Pharmacokinetics of cyclosporine in pediatric long-term liver transplant recipients converted from Sandimmun to Neoral

Absorption of cyclosporin from the microemulsion formulation Neoral is less variable than from Sandimmun. Because of a lack of data in pediatric liver transplant recipients, the pharmacokinetic profiles with Sandimmun and Neoral were compared in a conversion study. Thirty-eight children with stable graft function were converted 2–12.3 years post-transplant at a 1:1 ratio. The trough-level (C_min) with Neoral was 123 ± 39 ng/ml versus 134 ± 29 ng/ml with Sandimmun (P = NS), the area under the time-concentration curve (AUC) was 3325 ± 1125 ng_*h/ml versus 2423 ± 846 ng_*h/ml (P < 0.001), the peak concentration (C_max) was 650 ± 280 ng/ml versus 337 ± 142 ng/ml (P < 0.001), and the median time to C_max was 2 h (range 0.5–3 h) versus 4 h (range 1–8 h; P < 0.05). The weak correlation between C_min and AUC with Sandimmun (r = 0.5; P = NS) was improved by using Neoral (r = 0.7; P < 0.001). The best predictor of AUC was the 2-h concentration (C_{2 h}) of Neoral (r = 0.9; P < 0.001). Increased absorption and a more predictable pharmacokinetic profile with Neoral permit safer therapeutic monitoring in children. The exclusive measurement of Neoral-C_{2 h} allows one to estimate drug exposure with high precision ( > 90 %). Received: 12 February 1997 Received after revision: 16 May 1997 Accepted: 5 June 1997     

Neoral induction in pediatric renal transplantation

Neoral was instituted in pediatric renal transplant patients with the hypothesis it would have more predictable kinetics than Sandimmun. However, significant questions have arisen concerning potential toxicity and dosing interval related to its rapid absorption with subsequent high initial peak. This is compounded by the fact that children appear to metabolize cyclosporine at a greater rate than adults. This combination of a rapid peak and rapid absorption may then result in lower trough levels at 12 h. We compared the trough cyclosporine levels of nine children who received Neoral with nine who received Sandimmun at the time of initial transplantation. More frequent dosing (every 8 h) was required in the Neoral population compared with the Sandimmun population for the 1st month in order to obtain comparable trough levels. Beyond the initial 4–6 weeks, trough levels were similar for Neoral and Sandimmun. Whereas 1-month creatinine levels and blood pressures were similar, the number of blood pressure medications was significantly higher in the Neoral group. At 5.5 ± 1.1 months’ followup, a single patient in the current Neoral group and in the retrospective Sandimmun group each experienced a single OKT3 allograft-treated rejection. We suggest that the area under the curve is different in Neoral than Sandimmun, and the initial dosing frequency may need to be adjusted accordingly. Received August 21, 1996; received in revised form June 27, 1997; accepted June 30, 1997     

Influence of bile on cyclosporin absorption from microemulsion formulation in primary liver transplant recipients

We analysed the absorption, after oral application, of a new galenic form of cyclosporin A (CyA-NOF) in liver-grafted patients (n=12) during the 1st week (days 2–4) after transplantation. Pharmacokinetic profiling was performed with an open or clamped T tube in situ or with the T tube absent. The pharmacokinetic parameters of CyA-NOF were influenced by T tube clamping and bile diversion. The highest AUC, C_max and earliest T_max values were found in patients without a T tube in situ, indicating that absorption of CyA-NOF in patients during the early course after liver transplantation is not bile-independent. CyA-NOF, at a dose of 7.5 mg/kg, was enterally absorbed with appropriate AUC and C_max levels. Patients receiving a starting dose of 7.5 mg/kg were successfully maintained on CyA-NOF during the subsequent clinical course.     

Neoral吸收期血药浓度和药物暴露量在中国成人肝移植受体中的变异性分析

目的通过分析中国成人肝移植受体中Neoral吸收期血药浓度与药物暴露量的变异性，为临床上发展新的Neoral治疗药物监测方法提供理论依据。方法通过定期测定22例中国成人肝移植受体口服Neoral前及服药后1、2、3、4h的血药浓度，采用个体及群体药代动力学的方法计算出个体内和个体间变异系数(CV）。结果Neoral血药浓度和AUC0～4的个体内和个体间变异系数均在服药头2h达到高峰，此后逐渐下降。术后10～11d个体间的浓度及AUC变异系数均最高。结论Neoral吸收期的变异性主要集中在服药后头2h。服药后1w左右是变异性最大的时期。     

Comparison of Neoral and Sandimmun cyclosporin A pharmacokinetic profiles in young renal transplant recipients

A major factor influencing whole blood cyclosporin A levels in young children with renal transplants is the variable absorption of Sandimmun (SIM). Neoral (NEO) is a new microemulsion of cyclosporin A (CYA) that has been reported to have better absorption characteristics. We compared the pharmacokinetics of SIM and NEO in nine renal transplant recipients aged less than 11 years (range 4.8 – 10.9 years) and observed clinical parameters during 6 months of NEO therapy. Median CYA dosage was 149 mg/m² per day (range 98 – 226). We observed an increase in the maximum CYA concentration (C_max) of 114%, an increase in area under the curve (AUC) of 71% and the time to reach C_max was reduced from 1.75 h to 1.25 h with NEO, while 12-h trough levels (C12 h) did not change significantly. AUC correlated with C12 h for SIM (r ² = 0.833) and NEO (r ² = 0.699) and also C1.5 h for NEO (r ² = 0.775). During 24 weeks’ follow-up, the coefficient of variation of CYA levels was lower for NEO (13%) than for SIM (20%). Although CYA dosages at the start and the end of 6 months on NEO were similar, only one patient was maintained on a constant dose. Four patients had acute reversible rises in plasma creatinine which responded to a 11% reduction in NEO dose; their increase in AUC was greater than those patients not showing a rise in plasma creatinine. Overall, median plasma creatinine was unchanged at the end of the study. NEO was well tolerated by the patients; temporary nausea and headache were experienced by three patients and one of them stopped NEO after 20 days. Other biochemical parameters were not significantly different on NEO. Received May 28, 1996; received in revised form and accepted October 24, 1996     

Pharmacokinetics of a new microemulsion formulation of cyclosporin A (Neoral) in young patients after renal transplantation

Pharmacokinetics of the new galenic formulation of cyclosporin A, Neoral, (Sandoz) was examined in 12 stable young patients after renal transplantation. Six of these patients were tested before and 4 weeks after switching from the standard formulation Sandimmun to Neoral. No significant changes were observed in trough levels, t_max, C_max, and AUC_0–12h, but the absorption rate constant (K_a) increased (P=0.003). Glomerular filtration rate, as assessed by inulin clearance, increased by more than 10% in three patients and decreased in two, and was usually associated with a respective drop and rise in C_max and AUC_0–12h of cyclosporin A. The large interindividual variability in the response to the conversion to the new formulation points to a need for close monitoring of cyclosporin A trough levels and renal function after switching from Sandimmun to Neoral in this age group in order to avoid nephrotoxicity.     

Reduced variability of Neoral pharmacokinetic studies in pediatric renal transplantation

In adult renal transplant recipients the Neoral area under the curve (AUC) displays less inter- and intra- individual variability than Sandimmune, and those renal transplant recipients with reduced intra-individual variability of the AUC have a lower risk for chronic rejection. As variability of Neoral pharmacokinetic (Pk) parameters has not been investigated in pediatric renal transplant recipients, we retrospectively analyzed 453 Pk profiles in 14 pediatric patients who were switched from Sandimmune to Neoral and compared the inter- and intra-individual variability of the Pk profiles on both formulations. After the switch, we observed less inter- and intra-individual variability of AUC, the 2-h concentration, and the oral clearance. As clearance with both formulations is supposedly equal, the significantly lower intra-individual variability of oral clearance is most likely an effect of less variable absorption. While the lower inter-individual variability of the Pk parameters suggests increased success in keeping cyclosporine concentrations on target, the lower intra-individual variability leads to the hypothesis that with Neoral, a lower incidence of chronic rejection might be achieved. Received: 8 February 2000 / Revised: 17 May 2000 / Accepted: 22 May 2000     

Hypomagnesemia during pediatric orthotopic liver transplantation

We evaluated the incidence and severity of serum magnesium (Mg) abnormality along with other electrolyte and acid-base disturbances before and during the course of orthotopic liver transplantation (OLT) in pediatric patients. Serum Mg, Na, K, ionized Ca, pH, and blood gas measurements were performed before and hourly during the course of OLT. Hypomagnesemia was frequently observed in children undergoing OLT. Of a total of 30 recipients, 27 (90%) had hypomagnesemia before surgery; the mean serum Mg value at this time was 0.77±0.15 mmol/L. In most of the recipients, the serum Mg value showed a gradual decrease during the course of OLT until magnesium sulfate supplements were administered. On the other hand, the serum Na, K, and ionized Ca levels and acid-base balance were normal before the beginning of surgery. However, hypernatremia, hypokalemia, a decrease in ionized Ca, and metabolic acidosis were commonly observed during the course of OLT. We conclude that electrolyte abnormalities, including hypomagnesemia and metabolic acidosis, commonly develop in children during the course of OLT. The frequent assessment of electrolytes, pH and blood gases is essential for the correction of these abnormalities during the course of OLT.     

Neoral pharmacokinetics in Latino and Caucasian pediatric renal transplant recipients

Interpopulation variability of drug pharmacokinetics (PK) has been described. For example, the systemic clearance of nifedipine is higher in Mexicans than Caucasians. African-Americans have a lower cyclosporine bioavailability than Caucasians. Limited data are available in the Latino population. Under identical conditions, we compared the PK profile of Neoral (cyclosporine for microemulsion) obtained in stable pediatric renal transplant recipients of Latino and Caucasian origin. A slightly lower area under the curve (AUC) when corrected for dose per body surface area or per kilogram of body weight was observed in Caucasians compared with Latinos. This difference was more pronounced in the younger age group (<12 years) with a higher peak-to-trough ratio. However, the Caucasians required a higher dosage of Neoral than the Latinos to achieve that same AUC. There was no difference between the groups in the time (t_max) to reach maximal concentration (C_max) of Neoral. A higher apparent clearance of the drug was observed in the Caucasians compared with the Latinos, especially in the younger age group. No differences in pre- and post-dose levels were observed between the two groups. These differences might affect dose adjustment between the two subpopulations. Received: 30 June 2000 / Revised: 21 November 2000 / Accepted: 21 November 2000     

Impact of late conversion from C0 to C2 monitoring of microemulsified cyclosporine in pediatric living donor liver transplant recipients

The efficacy and feasibility of 2-h post-dose level (C2) monitoring of cyclosporine in long-term living donor liver transplantation (LDLT) is not clear. The aim of this study was to investigate the impact of late conversion from conventional trough-level (C0) monitoring to C2 monitoring of a microemulsion form of cyclosporine (Neoral) in pediatric LDLT recipients. From June 1994 to August 2002, we performed 116 LDLTs in 115 patients. Initially, we adapted conventional C0 monitoring of Neoral, which was converted to C2 monitoring starting in January 2002. The 60 patients who were enrolled in the study had the following characteristics: they were younger than or equal to 15 yr at transplantation, and they had survived LDLT, and they had received a Neoral-based immunosuppression regimen, and they underwent conversion to C2 more than 1 month after transplantation. We evaluated the impact of conversion on doses, blood levels, rejection, adverse effects, and patient/graft outcome. In the long-term patients, the mean C2 levels immediately after conversion were higher than the target levels at any time point selected after transplantation; thus, 34 patients (57%) finally required a dose reduction of Neoral. The current mean C2 level was significantly lower than that observed immediately after conversion (584.6 +/- 262.8 ng/ml vs. 893.1 +/- 260.2 ng/ml, mean +/- SD, p < 0.0001) with a mean follow-up period of 7.4 +/- 0.6 months (range: 5-8 months) after conversion. Only one patient encountered rejection after conversion (1.7%), and no de novo infection or adverse effects were observed. Traditional C0 monitoring of Neoral was safely replaced by C2 monitoring without an increase in the rejection rate or any adverse effects in pediatric LDLT patients. C2 monitoring contributed to the dose reduction of Neoral, which may lead to the avoidance of long-term complications due to immunosuppression.     

Standardized quick en bloc technique for procurement of cadaveric liver grafts for pediatric liver transplantation

This paper describes a quick procedure for cadaveric liver graft retrieval during multiple organ harvesting. The technique is based on minimal preliminary dissection, absence of in situ direct portal perfusion, and en bloc removal of the liver and pancreas, with an aortic patch encompassing the coeliac trunk and superior mesenteric artery. The results of 110 pediatric liver transplantations with 109 organs harvested using this technique are reported. There were no graft harvesting injuries. The liver graft primary nonfunction rate was 4.5% (5/110). The 3-month retransplantation rate was 10%. The actual patient survival rates were 93% at 3 months and 90% at 1 year; actual graft survival rates were 85.5% and 78%, respectively. The technique described was at least as safe as conventional procedures. A major advantage of the procedure is its flexibility, which allows for the easily combined procurement of other organs (whole pancreas and intestine).     

Liver and serum expression of matrix metalloproteinases in asymptomatic pediatric liver transplant recipients

We related hepatic gene and serum expression of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) to liver histology in pediatric LT recipients. Liver biopsies and serum samples were obtained from 52 patients 10.6 years post‐LT and age‐matched controls for analyses of MMPs and TIMPs. Patients with fibrosis had significantly higher hepatic gene expression of MMP‐2, MMP‐9, MMP‐14, TIMP‐1, and TIMP‐2 than patients without. Expression of these genes correlated with graft Metavir fibrosis stage (r = 0.494–0.684, P ≤ 0.006 for all). Gene expression of MMP‐1, MMP‐3, MMP‐8, TIMP‐3, and TIMP‐4 was undetectable in both patients and controls. Portal inflammation and cytokeratin 7 correlated positively with gene expression of TIMP‐1. Gene expression of MMP‐2, MMP‐9, and TIMP‐2 correlated negatively with the time of low‐dose cortisone usage (r = ?0.448 to ?0.422, P < 0.05 for all). Serum concentrations of MMP‐8 and TIMP‐1 were significantly increased and MMP‐9 decreased among patients compared with controls, but no correlations to graft histology or gene expression were observed. Hepatic gene expression of certain MMPs and TIMPs is increased in stable pediatric LT recipients displaying graft fibrosis, but this did not reflect to their serum concentrations. Increased hepatic gene expression of TIMP‐1 correlated with graft fibrosis stage, inflammation, and chronic cholestasis.     

Sotrastaurin single‐dose pharmacokinetics in de novo liver transplant recipients

Sotrastaurin is a protein kinase C inhibitor in development for prevention of rejection after liver transplantation. In a pharmacokinetic study, 13 de novo liver transplant recipients received 100 mg sotrastaurin once between days 1–3 and once between days 5–8 post‐transplant. Sotrastaurin absorption based on the area under the concentration‐time curve (AUC) of total drug in blood (3544 ± 1434 ng·h/ml) was similar to that of healthy subjects in a previous study (4531 ± 1650 ng·h/ml). However, the sotrastaurin binding protein, α1‐acid glycoprotein, was nominally higher in patients (1.07 ± 0.28 vs. 0.87 ± 0.16 g/l, P = 0.13) yielding a 60% lower AUC based on free drug versus that in healthy subjects (27 ± 13 vs. 62 ± 15 ng·h/ml, P < 0.0001). There was minor excretion of sotrastaurin in drained bile (1% of dose) consistent with the fact that sotrastaurin is extensively metabolized leaving little unchanged drug to excrete. In the first week after liver transplantation, sotrastaurin is bioavailable after oral administration. However, patients with elevated α1‐acid glycoprotein levels may have lower free drug concentrations. Whether a higher dose of sotrastaurin is needed to compensate for this in the short‐term after surgery will be addressed in future clinical trials.     

The management and long-term results of Japanese pediatric liver transplant recipients

We investigated the long-term results and ongoing management issues of 39 Japanese children who underwent liver transplantation in Brisbane, Australia. Whole liver grafts were used in 15 patients (Wh group) and reduced-size grafts were used in 24 patients (Re group). The 1-year and 3-year survival rates were 74% and 60%, respectively, and all cases of late mortality which occurred after 6 months were due to infection. Statistical analysis showed no differences between the Wh and Re groups with regard to late mortality or liver function tests, although 4 of 24 (16.7%) patients from the Re group developed a recurrence of esophageal varices. Three patients treated with cyclosporine developed lymphoproliferative disorders following transplantation, but none of the patients developed severe nephrotoxicity or hypertension. Although a cathch-up gain in weight was observed, poor growth in height was displayed, and there were no differences between the Wh and Re groups in this regard. Thus, we conclude that late complications of liver transplantation in children are common and further studies are necessary to evaluate the ongoing growth problems.     

A limited sampling strategy for the estimation of Neoral AUCs in pediatric patients

The improved pharmacokinetics of Neoral allows the development of an accurate estimate of the full area under the concentration time curve (AUC) from a limited sampling strategy. As no such strategy has been derived from pharmacokinetic data obtained from children on 12-hourly dosing, and as patient convenience demands shorter sampling times, we derived a limited sampling strategy from 45 AUCs obtained from 19 pediatric renal transplant patients by stepwise forward multiple regression, and prospectively tested them on a separate group of 49 AUCs obtained from 18 pediatric renal transplant patients. Full cyclosporine (CsA) AUCs were obtained from samples drawn pre dose (C0) and at 2, 4, 6, 8 and 12 h post dose (C2, C4, C6, C8, and C12). High-precision predictions of full AUC were obtained based on the formula: AUC = 444 + 3.69 × C0 + 1.77 × C2 + 4.1 × C4 (mean prediction error ± SD = 0.3 ± 6.4%, 95% confidence interval=–1.7% to 1.9%.) In conclusion, CsA exposure in pediatric renal transplant patients on 12-hourly Neoral dosing can be reliably predicted by an early time point-based limited sampling strategy in children. This formula has the advantage of obtaining trough as well as AUC from one brief, convenient sampling period. Received: 7 August 1998 / Revised: 23 November 1998 / Accepted: 25 November 1998     

Chronic rejection of liver transplants revisited

We examined 27 hept-ectomy specimens to assess the frequency of foam cell endovasculitis and bile duct loss in chronic rejection. Arterial lesions, defined as total occlusion by subintimal foam cells and/or fibromuscular proliferation, were found mainly in hilar and septal arteries, whereas bile duct loss, defined as the absence of bile ducts in more than 50% of portal tracts, affected aminly small tracts. Both were found in 20 livers (74%). In two livers (7%) there was significant bile duct loss but no arterial lesions, whilst in five cases (19%) there were occlusive arterial lesions but no bile duct loss. Small arteries were involved in only 10% of the cases. These results indicate that in one-third of the cases arterial and bile duct lesions develop independently of each other, suggesting different pathogenetic pathways. In addition, liver biopsy may not be pathognomonic since small arteries are involved in only 10% of cases and bile duct loss may not be extensive. In such cases the diagnosis of chronic rejection should only be made in the presence of progressive clinical deterioration.     

Biliary complications after paediatric liver transplantation: Birmingham's experience

Between 1983 and 1992, 112 children underwent liver transplantation. Of 138 grafts, 60 (43.4%) were whole livers, 77 (55.6%) were reduced livers, and 1 (0.7%) was a split liver. Biliary complications (BC) were defined as any abnormality, even minor, related to the biliary tract. Results were analysed with a minimum follow-up of 9 months. Some 36 grafts (26.1%) in 34 patients (30.4%) presented with BC: bile leaks (17 grafts), biliary obstructions or dilatations (16 grafts), and other complications (3 grafts). Management was mainly surgical with biliary reconstruction via a Roux-en-Y loop. Interventional radiology had an increasing role in recent years. BC were associated with a mortality of 1.8% (2/112), a graft loss rate of 4.3% (6/138), and significant morbidity. Among the various factors whose association with BC was studied, the date of transplantation, the use of reduced grafts and the use of gallbladder conduits appeared to be the main determining factors for BC. From multivariate analysis the use of reduced grafts emerged as the most important factor in reducing BC. We therefore conclude that BC are associated with significant morbidity, but general improvements in both surgical and medical management seem to account for better results in recent years.     

儿童肝移植治疗Alagille综合征的疗效分析

目的探讨Alagille综合征(AGS)的临床特点及肝移植治疗AGS的疗效及预后。 方法回顾性分析2015年4月至2019年3月在复旦大学附属华山医院普外科接受肝移植的6例AGS患儿临床资料。6例患儿中位年龄15个月(6～39个月),术前儿童终末期肝病模型评分平均(21±9)分;6例患儿均存在黄疸、瘙痒以及特殊面容等不同程度的终末期肝病表现,术前均通过基因诊断明确JAG 1基因突变。4例行左外叶活体肝移植,2例行经典原位肝移植。儿童肝移植受者术前与术后1个月ALT、血清总胆红素、总胆固醇及体质量Z值采用配对t检验进行比较,术前与术后身高Z值采用配对样本Wilcoxon符号秩和检验进行比较。 结果6例儿童肝移植手术均顺利完成。截至2019年7月,中位随访时间为12个月(3～50个月),6例受者及移植物均正常存活,均未发生急性肝衰竭、血管并发症或排斥反应等严重并发症,黄疸、瘙痒等症状消退,黄色瘤体积逐渐减少至消失,肝功能正常,生长发育均呈追赶增长。6例受者术前和术后1个月身高、体质量Z值分别为[-3.0(-1.97～-3.90)]和[-3.1(-2.38～-3.40)]、(-3.0±0.6)和(-1.6±0.8),差异均有统计学意义(Z＝2.201,t＝4.590,P均<0.05);ALT、血清总胆红素、总胆固醇分别为(680±481)和(37±16)U/L、(300±165)和(17±11)μmmol/L、(16.5±9.7)和(1.3±0.6)mmol/L,差异均有统计学差异(t＝3.119、4.316和3.984,P均<0.05)。 结论肝移植是治疗AGS的有效方法,内科治疗无效的患儿行肝移植可获得良好预后。     

Comparison of pharmacokinetics of Neoral and Sandimmune in stable pediatric liver transplant recipients.

Cyclosporine (Sandimmune; Novartis Pharmaceuticals UK Ltd) is an effective immunosuppressive drug, but its lipid formulation and variable absorption may expose children to the risk of rejection during episodes of gastroenteritis after liver transplantation. Neoral (Novartis) is a microemulsified form of cyclosporine that may be better absorbed. In this study, the pharmacokinetic profiles of Neoral and Sandimmune were compared in stable children after liver transplantation to evaluate whether Neoral is more predictably absorbed. Eight children, 6 boys and 2 girls, with a mean age of 4.5 years (range, 1.2-12) were studied between 4 and 12 months after liver transplantation. Pharmacokinetic profiles were performed on each child by using the same dose (mg/kg) of Neoral or Sandimmune. Tmax, Cmax, Ctrough, and the area under the curve (AUC) were calculated and side effects were documented in children taking either drug for more than 3 months. Mean peak cyclosporine levels were higher and were achieved significantly sooner with Neoral (Cmax 790.5 +/- 216.5 ng/mL, P =.06; Tmax 1.8 +/- 1.0 hr, P =.01) than with Sandimmune (Cmax 589.4 +/- 313 ng/mL, Tmax 2.5 +/- 1.7 hr), implying more rapid and better absorption. There was no significant difference in overall drug exposure (AUC) and 12-hour trough levels between the two formulations (P >.05). Children with Roux-en-Y loop biliary anastomosis taking Neoral, however, showed greater increases in AUC (mean increase = 37%) than those with duct-to-duct anastomosis (mean increase = 16%). There was no correlation between 12-hour trough level and AUC for either Neoral (r2 = 0.48) or Sandimmune (r2 = -0.08); however, for both drugs, AUC correlated very well with the 2-hour post-dose level (r2 = 0.68 and 0.7, respectively). Hirsutism was reported in 4 of 6 children on Neoral and may be associated with higher peak levels. Neoral is more consistently absorbed than Sandimmune in children after liver transplantation and may be more effective prophylaxis against rejection. Because of the increased peak levels and drug exposure, which may influence side effects, particularly in children with Sandimmune malabsorption, we recommend a 1:0.75 dose conversion ratio in patients being converted from Sandimmune to Neoral.