Impact of early cyclosporin average blood concentration on early kidney transplant failure

This retrospective study served to examine the correlation between the degree of cyclosporin (CyA) exposure, as estimated by a single pharmacokinetic (PK) profile performed at 1 week post-transplant, and the outcome of 290 consecutive renal transplants performed over a 6-year period. For this retrospective analysis patients were stratified into four historical groups based on 12- versus 24-h PK studies and on the use of radioimmunoassay versus fluorescence polarization immunoassay methods for estimates of CyA concentrations. Four PK measures – trough concentration (C₀), average concentration values (C_av; i. e., the dosing interval-corrected area under the concentration-time curve), maximum concentration (C_max), and time to maximum concentration (t_max) – were examined as predictors of patient, graft, and rejection-free survival rates for each of the four groups individually and for all groups combined. Patients with an initial C_av≥ 550 ng/ml had higher 1-year (88 %) and 6-year (66 %) graft survival rates than patients with C_av < 550 ng/ml, who had 1- and 6-year graft survival rates of 80 % and 59 %, respectively (P = NS). Statistically significant differences were observed in graft survival rates between patients with C_av < 550 versus C_av≥ 550 ng/ml at 30 (88 % vs 96 %; P < 0.02), 60 (85 % vs 94 %; P < 0.007), 90 (85 % vs 94 %; P < 0.02), and 180 (83 % vs 92 %; P < 0.05) days. Moreover, patients with C_av < 550 ng/ml displayed more severe rejection episodes, as judged by Banff classification, than patients who displayed C_av≥ 550 ng/ml (grades II and III; 71 % vs 50 %; P = 0.036). In contrast, the C₀, C_max, and t_max values did not correlate with patient, graft, or rejection-free survival rates. The pharmacokinetic parameter of C_av correlated strongly with early graft survival and may, therefore, be a useful predictor of those renal transplant patients who may require more intensive post-transplant monitoring of CyA concentrations by serial PK studies to improve graft survival. Received: 27 May 1997 Received after revision: 8 August 1997 Accepted: 21 August 1997     

A pharmacokinetic study of Neoral in childhood steroid-dependent nephrotic syndrome

Seven children with steroid-dependent nephrotic syndrome who were on stable remission under Sandimmun therapy were switched to Neoral at the same dosage. During the 4-month follow-up period, two patients relapsed, due to poor compliance in one of them. Serum creatinine remained stable in all patients. Pharmacokinetic profiles were performed at day 0 while on Sandimmun and 4 weeks after conversion to Neoral. Following conversion to Neoral, the peak concentration occurred earlier (2±1.4 h vs 3.9±2.4 h), and the maximum concentration (677±386 ng/ml vs 488±265 ng/ml) and the area under the curve (3082±1536 ng/ml/h vs 2201± 889 ng/ml/h) were higher. We conclude that Neoral results in an increased bioavailability of cyclosporine (CsA) as compared to Sandimmun in patients with steroid-dependent nephrotic syndrome in remission. Received: 28 April 2000 / Revised: 5 October 2000 / Accepted: 5 October 2000     

Plasma levels of endothelin-1 in patients with the hepatorenal syndrome after successful liver transplantation

The hepatorenal syndrome (HRS) is characterized by renal vasoconstriction leading to deterioration of renal function in patients with liver disease. A possible role of endothelin-1 (ET-1) in the pathogenesis of HRS has been suggested, but a correlation between ET-1 plasma levels and the development of HRS as well as the recovery from HRS following OLT has not been shown yet. We performed longitudinal measurements of ET-1 plasma levels in four groups of patients, 5 patients with HRS before and after orthotopic liver transplantation (OLT), 10 patients without HRS undergoing OLT, 20 patients with chronic renal failure but without liver disease, and 12 healthy controls. Before OLT, plasma levels of ET-1 were higher in patients with HRS (19.5 ± 8.6 ng/l, P < 0.001; n = 5) compared to patients without HRS (4.9 ± 1.1 ng/l; n = 10), normals (1.2 ± 0.18 ng/l; n = 12), and patients with chronic renal failure (2.4 ± 0.4 ng/l; n = 20). Patients with HRS compared to patients without HRS had higher levels for creatinine (2.42 ± 0.6 vs. 0.89 ± 0.05 mg/dl, P < 0.05), creatinine clearance (107 ± 9 ml/min vs. 44.6 ± 5.5 ml/min, P < 0.001), and bilirubin (11.4 ± 3.8 vs. 3.7 ± 1 mg/dl, P < 0.05) before OLT. Within one week after OLT, there was a rapid decrease in ET-1 levels in patients with HRS while creatinine and bilirubin levels decreased slower. Regression analysis revealed a weak correlation between serum creatinine and ET-1 (r = 0.192, P = 0.04) and a significant correlation between serum bilirubin and ET-1 (r = 0.395, P < 0.001). The means of the ET-1 levels decreases rapidly with improvement of liver function after OLT. Levels of ET-1 correlate with excretory liver function assessed by bilirubin. The fall in ET-1 levels preceding improvement of renal function further strengthens the concept of ET-1 being a causative factor in HRS. Received: 22 July 1999/Revised: 28 January 2000/Accepted: 11 May 2000     

Interindividual Variation of Maximal Blood Levels of Tacrolimus After Its Oral Administration in Hematopoietic Cell Transplant Recipients

We investigated the pharmacokinetics of oral tacrolimus in 31 hematopoietic cell transplant recipients, identifying 2 subgroups based on the differences between C₀ (trough) and C_max (maximal) levels: group A (n = 21; 68%) with a C_max-C₀ value of <10 ng/mL, and group B (n = 10; 32%) with a C_max-C₀ value of ≥10 ng/mL. Although the C₀ and C₁₂ values were not significantly different between the 2 groups, the mean area under the concentration curve for 12 hours (AUC_0–12) was significantly greater in group B than group A (200.9 ± 36.3 vs 155.1 ± 43.1 ng · h/mL; P < .05), and the mean half-life was significantly shorter in group B than group A (13.55 ± 6.70 vs 18.17 ± 6.30 hours; P < .05). Thus after the oral administration of tacrolimus, we observed a notably high AUC due to high peak level, which we were unable to predict simply by measuring the trough level. A pharmacokinetic analysis of each patient was essential to optimize the oral tacrolimus dose.     

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.     

Effect of maternal insulin deficiency on vitamin D metabolite concentrations in normoglycemic pregnant rats and their fetuses

Summary The effects on vitamin D metabolite concentrations of insulin deficiency, not accompanied by hyperglycemia, were investigated in pregnant rats and in their fetuses injected with 75 mg/kg BW streptozotocin (SZ). These concentrations were measured in maternal plasma and whole fetal body. In the insulinopenic mothers, the 25OHD concentration was found to rise compared with that of control pregnant rats (7.00±1.66 ng/ml, n=16, versus control 4.50±1.60, n=10, 0.001<P<0.01). The concentration of 1,25 (OH)₂D, which was previously found to decrease in pregnant rats that were both hypoinsulinic and hyperglycemic, was not different in our control and insulinopenic rats (107.36±38.25 pg/ml, n=11, versus control 122.90±18.20, n=8). In fetuses from our SZ-injected rats, the 24,25 (OH)₂D level diminished compared with the control level (2.12±0.70 ng/g, n=11, versus control 5.23±0.95 ng/g, n=13,P<0.001). The Ca/P ratio in fetal body also decreased (0.68 versus control 1.12). It is suggested that the placental metabolism is an important determinant of normal fetal growth.     

A comparative study of FK506 granules and capsules in renal transplant recipients

Nine renal transplant recipients in stable systemic condition on FK506 capsules were converted to FK506 granules in order to investigate the safety, efficacy, and pharmacokinetics of the granular formulation of FK506. The study period for the administration of FK506 granules was 4 weeks, and in principle, the oral dose was the same as that of the FK506 capsules. Renal graft function remained stable and no rejection signs were noticed while the patients were taking the granules. The area under the blood concentration-time curve (AUC), the maximum blood level (C_max), and the time to reach C_max (T_max) after FK506 capsules and FK506 granules were, respectively, 93.1 ± 66.4 and 97.0 ± 89.1 ng · h/ml (P = 0.81), 12.7 ± 7.1 and 15.2 ± 11.7 ng/ml (P = 0.39), and 2.0 ± 1.7 and 1.3 ± 0.6 h (P = 0.29). The mean trough blood level during FK506 medication was 4.25 ± 3.42 and 4.02 ± 3.83 ng/ml, respectively, for the capsules and the granules. FK506 granules, a new formulation, showed an efficacy comparable to that of the FK506 capsular formulation. Received: 28 July 1997 Received after revision: 25 November 1997 Accepted: 14 January 1998     

Serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 in children with chronic renal failure: relationship to growth and glomerular filtration rate

Growth retardation in children with chronic renal failure (CRF) is partly due to an inhibition of insulin-like growth factor (IGF) activity by an excess of high-affinity IGF-binding proteins (IGFBPs). The aim of this study was to analyze the serum levels and forms of IGFBP-4 and IGFBP-5 in CRF patients using specific, recently developed radioimmunoassays (RIAs) and immunoblot analysis. We examined 89 children [age 11.5 (2.8–19.0) years] with CRF [glomerular filtration rate 26.6 (7.0–67.4) ml/min per 1.73 m²], nine of them with end-stage renal disease undergoing peritoneal dialysis. Serum-immunoreactive IGFBP-4 levels were fourfold increased in CRF (prepubertal 1080±268 ng/ml; pubertal 989±299 ng/ml) compared to healthy prepubertal controls (265±73 ng/ml). In contrast, serum IGFBP-5 levels were not significantly increased neither in prepubertal (361±120 ng/ml vs 282±75 ng/ml in controls) nor pubertal CRF children (478±165 ng/ml vs 491±80 ng/ml in controls). Immunoblot analysis showed the presence of intact as well as fragmented IGFBP-4 and IGFBP-5. Serum IGFBP-4, but not IGFBP-5, levels were inversely correlated with GFR (r=–0.39, P<0.001). In prepuber- tal children, IGFBP-4 levels were inversely correlated with standardized height (r=–0.40; P<0.005). In contrast, IGFBP-5 levels were positively correlated both with standardized height (r=0.32, P<0.02) and baseline height velocity (r=0.45, P<0.005). A 3-month therapy with rhGH stimulated serum IGFBP-5 levels by 43% (P<0.01); there was no consistent effect on IGFBP-4 levels. There was a positive correlation between IGFBP-4 and IGFBP-2 (r=0.46, P<0.001); IGFBP-5 was positively correlated with IGF-I (r=0.59, P<0.001), IGF-II (r=0.42, P<0.001) and IGFBP-3 (r=0.47, P<0.001) and inversely correlated with IGFBP-1 (r=–0.41, P<0.001). In summary, serum IGFBP-4 is fourfold elevated in children with CRF in relation to the degree of renal dysfunction and contributes to the marked increase in IGF-binding capacity in CRF serum. The inverse correlation of serum IGFBP-4 with standardized height is consistent with its role as another inhibitor of the biological action of the IGFs on growth plate cartilage. In contrast, serum IGFBP-5 is not elevated in CRF serum and circulates mainly as proteolysed fragments. The positive correlation of serum IGFBP-5 with growth and its increase during GH therapy indicate that IGFBP-5 is a stimulatory IGFBP in patients with CRF, either by enhancing IGF activity through better presentation of IGF to its receptor or by an IGF-independent effect through activation of a specific, recently described putative IGFBP-5-receptor. Received: 24 September 1999 / Revised: 6 January 2000 / Accepted: 13 January 2000 / Accepted: 13 January 2000     

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.     

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 cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values ( ± SD) of C_max, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 ± 9 ng kg/mg ml, 210 ± 70 ng h kg/mg ml and 2.6 ± 0.9 ng kg/mg ml, respectively. For intramuscular administration, levels were about 5.5-fold, 9-fold and 22-fold higher. Based on pharmacokinetic data, the efficacy of oral cyclosporine treatment (without any other immunosuppressant) was evaluated in life-supporting cynomolgus monkey kidney allotransplantation. Rejection-free kidney allograft survival could be achieved using oral cyclosporine monotherapy with average 24-h trough concentrations above 100 ng/ml during maintenance treatment. Typically, daily oral doses of 100 mg/kg–150 mg/kg during the first two weeks post-transplantation, followed by daily 30 mg/kg–100 mg/kg dose levels during subsequent maintenance can result in long-term allograft survival, with 24-h average trough levels in individual animals during maintenance between 110 ng/ml and 700 ng/ml. Received: 1 October 1997 Revised: 20 April 2001 Accepted: 7 June 2001     

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     

Fasting‐induced Changes in Ovulation Rate,Plasma Leptin,Gonadotropins, GH,IGF‐I and Insulin Concentrations During Oestrus in Ewes

The aim of this experiment was to study the changes in the hormonal status and ovulation rate (OR) evoked by starvation during the follicular phase of the oestrous cycle in ewes. To achieve this goal, 12 female crossbreed sheep were synchronized and then half of them were fasted from the 12th to the 16th day of the oestrous cycle. On the 16th day, analysis of hormones and insulin‐like growth factor‐I (IGF‐I) were performed in 10‐min intervals. Then, on the 6th day of the following oestrous cycle, the OR in all ewes was determined by laparoscopy. Fasting reduced significantly (P < 0.05) the OR in ewes (1.25 ± 0.50) in comparison with control (1.75 ± 0.50). The drop in the OR was coincident with a significant (P < 0.001) decrease in the plasma concentration and pulse amplitude of leptin (0.29 ± 0.08 ng/ml versus control 0.53 ± 0.14 ng/ml), the plasma level of luteinizing hormone (LH) (0.19 ± 0.06 IU/l versus 0.25 ± 0.09 IU/l in control; P < 0.05) and the mean frequency of LH pulses (2.0/h versus 2.5/h in control). Fasting resulted also in a significant (P < 0.05) decrease in the plasma concentration and pulse amplitude of follicle stimulating hormone (FSH) in comparison with the control. Simultaneously, a significant (P < 0.001) drop in the IGF‐I concentration in the fasted ewes (4.78 ± 0.91 ng/ml) was found in comparison with control (7.63 ± 1.85 ng/ml). Also the level of insulin were significantly (P < 0.001) lower in the fasted (178.99 ± 39.08 pm /l respectively) than in the control sheep (302.66 ± 49.01 pm /l respectively). Meanwhile, a double increase in the growth hormone (GH) pulses frequency and an augmentation in its plasma concentrations as a result of starvation was found. The obtained results shows that the acute fasting exerts an inhibitory effect on the ovulation rate in ewes coincident with suppression in leptin, FSH and LH secretion and changes in signalization mediated by GH.     

Abbreviated cyclosporine AUCs on Neoral – the search continues!

 Cyclosporine is a powerful immunosuppressant with a narrow therapeutic window and considerable inter- and intrapatient variability. The pre-dose trough concentration (C_min) is commonly used for therapeutic drug monitoring. With the new microemulsion (Neoral), intrapatient variability was reduced. However, the usefulness of Neoral C_min was questioned. Firstly, because of the improved and more-rapid absorption, accidental intake before blood sampling has a greater impact on C_min than with classic cyclosporine. Secondly, C_min may be low despite high drug exposure, due to rapid clearance in children. A full pharmacokinetic (PK) profile with determination of the area under the curve (AUC) is expensive and cumbersome, and therefore a search for an abbreviated AUC began. Here, we present a retrospective analysis of 84 PK profiles from 78 pediatric renal transplant recipients. By analysis of rejection episodes and toxicity, we estimated a target AUC above 5,000 ng×h/ml in the early post-transplant period and 3,900 ng×h/ml beyond 100 days. The abbreviated AUC using the 2- and 6-h concentrations (C2 and C6) and a simple estimate derived from the 3-h concentration (C3) were equally well correlated with the AUC. From our data, we recommend a target C3 at approximately 800 ng/ml early after transplantation and 450–550 ng/ml beyond 100 days. Received: 28 January 1998 / Revised: 10 June 1998 / Accepted: 15 June 1998     

Acute Effects of Ethanol on Mineral Metabolism and Trabecular Bone in Sprague-Dawley Rats

In order to assess the effects of acute ethanol intoxication on bone, 45 female Sprague-Dawley rats were studied. Five rats were sacrificed at baseline. The remainder received either ethanol (2 g/kg of body weight) intraperitoneally or isotonic saline. Rats were sacrificed in groups of 10 (5 intoxicated and 5 placebo) at 1, 4, 8, and 24 hours after injection. At the time of sacrifice, a blood sample was obtained and the 4th vertebra was excised for histomorphometric analysis of undecalcified bone. Effect of ethanol was assessed by an analysis of variance test using a Scheffé procedure. In ethanol-treated rats we observed (mean ± SD, ethanol versus controls, maximum difference point, P value) a significant decrease in osteiod surface with osteoblasts (42.86 ± 15.61% versus 64.57 ± 6.24%, P < 0.05); osteoclast number (0.05 ± 0.02 n/mm² versus 0.17 ± 0.09 n/nm², P < 0.05), and osteocalcin (36.9 ± 2.21 ng/ml versus 45.8 ± 5.1 ng/ml, P < 0.05). Osteoclast surface was initially reduced (0.129 ± 0.09% versus 0.425 ± 0.26%, P < 0.01) but showed a subsequent increase (0.765 ± 0.24% versus 0.226 ± 0.17%, P < 0.01) attributable to alcohol. There was also a significant decrease in serum Ca (8.51 ± 0.23 mg/dl versus 9.10 ± 0.29 mg/dl, P < 0.01) and parathyroid hormone values (23.51 ± 5.72 pg/ml versus 76.39 ± 11.66 pg/ml, P < 0.001). We conclude that acute alcohol intoxication in rats induces early striking changes in bone histology and analytical parameters, not completely reversed after 24 hours. These data are consistent with a toxic effect induced by alcohol on bone. Received 30 May 1996 / 31 December 1996     

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     

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.     

Contemporary Oxygenator Design: Shear Stress‐Related Oxygen and Carbon Dioxide Transfer

Design of contemporary oxygenators requires better understanding of the influence of hydrodynamic patterns on gas exchange. A decrease in blood path width or an increase in intraoxygenator turbulence for instance, might increase gas transfer efficiency but it will increase shear stress as well. The aim of this clinical study was to examine the association between shear stress and oxygen and carbon dioxide transfer in different contemporary oxygenators during cardiopulmonary bypass (CPB). The effect of additional parameters related to gas transfer efficiency, that is, blood flow, gas flow, sweep gas oxygen fraction (FiO₂), hemoglobin concentration, the amount of hemoglobin pumped through the oxygenator per minute—Qhb, and shunt fraction were contemplated as well. Data from 50 adult patients who underwent elective CPB for coronary artery bypass grafting or aortic valve replacement were retrospectively analyzed. Data included five different oxygenator types with an integrated arterial filter. Relationships were determined using Pearson bivariate correlation analysis and scatterplots with LOESS curves. In the Capiox FX25, Fusion, Inspire 8F, Paragon, and Quadrox‐i groups, mean blood flows were 4.8 ± 0.9, 5.3 ± 0.7, 4.9 ± 0.7, 5.0 ± 0.6, and 5.7 ± 0.6 L/min, respectively. The mean O₂ transfer/m² membrane surface area was 44 ± 14, 51 ± 9, 60 ± 10, 63 ± 14, and 77 ± 18, respectively, whereas the mean CO₂ transfer/m² was 26 ± 14, 60 ± 22, 73 ± 29, 74 ± 19, and 96 ± 20, respectively. Associations between oxygen transfer/m² and shear stress differed per oxygenator, depending on oxygenator design and the level of shear stress (r = 0.249, r = 0.562, r = 0.402, r = 0.465, and r = 0.275 for Capiox FX25, Fusion, Inspire 8F, Paragon, and Quadrox‐i, respectively, P < 0.001 for all). Similar associations were noted between CO₂ transfer/m² and shear stress (r = 0.303, r = 0.439, r = 0.540, r = 0.392, and r = 0.538 for Capiox FX25, Fusion, Inspire 8F, Paragon, and Quadrox‐i, respectively, P < 0.001 for all). In addition, O₂ transfer/m² was strongly correlated with FiO₂ (r = 0.633, P < 0.001), blood flow (r = 0.529, P < 0.001), and Qhb (r = 0.589, P < 0.001). CO₂ transfer/m² in contrast was predominately correlated to sweep gas flow (r = 0.567, P < 0.001). The design‐dependent relationship between shear stress and gas transfer revealed that every oxygenator has an optimal range of blood flow and thus shear stress at which gas transfer is most efficient. Gas transfer is further affected by factors influencing the O₂ or CO₂ concentration gradient between the blood and the gas compartment.     

Clearance of Drugs for Multiple Myeloma Therapy During In Vitro High‐Cutoff Hemodialysis

Current chemotherapy for multiple myeloma is based on bortezomib (BOR), dexamethasone (DEX), and thalidomide (THA). The purpose of the present study was to examine their clearance during high‐cutoff (HCO) hemodialysis and to accordingly apply the results to the dialytic removal of protein‐bound substances in general. During in vitro hemodialysis with human blood (blood, dialysate, and ultrafiltration flow rates 250, 500 and 5 mL/min, respectively) comparing a highly permeable HCO dialyzer (Theralite, 2.1 m²) to a high‐flux dialyzer (PFX; 2.1 m²), ultrafiltered volume was replaced by saline containing 30 g/L urea. After recirculation for equilibration, BOR was injected, and arterial and venous samples were drawn after 10, 11, and 12 min to measure the plasma clearance (K) of both urea and BOR. The same procedure was performed with THA and DEX. By mathematical simulation, the influence of varying plasma albumin concentrations (C_HSA) on the protein‐bound drug fraction (PBF) and K was assessed. Plasma K values of HCO and PFX for THA, BOR, and DEX were about 40% (80 ± 7 vs. 65 ± 6 mL/min; P < 0.05), 70% (40 ± 8 vs. 33 ± 4 mL/min; P < 0.05), and 65% (47 ± 11 vs. 38 ± 7 mL/min; P < 0.05), respectively—lower (P < 0.0001) compared with urea (125 ± 7 vs. 122 ± 5 mL/min). K was highest (P < 0.0001) for THA. K was negatively correlated with C_HSA (THA, r² = 0.58, P < 0.001; BOR, r² = 0.24, P < 0.05; DEX, r² = 0.22, P < 0.05). C_HSA continually decreased (P < 0.05) over time only with HCO, resulting in lower calculated PBF. Compared with BOR and DEX (minimum 72 and 56%, respectively), the PBF of THA (37%) was significantly lower (P < 0.001). A mathematical simulation based on the K values of urea and the drugs reliably estimated PBF (r² = 0.886, P < 0.001). Drugs for multiple myeloma therapy are significantly removed with both HCO and PFX, with important implications for the dosing and timing of administration, particularly in patients with cast nephropathy receiving extended dialysis. If the K_urea of a dialyzer and the PBF of any given drug are known, K_drug can be reliably estimated by mathematical simulation.     

Safety and efficacy of generic cyclosporine arpimune in Filipino low-risk primary kidney transplant recipients

Background

In the Philippines, maintenance of immunosuppression may not always be affordable, leading to acute rejection and graft loss. The availability of the generic cyclosporine Arpimune could be economically beneficial, but its safety and efficacy should be established.

Methods

This prospective cohort study enrolled 30 renal transplant patients who received Arpimune with mycophenolate/prednisone. Their results were compared up to 6 months with 30 matched control patients who received Neoral during the same period. Areas under the receiver operating characteristic curves (AUC) after intake of Arpimune and therapeutic drug monitoring using cyclosporine levels 2 hours after each dose were done. Pearson correlation was performed to determine linearity of relationship between the generic cyclosporine concentrations and AUC 0-4. Chi-square test was used in obtaining cyclosporine Arpimune concentrations.

Results

The abbreviated concentration AUC of Arpimune was similar to that of Neoral, and the 2-hour sampling point (r = 0.813; P < .001) showed the best correlation. Calculated creatinine clearance (mL/min) versus Neoral was 71.36 ± 13 versus 68.03 ± 16.6 (P = .61) at 1 month, 70.4 ± 14.8 versus 64.2 ± 11.4 (P = .12) at 3 months, and 74.02 ± 15.8 versus 62.03 ± 12.1 (P = .002) at 6 months. Two Arpimune versus 4 Neoral patients (P = .67) developed biopsy-proven acute rejection. One septic death occurred in the Arpimune group. Graft survival was 100% in both groups. Hyperlipidemia was the most frequent side effect for both.

Conclusions

The AUC of Arpimune was similar to that of Neoral. Use of the generic cyclosporine Arpimune provided effective immunosuppression in the 6 months after transplantation. Renal allograft function was similar to that of Neoral, with minimal rates of acute rejection and adverse events.