood samples were collected after 20-30 minute IV infusion of MEPN. This group was compared to 16 male counterparts (CrCl: 81 ± 20 ml/min) receiving chronic MEPN (mean dose: 11.4 mg/day). MEPN and cortisol were analyzed by HPLC with pharmacokinetics parameters generated by WINNONLIN. The mean clearance (CL) of MEPN for the PRE patients was 225 ± 89.4ml/hr/kg compared to 260 ml/hr/kg (p=0.6) in males with no significant difference noted in volume of distribution or half-life between groups. Dose-normalized AUC of MEPN reflected greater drug exposure in PRE RTR (66 ± 20 ng · hr/ml) compared to males (46 ± 20 ng · hr/ml; p=0.174). In the POST patients, the MEPN CL was significantly slower (146 ± 33 ml/hr/kg; p< 0.05) than noted in males. The dose-normalized AUC of MEPN in POST was significantly greater (104 ± 21 ng·hr/ml; p< 0.05) than in male RTR. A defined 24-hour cortisol pattern was noted in 9/13 PRE and 5/9 POST patients. A mean 8 AM cortisol concentration of 111.2 ng/ml in the PRE and 103.4 ng/ml in the POST groups was found. Cortisol declined in a mono-exponential fashion in both groups. Male RTR demonstrated similar cortisol responses and no statistical differences were noted. The results in PRE RTR contradict data documenting a more rapid CL of MEPN in young women with the potential of increased drug exposure. The significant reduction in MEPN CL in the POST group suggest that increased drug exposure may impact on the development of steroid-induced adverse effects. Coupling the defined cortisol response noted in these female RTR with these pharmacokinetic findings, the likelihood of increased adverse effects in women requiring individualized dose adjustments should be considered.