Achieve Target Trough Research Articles

Prospective Trial of a Novel Nomogram to Achieve Updated Vancomycin Trough Concentrations

Purpose. To determine if the use of a novel vancomycin nomogram predicts dosing regimens that achieve target trough concentrations equal to or more accurate than dosing regimens calculated using traditional pharmacokinetic calculations, evaluate the incidence of subtherapeutic and supratherapeutic troughs, and assess pharmacist's impressions of the nomogram. Methods. Prospective, open-label study in 473 patients who had a new order for vancomycin and were >18 years of age and ≤120 kg. Patients were randomized to the active group, dosed using the nomogram, or to the control group, dosed using traditional pharmacokinetic calculations already in place at our institution. Results. Patients dosed via nomogram were within the appropriate trough range in 44% of cases compared to 33% in the control group (P = 0.014). Vancomycin troughs less than 10 mcg/mL were significantly decreased with the use of nomogram (P = 0.032). Incidence of supratherapeutic troughs, greater than 20 mcg/mL, was not significantly different between groups (P = 0.706), and pharmacists agreed that the nomogram was easy to use and saved their time. Conclusions. A novel vancomycin nomogram was prospectively validated and found to be more effective than traditional pharmacokinetic dosing. The nomogram is being implemented as the standard dosing protocol at our institution.

Utility of Voriconazole Monitoring and Factors Affecting Its Levels in Patients Undergoing Hematopoietic Stem Cell Transplantation. Single Center Experience From India.

AbstractAbstract 3035 Background:Voriconazole (vori) is used for prophylaxis against fungal infections in BMT. Under and over-dosing of vori may influence the efficacy and safety of therapy, respectively. There is large variability in vori exposure following standard dose administration. Utility of Therapeutic Drug Monitoring (TDM) of vori in patients with invasive mycoses has been demonstrated and recommended that trough concentrations should be maintained between 1–5.5 μg/mL. Based on these observations we started TDM of vori in BMT patients at our centre to target trough plasma concentration of 1–6 μg/mL. Few reports are available on the TDM of vori in BMT. We report our experience. Methods:All patients (autologous-65, allogeneic-64) who received vori prophylaxis during peritransplant period between September 2008 and January 2012 were included. Vori prophylaxis was started atleast 3 days prior to start of conditioning regimen in all patients before April 2011. Since April 2011, patients undergoing autologous transplant received vori 1 day after completion of chemotherapy. All patients above 12 years received oral loading dose of 6 mg/kg (upto maximum of 400 mg) 12 hourly on first day followed by 4mg/kg as maintenance. Intravenous dosing was used if patients had severe mucositis or developed febrile neutropenia. Patients less than 12 years received 7mg/kg 12 hourly continuously. Vori levels were measured on 5th-7th day after start of loading dose. Subsequent levels were done 2– 4 weekly till discontinuation of drug. If first level was < 1 or > 6 μg/ml, each dose was increased or decreased by 50% respectively and levels repeated after a week. Vori was continued for at least 100 days for all patients undergoing allogeneic transplant and longer if patients were on steroids due to graft vs host disease. Autologous transplant patients received it for 28 days. Incidence of breakthrough fungal infection was recorded as definite (blood culture positivity or histological evidence), probable (CT scan evidence with positive fungal PCR or galactomannan positivity) or possible (CT evidence only). Demographic and laboratory factors affecting the levels evaluated were age, sex, height, weight, body surface area (BSA), liver and renal function parameters. Concomitant drugs being used were recorded for any effect on vori levels. Vori levels in plasma were determined by a validated HPLC assay. Paired samples were compared using t-test or Wilcoxin sign rank test. Influence of covariates on vori levels were analyzed by linear regression with backward elimination. Interaction between concomitant drugs and their effects on vori levels was determined by ANCOVA after adjusting for baseline values. Results:One hundred twenty-nine patients were monitored during this period. The median age was 24.6 years. The median number of TDM was 3 (1–32) per patient. High inter and intra-patient variability was observed (coefficient of variation = 73% and 45% respectively). Twenty-eight patients (21.7%) had trough levels < 1 μg/mL after the first monitoring. Twenty-one patients had their dose modified after first monitoring (16 due to very low levels and 5 due to high levels). Thirteen (80%) patients achieved target trough concentration after dose escalation. Dose reduction resulted in sub-optimal levels in 3 of 5 patients. Twenty – four patients who had adequate levels at first TDM had fall in level below 1 μg/mL subsequently during the 2nd or 3rd TDM. This coincided with the introduction of steroids for treatment. Introduction of steroids significantly reduced vori trough levels (presteroid mean- 2.67 μg/ml, post steroid mean- 1.47μg/ml; P=0.014).Similarly use of cyclosporine (CSA) also significantly decreased vori levels (pre CSA mean-2.65μg/ml, post CSA mean-1.91μg/ml; P=0.023). The effect of steroids and CSA on vori levels were independent of each other. None of the demographic or laboratory parameters influenced vori levels. Breakthrough fungal infections were seen in 5 patients (definite-1, probable-3, possible-1). Conclusions:Voriconazole level monitoring should be done in all patients who are on steroids and CSA post transplant. No demographic or laboratory parameter affected voriconazole levels in our study. Incidence of breakthrough fungal infection is low in patients who are monitored with drug levels. Disclosures:No relevant conflicts of interest to declare.

Everolimus alters white matter diffusion in tuberous sclerosis complex

Diffusion tensor imaging (DTI) analysis was performed on patients with tuberous sclerosis complex (TSC) to investigate potential changes in normal-appearing white matter after treatment with everolimus, a mammalian target of rapamycin (mTOR) inhibitor. Recently, a phase I/II trial of everolimus demonstrated significant reductions in subependymal giant cell astrocytoma (SEGA) volume and decreased seizure frequency. Subgroup analysis was performed on DTI data available from this study. TSC patients with SEGA received everolimus, titrated to tolerability to achieve target trough concentrations of 5-15 ng/mL. DTI (1.5 T, 15 directions) was used to calculate fractional anisotropy (FA) and axial, radial, and mean diffusivity within regions of interest (ROIs). Baseline scans were compared to 12-18 months post-treatment and compared to a TSC age- and gender-matched nontreatment control cohort. Of 28 enrolled patients, 20 had sufficient DTI data. Comparing baseline values with those acquired 12-18 months after treatment, a significant change in FA was observed in the corpus callosum, internal capsule, and geniculo-calcarine region (p < 0.05). Mean change in FA was 0.04 (p < 0.01), driven primarily by a significant decrease in radial diffusivity. Mean diffusivity of the combined ROIs decreased slightly (p < 0.05), axial diffusivity remained stable. The control group showed no change over time. Significant changes in FA and radial diffusivity were observed after treatment with everolimus in patients with TSC, suggesting that the genetic defect of TSC in the brain may be modified pharmacologically, even in normal-appearing white matter.

Steady‐State Pharmacokinetics of Intravenous Levetiracetam in Neurocritical Care Patients

To characterize the steady-state pharmacokinetics of intravenous levetiracetam in neurocritical care patients requiring seizure prophylaxis after a neurologic injury and to determine which dosing regimens achieve serum concentrations within the recommended therapeutic range of 6-20 μg/ml. DESIGN. Prospective, open-label, steady-state pharmacokinetic study. Neurocritical care unit in a tertiary care medical center. PATIENTS. Twelve adults (five men, seven women) admitted to the neurocritical care unit who required prophylactic anticonvulsant therapy after subarachnoid hemorrhage, subdural hematoma, or traumatic brain injury. Patients received an intravenous infusion of levetiracetam 500 mg over 15 minutes every 12 hours. Serial blood samples were collected from all patients after a minimum of four doses of therapy. Serum levetiracetam concentrations were determined by ultraperformance liquid chromatography with tandem mass spectrometry detection, and pharmacokinetic data were analyzed by compartmental and noncompartmental methods. Monte Carlo simulations were performed for multiple levetiracetam dosing regimens to determine the probability of achieving a target trough concentration of 6 μg/ml or greater, 20 μg/ml or greater, and 6-20 μg/ml. The mean ± SD levetiracetam maximum serum concentration was 28.0 ± 8.0 μg/ml, minimum serum concentration 3.1 ± 1.8 μg/ml, half-life 5.2 ± 1.2 hours, systemic clearance 5.6 ± 1.8 L/hour, and volume of distribution at steady state 36.8 ± 6.3 L. Increasing the doses of levetiracetam increased the probability of achieving a target trough concentration of 6 μg/ml or greater but also increased the probability of achieving trough concentrations greater than 20 μg/ml. Levetiracetam doses of 1000 mg every 8 hours and 1500-2000 mg every 12 hours provided the highest probability of achieving a target trough concentration between 6 and 20 μg/ml. Compared with previously published results in healthy volunteers and adults in status epilepticus, levetiracetam systemic clearance was faster and the terminal elimination half-life was shorter in neurocritical care patients. Higher doses or more frequent dosing may be needed to achieve target trough concentrations of 6-20 μg/ml.

Implementation of a Dose Calculator for Vancomycin to Achieve Target Trough Levels of 15-20 g/mL in Persons Undergoing Hemodialysis

(See the article by Brown et al, on pages 164-166.) Vancomycin is a key antibiotic for the treatment of Gram-positive bacterial infections in patients undergoing dialysis. Vancomycin has a narrow therapeutic range. Overdosing imposes a risk of nephro- and ototoxicity, wherease underdosing predisposes to treatment failure and the emergence of drug resistance. Trough levels of 15-20 μg/mL have been identified as the optimal target trough levels. A multivariate model called the vancomycin dose calculator (VDC) was prospectively developed and validated to permit accurate vancomycin dosing in persons undergoing hemodialysis. The model identified 3 simple parameters that were responsible for 94.6% of the variance observed: predialysis vancomycin trough level, dry body weight, and period to the next dialysis session. Maintenance dosing was accurate in 77.9% of patients, whereas major over- and underdosing were avoided in the remaining patients. The mean measured trough level of 16.5 μg/mL was 5.6% lower than the mean predicted trough level of 17.5 μg/mL. With regard to loading doses, a fixed loading dose of 20 mg/kg led to subtherapeutic trough levels in one-half of patients. The VDC permits accurate vancomycin maintenance dosing based on predialysis trough level, dry body weight, and period to the next dialysis session in the majority of patients undergoing hemodialysis. Higher loading doses that accounted for the period to the next dialysis may be more appropriate than fixed loading doses used in this study.

Validation of the Effectiveness of a Vancomycin Nomogram in Achieving Target Trough Concentrations of 15–20 mg/L Suggested by the Vancomycin Consensus Guidelines

To assess and validate the effectiveness of a newly constructed vancomycin dosing nomogram in achieving target trough serum concentrations of 15-20 mg/L. Prospective multicenter study. Five tertiary care teaching hospitals. A total of 200 adults who required vancomycin dosages targeted to attain recommended trough vancomycin serum concentrations of 15-20 mg/L. The new nomogram, which based dosing on weight and renal function, was used to calculate patients' initial vancomycin dosages. Serum trough concentrations were measured before the fourth or fifth dose, and dosages were adjusted as needed. Median patient age was 56 years (interquartile range [IQR] 49-65 yrs), median weight was 71.2 kg (IQR 63-85 kg), and median creatinine clearance was 66.5 ml/minute (IQR 52-82 ml/min). The median initial vancomycin trough concentration achieved was 17.5 mg/L (IQR 15.0-20.0 mg/L), with 116 patients (58%) achieving the initial target trough of 15-20 mg/L. The median percent error was 13.6%, and the mean ± SD error for predicted versus actual serum trough concentrations was -0.50 ± 0.021 mg/L. One hundred fifty-four patients (77%) eventually achieved the trough target concentration within a median of 2 days. One hundred forty patients (70%) achieved initial troughs of 14-21 mg/L and 160 (80%) achieved troughs of 13-22 mg/L. Nine patients (4.5%) experienced nephrotoxicity while receiving vancomycin, which occurred after a median of 8 days of therapy. The median initial vancomycin trough concentration for these patients was 18.5 mg/L (IQR 15.3-19.3 mg/L), with eight of the nine patients having trough concentrations of 15 mg/L or greater. Fifty-eight percent of patients achieved the target trough of 15-20 mg/L (median 17.5 mg/L). The performance of the nomogram improved to 80% when the trough range was adjusted to 13-22 mg/L. Caution should be applied when using this nomogram. The nomogram should not replace clinical judgment, and dosage adjustments should be based on pharmacokinetic-pharmacodynamic targets and clinical response.

Within-Patient Atazanavir Trough Concentration Monitoring in HIV-1-Infected Patients

Objective: Protease inhibitors (PIs) exhibit considerable interpatient pharmacokinetic variability in plasma trough concentrations. Therapeutic drug monitoring (TDM) is occasionally used to guide chronic dosing to achieve target trough concentrations, but its clinical success assumes minimal intrasubject variability. Therefore, our primary objective was to evaluate intrapatient variability in atazanavir (ATV) plasma trough concentrations in HIV-1-infected patients. Design/Methods: In a single-site, prospective, cohort study, patients on atazanavir with or without ritonavir (ATV/r or ATV) for 2 clinic visits were enrolled. Adherence and time since last dose (TSLD) were verified at each visit. ATV was assayed with high-performance liquid chromatography. Intra- and interpatient variation was evaluated using the median intraindividual percentage coefficient of variation (ICV). Results: The mean 24-hour ATV trough concentrations for the first and second visit for the ATV/r group (n = 10) was 598 (CV 84%) and 525 ng/mL (CV 66%), respectively (P = .511), and 300 (CV 81%) and 434 ng/mL (CV 106%) for the ATV group (n = 4), respectively (P = .369). Median ICV was 43.1% for all patients (range: 0.6%-107.6%), 38.1% (0.6%-107.6%) for the ATV/r group, and 33.1% (2.3%-87.6%) for the ATV group. Conclusions: Potential intrapatient variability in ATV troughs suggests that repeated measurements may be required to ensure that target values are maintained.

Audit of vancomycin TDM in ECMO patients

ObjectiveThe aim of this investigation was to evaluate current vancomycin dosing schedules and TDM in patients on ECMO at Glenfield Hospital following the introduction of a new ECMO circuit. Specifically...

Everolimus for subependymal giant-cell astrocytomas (SEGAs) in tuberous sclerosis (TS).

2004 Background: TS is a potentially devastating disorder characterized by hamartoma formation in multiple organ systems. SEGAs develop in 5-15% of TS patients and represent a significant medical risk, including the potential for sudden death secondary to acute hydrocephalus (as a result of their location adjacent to the foramen of Monro). Neurosurgical resection is the current standard treatment and no effective alternative has been identified. Methods: Patients ≥3 years with a definitive TS diagnosis and evidence of serial SEGA growth (on MRI) were eligible for this prospective, open-label, phase II study. The primary efficacy endpoint was change in SEGA volume from baseline to 6 months (mo). Everolimus dose (3 mg/m2 QD orally) was titrated subject to tolerability to achieve target trough concentrations of 5-15 ng/mL. Results: 28 patients were enrolled between 1/07 and 12/08; median duration of treatment was 22 mo (range 5-34). Everolimus was associated with a clinically meaningful reduction in SEGA volume (p<0.001); marked reductions were seen within the initial 3 mo and subsequently sustained or further improved (see table). No patient developed new lesions, worsening hydrocephalus, or worsening signs or symptoms of increased intracranial pressure; none required surgical resection or other therapy for SEGA. Of 16 patients for whom video-EEG data were available, 9 experienced decreases in seizure frequency (across all types of seizure), 6 reported no change (all were event-free at both timepoints), and 1 patient experienced an increase (median change -1.0, p=0.012). Grade 3 adverse drug reactions were single cases of sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia; no grade 4 events were reported. Conclusions: Everolimus is effective in TS-associated SEGA with 78% of patients achieving the prespecified ≥30% reduction at 6 mo; it is also well tolerated and offers a viable alternative to surgical resection. SEGA volume (independent central review) % reduction from baseline, n (%) 3 mo n=26 6 mo n=27 12 mo n=26 18 mo n=18 24 mo n=8 ≥50% 10 (38) 9 (33) 9 (35) 8 (44) 3 (38) ≥30% 17 (65) 21 (78) 20 (77) 12 (67) 6 (75) >0% 25 (96) 27 (100) 26 (100) 16 (89) 8 (100) No change 0 0 0 1 (6) 0 Growth 1 (4) 0 0 1 (6) 0 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis Novartis

A Phase I Pharmacologic Study of Necitumumab (IMC-11F8), a Fully Human IgG1 Monoclonal Antibody Directed Against EGFR in Patients with Advanced Solid Malignancies

This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG(1) monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab. Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy. Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose-related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with >or=600 mg necitumumab achieved target trough concentrations (>or=40 microg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively. Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting.

Campath-1H (Alemtuzumab) as an Induction Agent for the Prevention of Graft Rejection and Preservation of Renal Function in Kidney Transplant Patients: Philippine 3-Year Follow-up

Objective The purpose of this study was to evaluate the safety and efficacy of induction with Campath-1H with low-dose cyclosporine (CsA) monotherapy using outcome measures of acute rejection episodes (ARE), chronic allograft nephropathy (CAN), graft and patient survivals, as well as malignancies and infections. Materials and Methods Fourteen kidney transplant recipients were randomized to receive either Campath 1H induction with CsA monotherapy (9 patients) or immunosuppression with CsA, azathioprine, and steroids (5 patients). Campath (20 mg IV) was administered within 6 hours after the anastomosis and repeated 24 hours later. Cyclosporine was started 72 hours after the first Campath dose (10 mg/kg on the first day, then 4 mg/kg/d), seeking to achieve target trough CsA levels of 90 to 110 ng/mL. This is a 3-year follow-up of the 9 patients who received Campath-1H induction. Results Six of 9 (67%) patients developed ARE (borderline ARE to Banff IB) in the Campath group compared with 1 of 5 (20%) in the other group (ARE Banff IIA). They all received methylprednisolone for 3 days with good responses. One of the 6 patients in the Campath group with ARE also displayed CAN and was converted to sirolimus; 2 others had mycophenolate mofetil and steroids added to their immunosuppression after the ARE. Creatinine levels ranged from 1 to 1.7 mg/dL at 24 to 36 months posttransplantation in both groups. Among the Campath group, 1 patient died 6 months posttransplantation with sepsis secondary to infectious diarrhea. Upper respiratory tract infections comprised the majority of infections at 24 to 36 months. No malignancies were observed. Conclusions Three years posttransplantation, patients given Campath induction with CsA monotherapy showed a greater incidence of ARE, although renal function remained comparable to CsA-azathioprine-prednisone therapy. AREs were easily reversed with steriods. Infections were minor.

Everolimus With Reduced-Dose Cyclosporine in De Novo Renal Transplant Recipients: Philippine Experience

Objective The objective of this study was to describe the appropriate dose of everolimus to achieve target trough concentrations in standard-risk Filipino kidney transplant recipients. Methodology We reviewed all kidney transplant recipients from December 1, 2006 to June 15, 2007 who were given everolimus (1.5 mg/d) in combination with low-dose cyclosporine (5 mg/kg/d) and prednisone but without induction therapy for their immunosuppressive doses, trough levels, as well as hematologic and blood chemistry profiles. Target everolimus trough concentration was 3–8 ng/mL and C2 level was 1000–1400 ng/mL for the first 3 months. Results Among 148 patients who underwent transplantation during the study period, 26 comprised the study population but only 15 patients completed the 3-month follow-up and are the subject of this report. Their mean age was 33 years, average PRA 2%, and mean HLA mismatches 3. All were from living donors. At 7 days posttransplantation, all patients achieved or exceeded the target everolimus trough and cyclosporine C2 level. At 1 and 3 months posttransplantation the mean everolimus dose was 1.17 and 0.78 mg/d, respectively, whereas the cyclosporine dose was 195 and 148 mg/d, respectively. Three patients showed elevated alanine aminotransferase (ALT) and all patients had hypercholesterolemia after 1 month, which improved with everolimus dose reduction (half required statins). One patient experienced a Banff Grade IA acute rejection episode at 2 months posttransplantation with a serum creatinine value of 2 mg/dL after steroid pulsing. Conclusions Most standard-risk Filipino kidney transplant recipients required a maintenance everolimus dose of 1 mg/d at 1 month. The cyclosporine dose requirement was also lower. A larger sample size is needed to provide a level of significance compared with other populations.

Pharmacokinetics of factors IX, recombinant human activated factor VII and factor XIII

Summary. There is now a volume of literature on the pharmacokinetics (PK) of coagulation factor concentrates, although the majority is on factor VIII (FVIII) and factor IX (FIX). PK of FIX and FVIII are different with FIX having a larger volume of distribution (Vdss), higher elimination clearance (CL), longer mean resident time (MRT) and longer terminal half‐life (T1/2,β). Factor IX in vivo recovery (IVR) is also much shorter possibly due to reversible binding of FIX to the endothelium and possibly to platelets. There is considerable FIX PK variability between products (particularly between plasma‐derived FIX and recombinant FIX), and between individuals. Important inter‐individual factors leading to PK variability include age and body weight because plasma volume as a fraction of body weight decreases with increasing weight and hence age. Thus, IVR increases with body weight and hence age and is consequently lower in children than in adults. Absolute Vdss and CL increase linearly with body weight and age in children and adolescents, becoming stable in adults with more stable weight. Inter‐individual variability also likely applies to other clotting factors, particularly to recombinant activated FVII (rFVIIa) but likely also to the less well studied factor XIII (FXIII). The former is known to have an extremely short T1/2,β, large Vdss, high CL, short MRT, whereas the latter has an extremely long T1/2,β, large Vdss, short CL and long MRT. Both are discussed in this article. Understanding of PK of specific clotting factors in individual patients is important in order to make decisions regarding appropriate dosage and dosage intervals to treat patients, and to allow by means of computer modelling the determination of dosage to achieve target trough level at various dosing intervals for patients undergoing prophylaxis.

Conversion to everolimus in a patient with arterial hypertension and recurrent cutaneous neoplasia—a case report

Calcineurin inhibitors (CNIs) are frequently associated with side effects such as nephrotoxicity and hypertension, so CNI withdrawal from immunosuppressive regimens is desirable in certain cases. The proliferation signal inhibitors/mammalian target of rapamycin inhibitors everolimus and sirolimus may play an important role in achieving CNI withdrawal. Studies on sirolimus have shown that conversion from CNIs is associated with improvements in renal function and hypertension. A case report is presented of a renal transplant recipient who experienced hypertension and recurrent cutaneous neoplasia while receiving a ciclosporin (CsA)-based immunosuppressive regimen. After transplantation, the patient received full-dose CsA and prednisolone. After 7 years, the patient's serum creatinine increased from 1.9 mg/dl to 2.5 mg/dl, and mycophenolate mofetil (MMF, 1000 mg/day) was introduced, enabling the CsA dose to be reduced to 100 mg b.i.d. The patient also required resection of five cutaneous neoplastic lesions; this led to the decision to stop CsA and start treatment with everolimus 1.5 mg/day, which was increased to 3.0 mg/day to achieve target trough blood levels of 3 ng/ml. To avoid over-immunosuppression, the MMF dose was reduced to 500 mg/day. After conversion, the patient experienced a substantial improvement in blood pressure, from 175/85 mmHg to 155/70 mmHg. Serum creatinine levels decreased to 1.6 mg/dl, and there has been no recurrence of cutaneous neoplasia in 9 months of follow-up. Therefore, conversion to everolimus from CsA in a renal transplant recipient led to improvements in blood pressure and resolution of recurrent cutaneous neoplasia, with no evidence of rejection or changes in renal function.

Sirolimus pharmacokinetics in pediatric renal transplant recipients receiving calcineurin inhibitor co‐therapy

We have previously reported sirolimus (SRL) pharmacokinetics (PK) in pediatric renal transplant recipients on a calcineurin inhibitor (CNI)-free protocol. We now report pediatric SRL PK in pediatric renal transplant patients receiving SRL + CNI. SRL was dosed to achieve target trough levels between 10 and 20 ng/mL. We performed 49 SRL PK profiles in pediatric renal transplant recipients receiving SRL in combination with either cyclosporine (CsA; 25 profiles), or tacrolimus (TCL; 24 profiles). Ten of the SRL + TCL profiles were obtained from children receiving SRL on a b.i.d. dosing regimen. All other SRL profiles were q.d. regimens. We calculated, the maximum concentration (C(max)), AUC, apparent clearance (aCL; dose/AUC) for dose in mg/m(2), and mean residence time (MRT). SRL levels were measured at 6 and 7 time points for b.i.d. and q.d. dosing, respectively. Regression analysis of SRL trough values vs. AUC showed good correlation in the SRL q.d. + CsA, SRL q.d. + TCL, and SRL b.i.d. + TCL groups (r(2) = 0.95, 0.68, and 0.44, respectively). SRL aCL corrected for body surface area was higher in children aged 0-5 yr receiving SRL with either CsA or TCL. SRL dosing schedule should be tailored to each patient. Higher SRL aCL may be present in younger children when administered with CNI.

Primary immunosuppression with tacrolimus and low-dose mycophenolate mofetil in renal transplant recipients

Both tacrolimus and mycophenolate mofetil (MMF) are potent immunosuppressive agents used in combination for prevention of acute rejection in renal transplantation. We studied the efficacy and safety of tacrolimus/MMF–based primary immunosuppression as well as their pharmacokinetics (PK) in Chinese renal transplant recipients. Oral tacrolimus was initiated at about 0.2 mg/kg/d, dose which was adjusted to achieve target trough levels of 10 to 20 ng/mL at 3 months and 5 to 10 ng/mL thereafter. The patients also received MMF (0.5 g bid) and prednisolone. PK profiles were studied at 1 week, and 1, 3, and 6 months posttransplant. Blood samples were taken at 0 (predose), 20, 40, 60, 75, and 90 minutes and 2, 4, 6, 8, 10, and 12 hours postdose for each profile. Plasma MPA and whole blood tacrolimus levels were determined by HPLC and EMIT methods respectively. Eight patients were studied with mean follow-up of 16.1 ± 2.4 months. One patient (12.5%) experienced a borderline acute rejection episode. Both 1-year graft and patient survival rates were 100%. Posttransplant diabetes, diarrhea, and hand tremor occurred in 12.5%, 12.5%, and 37.5%, respectively. No patient had an opportunistic infection. Tacrolimus trough concentrations showed a fair correlation with AUC 0–12h (R 2 = 0.587). Mean MPA AUC values at 1, 3, and 6 months were 40.5 ± 9.4, 44.4 ± 17.3, and 57.2 ± 20.7 μg*h/mL, respectively ( P = .0486, n = 7). In conclusion, primary immunosuppression with tacrolimus, low-dose MMF (0.5 g bid), and prednisolone is effective and safe with adequate systemic MPA exposure in renal transplant recipients.

Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation.

Tacrolimus is an immunosuppressive drug that is a substrate of cytochrome P450 3A (CYP3A) enzymes and P-glycoprotein (P-gp). After transplantation, many pharmacological interactions have been described. Corticosteroids induce both CYP3A and P-gp activity. This study was designed to investigate the presence of a clinically significant interaction between steroids and tacrolimus after renal transplantation. We studied 83 renal transplant recipients receiving tacrolimus after transplantation. Patients were divided into three groups, according to steroid dose (low: 0-0.15 mg/kg/day; intermediate: 0.16-0.25 mg/kg/day; and high: >0.25 mg/kg/day). All other medications, including those known to interact with CYP3A and/or P-gp, were recorded. Steroid dosage, tacrolimus dosage, tacrolimus trough concentration (C0) and tacrolimus concentration/dose ratio [C0 divided by the 24 h dosage (mg/kg)] were assessed for each dosage group after 1 and 3 months of tacrolimus treatment. The three groups were not different as regards the use of non-immunosuppressive treatments or clinical events. At 1 and 3 months, the tacrolimus doses and concentration/dose ratios differed significantly in the three steroid dosage groups. With the higher doses, higher tacrolimus doses were needed to achieve the blood tacrolimus targeted trough level. We demonstrated that pharmacokinetic interaction occurs between steroids and tacrolimus in renal transplant patients. The higher the steroid dosage, the higher the dosage of tacrolimus needed to achieve target trough levels in these patients. The most likely interaction mechanism is specific enzymatic induction of CYP3A and/or P-gp. Interaction is present, even when the steroid dosage is low. The clinical events liable to occur during steroid sparing or tapering must be taken into account because it may be associated with episodes of tacrolimus-related nephrotoxicity.

NEORAL VS SANDIMMUNE IN HEART TRANSPLANTATION: ONE YEAR RESULTS OF A DOUBLE-BLIND, INTERNATIONAL STUDY

3 A prospective, two year, randomized (1:1), double-blind study comparing the safety and efficacy of the conventional cyclosporine A (CyA) formulation, Sandimmune (SIM) to the microemulsion formulation Neoral in 380 recipients of primary heart allografts is being performed at 24 centers in 5 countries. An analysis after one year of treatment was performed. Patients were treated with SIM or Neoral as part of a triple immunosuppressive regimen including steroids and azathioprine. Antibody (Ab) induction (41% Neoral; 42% SIM) was allowed per local standard practice. Demographic and baseline characteristics were comparable. In the Neoral group, CyA troughs were significantly higher early after Tx, and lower CyA dosages were needed to achieve target trough levels (p=0.024). Patient/graft survival was 90.4% (Neoral) vs 90.1% (SIM). Mean biopsy scores and incidence of rejections with ISHLT ≥3A (45.2% Neoral; 43.2% SIM) were comparable, however the incidence of rejections requiring Ab therapy was significantly lower with Neoral (6.4% vs 16.7%, p=0.002). In female patients fewer rejections with ISHLT ≥3A (34.4% Neoral vs 57.6% SIM, p=0.083) and lower mean biopsy scores (0.94 Neoral vs 1.39 SIM, p=0.047) were recorded in the Neoral group. Fewer patients on Neoral discontinued the study prematurely (14.9% vs 24.0%, p=0.028). This was due to fewer Neoral patients discontinuing the drug for lack of efficacy (2.7 % vs 8.3%, p=0.023). More Neoral patients experienced headache and nausea/vomiting which were transient and of mild to moderate severity. Although not clinically significant, mean triglycerides (213 vs 190 mg/dL, p=0.037), mean creatinine (1.84 vs 1.71 mg/dL, p=0.018), mean BUN (36.5 vs 32.0 mg/dL, p=0.002) and mean diastolic blood pressure (90.0 vs 86.4 mmHg, p=0.008) were higher in the Neoral group compared with SIM at month 12. Otherwise, there was no difference in the spectrum of CyA-related side effects. However, there were significantly fewer CMV infections in the Neoral arm (11.2% vs 18.8%, p=0.044) possibly related to the decreased need for supplemental antilymphocyte antibodies in Neoral-treated patients. One patient in each arm developed PTLD. The following baseline and/or time dependent variables influencing the clinical outcome were identified by Cox regression analysis: PRA level, Ab induction, donor age, blood pressure, SGPT, SGOT, BUN, magnesium and triglyceride levels. In conclusion, this study demonstrates that the improved pharmacokinetics of Neoral translate into clinical advantages over SIM without a major impact on safety.

RANDOMIZED COMPARATIVE TRIAL OF PROGRAF (TACROLIMUS) IN COMBINATION WITH AZATHIOPRINE OR MYCOPHENOLATE MOFETIL VS. NEORAL (CYCLOSPORINE) WITH MYCOPHENOLATE MOFETIL AFTER KIDNEY TRANSPLANTATION

662 A randomized three arm, parallel group open label prospective study was performed at 15 North American centers to compare the efficacy and safety of three immunosuppressive regimens (Prograf + mycophenolate mofetil (MMF) vs. Prograf + azathioprine (AZA) vs. Neoral + MMF) after first cadaveric kidney transplantation. All patients received the same steroid regimens and antilymphocyte induction only with DGF/ATN. Prograf was initially dosed to achieve target trough levels of 8-16 ng/mL in the first 3 months and 5-15 ng/mL thereafter. Neoral was dosed to target trough levels of 200-400 ng/mL for the first 3 months post transplant and 100-300 ng/mL thereafter. Patients receiving azathioprine were dosed at 1.5-2.0 mg/kg/day and patients receiving MMF were dosed at 2 grams/day. 224 patients were randomized and transplanted. To date, 156 patients have completed the study (6 months post-transplant follow-up or terminated due to death or graft loss). There was no significant difference in baseline demography between the treatment groups. To date there have been 7 graft losses in the Prograf + AZA group, 7 in the Neoral+MMF group and 6 in the Prograf+MMF group. The rejection results are as follows:TableAt baseline through 6 months, chemistry and hematology lab values were similar across treatment groups with the exception of total cholesterol and LDL which were higher during follow-up in the Neoral+MMF group. The incidence of new onset post-transplant diabetes mellitus (defined as new insulin use for>30days) was: Prograf+AZA group (10.5%), Neoral+MMF group (6.5%), and Prograf+MMF group (0%). The frequency of serious adverse events, including infections, were similar across treatment groups. All regimens yielded similar acute rejection rates, but the Prograf+MMF regimen was associated with the lowest rate of OKT3 use. The Prograf regimens were associated with lower rates of hyperlipidemia than the Neoral regimen, and post-transplant diabetes did not appear different in the Prograf groups vs. the Neoral group. Further follow-up is required to define the long-term impact of these early results.