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     

Chronology of renal scarring in males with Alport syndrome

We investigated the onset of renal scarring in 62 males (aged 4 – 26 years) with Alport syndrome by measuring cortical interstitial volume fraction [Vv (interstitium/cortex)] and percentage global glomerular sclerosis in kidney biopsies. Male pediatric (n = 9) and adult (n = 7) donor kidneys served as controls. Creatinine clearance at the time of biopsy was available for 43 Alport patients. A statistically insignificant correlation between age and Vv (interstitium/cortex) was observed in normal subjects (r = +0.47, slope = 0.0009, P = 0.07). In the Alport patients, age was significantly correlated with Vv (interstitium/cortex (r = +0.49, slope = 0.01, P = 0.001) and global glomerular sclerosis (r = +0.41, P = 0.01), and inversely correlated with creatinine clearance (r = –0.33, P = 0.04). Creatinine clearance was inversely correlated with Vv (interstitium/cortex) (r = –0.78, P = 0.001) and global glomerular sclerosis (r = –0.74, P = 0.001). The correlation with creatinine clearance was especially strong for Vv (interstitium/cortex) values above the normal range, i. e., >0.2 (r = –0.82, P = 0.001), and was absent for Vv (interstitium/cortex) <0.2 (r = –0.119, P = 0.55). Creatinine clearance values less than 80 ml/min per 1.73 m² occurred more frequently in patients with Vv (interstitium/cortex) values >0.2 (P <0.0001) and in patients with >10% globally sclerosed glomeruli (P <0.001). Patients ≤ or >10 years of age differed in Vv (interstitium/cortex) [0.13±0.09 (mean ±SD) vs. 0.24±0.026, P <0.001], the frequency of Vv (interstitium/cortex) >0.2 (3/32 vs. 15/31, P <0.0001), the frequency of >10% globally sclerosed glomeruli (3/33 vs. 11/30, P <0.05), mean creatinine clearance (113±7 vs. 84±10 ml/min per 1.73 m², P = 0.057), and the frequency of creatinine clearance <80 ml/min per 1.73 m² (1/20 vs. 11/23, P <0.01). Thus, reduced creatinine clearance in males with Alport syndrome is associated with Vv (interstitium/cortex) >0.2 and >10% globally sclerosed glomeruli. These are frequently detectable in the 2nd decade. We hypothesize that most Alport males will require intervention during the 1st decade for optimal preservation of kidney function. Received July 7, 1997; received in revised form October 23, 1997; accepted October 26, 1997     

Pharmacokinetics of cyclosporin in children with stable renal transplants

Fourteen children, aged between 5 and 17 years, with stable renal graft function and stable cyclosporin A (CSA) trough levels (Cmin) were studied. They had been taking CSA 12-hourly since their transplant 1.5–9 years previously, with the average dose of Neoral being 6.4 (range 4.4–8.4) mg/kg per day. CSA whole blood levels were measured at 0, 20, and 40 min, and at 1, 1.5, 2, 2.5, 3, 4, 6, and 8 h following the morning dose using the Abbott TDx fluorescence polarization immunoassay. The area under the concentration time curve (AUC), clearance adjusted for bioavailability (CL/F), and steady-state volume of distribution adjusted for bioavailability (Vss/F) were determined using model-independent pharmacokinetic analysis. Delay time (Tdel), peak concentration (Cmax), time to peak concentration (Tmax), and Cmin were also determined and correlated with AUC and other parameters. The Tdel in absorption varied from 0.3 to 1.6 (mean 0.73) h, resulting in a similarly variable time to Tmax of 1–2.4 h (mean 1.59). Tmax was related to the age of the patient (Tmax=0.027age+1.41, r ²=0.56, P<0.005). The AUC showed good correlation with Cmax (Cmax=0.25AUC+423.32, r ²=0.96, P<0.0005). Cmax appears to be a more-suitable measure of exposure to CSA than Cmin. Prediction of Tmax from the age of the child may help to overcome the problem of when to collect blood for peak levels. Received: 23 July 1998 / Revised: 4 February 2000 / Accepted: 9 February 2000     

Renal functional reserve after acute poststreptococcal glomerulonephritis

 We evaluated renal functional reserve (RFR) in 36 patients aged 5 – 21 years, who had recovered from an acute episode of poststreptococcal glomerulonephritis (PSGN) 1 – 16 years previously, without apparent sequelae, as evidenced by normal serum creatinine, blood pressure, and urinary sediment. The control group consisted of 12 children aged 2 – 12 years with recurrent urinary tract infections or nocturnal enuresis, without active infection or anatomical anomalies. The basal creatinine clearance was similar in the PSGN and control groups: 140.0±27.4 ml/min per 1.73 m² and 142.9±15.5 ml/min per 1.73 m², respectively. The RFR in the PSGN group was significantly reduced compared with that of the control group: 18.6±12.9 ml/min per 1.73 m² and 41.1±25.3 ml/min per 1.73 m², respectively (P <0.02). In 7 PSGN patients (19.4%), no RFR was found. In 69% of patients who had recovered from PSGN more than 10 years before the protein loading tests, a significantly reduced RFR (less than 10% of baseline) was found. The same degree of reduction in RFR was found in only 26% of patients who had suffered from PSGN less than 10 years ago. Received May 23, 1996; received in revised form November 11, 1996; accepted November 27, 1996     

Cyclosporine A monitoring – how to account for twice and three times daily dosing

Cyclosporine A (CsA) dose-interval pharmacokinetic profiles, performed 1–4 years post-transplantation, were collected from 74 renal transplanted children. Forty patients were on three times daily dosing (t.i.d.) and 34 on twice daily dosing (b.i.d.). Regression models for prediction of area under the curve (AUC) using 1–3 concentration time points as independent variables were developed. With similar weight-adjusted single doses (mg kg^–1) of CsA, t.i.d. dosing resulted in a trough-concentration (C₀) similar to that from b.i.d. dosing, but a 30% lower 2 h post-dose concentration (C₂). For b.i.d. dosing the relationship between C₀ and AUC was poor (r²=0.23) and the prediction error was large (5.8±33.5%). For t.i.d. dosing the relationship was better (r²=0.79), but prediction error was still large (4.5±24.9%). For C₂ relationships were similar to those for the b.i.d. (r²=0.59) and t.i.d. (r²=0.63) groups, but explained modestly the variations of AUC (prediction error=2.6±16.8% b.i.d., 4.8±23.2% t.i.d.). Both C₀ and C₂ are useful monitoring methods when CsA is administered t.i.d. If the aim is similar specified daily drug exposure, the target C₂ should be roughly 30% smaller in t.i.d. dosing than in b.i.d. dosing and the target C₀ could be similar. The prediction error of AUC can be large in individual patients when using single time-point determinations, however. The use of multiple time points reduces the variation, but is less feasible.     

Hypotension during transsphenoidal pituitary surgery associated with increase in plasma levels of brain injury markers

Background

Patients undergoing pituitary surgery may experience short- and long-term postoperative morbidity. Intraoperative factors such as hypotension might be a contributing factor. Our aim was to investigate the association between intraoperative hypotension and postoperative plasma levels of tau, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) as markers of perioperative brain injury.

Methods

Between June 2016 and October 2017, 35 patients from the Gothenburg Pituitary Tumor Study were included. For tau, NfL, and GFAP, concentrations were measured in plasma samples collected before and immediately following surgery, and on postoperative days 1 and 5. The difference between the highest postoperative value and the value before surgery was used for analysis (∆tau_peak, ∆NfL_peak, ∆GFAP_peak). Intraoperative hypotension was defined as the area under the curve of an absolute threshold below 70 mmHg (AUC70) and a relative threshold below 20% (AUC20%) of the baseline mean arterial blood pressure.

Results

Plasma tau and GFAP were highest immediately following surgery and on day 1, while NfL was highest on day 5. There was a positive correlation between AUC20% and both ∆tau_peak (r² = .20, p < .001) and ∆NfL_peak (r² = .26, p < .001). No association was found between AUC20% and GFAP or between AUC70 and ∆tau_peak, ∆NfL_peak or ∆GFAP_peak.

Conclusion

Intraoperative relative, but not absolute, hypotension was associated with increased postoperative plasma tau and NfL concentrations. Patients undergoing pituitary surgery may be vulnerable to relative hypotension, but this needs to be validated in future prospective studies.     

Abbreviated mycophenolic acid AUC from C0, C1, C2, and C4 is preferable in children after renal transplantation on mycophenolate mofetil and tacrolimus therapy

In order to allow a similar algorithm to be used for both adults and children on tacrolimus-based and mycophenolate mofetil [MMF, a pro-drug for mycophenolic acid (MPA)]-based immunosuppression, a limited sampling technique from the trough level (C0) and the levels 30 min (C0.5) and 2 h (C2) after intake was to be developed from MPA area under the time–concentration curves (AUC). We retrospectively analyzed 49 full ten-point pharmacokinetic (PK) profiles from 29 pediatric patients on MMF and tacrolimus. We used stepwise multiple regression analysis to calculate limited sampling approaches. Agreement with the AUC was tested by means of Bland and Altman analysis. The correlation between AUC and pre-dose trough concentration was r²=0.5188 (P<0.0001) and between AUC and post-dose trough concentration r²=0.6924 (P<0.0001). The next best correlations were with 2 h (C2, r²=0.6711, P<0.0001), 4 h (C4, r²=0.6411, P<0.0001), 1.5 h (C1.5, r²=0.6344, P<0.0001), and 6 h (C6, r²=0.6219, P<0.0001). Three-point estimates at C0, C0.5, and C2 resulted in an acceptable correlation between predicted AUC and AUC from the full profile when we used the formula AUC = 10.01391+3.94791×C0+3.24253×C0.5+1.0108×C2, Pearsons r=0.8996, 95% confidence interval 0.8277–0.9424. However, even better results could be obtained when we used AUC = 8.217+3.163×C0+0.994×C1+1.334×C2+4.183×C4, Pearsons r=0.9456, 95% confidence interval 0.9051–0.9691. Bland and Altman analysis revealed good agreement between AUC predicted from C0, C0.5, and C2 and AUC from the full profile, but was inferior to the four-point approach. Also, the previously reported formula derived for adults was not usable in these patients. A special formula must be used for children. The AUC of MPA can be predicted by limited sampling including C0, C0.5, and C2, while an approach using C0, C1, C2, and C4 is preferable.     

Pharmacokinetic studies of cyclosporine in Oriental kidney transplantation patients

SUMMARY: Pharmacokinetic studies were performed in 10 stable kidney transplantation patients who received microemulsion formulation (Neoral^®) of cyclosporine A (CsA) twice daily. No agents having pharmacokinetic effects on CsA had been used in these patients. The values of various basic pharmacokinetic parameters were similar to those reported in Western literature. The complete area under the blood concentration–time curve (AUC) of CsA for the duration of 12 h (12‐h AUC) was determined using the linear trapezoidal rule from seven concentrations at 0, 1, 2, 4, 6, 8, and 12 h after CsA administration. The mean values of 12‐h AUC were 4603.63 ± 344.61 ng h/mL. CsA concentrations at 2 h after dosing (not the trough levels) showed the best correlation with the complete AUC (r² = 0.9322). The abbreviated AUC of CsA was calculated either by stepwise multiple linear regression analysis or by the linear trapezoidal rule from a few sampling time points. Using stepwise multiple linear regression analysis, which was used in calculating abbreviated AUC in all previous studies, the model equation that had the highest correlation and the lowest prediction error with the complete AUC was derived by using CsA concentrations at 2 and 8 h after dosing (12‐h AUC = 4.262C₂ + 8.390C₈? 669.417; r² = 0.9808, absolute prediction error = 3.97 ± 0.96). Two model equations derived using the linear trapezoidal rule provided the best correlation with the complete AUC: (1) The two time points selected model equation 12‐h AUC = 4C₂ + 5C₈; r² = 0.9780, absolute prediction error = 6.41 ± 1.22). (2) The three time points selected model equation 12‐h AUC = 4C₀ + 3C₂ + 5C₆; r² = 0.9475, absolute prediction error = 5.00 ± 1.41). When different pharmacokinetic data sets were applied to the model equations derived using regression analysis, the values of coefficients and the constant of the regression equation had changed from the initial equation. Thus, new model equations will emerge every time the new data are applied. In contrast, the values of coefficients in the model equation calculated using trapezoidal rule were unaltered when tested by the new pharmacokinetic data set. Thus, the abbreviated AUC derived using the linear trapezoidal rule would be simpler than and superior to that obtained using stepwise multiple linear regression analysis in prediction of the complete AUC.     

Urinary excretion substances in patients with cystic fibrosis: risk of urolithiasis?

Patients with cystic fibrosis (CF) have an increased risk of urolithiasis/nephrocalcinosis. To determine potential mechanisms responsible, we studied the urinary excretion of lithogenic and stone-inhibitory substances and calculated the urinary saturation for calcium-oxalate (CaOx), brushite (CaHPO₄), and uric acid (UA). We examined 24-h urines in 63 patients with CF (34 female, 29 male) aged 5 months to 36 years. Renal ultrasonography was performed at the time of urine collection. Hyperoxaluria was found in 25 patients (range 0.51 – 1.71 mmol/1.73 m² per 24 h). Urinary Ca was increased in 13 patients (4.1 – 8.22 mg/kg per 24 h). Hyperuricosuria was found in 16 patients (5.2 – 18.0 mmol/1.73 m² per 24 h) and hypocitraturia in 14 patients (0.07 – 1.14 mmol/1.73 m² per 24 h). CaOx saturation was elevated in 26 patients, related to hyperoxaluria in 19 patients. CaHPO₄ saturation was increased in 19 patients and UA saturation in 11 patients. Urolithiasis in situ was diagnosed in 1 patient; 3 patients previously had renal stones; 4 patients had present nephrocalcinosis. Elevated excretion of lithogenic substances and urinary supersaturation might lead to the higher risk of urolithiasis/nephrocalcinosis in patients with CF. Received March 5, 1997; received in revised form September 19, 1997; accepted September 24, 1997     

Diagnostic sensitivity of serum cystatin for impaired glomerular filtration rate

Recently, the reciprocal of cystatin C (Cys-C), a non-glycosylated 13-kilodalton protein that is produced by all investigated nucleated cells, was found to correlate closely with glomerular filtration rate (GFR). In order to determine the diagnostic validity in children for the detection of impaired GFR, venous blood samples from 381 children (aged 1.7–18 years) with various renal pathology referred for ⁵¹Cr-EDTA clearance investigations were obtained for measurement of Cys-C as well as β₂-microglobulin (β2-MG) and serum creatinine. Two hundred and sixteen children with clearance values >90 ml/min per 1.73 m² constituted a control group, with a normal GFR. In the control group, Cys-C values were normally distributed with a mean of 0.94±0.27 mg/l and an upper reference limit (97.5th percentile) of 1.47 mg/l. In all children, there was a positive correlation between ⁵¹Cr-EDTA clearance and the reciprocal of Cys-C (r=0.64, P<0.0001), β₂-MG (r=0.59, P<0.0001), creatinine (r=0.55, P<0.0001), and the height/creatinine ratio (r=0.73, P<0.0001). Receiver-operating characteristics analysis showed that there were no significant differences between these three parameters for discriminating between patients with normal and reduced GFR, although there was a tendency towards the best diagnostic sensitivity of the GFR estimate according to the Schwartz formula. We conclude that for the detection of mildly impaired GFR, a full clearance study cannot be replaced by measurement of serum Cys-C or β2-MG concentrations. Received: 15 June 1998 / Revised: 22 September 1998 / Accepted: 23 September 1998     

HLA-DQB1 and DRB1 alleles in Egyptian children with steroid-sensitive nephrotic syndrome

Steroid-sensitive nephrotic syndrome (SSNS) of children has been associated with several HLA-DR and DQ alleles. To investigate this association in Egyptian children, 27 patients with SSNS were typed for HLA-DRB1 and DQB1 alleles using DNA polymerase chain-reverse hybridization technique. The results were compared with 121 healthy subjects for HLA-DRB1 and 59 subjects for DQB1 alleles. We found that: (1) patients have higher frequencies of both DQB1 ^* 0601 (81.5% vs. 10.2% in controls, Pc = 0.0001) and DRB1 ^* 01 (44.4% vs. 3.3% in controls, Pc = 0.00003). Their relative risks are significantly high [38.9, confidence interval (CI) = 10.7–140.7, and 23.4, CI=6.7–81.9, respectively]; (2) the frequency of DRB1 ^* 11 alleles was low in SSNS patients (3.75% vs. 32.2% in controls), but was not significant when P was corrected (P = 0.005, Pc = NS). These findings suggest that DQB1 ^* 0601 and DRB1 ^* 01 or closely associated unknown genes confer susceptibility to SSNS. However, further studies with larger numbers of patients are needed. Received June 27, 1997; received in revised form October 23, 1997; accepted October 26, 1997     

Delayed acute renal failure in post-transplant period in young children from unexplained etiology

This report describes six young children (5 male) who developed delayed acute renal failure (DARF) in the early post-kidney-transplant (Tx) period in the absence of acute rejection (AR) or other diagnosable conditions. These young children, aged 16.5 ± 3.1 (12–21) months [mean ± SD, (range)] and weighing 8.5 ± 1.7 (7.1 – 11.4) kg received a primary renal Tx (5 living-related donor, 1 cadaver) between 1984 and 1992. Immunosuppression included prednisone, azathioprine, and Minnesota antilymphocyte globulin (MALG, n = 5); one patient received cyclosporine and no MALG. Initially, all patients had good urine output (UO). They became systemically ill and abruptly developed diminished UO on post-operative day (POD) 6.5 ± 1 (4 – 8). DARF was accompanied by fever (39.1 – 40.4°C, n = 6), thrombocytopenia (platelets <100,000/mm³, n = 6), leukocytosis, or leukopenia (white cell count >20,000/mm³, n = 4 or <1,000/mm³, n = 1). Four patients had diarrhea. Three had ascites and one was surgically explored for suspected urinary leak. None showed significant urinary obstruction by renal ultrasound. Renograms showed intact blood flow. Renal biopsy showed tubular ectasia (n = 6), vascular congestion (n = 5), focal glomerular endothelial swelling (n = 4), and capillary thrombi (n = 3). None showed AR. Five patients required dialysis for 11 ± 4 (7 – 15) days. All patients survived. One patient, treated for suspected AR with the monoclonal antibody OKT3, developed shock and lost her graft on POD 12 due to vascular thrombosis. Renal functional recovery in the remaining five patients took 14 ± 5 (6 – 20) days and their serum creatinine at discharge was 0.7 ± 0.5 (0.3 – 1.6) mg/dl. We report DARF from undetermined etiology occurring in the first 2 weeks of renal Tx in young children. Treatment is supportive care including dialysis. Recognition of this complication will help avoid risky investigations or unnecessary treatment for rejection. Received August 21, 1996; received in revised form February 14, 1997; accepted March 4, 1997     

Incidence of microalbuminuria in children with pyelonephritic scarring

There is experimental evidence that loss of renal parenchyma results in hyperfiltration in the remnant glomeruli followed by development of glomerulosclerosis. Microalbuminuria, i.e., a urinary albumin excretion rate of 20 – 200 μg/min, is considered to be an early predictor of diabetic glomerulosclerosis. Hypothetically, increased urinary albumin excretion in patients with pyelonephritic scarring may also indicate glomerulosclerosis, with risk for future deterioration of renal function. This study was performed to determine the incidence of increased albumin excretion in children with mild to moderate pyelonephritic scarring, and to relate the information to glomerular filtration rate (GFR; clearance of inulin) and effective renal plasma flow (clearance of para-aminohippuric acid), as well as to the degree of scarring. The functional investigations were performed under water diuresis. Fifty-seven children, aged 1.7 – 17.9 years, with pyelonephritic renal scarring were included in the study. Nine young healthy adults were used as controls. The GFR was significantly lower in the children with pyelonephritic scarring than in the controls (median 93 ml/min per 1.73 m², range 48 – 133 vs. 111 ml/min per 1.73 m², range 89 – 121, P<0.05), and the urine albumin excretion was significantly higher (median 20 μg/min per 100 ml GFR, range 0.8 – 170 vs. 9.2 μg/min per 100 ml GFR, range 3.3 – 21, P<0.05). An inverse correlation was found between urine albumin excretion and GFR. Increased urine albumin excretion was found in 70% of the children with a GFR below 90 ml/min per 1.73 m² compared with 41% of the children with a GFR above this level. Increased urine albumin excretion (>20 μg/min per 100 ml GFR) was found in 51% of the children with pyelonephritic scarring, while only 14% had increased age-adjusted serum creatinine concentrations. The high incidence of microalbuminuria in children with pyelonephritic scarring indicates long-term follow-up until the ultimate outcome has been better defined. Received January 17, 1995; received in revised form and accepted April 2, 1996     

Interleukin-1&; and interleukin-6 in the urine,kidney, and bladder of mice inoculated with Escherichia coli

After bladder inoculation of mice using the pyelonephritogenic Escherichia coli strain DS17, urinary interleukin-1α (IL-1α) peaked at 0.5 h post infection (mean 233 pg/ml), interleukin-6 (IL-6) at 2 h (mean 572 pg/ml), and leukocyturia at 4 h, all three persisting for more than 24 h. In the kidneys IL-1α peaked at 2 h, persisted over 24 h (mean 900 – 1,000 pg/ml), and decreased over 2 – 6 days post inoculation to a mean value of 208 pg/ml. Control kidneys showed low IL-1α values. IL-6 in the kidneys peaked at 5 h (mean 9,999 pg/ml) but normalized, i.e., similar to control kidneys, by 48 h (mean 105 pg/ml). A similar cytokine response, but with tenfold lower levels, was found in the bladder tissue. The isogenic P-negative E. coli mutant DS178 elicited lower IL-6 in the kidneys at 5 h, but persisted in higher numbers in the kidneys at 6 days. Bacterial counts and cytokine levels correlated both in the kidneys and in bladder tissue, (r = 0.50 – 0.76, P <0.001). Characterization of the immune response gives a better understanding of the relative importance of different bacterial characteristics for the local inflammatory process and is needed for studies of its pharmacological downregulation. Received May 4, 1995; received in revised form and accepted November 21, 1995     

Annual change in bone mineral density in predialysis patients with chronic renal failure: significance of a decrease in serum 1,25-dihydroxy-vitamin D

Bone disease occurs in the predialysis phase of chronic renal failure (CRF). The aim of this study was to examine how a decrease in renal function affects annual bone mineral density (BMD) changes in predialysis CRF patients and to examine the factors that affect BMD. The BMD of the distal radius in 53 predialysis CRF patients (age, 61.3 ± 10.8 years; serum creatinine 2.7 ± 1.2 mg/dl) was measured by peripheral quantitative computed tomography (pQCT) twice with a 1-year interval. The total BMD of the radius significantly decreased over a year (P < 0.001), and both trabecular and cortical BMD showed a significant decrease. Significant positive correlations with BMD changes were found for estimated creatinine clearance (r = 0.375, P < 0.01) and baseline serum 1,25(OH)₂D (r = 0.434, P < 0.005), indicating that BMD decreased to a greater extent with larger reductions in creatinine clearance and serum 1,25(OH)₂D. Of several bone metabolic markers examined, baseline serum osteocalcin was significantly positively correlated with annual BMD changes (r = −0.276, P < 0.05). Multiple regression analysis showed that baseline serum 1,25(OH)₂D (β = 0.434) was a significant predictor of decreases in total and trabecular BMD (R ² = 0.188, P < 0.01; and R ² = 0.207, P < 0.01), independent of other confounding factors. These results indicate that BMD decreases as renal function deteriorates in predialysis CRF patients, and that osteocalcin is a clinically useful marker associated with the decrease in BMD. The serum 1,25(OH)₂D level is the principal factor affecting BMD of the radius, suggesting that supplementation with an active form of vitamin D is of importance for predialysis CRF patients.     

Clinical pharmacokinetics of Neoral in pediatric recipients of primary liver transplants

Pediatric liver transplant recipients constitute a population characterized by a particularly unpredictable and poor bioavailability of cyclosporin (CyA). Even though several adult studies show that the new oral formulation of CyA, Neoral (NEO), produces better bioavailability and blood level predictability, few data describe its pharmacokinetics in children. We performed a complete analysis of the pharmacokinetics of NEO in ten small children after primary liver transplantation. Three pharmacokinetic profiles were set up with data obtained from tests taken during i. v. administration of CyA, after the first oral NEO dose, and after the last NEO dose before discharge from the hospital. The mean half-lives obtained were 8.1, 7.7, and 6.9 h, respectively, and the bioavailabilities were 22 % and 21 % for the first and last NEO doses. A large interpatient variability was observed. This was due, in part, to episodes of diarrhea that interfered with the pharmacokinetic evaluation and, in part, to the variability of post-transplant hepatic function. There was a good correlation between CyA trough levels and their related AUCs for both NEO profiles (r = 0.93 and r = 0.74, respectively). We conclude that, even though the pediatric OLT population remains more unpredictable than that of adults, NEO has a relatively rapid half-life and a remarkably improved bioavailability. Received: 29 November 1996 Received after revision: 10 April 1997 Accepted: 15 May 1997     

Long‐term follow‐up of immunosuppressive monotherapy in liver transplantation: tacrolimus and microemulsified cyclosporin

Cholongitas E, Shusang V, Germani G, Tsochatzis E, Raimondo ML, Marelli L, Senzolo M, Davidson BR, Patch D, Rolles K, Burroughs AK. Long‐term follow‐up of immunosuppressive monotherapy in liver transplantation: tacrolimus and microemulsified cyclosporin.
Clin Transplant 2011: 25: 614–624. © 2010 John Wiley & Sons A/S. Abstract: Background: Early withdrawal of steroids after liver transplantation has benefits, but rarely is total avoidance of steroids used. We evaluated long‐term results of patients with ab initio monotherapy with cyclosporin (CYA) vs. tacrolimus (TAC), in randomized and cohort studies. Methods: We evaluated long‐term outcomes in 66 adults randomized to TAC or CYA and 94 subsequent patients who received TAC. Protocol liver biopsies were performed. Rejection was treated with three 1 g/d methylprednisolone. Further rejection after two courses of methylprednisolone was defined as monotherapy failure. Results: Actuarial five‐yr survival was 68% in TAC and 70% CYA. Monotherapy failed in 8% TAC and 13% CYA patients; no rejection in 24% TAC and 19% CYA patients; 42% TAC and 33% CYA patients were not exposed to any steroids. Rejection episodes were less with TAC, compared to CYA: mean 1.8 vs. 2.5, p = 0.042. Chronic rejection occurred in only 4 (11%) CYA patients. During follow‐up of median 97 months (range: 0.06–145), there were 16 (44%) deaths in CYA and 48 (39%) in TAC patients (p > 0.05). Conclusions: TAC monotherapy ab initio is a viable immunosuppressive strategy in liver transplantation and was associated with lower rejection rates and renal complications, compared to CYA.     

Variable effect of ursodeoxycholic acid on cyclosporin absorption after orthotopic liver transplantation

The acute effects of administering a single dose of ursodeoxycholic acid (UDCA) on cyclosporin pharmacokinetics were recorded during paired studies in twelve liver transplant recipients, six of whom were cholestatic. Cyclosporin was measured using monoclonal selective antibodies (for parent drug) and nonselective antibodies (for cyclosporin plus metabolites). UDCA resulted in more rapid absorption of cyclosporin in 8 of 12 cases (67%) but had no effect in two patients with and two patients without cholestasis. Median t_max did not change significantly after UDCA (3.0vs 4.0 h without UDCA) and only 7 of 12 patients (58%) showed a rise in the amount of cyclosporin absorbed over 24 h with the AUC not having changed significantly (median 4527 vs 4979 g·h·1^-1 without UDCA). Median C_max and C₂₄ also increased only marginally following UDCA administration (616 vs 587 g·1^-1 and 87 vs 58 g·1^-1 without UDCA, respectively). In the cholestatic patients, median AUC was 50% smaller (3223 vs 6439 g·h·1^-1) and median t1/2a was 100% longer (1.58 vs 0.8 h) than in patients without cholestasis. There was no consistent improvement in cyclosporin pharmacokinetics in the cholestatic patients following UDCA, although the significantly elevated ratio of non-selective:selective AUC measurements (median 4.8 vs 2.7) fell markedly in the two most severely affected, possibly as a result of an increased clearance of cyclosporin metabolites by choleresis.     

Correlation between finger-prick and venous ciclosporin levels: association with gingival overgrowth and hypertrichosis

The aims of this study were (1) to ascertain ciclosporin C₂ levels currently being achieved in children with steroid-sensitive nephrotic syndrome (SSNS) and renal transplants (RTs), (2) to determine the feasibility of the use of finger-prick samples for the measurement of ciclosporin levels, and (3) to identify any correlation between hypertrichosis or gingival overgrowth (GO) and level of ciclosporin 2 h post-dose (C₂). Seventy-two children (39 with SSNS, 33 with RT) participated. Ciclosporin 12 h trough (C₁₂) and C₂ levels were measured in venous and finger-prick samples by high-performance liquid chromatography tandem mass spectroscopy. Photographs of the teeth and back were taken for assessment of GO and hypertrichosis. Mean (±SD) C₂ levels in the SSNS and RT groups were 512 (±181) μg/l and 471 (±229) μg/l. There was a highly significant relationship between venous and finger-prick ciclosporin levels (r² = 0.96, P < 0.0001). Fourteen children had severe GO. There was a small, though statistically significant, impact of ciclosporin level on GO (C₂ r² = 0.12, P = 0.003 and C₁₂ r² = 0.06, P = 0.038) but no correlation with dose (milligrammes per kilogramme per day or milligrammes per square metre per day) or duration. Seventeen children had moderate or severe hypertrichosis, this being more common in children of South Asian ethnicity (P < 0.0001). There was no correlation between ciclosporin exposure or duration and hypertrichosis. Finger-prick blood sampling may serve as a practical alternative to venepuncture in children receiving ciclosporin.     

Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: results of a prospective, randomized comparison of neoral and sandimmune for liver transplantation (NOF-8)

BACKGROUND: Despite two decades of use, there are limited data on the best way to administer and monitor cyclosporine (CsA) for liver transplantation. The present study was undertaken (1) to determine whether treatment with a new formulation of CsA, Neoral, would improve the results of liver transplantation; and (2) to study the relationships between pharmacokinetic parameters and clinical outcomes after transplantation. METHODS: A double-blind, randomized, comparison of Sandimmune (SIM) with Neoral (NEO) was conducted at five Canadian centers in 188 consecutive adults undergoing primary orthotopic liver transplantation. Patients were induced with intravenous CsA then switched to NEO or SIM. Dose adjustments were made daily, or as needed, to reach a target trough CsA level of 350 ng/ml in both groups. Pharmacokinetic studies were performed on days 5, 10, 15, and 16 weeks after transplantation. RESULTS: The NEO group was slightly younger, with a median age of 50 years (range: 23-70) versus 55 years (range: 24-71) for SIM (P = 0.007); otherwise the two groups were well balanced. The NEO group stopped intravenous CsA earlier (5.8+/-2.6 days vs. 8.7+/-4.7 days, P<0.0001). This group required a lower median daily oral dose (7.5 mg/kg vs. 9.0 mg/kg, P<0.01) to maintain comparable trough CsA levels. Five SIM patients, but no NEO patients, discontinued the study due to the inability to reach target trough levels of CsA within the prescribed time (P<0.05). At 4 months, there were no differences between the two groups with respect to patient survival (93% NEO vs. 91% SIM), graft survival (90% NEO vs. 86% SIM), and rejection-free survival (54.1% NEO, 51.8% SIM). The incidence of serious adverse events was also similar and did not correlate with CsA pharmacokinetic profiles. The NEO group had a higher area under the drug concentration curve for the first 6 hr after the dosing interval (AUC0-6) and peak CsA levels (Cmax). There was a strong correlation between freedom from graft rejection during the first month after transplantation and (a) AUC0-6 and (b) Cmax at days 5 and 10 after transplantation, but only in the NEO group did this reach statistical significance. In contrast, there was a poor correlation between trough CsA and graft rejection. In patients on NEO, the concentration of CsA 2 hr after dosing (C2) closely reflected AUC0-6 (r2 = 0.93), whereas there was a poorer correlation in patients on SIM (r2 = 0.73) CONCLUSIONS: Cmax and/or AUC0-6 may provide better markers than trough levels for monitoring CsA-based immune suppression after orthotopic liver transplantation. Prospective studies are underway to determine whether dosing to C2, which provides a good estimation of Cmax, can be used to take full advantage of NEO's improved absorption profile.