Patient demographics and characteristics are shown in Table 1 and individual subject pharmacokinetic profiles 24 h after single oral dose of tacrolimus PR formulation are presented in Figure 1. The corresponding parameters at different dosages are shown in Table 2. Plasma concentration time curves for each dose level are shown in Figure 2. There were two peaks in drug concentrations; a primary peak appeared at the end of about 2 h followed by a small secondary peak at h 12 which was more noticeable in the 0.10 mg/kg dose group than in the two lower dosages.

In the 3 ascending dosage groups (0.02, 0.05 and 0.10 mg/kg), the mean C_max normalized for the administered dose(C_max/D) were 1.7, 2.1, 1.9 kg· μ g/(L· mg), respectively; Average AU C0-∞norma-lized for the administered dose(AU C0-∞/D) were 25.2, 62.9, 39.9 kg· h· μ g/(L· mg), respectively. Both the mean C_max/D and average AU C0-∞/D were higher in the 0.05 mg/kg dosage group than in the 0.02 and 0.10 mg/kg dosage groups (Table 3). V/F normalized for body weight were 6.6, 10.8 and 44.0 L/kg, respectively. CL/F were 0.5, 0.4 and 1.5 L/(h· kg), resulting in a relative longer half-life of 9.3, 18.5 and 19.9h, respectively. Both V/F and CL/F were higher in the 0.10 mg/kg dosage group than in the other two groups.

Table 1

Table 1

Table 1 Demographic, laboratory, and renal function data Characteristic Total(n=8) Dosage regimen/ (mg/kg) 0.02(n=2) 0.05(n=2) 0.10(n=4) Age/years 11.7(7.5-14.5) 12.0, 10.1 7.5, 8.2 12.1(11.5-14.5) M/F, n 6/2 2/0 1/1 3/1 Weight/kg 38.1(22.3-48.2) 46.1, 48.2 22.3, 31.3 40.0(32.0-48.0) Height/cm 144.0(120.0-162.0) 139.0, 148.0 120.0, 127.0 144.0(142.0-162.0) BMI/(kg/m2) 18.0(14.8-23.8) 23.8, 21.9 15.2, 19.8 19.4(14.8-23.8) Primary nephritic syndrome Steroid-dependent 2 2 0 0 Steroid-resistant 6 0 2 4 CrCl/(mL/min) 170.2(139.5-237.8) 139.5, 159.7 224.6, 237.8 170.2(159.7-180.6) Results are presented as the number, or median (range). BMI, body mass index; CrCl, creatinine clearance rate.

Table 1 Demographic, laboratory, and renal function data

Table 2

Table 2

Table 2 Tacrolimus PR single-dose pharmacokinetic parameters by subject Subject Dosage/ (mg/kg) t1/2/h tmax /h Cmax/ (μ g/L) AUC0-24/ (h· μ g/L) AUC0-∞ / (h· μ g/L) V/F/ (L/kg) CL/F / [L/(kg· h)] MRT0-24 /h MRT0-∞ /h 1 0.02 4.5 2.0 1.0 13.4 13.9 9.4 1.5 8.5 9.4 2 0.02 19.0 1.0 2.4 44.4 80.5 4.6 0.2 10.9 42.1 3 0.05 28.1 4.0 1.8 31.4 74.7 18.3 0.5 11.3 29.1 4 0.05 12.2 6.0 4.4 70.0 93.3 6.4 0.4 9.7 17.6 5 0.10 14.5 2.0 3.3 59.1 86.6 14.7 0.7 10.6 21.5 6 0.10 31.3 2.0 11.4 125.0 284.5 143.6 3.2 10.1 43.2 7 0.10 11.0 2.0 9.8 44.0 80.6 14.7 0.9 5.0 15.4 8 0.10 31.2 1.0 7.4 106.2 250.5 121.4 2.7 10.3 44.1 t12,terminal elimination half-life; tmax, time to reach the maximum drug concentration ; Cmax , maximum drug concentration; CL/F, oral clearance; V/F, volume of distribution by body surface area; AUC0-24 , area under the drug concentration-time curve during 24 h; AUC0-∞ , total area under the drug concentration-time curve; MRT, mean retention time.

Table 2 Tacrolimus PR single-dose pharmacokinetic parameters by subject

Figure 1

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	Figure 1 Tacrolimus PR individual blood concentrations curve for 0-24 hours after oral administration once(n=8) Curve 1 to 8 represented tacrolimus PR blood concentrations of patient 1 to 8, respectively.

Figure 2

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	Figure 2 Tacrolimus PR average blood concentrations curve with different dosage group for 0-24 hours after oral administration once

Table 3

Table 3

Table 3 Tacrolimus PR single-dose pharmacokinetic parameters by dosage group Parameter Total(n=8) Dosage/ (mg/kg) 0.02(n=2) 0.05(n=2) 0.10(n=2) Cmax/(μ g/L) 5.2± 3.9 1.0, 2.4 1.8, 4.4 8.0± 3.1 Cmax/D/[kg· μ g/(L· mg)] 1.9± 1.3 1.1, 2.3 1.4, 2.8 1.9± 0.8 t1/2 /h 19.0± 5.9 4.5, 19.0 28.1, 12.2 22.0± 9.3 AUC0-24/ (h· μ g/L) 61.7± 35.2 13.4, 44.4 31.4, 70.0 83.6± 33.1 AUC0-∞ /(h· μ g/L) 120.6± 88.3 13.9, 80.5 74.7, 93.3 175.6± 92.8 AUC0-∞ /D /[kg· h· μ g/(L· mg)] 42.5± 16.4 14.1, 36.3 56.3, 69.5 39.9± 15.7 CL/F/ [L/(kg· h)] 1.2± 1.1 1.5, 0.2 0.5, 0.4 1.9± 1.1 V/F /(L/kg)a 14.7(4.6-143.6) 9.4, 4.6 18.3, 6.4 68.1(14.7-143.6) MRT0-24/ha 10.2(5.0-11.3) 8.5, 10.9 11.3, 9.7 10.2(5.0-10.6) MRT0-∞ /ha 25.3(9.4-44.1) 9.4, 42.1 29.1, 17.6 32.3(15.4-44.1) Results are presented as the number, or mean± SD. a, presented by median and range. Cmax, maximum drug concentration; AUC0-24 , area under the drug concentration-time curve during 24 h; AUC0-∞ , total area under the drug concentration-time curve; Cmax/D and AU C0-∞/D are dose norma-lized Cmax and AU C0-∞, respectively ; t12,terminal elimination half-life; CL/F, oral clearance; V/F, volume of distribution by body surface area; MRT, mean retention time.

Table 3 Tacrolimus PR single-dose pharmacokinetic parameters by dosage group

No adverse events were reported during the 7 days observation period and there were no cases of dose modification, interruption, or withdrawal from the study.

This is a pharmacokinetic study of prolonged-release formulation of tacrolimus in pediatric nephrotic syndrome recipients. The study population included two subjects with steroid-dependent primary nephritic syndrome, neither of whom was taking prednisone or methylprednisolone. We also wanted to see if the pharmacokinetics of tacrolimus was affected by disease type. Whereas the two steroid dependent patients did not need much dose, the two were brought into the lowest dosage group, which was also in the consideration of the morality and ethics. Maybe somebody would query the potential bias on the data, the patient’ s benefit was first.

It was found that the measurement of drug exposure per individual patient determined using the AUC de-pended on the dosage, suggesting that the higher group required a higher AUC than the lower group. However, no clear relationship was established when AUC was normalized to the administered dose (Table 3).

Half-life is a measurement of how rapidly drugs are cleared from the body, and is determined by the status of relevant drug-metabolizing enzymes and transporters. As shown in Table 3, the 0.02 mg/kg dose level exhibited a significantly faster tacrolimus clearance than that in the two higher dosage groups.

The present data for C_max/D, AUC_0-∞ /D and t_1/2 are similar to those reported in a study comparing Hispanic and non-Hispanic children with kidney transplants, although CL/F in the present study is lower than that in the previously reported study ^[3].Multiple factors may be responsible for differences in long-term outcomes among children of different ethnic backgrounds, including biological differences in drug metabolism and pharmacokinetics. However, it has been reported that CL/F data are inconclusive for pediatric Chinese kidney disease recipients with some reports suggesting similar trends as in adults^[15]. The mean CL/F across all doses of tacrolimus in the present study (Table 3) is in agreement with previously reported va-lues of 0.76 L/(h· kg) in 50 pediatric kidney transplant patients ^[16].

A study of 30 children reported that the tacrolimus AUC at a mean dosage of 0.12 mg/kg tacrolimus was 192 h· μ g/L ^[6]. Another group of workers reported that a mean dosage of 0.15 mg/kg resulted in a mean AUC of 197 h· μ g/L in 18 children 2 weeks after transplantation ^[7]. These values are higher than the mean AUC values obtained across all doses in our stu-dy. However, the mean doses in these two studies were also notably higher than those in our study.

A limited retrospective review of published tacrolimus pharmacokinetic profiles in Chinese pediatric recipients with kidney disease suggests that important dose-related differences may exist for various pharmacokinetic parameters^[3]. However, in our study it was not possible to estimate these differences due to the small sample size and high degree of inter-individual variation. But despite the large interindividual variabi-lity in absolute values the overall drug concentration-time profile curves for tacrolimus PR formulation appear to be similar (Figure 1 and 2).

The pharmacokinetics parameters of tacrolimus are affected by various factors. Associated clinical covariates reported include genetic variation in CYP3A4 and CYP3A5, ABCB1 genotype and levels of hematocrit^[5]. Ethnic variability in hepatic CYP3A activity or expression is inconsistent among different publications and is poorly characterized in the literature^[17]. Stu-dies in adult kidney transplant recipients show different pharmacokinetic profiles in White subjects compared with African Americans and Asian subjects^{[3, 4]}. This may be due to the higher expression of drug-metaboli-zing enzymes and/or transporters leading to faster tacrolimus clearance. However, one study^[12] found no differences in intravenous tacrolimus pharmacokinetic profiles in healthy adult White, African American, and Hispanic volunteers. These observations may be attri-buted to ethnically associated differences in intestinal CYP3A and/or P-glycoprotein activity rather than to hepatic CYP3A activity. P-glycoprotein (P-gp) is the product of ABCB1 gene and acts as transmembrane efflux pump for many drugs^[18]. It has been published in the literature that changes in the activity and levels of P-gp are one of the possible mechanisms of drug resis-tance^[19].Significantly higher expression of ABCB1 and P-gp activity in T lymphocytes was detected in steroid-resistant nephrotic syndrome children compared with sensitive children^[20].Corticosteroids are strong indu-cers of CYP3A4 and ABCB1, resulting in influences on trough concentrations of tacrolimus as well. Additionally, a study in pediatric liver recipients has showed that younger children need more tacrolimus than older children to reach the same tacrolimus target concentration but the reason is unknown. A wide range of age-related differences in drug disposition, such as CYP3A4/5 metabolism and P-gp transport, protein and erythrocyte binding was suggested^[5].

A major limitation of this small retrospective ana-lysis was that it included only patients with problems achieving adequate target tacrolimus trough levels, and this selection bias limited the scope of our conclusions. In addition, due to the small sample size, this study was unable to consider other independent variables such as age. Given these limitations, our review stresses the need for a larger number of prospective studies in pediatric subjects in order to help us understand ethnic differences in children with nephrotic syndrome. This population, who often exhibit lower AUC at a given dose when adjusted for weight or surface area, and a larger volume of distribution, require a higher or more frequent dose. This highlights the need to perform larger scale pharmacokinetic studies in Chinese children with nephrotic syndrome who fail to achieve target tacrolimus trough levels.

Pharmacokinetics of tacrolimus PR formulation in pediatric nephrotic syndrome recipients showed inter-individual variation. Our data for C_max/D, AUC_0-∞ /D and t_1/2 are similar to previously published findings but the values of CL/F were lower than those documented in the literature. Higher C_max/D and AU C0-∞/D were observed in the 0.05 mg/kg dose group and higher V/F and CL/F in the 0.10 mg/kg dosage group. These phenomena form bases for subsequent larger scale pharmacokinetic studies in Chinese children with nephrotic syndrome.