David I. Min

The pharmacokinetics of a microemulsion formulation of cyclosporine in primary renal allograft recipients

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.

C3435T mutation in exon 26 of the human MDR1 gene and cyclosporine pharmacokinetics in healthy subjects.

To determine the relationship between C3435T mutation in exon 26 of the human multidrug resistant 1 (MDR1) gene and cyclosporine pharmacokinetic parameters among healthy volunteers, the oral cyclosporine pharmacokinetic study was performed for 14 healthy subjects. Blood cyclosporine concentrations were measured by HPLC. Concentration–time data were analyzed by a noncompartmental method using WinNonLin, and the blood samples were genotyped for the C3435T polymorphism of MDR1 gene using the PCR and a restriction digest. Each cyclosporine pharmacokinetic parameter was compared using the Mann-Whitney U test according to his or her P-gp genotype. There were seven (7) homozygous C/C, six (6) C/T, and one (1) homozygous T/T genotypes in these 14 healthy volunteers. According to their genotypes, mean tmax 1.6 ± 0.3 hours, mean Cmax 1337 ± 329 ng/mL, mean Cl/F 66.5 ± 18.3 L/h, and mean AUC 5642 ± 1577 ng·h/mL in C/C group and mean tmax 2.0 ± 0.6 hours, mean Cmax 1540 ± 721 ng/mL, mean Cl/F 55.2 ± 18.9 L/h, and mean AUC 6902 ± 1405 ng·h/mL in C/T+T/T group. Although Cmax and AUC in C/T and T/T group were 15% and 22% larger than those in C/C group, none of these parameter comparisons was statistically significant. There were no statistical differences in cyclosporine pharmacokinetics among different MDR1 genotypes in these 14 healthy subjects.

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·hr/mL per milligram and 18.1 ± 4.1 ng·hr/mL per milligram, respectively, in African Americans and 61.9 ± 6.8 ng·hr/mL per milligram and 24.2 ± 4.6 ng·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.

CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects

To determine the relationship between CYP3A5 polymorphism and cyclosporine pharmacokinetic parameters among healthy volunteers, an oral cyclosporine (CsA) pharmacokinetic study was performed in 16 healthy subjects. Blood CsA concentrations were measured by high-performance liquid chromatography. Concentration-versus-time data were analyzed by a noncompartmental method using WinNonLin, and the blood samples were genotyped for the CYP3A5 using the polymerase chain reaction and pyrosequencing. CsA pharmacokinetic parameters were dichotomized and compared using the 1-way ANOVA test according to the CYP3A5*3C genotype. There were 6 homozygous A/A (wild type), 6 homozygous G/G (variant), and 4 heterozygous A/G genotypes for CYP3A5*3 C in these 16 healthy volunteers. All whites were G/G group, and all African Americans except 1 were either A/A or A/G group. The mean AUC (ng·h/mL) of CsA for the 3 genotype groups were 4962 ± 1074 (A/A), 6677 ± 1153 (G/G), and 5416 ± 1817 (A/G), (A/A versus G/G, P = 0.03), and the mean CL/F (mL/min/kg) were 15.6 ± 3.1 (A/A), 12.0 ± 2.3 (G/G), and 14.7 ± 5.9 (A/G), (A/A versus G/G, P = 0.04). None of the other parameters were significantly different among the 3 genotypes. In conclusion, the CYP3A5*3C polymorphism appears to affect AUC and CL/F of oral CsA significantly in healthy subjects, which may partly explain some of the differences of pharmacokinetics in CsA between African Americans and whites.

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‐performace 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.

Association of the CYP3A4*1B 5′-flanking region polymorphism with cyclosporine pharmacokinetics in healthy subjects

To determine the relationship between CYP3A4*1B polymorphism and cyclosporine pharmacokinetic parameters among healthy volunteers, the oral cyclosporine pharmacokinetic study was performed in 14 healthy subjects. Blood cyclosporine concentrations were measured by a high performance liquid chromatography. Concentration–time data were analyzed by a non-compartmental method using WinNonLin, and the blood samples were genotyped for the CYP3A4*1B 5´-promotor region using the polymerase chain reaction and a restriction digest. Each cyclosporine pharmacokinetic parameter was compared using the one-way ANOVA test according to his or her CYP3A4*1B genotype. There were four (4) homozygous A/A (wild-type), four (4) homozygous G/G (variant) and six (6) heterozygous A/G genotypes for CYP3A4*1B in these 14 healthy volunteers. The mean AUC/D (ng.hr/mL/mg) of CsA were 21.5 ± 6.0 (A/A), 11.7 ± 3.2 (G/G) and 19.2 ± 2.3 (A/G), P = 0.0103 and the mean CL/F (L/hr) were 49.4 ± 13.9 (A/A), 83.5 ± 16.0 (G/G), and 52.5 ± 5.6 (A/G), P = 0.0024. All other parameters were not significantly different among the three genotypes.

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.

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.

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 GJ as well as IV 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.

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

A 12-week, randomized, double-blind, multicenter pharmacokinetic 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 emulsion group than 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.