Kathleen M. Tornatore

Methylprednisolone Pharmacokinetics, Cortisol Response, And Adverse Effects In Black And White Renal Transplant Recipients

It is generally assumed that chronic glucocorticoid therapy is similar pharmacologically when administered to either black or white renal transplant recipients, resulting in adrenal suppression, low circulating plasma cortisol concentrations, and a similar degree of drug exposure and toxicity. To examine this theory and to investigate the relationship of glucocorticoid metabolism to steroid-induced adverse effects among specific ethnic groups of renal transplant recipients, 9 black and 9 white male patients chronically receiving methylprednisolone were enrolled. All patients had stable renal function and were matched for age, weight, and time since transplant. Standard pharmacokinetic parameters for methylprednisolone were determined and cortisol responses were characterized by total cortisol area under the concentration curve (AUC), return cortisol AUC, and cortisol suppression half-life. All patients received their daily oral dose of methylprednisolone (mean daily dose = 11 mg for blacks and 11 mg for whites) as an intravenous infusion with serial plasma samples obtained over 24 h. The patients were assessed for the presence of specific cushingoid manifestations (buffalo hump, moon facies) and steroid-associated diabetes. Methylprednisolone and cortisol were analyzed via HPLC. In the black patients, the mean clearance of methylprednisolone (206 +/- 70 ml/hr/kg) was significantly slower with a smaller volume of distribution (0.95 +/- 0.32 L/kg) when compared with the white group (327 +/- 129 ml/hr/kg, P = 0.03; volume of distribution = 1.33 +/- 0.27 L/kg, P = 0.015). Despite chronic methylprednisolone therapy, a definite 24-hr cortisol response pattern was noted in 15 of the 18 patients with a mean total cortisol AUC of 732 +/- 443 ng.hr/ml in blacks and 539 +/- 361 ng.hr/ml in whites (P = 0.17, black vs. white). The mean cortisol suppression half-life was 4.31 +/- 1.54 hr in black recipients and 4.11 +/- 1.49 hr in whites (P = 0.48). The mean return cortisol AUC for the black patients was 327 +/- 279 ng.hr/ml and 370 +/- 207 ng.hr/ml for white patients (P = 0.28). The serum cortisol nadir for black patients was 12.3 +/- 7.2 ng/ml, which was significantly higher than the cortisol nadir in white patients (6.4 +/- 4.4 ng/ml; P = 0.03). A majority (94%) of patients (9 black, 8 white) had moon facies and 27% of patients (3 black, 1 white) had a buffalo hump. While 5 of 9 black patients had steroid-associated diabetes, no white patients manifested this adverse effect. The black patients with diabetes had higher cortisol AUCs with lower methylprednisolone clearances than the white group.(ABSTRACT TRUNCATED AT 400 WORDS)

The clinical impact of 1:1 conversion from Neoral to a generic cyclosporine (Gengraf) in renal transplant recipients with stable graft function.

Abstract:  The introduction of cyclosporine (CYA) to the immunosuppressive armamentarium has had a significant effect on graft survival. An improvement in the formulation from the oil‐based to a microemulsion‐based form has resulted in better absorption and more predictable CYA bioavailability. Since the introduction of the first microemulsion form (Neoral), several bioequivalent formulations are now available and are switched in a 1:1 fashion at pharmacies to curtail costs. The purpose of our study was to study the effect of a 1:1 switch from Neoral to Gengraf on CYA trough levels and serum creatinine (SRC) in renal transplant recipients with stable graft function. Eighty‐two renal transplant recipients with stable graft function were enrolled in the study, and of these, 73 were switched to Gengraf, whereas nine remained on Neoral. The 13 patients switched to Gengraf required a dosage change after the mean CYA trough levels changed from 234±96 ng/mL at baseline to 289±102 ng/mL (p<0.05) at 2 wk. With the adjustments in dosage, the levels approached the baseline trough concentrations (239±151 ng/dL). The nine patients who remained on Neoral had no change in the CYA levels or SCR. Nearly 20% of patients who switched to a bioequivalent CYA preparation required a dose adjustment to return to pre‐conversion CYA trough levels. Our study raises serious concerns regarding the switchability of generic CYA for Neoral without careful follow‐up therapeutic drug monitoring.

Cortisol pharmacodynamics after methylprednisolone administration in young and elderly males

Glucocorticoids are commonly prescribed in the elderly on an empiric basis with little consideration for the age‐related alterations in pharmacologic response. The objectives of this study were to compare the effect of methylprednisolone on cortisol patterns in elderly and young healthy men, to define the relationship between pharmacokinetic parameters of methylprednisolone and pharmacodynamics of cortisol in the elderly and young men. Seven healthy, elderly males (69–82 years old) and five healthy, young males (24–37 years old) participated in a 24‐hour pharmacodynamic trial with randomized assignment to a control period (Phase I) and a methylprednisolone period (Phase II). Serial blood samples were obtained throughout both study periods. Cortisol measurements included the total area under the concentration—time curve (AUC), return AUC, and suppression ratio. During Phase I, a circadian pattern was noted in both groups. After exposure to methylprednisolone (Phase II), a linear decline in serum concentrations of cortisol was observed in both groups. The return AUC of cortisol (425 ± 357 ng·hr/mL [elderly] versus 854 ± 216 ng·hr/mL [young]) and the total AUC 764 ± 340 g·h/mL [elderly] versus 1,230 ± 258 g·hr/mL [young]) were significantly lower in the older men. In addition, a significant decline in total AUC and nadir concentration of cortisol from Phase I to Phase II was noted within both groups. The suppression ratio was significantly greater in the elderly men (mean, 0.38 versus 0.58 in young), which indicates a greater degree of adrenal suppression after administration of methylprednisolone. Exposure to methylprednisolone, as measured by AUC, was 554 ± 215 ng·hr/kg (elderly) and 389 ± 102 ng·hr/kg (young). The greater exposure to methylprednisolone noted in the elderly yielded significant combined correlations for both groups with AUC, return AUC, and suppression ratio of cortisol. A more significant response of cortisol to the exogenous glucocorticoid was apparent in the elderly men. In addition, a slower clearance of methylprednisolone was noted in the elderly group compared with their young counterparts. The effect of reduced clearance of methylprednisolone on the suppression ratio indicates the interrelationship between the disposition of a single dose of an exogenous glucocorticoid and response patterns of cortisol.

Pharmacokinetics of methylprednisolone in elderly and young healthy males

OBJECTIVE: To characterize and compare the pharmacokinetics of a single intravenous dose of methylprednisolone in elderly and young healthy males.

Pharmacokinetics of single and multiple doses of ethinyl estradiol and levonorgestrel in relation to smoking

The effects of tobacco and oral contraceptive (OC) use (Ovral) on the pharmacokinetics of levonorgestrel (0.25 mg) and ethinyl estradiol (50 μg) were examined. Young women (n = 27) were grouped as follows: I: non‐OC users/nonsmokers; II: OC users/nonsmokers; III: non‐OC users/smokers; and IV: OC users/smokers. The apparent clearance of levonorgestrel in group I was 80.9 ± 15.6 ml/hr/kg and the half‐life was 19.3 hours. A significant decrease in levonorgestrel clearance was seen in the chronic OC users (groups II and IV). The apparent oral clearance of ethinyl estradiol was 1002 ± 398 ml/hr/kg in group I and the half‐life averaged 7.7 hours. Groups II and III showed decreased (not significant) clearances of ethinyl estradiol. Tobacco use had no effect on steroid pharmacokinetics in the non‐OC users. Although chronic OC use did not affect ethinyl estradiol clearance, a joint effect of tobacco/OC use on enhancing clearance of ethinyl estradiol appeared to occur. A linear relationship was found between 24‐hour trough serum concentrations and AUC values of both steroids that may facilitate population monitoring studies of OC exposure.

Mycophenolic Acid Pharmacokinetics During Maintenance Immunosuppression in African American and Caucasian Renal Transplant Recipients

Renal transplant recipients exhibit variability in mycophenolic acid (MPA) and MPA glucuronide (MPAG) pharmacokinetics, which are influenced by clinical and demographic factors. Racial influence on MPA and MPAG pharmacokinetics was investigated in 53 patients: 17 African American males, 22 Caucasian males, and 14 females receiving mycophenolate mofetil (MMF) and cyclosporine. A 12‐hour steady‐state pharmacokinetic study was conducted. Enterohepatic circulation of MPA was characterized by a second plasma concentration peak and was included in a novel statistical model with MPAG. MPA clearance in African American males was 26.5 ± 14.4 L/h versus 17.9 ± 6.1 L/h in Caucasian males (P = .035) and 16.1 ± 4.6 L/h in Caucasian females (P = .024) with no difference noted in MPA troughs. Enterohepatic circulation occurred less frequently in African American males (23%) compared with Caucasian males (42%) and Caucasian females (50%) (P > .05). Cyclosporine exposure was correlated with MPA and MPAG pharmacokinetics, whereas creatinine clearance influenced MPAG pharmacokinetics. A racial difference was noted with more rapid MPA clearance in African American males compared with Caucasians. The results support differential MPA dosing and the role of therapeutic drug monitoring in addition to considering the influence of renal function and concurrent immunosuppressives on MPA and MPAG pharmacokinetics.

Kidney transplantation and pregnancy.

Purpose of reviewThe purpose of this review is to improve the basis upon which advice on pregnancy is given to renal transplant recipients in the reproductive age group. The review attempts to impart up-to-date evidence-based information on the predictable outcome and the risk of pregnancy after kidney transplantation. Recent findingsA current change in the consensus opinion of American Society of Transplantation regarding timing of pregnancy after transplantation. There are conflicting data regarding the utility of drug monitoring and dose adjustments of immunosuppressive medications during pregnancy and breast feeding. There is a recent change in the U.S. Food and Drug Administration category of mycophenolate mofetil from pregnancy Class C to D based on recent adverse fetal and neonatal outcome. SummaryCounseling regarding pregnancy should be an integral part of caring for the kidney transplant patient in the reproductive age group. Ethical concerns exist about advising pregnancy and fertility treatment for a woman whose life expectancy may be affected by outcome of pregnancy. Toxic effects of newer immunosuppressive medications exposed in utero and during breast feeding and its long-term effects in the offspring have to be clearly defined. The need for longitudinal studies and multicenter observational studies cannot be over emphasized to help answer our considerable gaps in this area.

Racial differences in the pharmacokinetics of methylprednisolone in black and white renal transplant recipients

Study Objective. To examine the comparative pharmacokinetics of long‐term methylprednisolone therapy in black and white renal transplant recipients.

Sex differences in cyclosporine pharmacokinetics and ABCB1 gene expression in mononuclear blood cells in African American and Caucasian renal transplant recipients

Cyclosporine exhibits pharmacokinetic and pharmacodynamic variability in renal transplant recipients (RTR) attributed to P‐glycoprotein (P‐gp), an ABCB1 efflux transporter that influences bioavailability and intracellular distribution. Data on race and sex influences on P‐gp in RTR are lacking. We investigated sex and race influences on cyclosporine pharmacokinetics and ABCB1 gene expression in peripheral blood mononuclear cells (PBMC). Fifty‐four female and male African American and Caucasian stable RTR receiving cyclosporine and mycophenolic acid completed a 12‐hour study. ABCB1 gene expression was assessed in PBMCs pre‐dose and 4 hours after cyclosporine. Statistical analysis used mixed effects models on transformed, normalized ABCB1 expression and cyclosporine pharmacokinetics. Sex and race differences were observed for the dose‐normalized area under the concentration curve (AUC0–12/Dose) [P = .0004], apparent clearance [P = .0004] and clearance/body mass index (CL/BMI) [P = .027] with slowest clearance and greatest drug exposure in females. Sex and race differences were found pre‐dose and 4 hours for ABCB1 [P < .0001] with females having less expression than males. ABCB1 differences were observed between pre‐dose and 4 hours [P = .0009]. Female RTR had slower cyclosporine clearance and lower ABCB1 gene expression in PBMC suggesting reduced efflux activity and greater intracellular drug exposure.

Cortisol pharmacodynamic response to long-term methylprednisolone in renal transplant recipients.

Study Objective. To examine the pharmacodynamic patterns of cortisol and pharmacokinetic values of long‐term methylprednisolone in renal transplant recipients.