Effect of grapefruit juice on pharmacokinetics of microemulsion cyclosporine in African American subjects compared with Caucasian subjects: does ethnic difference matter?

This study aims to determine the effect of grapefruit juice (GJ) on microemulsion cyclosporine (CsA) in 11 African American subjects, and it was compared to those in 11 Caucasian subjects. Each subject received two oral doses of CsA with water (W) or GI as well as i.v. CsA. Regardless of race, GJ significantly increased the peak concentration (Cmax) and area under the time-curve (AUC) of CsA; however, the magnitude of GJ effects was different between African American subjects and Caucasian subjects (p = 0.0003). GJ increased peak concentration of CsA by 39% in African American subjects, while the difference in Caucasian subjects was only 8% (p > 0.05). GJ also increased AUC of CsA in African American subjects by 60%, while GJ increased that in Caucasian subjects by 44% (p = 0.0001). The absolute bioavailability of CsA was 21% lower in African American subjects compared with Caucasian subjects when it was given with water (p = 0.048), but these differences disappeared when it was given with GJ (p = 0.6). These findings suggest that concurrent administration of GJ increases the bioavailability of CsA in African American subjects in greater magnitude compared with Caucasian subjects.

Determination of sildenafil citrate in plasma by high-performance liquid chromatography and a case for the potential interaction of grapefruit juice with sildenafil citrate.

This study was designed to establish a simple and reliable assay method that could be routinely used in the clinical laboratory setting using liquid extraction and high-performance liquid chromatography (HPLC). In addition, a case of potential interaction of grapefruit juice with sildenafil citrate is presented. The peaks of sildenafil (measured as sildenafil salt) and internal standard were identified with an ultraviolet detector at 230 nm and detection limit at 10 ng/mL. In a single elderly male patient, grapefruit juice increased the Cmax of sildenafil by 42% (1067.7 ng/mL to 1517.0 ng/mL) although AUC was not significantly altered (4082.9 ng x h/mL to 4171.9 ng x h/mL) by grapefruit juice. Sildenafil could be determined in a simple and reliable method using HPLC with liquid extraction. This case indicated that grapefruit juice might increase the Cmax of sildenafil without significant change in AUC. A further study with an appropriate number of subjects is needed before determining the degree of interaction between grapefruit juice and sildenafil.

Gender-dependent racial difference in disposition of cyclosporine among healthy African American and white volunteers.

Pharmacokinetic studies of intravenous and oral cyclosporine (cyclosporin) were performed in 22 healthy African American (n = 11) and white (n = 11) volunteers. Blood cyclosporine concentrations were measured by high performance liquid chromatography. Concentration versus time data were analyzed by noncompartmental models, and statistical analyses were performed by ANOVA. The clearance of intravenous and oral cyclosporine was 4.3 +/- 0.9 mL/min/kg and 13.5 +/- 4.5 mL/min/kg, respectively, in African Americans and 3.7 +/- 0.5 mL/min/kg and 9.6 mL/min/kg, respectively, in the white volunteers (P = .0001). There was a significant race and gender interaction (P = .038). Bioavailability was lower in African Americans (32.8 +/- 6.6%) compared with white volunteers (39.3 +/- 7.1%; P = .049), with a significant race and gender interaction (P = .048). The dose-adjusted area under the curve (AUC) of intravenous and oral cyclosporine was 54.3 +/- 10.6 ng x hr/mL per milligram and 18.1 +/- 4.1 ng x hr/mL per milligram, respectively, in African Americans and 61.9 +/- 6.8 ng x hr/mL per milligram and 24.2 +/- 4.6 ng x hr/mL per milligram, respectively, in white volunteers (P = .023). These findings suggest that disposition of cyclosporine is dependent both on race and on gender.

A urine metabolic ratio of dextromethorphan and 3-methoxymorphinan as a probe for CYP3A activity and prediction of cyclosporine clearance in healthy volunteers.

Dextromethorphan (DM) is metabolized in the body to dextrophan (DT) and 3-methoxymorphinan (3-MM) by cytochrome P450 (CYP) 2D6 and 3A4, respectively, and cyclosporine (CsA) is a known substrate of CYP3A4. We attempted to determine if the urine metabolic ratio of DM:3-MM at various time intervals during 24 hours is predictive of CsA clearance in 11 healthy volunteers. Each subject took DM 30 mg orally, and serial urine samples were collected at 0-4, 4, and 4-24, and 0-24 hours. Subjects then were randomly assigned to receive either oral microemulsion CsA 5 mg/kg or intravenous CsA 1.5 mg/kg in a crossover fashion in a two-sequence pharmacokinetic study with a wash-out period of at least 7 days. A total of 17 blood samples were collected from each subject in the CsA pharmacokinetic study over 24 hours. Urinary DM, DT, and 3-MM were quantified by high-performance liquid chromatography (HPLC) with a fluorescence detector, and blood CsA concentrations were analyzed by HPLC with ultraviolet detection. All subjects were extensive metabolizers of CYP2D6 as determined by metabolic ratios of DM:DT (mean+/-SD 0.0255+/-0.048). There was no correlation between CYP2D6 and CYP3A4 (p=0.38). The metabolic ratios of DM:3-MM in any urine samples during the 24-hour collection period did not predict CsA pharmacokinetics, although the 0-24 hour sample had an unexpected positive correlation with CsA clearance (r2 = 0.38, p<0.0001). The correlation was similar for metabolic ratios of DM:3-MM with intravenous CsA clearance (r2 = 0.5, p<0.0001). Metabolic ratios of DM:3-MM based on 24-hour cumulative urine collection did not appear to have clinical utility in predicting CYP3A activity measured by CsA clearance.

Sudden hearing loss associated with tacrolimus in a kidney-pancreas allograft recipient.

A 38-year-old woman with type 1 diabetes underwent kidney-pancreas transplantation. Her postoperative course was complicated due to recurrent acute graft rejections and pancreatitis. After initial immunosuppression with microemulsion cyclosporine, mycophenolate mofetil, and prednisone with muromonab-CD3 induction, cyclosporine was switched to tacrolimus on day 44. The initial dosage was 5 mg twice/day, but it was gradually increased to 10 mg twice/day, aiming at 15-20 ng/ml. On day 17 of tacrolimus therapy the woman developed sudden hearing loss with tinnitus. The serum tacrolimus level was 28.3 ng/ml (therapeutic range 10-20 ng/ml) on day 20 of tacrolimus therapy, and peaked at 34.9 ng/ml on day 28. Two audiograms performed on days 28 and 29 confirmed bilateral hearing loss of 80% for speech perception, characterized as mild to moderate sensorineural hearing loss with speech reception threshold of 35 dB (normal < 20 dB) in both ears. The tacrolimus dosage was gradually reduced to 6 mg twice/day by day 36, with drug level 9.7 ng/ml, after which her hearing gradually recovered.

Transplant pharmacists' opinions on generic product selection of critical-dose drugs.

Factors considered important by transplant pharmacists in decisions about generic product selection and in defining critical-dose drugs, as well as transplant pharmacists' attitudes about bioequivalence testing, were studied. Surveys, completed by telephone and fax in 1997, were used to assess pharmacists' role at solid-organ transplant centers, factors the pharmacists considered important for generic product selection, and pharmacists' attitudes about the FDA guidelines on bioequivalence testing. Surveys were completed by 59 pharmacists. The factors considered important by pharmacists for inclusion of generic products on the formulary were safety (97% of respondents), clinical consequences (97%), efficacy (92%), and bioequivalence (92%). Nearly all the pharmacists (95%) expressed a belief that generic products of some critical-dose drugs should not be dispensed. Only 12% of the respondents said they thought that the FDA guidelines on bioequivalence testing were appropriate for critical-dose drugs, and 92% thought that bioequivalence testing for this category of drugs should be conducted in actual patients. Efficacy, safety, the presence of a narrow therapeutic index, bioequivalence, and clinical consequences were identified by transplant pharmacists as important factors in decisions about generic product selection; current FDA guidelines for establishing bioequivalence were viewed as possibly not appropriate for critical-dose drugs.

Prediction of tacrolimus blood levels by using the neural network with genetic algorithm in liver transplantation patients.

The neural network (NN) is a technique using an artificial intelligent concept in predicting outcomes by using various input variables. Tacrolimus pharmacokinetics has wide inter- and intra-subject variability and it is often difficult to predict its blood concentrations by dose alone. The objectives of this study are to select the clinically significant variables and to predict the blood concentration of tacrolimus in liver transplant patients by NN combined with genetic algorithm (GA). A total of thirty-two adult liver transplant patients from the University of Iowa Hospitals and Clinics were selected and the patients' data were retrospectively collected. These patient were randomly assigned into two groups: either the training group (n = 10), or testing group (n = 22). A back propagation (BP) NN was developed which contained two hidden layers. A dynamic BP NN based on the time series concept was trained by using the current and previous data sets to predict the trough levels of tacrolimus. The mean of the NN prediction for tacrolimus blood levels was not significantly different from the observed value by a paired t-test comparison (12.05+/-2.67 ng/ml vs. 12.14+/-2.64 ng/ml, p = 0.80). The average difference of the testing sets between the observed and predicted levels was 1.74 ng/ml with a range from 0.08 to 5.26 ng/ml which is clinically acceptable range. Thirty-seven out of 44 data sets (84%) in the testing group were within 3.0 ng/ml of the observed values. This study demonstrated that tacrolimus blood concentrations are precisely predictable in liver transplant patients using patients variables by NN.

Effect of grapefruit juice on the pharmacokinetics of microemulsion cyclosporine and its metabolite in healthy volunteers: does the formulation difference matter?

This study was conducted to determine the effect of grapefruit juice on the pharmacokinetics of microemulsion cyclosporine and its major metabolites, M1 and M17, in 12 healthy volunteers. Each subject received two oral doses of microemulsion cyclosporine with water or grapefruit juice. Each subject also received intravenous cyclosporine on a separate occasion. Blood samples were collected for assay of cyclosporine, M1, and M17 during a 24-hour period, and were analyzed by a high-performance liquid chromatography method. Compared with water, administration with grapefruit juice significantly increased peak concentration (Cmax) and area under the concentration-time (AUC) of cyclosporine. Administration with grapefruit juice increased the absolute bioavailability of microemulsion cyclosporine by 45%. For cyclosporine metabolites, administration with grapefruit juice decreased the Cmax and AUC of M1 by 21% and 15%, respectively. These findings suggest that concurrent administration with grapefruit juice increases the bioavailability of microemulsion cyclosporine significantly compared with water in healthy volunteers. The grapefruit juice affects each metabolite formation and its pharmacokinetics differently, which suggests that the major site of its formation is different.

An abbreviated area-under-the-curve monitoring for tacrolimus in patients with liver transplants.

This study aims to assess the predictability of individual tacrolimus (FK) concentrations at different time points for the area under the curve (AUC) and to find the best sampling time for the abbreviated AUC to predict the total body exposure of FK. A total of 23 FK blood concentration versus time profiles (11 blood samples per 12 hours) was studied in 12 stable patients with liver transplants at steady state. Each AUC was calculated by the trapezoidal rule, and the relationship between individual concentrations or abbreviated AUC and total AUC was determined by linear regression. The trough concentrations from the morning dose predict AUC better than the trough concentration from the evening dose (r2 = 0.71 for morning dose and r2 = 0.35 for evening dose). In the case of single drug concentration, the 4-hour concentration could predict the total AUC reasonably well (r2 = 0.73). From stepwise multiple regression, the abbreviated AUC at 1, 2.5, 6, and 9 hours could predict the total AUC most accurately (r2 = 0.99). This study shows that the four levels at 1, 2.5, 6, and 9 hours or 1, 4, and 12 hours as an abbreviated AUC is as good as a full pharmacokinetic study. Alternatively, 4-hour concentration is a good predictor of the total body exposure of FK in the stable patients with liver transplants.

Cyclosporine trough concentrations in predicting allograft rejection and renal toxicity up to 12 months after renal transplantation.

STUDY OBJECTIVE: To evaluate the utility of cyclosporine (CsA) trough concentrations as a monitoring tool for acute graft rejections and CsA nephrotoxicity. DESIGN: Retrospective chart review. SETTING: University-affiliated teaching hospital. PATIENTS: One hundred thirty-seven adults who had undergone kidney transplantation. MEASUREMENTS AND MAIN RESULTS: Clinical data extracted from the charts were CsA dosage, CsA trough levels (whole blood, HPLC method), biopsy findings to confirm acute rejections, and serum creatine to determine clearance by the Jelliffe method. Data were collected at up to 1 month, between 1 month and 3 months, and between 3 and 12 months after transplantation. For each time period, receiver's operating characteristics curves were generated to identify the optimum CsA concentration for avoiding acute rejection and CsA nephrotoxicity. At up to 1 month, the CsA therapeutic response threshold was 182 ng/ml (sensitivity 69%, specificity 84%, p<0.0001) and toxicity threshold for CsA nephrotoxicity was 204 ng/ml (sensitivity 89%, specificity 56%, p<0.0001). Between 1 month and 3 months, the respective figures were 175 ng/ml (sensitivity 58%, specificity 89%, p<0.0002) and 189 ng/ml (sensitivity 87%, specificity 65%, p<0.0001). Between 3 and 12 months, the CsA therapeutic response threshold decreased to 135 ng/ml (sensitivity 56%, specificity 40%, p>0.1) and the toxicity threshold for CsA nephrotoxicity remained relatively static at 204 ng/ml (sensitivity 100%, specificity 14%, p<0.0001). CONCLUSION: Early in CsA therapy it is essential to prevent graft rejection. Drug concentrations exceeding approximately 182 ng/ml threshold accomplish this goal. Later, successful therapy demands that CsA nephrotoxicity be avoided. This goal is accomplished by not exceeding a CsA concentration of 204 ng/ml.

Time-dependent disposition of tacrolimus and its effect on endothelin-1 in liver allograft recipients.

STUDY OBJECTIVE: To characterize a time-dependent disposition of oral tacrolimus and its relationship with plasma endothelin-1 concentrations. DESIGN: Randomized, crossover study. SETTING: Clinical research center of a university-affiliated hospital. PATIENTS: Twelve stable liver transplant recipients. INTERVENTIONS: In the steady state, 23 blood samples were taken from each patient before and after tacrolimus administration over 24 hours. MEASUREMENTS AND MAIN RESULTS: Whole blood samples for tacrolimus and plasma endothelin-1 were analyzed by enzyme immunoassay. The relationship of their concentrations and their pharmacokinetic parameters between morning and evening doses were compared. The area under the curve (AUC) of tacrolimus in the morning dose was significantly larger than that in the evening dose (219 +/- 54 ng.hr/ml and 188 +/- 57 ng.hr/ml, respectively, p = 0.004). The mean time to peak concentration (Tmax) was significantly shorter for the morning dose than for the evening dose (1.6 +/- 0.7 hrs and 3.5 +/- 2.9 hrs, respectively, p = 0.01). The mean peak concentration (Cmax) was significantly higher in the morning dose than in the evening dose (32.2 +/- 9.1 ng/ml and 21.6 +/- 8.3 ng/ml, respectively, p = 0.008). However, the mean through concentration (Cmin) was not significantly different between doses. Endothelin-1 concentrations followed the same pattern as tacrolimus, with AUC and Cmax for the morning significantly higher than those for the evening dose of tacrolimus (AUC 13.8 +/- 3.7 pg.hr/ml, morning, and 11.0 +/- 3.5 pg.hr/ml, evening, p = 0.005; Cmax 2.4 +/- 1.1 pg/ml morning, and 1.5 +/- 0.6 pg/ml evening, p = 0.02). Tacrolimus levels did not correlate with endothelin-1 levels (r2 = 0.06, p = 0.001). CONCLUSIONS: Tacrolimus disposition in liver transplant patients is determined by time of administration. Plasma endothelin-1 concentrations follow the same pattern as blood tacrolimus concentrations.

Safety and tolerability of cyclosporine microemulsion versus cyclosporine: two-year data in primary renal allograft recipients: a report of the Neoral Study Group.

BACKGROUND: The new microemulsion formulation of cyclosporine (CsA-ME) is more bioavailable than cyclosporine (CsA) in de novo renal transplant patients. Therefore, it was of interest to compare the safety profile of each formulation in such patients. METHODS: In a multicenter, double-blind, parallel-group study, 101 renal transplant recipients were randomized after transplantation to receive either CsA (n=50) or CsA-ME (n=51) capsules twice daily for 2 years. Of these patients, 54 (CsA, n=26; CsA-ME, n=28) completed 1 year of the study and entered the second-year, double-blind extension. Initial dose at the time of transplantation was 5 mg/kg b.i.d.; doses were titrated to target trough levels. METHODS: The mean (+/- SD) doses at the end of 2 years were 4.6 +/- 1.8 and 3.8 +/- 1.1 mg/kg per day for CsA- and CsA-ME-treated patients, respectively. The mean (+/- SD) CsA trough levels at end point were 187 +/- 63 and 210 +/- 95 ng/ml for CsA- and CsA-ME-treated patients, respectively. At least one adverse event was reported by 25/26 (96%) of CsA- and 27/28 (96%) of CsA-ME-treated patients. No patient discontinued the study because of adverse events. No deaths occurred during the study. Renal function, as measured by serum creatinine levels, and blood pressure were comparable over time in both treatment groups. CONCLUSIONS: There was no significant difference in safety and tolerability between CsA- and CsA-ME-treated kidney recipients for 2 years after transplantation.

Circadian variation of tacrolimus disposition in liver allograft recipients.

The aim of this study was to characterize the circadian variation of oral tacrolimus disposition in 8 stable liver allograft recipients. In the steady state, a total of 23 blood samples was taken before and after tacrolimus administration during a 24-hr period and the pharmacokinetic parameters were compared. The area under the curve (AUC) of tacrolimus after the morning dose was significantly larger than after the evening dose (211+/-43 ng x hr/ml [morning] vs. 179+/-45 ng x hr/ml [evening], P=0.02). The time to peak (Tmax) was significantly shorter after the morning dose than after the evening dose (1.6+/-0.7 hr [morning] vs. 2.9+/-0.6 hr [evening], P=0.002). The peak (Cmax) was significantly higher after the morning dose than after the evening dose (32.2+/-10.2 ng/ml [morning] vs. 19.1+/-4.3 ng/ml [evening], P=0.003). However, the trough (Cmin) was not significantly different between the morning dose and the evening dose (13.1+/-3.9 ng/ml [morning] vs. 13.3+/-4.4 ng/ml [evening], P=0.4). This study demonstrated that tacrolimus disposition in liver transplant patients was determined by administration time.

Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients.

This study investigated the effect of grapefruit juice on cyclosporine A (CsA) bioavailability in 10 renal transplant patients. Under CsA steady state conditions, patients were randomly administered their usual dose of CsA with either 8 ounces of grapefruit juice or 8 ounces of water. Using a crossover design, a 12-hr pharmacokinetic study was then conducted. Grapefruit juice increased the area under the concentration versus time curve (4218+/-1497 ng x hr/ml [grapefruit juice] vs. 3415+/-1288 ng x hr/ml [water], P=0.029) and 12-hr trough (244+/-214 ng x ml [grapefruit juice] vs. 132+/-56 ng x ml [water], P=0.09), but it did not change peak concentration (734+/-290 ng x ml [grapefruit juice] vs. 708+/-305 ng x ml [water], P=0.76). In addition, grapefruit juice delayed the time to peak concentration compared with water (5.4+/-3.0 hr [grapefruit juice] vs. 2.8+/-0.8 hr [water], P=0.025). These data suggest that concurrent administration of grapefruit juice with CsA will delay the absorption of CsA and increase the drug exposure of CsA without changing peak concentration.

Effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of quinidine in healthy volunteers.

A study was conducted to examine the effect of grapefruit juice on the disposition of quinidine sulfate and changes of QT intervals after oral administration to twelve healthy male volunteers. Participants received two oral doses of quinidine sulfate tablets (400 mg) with 240 mL of water or grapefruit juice, each separated by a 1-week washout period. Plasma samples for analysis of quinidine and its major metabolite, 3-hydroxyquinidine, were collected for a 24-hour period and analyzed by a high-performance liquid chromatography method. For pharmacodynamic data, the electrocardiograms (ECGs) were performed for 12 hours, and the recordings were marked for ECG interval at all blood collection time periods. There was no significant difference in pharmacokinetic parameters of quinidine when administered with grapefruit juice or water, except for time to maximum concentration (tmax), which was 1.6 hours after administration with water and 3.3 hours after administration with grapefruit juice. Administration with grapefruit juice also resulted in a 33% decrease in the area under the concentration-time curve (AUC) of 3-hydroxyquinidine compared with water, but did not increase the AUC of quinidine or change the ratio of AUC of 3-hydroxyquinidine to the AUC of quinidine. Pharmacodynamic parameters, including changes in the rate-corrected QT (QTc) interval, closely paralleled the pharmacokinetic data, in that administration with grapefruit juice led to delayed maximal effect on QTc and reduction in maximal effect. Administration with grapefruit juice therefore delays the absorption of quinidine and inhibits the metabolism of quinidine to 3-hydroxyquinidine.

The pharmacokinetics of a microemulsion formulation of cyclosporine in primary renal allograft recipients. The Neoral Study Group.

This study was a randomized, double-blind, 12-week comparison of the pharmacokinetics, safety, and tolerability of two cyclosporine (CsA) formulations, cyclosporine emulsion capsules and oral solution for microemulsion and cyclosporine, in the postoperative management of renal transplant patients. Of the 101 patients, aged 18 to 65, who entered the study, 89 were evaluable for pharmacokinetics. Initial dosage was 10 mg/kg per day, administered twice daily in two equal doses. Dosages were adjusted to achieve target CsA concentrations. The pharmacokinetic (PK) parameters (dose-normalized) of greatest interest were maximum blood concentration (C(max)/dose), time to reach maximum concentration (t(max), area under the blood concentration-vs.-time curve (AUC/dose), and trough blood concentrations (Co h/dose). The relative CsA bioavailabilty was found to be significantly enhanced with cyclosporine emulsion compared with cyclosporine with a 16% to 31% increase in AUC and a 32% to 42% increase in C(max). Intrapatient variability of PK parameters was significantly lower with cyclosporine emulsion than with cyclosporine for AUC, C(oh), t(max), and C(max) in many instances. This indicates a more consistent, rapid, and more complete total absorption of CsA. Despite higher CsA C(max) levels and AUCs with cyclosporine emulsion, safety and tolerability (detailed in a parallel report) were comparable to those of cyclosporine. The PK advantages of cyclosporine emulsion over cyclosporine are either independent of food conditions or possibly reflective of more consistent absorption of CsA with cyclosporine emulsion. The findings suggest that de novo use of cyclosporine emulsion may simplify and improve management of organ transplant recipients and that the PK advantages of cyclosporine emulsion may translate into clinical benefits.

The safety and tolerability of cyclosporine emulsion versus cyclosporine in a randomized, double-blind comparison in primary renal allograft recipients. The Neoral Study Group.

A 12-week, randomized, double-blind, multicenter pharmacokinetics study was conducted to compare the clinical safety and tolerability of cyclosporine capsules and oral solution for microemulsion and cyclosporine in 101 primary renal transplant recipients Cyclosporine emulsion has more complete absorption and improved bioavailability compared with cyclosporine, and dosing of both cyclosporine formulations was adjusted to achieve comparable whole-blood trough levels. Mean serum creatinine values were higher in the cyclosporine emulsion group at baseline, 8, and 12 weeks (P<0.05). The incidence of acute rejection was similar in both treatment groups although fewer patients required monoclonal antibody therapy in the cyclosporine group (31% vs. 82%, respectively). Despite the increased bioavailability of cyclosporine emulsion, no significant differences in the incidence of adverse events were observed; the safety, tolerability, and efficacy of cyclosporine emulsion and cyclosporine were comparable.

Neoral: a microemulsion cyclosporine.

Cyclosporine (Sandimmune), introduced in the 1980s, improved patient and graft survival rates primarily by decreasing the frequency and severity of early, acute rejection. Today, the challenge for coordinators and clinicians is to promote long-term clinical stability in transplant recipients. This requires maintaining the cyclosporine blood level within a relatively narrow therapeutic range to ensure adequate and stable immunosuppression, thus reducing the risk of rejection caused by a suboptimal drug level or drug-related toxicity because of a level above the therapeutic range. However, the clinical use of Sandimmune is complicated by low bioavailability and highly variable pharmacokinetics that provide management challenges and can affect clinical outcomes adversely. Neoral, a new oral microemulsion formulation (in capsules and oral solution) of cyclosporine, improves the bioavailability and pharmacokinetics of cyclosporine and reduces inter- and intraindividual pharmacokinetic variability with a safety profile comparable to that of Sandimmune.