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Biomedical subjects

K L Brayman

Publications and source records attributed to K L Brayman.

At least 19 recordsLinked to original sources
PubMed2001

Pharmacokinetic, pharmacodynamic, and outcome investigations as the basis for mycophenolic acid therapeutic drug monitoring in renal and heart transplant patients.

Mycophenolate mofetil is widely used in combination with either cyclosporine or tacrolimus for rejection prophylaxis in renal and heart transplant patients. Although not monitored routinely nearly to the degree that other agents such as cyclosporine or tacrolimus, there is an expanding body of experimental evidence for the utility of monitoring mycophenolic acid, the primary active metabolite of mycophenolate mofetil, plasma concentration as an index of risk for the development of acute rejection. The following are important experimentally-based reasons for recommending the incorporation of target therapeutic concentration monitoring of mycophenolic acid: (1) the MPA dose-interval area-under-the-concentration-time curve, and less precisely, MPA predose concentrations predict the risk for development of acute rejection; (2) the strong correlation between mycophenolic acid plasma concentrations and expression of important cell surface activation antigens, whole blood pharmacodynamic assays of lymphocyte proliferation and median graft rejection scores in a heart transplant animal model; (3) the greater than 10-fold interindividual variation of MPA area under the concentration time curve values in heart and renal transplant patients receiving a fixed dose of the parent drug; (4) drug-drug interactions involving other immunosuppressives are such that when switching from one to another (eg, from cyclosporine to tacrolimus or vice-versa) substantial changes in MPA concentrations can occur in patients receiving a fixed dose of the parent drug; (5) significant effects of liver and kidney diseases on the steady-state total and free mycophenolic acid area under the concentration time curve values; (6) the need to closely monitor mycophenolic acid when a major change in immunosuppression is planned such as steroid withdrawal. Current investigations are focused on determination of the most optimal sampling time and for mycophenolic acid target therapeutic concentration monitoring. Further investigations are needed to evaluate the pharmacologic activity of the newly described acyl glucuronide metabolite of mycophenolic acid which has been shown to inhibit, in vitro, inosine monophosphate dehydrogenase.

Area Under Curve↗
PubMed2001

Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients.

The relationship between the dose of tacrolimus, trough tacrolimus blood concentration, and selected clinical endpoints (acute rejection, nephrotoxicity, and other toxicities) were examined in a prospective, multicenter clinical trial to validate the use of an enzyme-linked immunosorbent assay (ELISA) for monitoring whole-blood concentrations of tacrolimus in liver transplant patients. A total of 111 subjects from six transplant centers were evaluated over 12 weeks posttransplantation. In addition to trough tacrolimus blood concentrations, hematocrit, ALT, AST, GGTP, alkaline phosphatase, total bilirubin, serum creatinine, BUN, serum potassium, serum magnesium, blood glucose, and serum albumin were also measured. The relationship between trough tacrolimus blood concentrations and clinical endpoints was analyzed using both a logistic regression model and a Cox proportional hazard model. By logistic regression analysis, a statistically significant (p = 0.0465) relationship between increasing trough tacrolimus blood concentrations and decreasing risk of acute rejection was demonstrated over a 7-day time window. Nephrotoxicity and other toxicities also demonstrated statistically significant relationships with trough tacrolimus blood concentrations. The results of the Cox analysis were consistent with the logistic regression analysis. Using receiver operator characteristic curves, trough tacrolimus concentrations as measured by the ELISA method were able to differentiate the occurrence of nephrotoxicity and toxicity from nonevents. To minimize nephrotoxicity of tacrolimus, it is necessary to maintain trough blood concentrations below 15 ng/ml. This study demonstrates that the ELISA method used to measure tacrolimus blood concentrations in this study provides information of predictive value for managing the risk of nephrotoxicity, other toxicity, and rejection in liver transplant patients.

Administration, Oral↗
PubMed2000

Pharmacokinetics and concentration-control investigations of mycophenolic acid in adults after transplantation.

Data have emerged that provide the scientific basis for therapeutic drug monitoring of mycophenolic acid (MPA) in transplant patients receiving mycophenolate mofetil (MMF), the parent drug, in combination with other immunosuppressive agents. There is a significant relationship between the dose-interval MPA AUC and risk for acute rejection based on retrospective investigations in renal and heart transplant patients and on prospective investigations in renal transplant patients. The MPA dose-interval AUC varies naturally by more than 10-fold in renal and heart transplant patients. Other significant sources of pharmacokinetic variability for MPA include the effects of concomitant medications, and the effects of disease states such as renal dysfunction and liver disease on the steady state MPA AUC. Individualized MMF dose evaluation, guided by MPA plasma concentrations, is becoming the standard of practice at a growing number of transplant centers worldwide because of these factors and because of the need to closely evaluate the immunosuppression afforded by MPA when a change in the immunosuppression regimen in stable transplant patients is planned. Investigations of therapeutic drug monitoring strategies with an emphasis on identifying an optimal abbreviated sampling strategy for MPA AUC estimation are ongoing. Based on the concentration-outcome studies and experience at the authors' institutions and other centers, the authors propose a set of therapeutic drug monitoring guidelines for MPA in stable renal and heart transplant patients for the immediate (first 3 months posttransplant) and maintenance (>3 months) periods. When MPA binding to human serum albumin is altered, as occurs in patients with significant renal dysfunction, liver disease, or a substantial reduction in human serum albumin concentration, the possibility of increased MPA free fraction and free concentration will need to be taken into account in the interpretation of MPA total concentrations.

Area Under Curve↗
PubMed1999

Gene therapy strategies to facilitate organ transplantation.

Organ transplantation is now the definitive therapy for many forms of end-organ disease, but chronic allograft rejection, the side effects of chronic immunosuppressive therapy and the severe donor organ shortage continue to limit its success. Gene therapy has the potential to prevent graft rejection by manipulating the immune response in the microenvironment of the graft or by facilitating the induction of tolerance. Genetic manipulation of stem cells to create transgenic and/or knockout animals that could serve as organ or cell donors could be combined with gene therapy approaches to overcome the problem of limited allogeneic donor organ supply.

Animals↗
PubMed1999

The effect of renal insufficiency on mycophenolic acid protein binding.

Mycophenolate mofetil (MMF) is commonly used in solid organ transplant recipients. MMF is converted to mycophenolic acid (MPA) upon reaching the systemic circulation. Many acidic drugs have altered protein binding in renal failure, and it is possible that MPA protein binding may be decreased. The authors studied 23 renal transplant recipients: 8 transplant patients (7 kidney, 1 kidney/pancreas) with chronic renal insufficiency (CRI) and 15 renal transplant patients with preserved renal function. Plasma was obtained for kinetic profiles of total MPA, free MPA, and its glucuronide metabolite (MPAG). Plasma was obtained from 10 hemodialysis patients and 8 healthy control volunteers to assess in vitro differences in MPA protein binding. Average free fraction of MPA in patients with chronic renal insufficiency was more than double that of patients with normal renal function (5.8 +/- 2.7 vs. 2.5 +/- 0.4, p < 0.01). Free MPAAUC was almost doubled in the patients with chronic renal insufficiency versus controls (2.04 +/- .08 vs. 1.03 +/- 0.6, p < 0.01). MPA protein binding is decreased, and free MPA concentrations are increased in patients with chronic renal failure.

Abdominal Pain↗
PubMed1998

Interaction between tacrolimus and chloramphenicol in a renal transplant recipient.

BACKGROUND: The metabolism of tacrolimus is influenced by several medications when they are given concurrently. We report the interaction between tacrolimus and chloramphenicol in a renal transplant recipient. METHODS: An adolescent with vancomycin-resistant Enterococcus was given standard doses of chloramphenicol. Tacrolimus trough levels increased, and the dose was adjusted to maintain the target trough level. Pharmacokinetic studies were obtained during chloramphenicol administration and 14 days after its discontinuation. RESULTS: Toxic levels of tacrolimus were seen on the second day of chloramphenicol administration, requiring an 83% reduction in the tacrolimus dose. The dose-adjusted area under the curve value for tacrolimus was 7.5-fold greater while the patient was on chloramphenicol. These data are consistent with inhibition of tacrolimus clearance by chloramphenicol CONCLUSIONS: Chloramphenicol interferes with tacrolimus metabolism. Careful monitoring of tacrolimus trough levels during concomitant chloramphenicol therapy is recommended to avoid toxicity.

Adolescent↗
PubMed1998

Pharmacokinetics of mycophenolic acid in renal transplant patients with delayed graft function.

The pharmacokinetics of mycophenolic acid (MPA), the immunosuppressant form of the prodrug mycophenolate mofetil (MMF), and the primary glucuronide metabolite, MPAG, were characterized in renal transplant patients with delayed graft function using random effects piecewise linear models. Eight patients were evaluated after receiving their first and subsequent daily oral doses of 1.5 g mycophenolate mofetil twice daily on study days 1 (n = 8), 7 (n = 8), 14 (n = 5), 21 (n = 2), and 28 (n = 7). The area under the concentration-time curve from zero to 12 hours (AUC0-12) for MPA, MPAG, MPA free fraction, and free MPA were analyzed in serial plasma samples using validated high-performance liquid chromatography and ultrafiltration procedures. Random effects piecewise linear models, fit by maximum likelihood methods, were applied to AUC0-12 of MPA and MPAG, MPA free fraction, AUC0-12 of free MPA, and serum creatinine concentration, the index of renal function used in this study. Two hemodialysis sessions did not lower MPA plasma concentration, although some MPAG was removed. The AUC0-12 of MPA increased as a function of time, although it was not possible to fit a statistical model to the data due to considerable among-patient variation in the pattern of increase with time. The AUC0-12 of MPAG, MPA free fraction, and AUC0-12 of free MPA reached maximal values on day 7; each of these parameters had unique day 1 to 7 positive slope values and unique day 7 to 28 negative slope values. The average creatinine concentration was maximal at day 1 and a unique negative slope was obtained between days 7 and 28. Thus, this study provides statistical models for the alteration of AUC0-12 of MPAG, MPA free fraction, AUC0-12 of free MPA, and serum creatinine in renal transplant patients with delayed graft function. These results provide evidence that renal dysfunction is associated with altered pharmacokinetics of MPA, particularly increased AUC0-12 of MPAG, MPA free fraction, and AUC0-12 of free MPA. The perturbed pharmacokinetics normalized with improving renal function.

Adult↗
PubMed1998

Organ transplantation in the twenty-first century.

Major advances in the understanding of the immunologic process responsible for organ or cellular transplant rejection, a dramatic improvement in available immunosuppressive drugs, development of more sophisticated surgical techniques, and important progress in posttransplant intensive care over the last 30 years have led to a remarkable improvement in success following organ transplantation. Whereas excellent short-term survival of most transplanted organs is readily achieved, graft loss because of chronic rejection and the worsening problem of organ donor shortage remain major concerns in the field of transplantation. Recent advances in immunosuppressive drugs, induction of immunologic tolerance, and gene therapy strategies may help to prolong organ allograft survival in the future. Revised criteria for organ donation and xenotransplantation may one day solve the problem of organ supply. Today, as we approach the next millennium, we are optimistic that the elusive goal of immunologic tolerance will be achieved and perhaps applied to animal tissue. Such will certainly be the challenge for the next century.

Forecasting↗
PubMed1998

Race and delayed kidney allograft function.

BACKGROUND: Allograft survival among black recipients is poorer than among whites. Delayed allograft function is associated with a significant reduction in renal allograft survival. The relationship between delayed allograft function and black race is incompletely specified and was the focus of this investigation. METHODS: A non-concurrent study of 325 recipients of cadaveric allografts followed for the occurrence of delayed allograft function defined as dialysis during the first week following transplantation for the principal analysis. A secondary definition of delayed allograft function was formulated based on the serum creatinine 2 weeks after transplantation. Unadjusted and adjusted logistic regression analysis were used to examine the unconfounded relationship between race and delayed allograft function. RESULTS: Fifty-seven of 91 (62.6%) black recipients experienced delayed allograft function compared to 113 of 234 (48.3%) whites. The odds ratio for black race as a predictor of delayed allograft function was 1.80, P=0.02, (95% CI, 1.09, 2.95). This finding was stable despite adjustment for other predictors of delayed allograft function in a multivariate model, but the precision of this estimate was less (P=0.10) because of missing data. Additionally, adjusted models with imputed values for missing covariates, models using a secondary definition of delayed allograft function, and models excluding patients whose cyclosporin therapy was delayed, all consistently demonstrated a similar association between black race and delayed allograft function. CONCLUSIONS: This study demonstrated an increased risk of delayed allograft function among black recipients. This relationship may play a role in the poorer allograft outcomes experienced by black recipients. Given the negative effect of delayed allograft function on allograft survival, efforts to identify its modifiable risk factors should be a high priority.

Adult↗
PubMed1998

Prospective investigations of concentration-clinical response for immunosuppressive drugs provide the scientific basis for therapeutic drug monitoring.

The performance of prospective concentration-clinical response investigations during the early stages of the development of new therapeutic agents can provide a more rigorous basis for therapeutic drug monitoring than the traditional retrospective review of drug concentrations vs clinical outcome. Here we discuss the application of the multicenter randomized concentration-controlled clinical trial study design, and related study designs, as applied to older commonly used and monitored drugs and to two new immunosuppressant drugs, mycophenolate mofetil and tacrolimus. Such studies can provide a more rigorous basis for assessing the risk/benefit associated with a target drug concentration in the individual patient and for designing future prospective pharmacokinetic and therapeutic drug monitoring investigations.

Clinical Trials as Topic↗
PubMed1997

Adenoviral transfection of isolated pancreatic islets: a study of programmed cell death (apoptosis) and islet function.

Gene therapy provides a potential technique to modify immunity in vitro and therefore may prolong graft survival in vivo. However, viral infection and gene transfer may damage target cells and interfere with biologic function. Viruses, including adenovirus, are known to be capable of modulating apoptosis and initiating cell death by either inducing or suppressing specific processes, depending on the virus and cell system studied. The effect of adenovirus on islet cell viability and function has not been examined in detail. In this study, the dose-dependent effect of an adenoviral vector on islet cell death and glucose-stimulated insulin secretion (GSIS) was investigated to establish a therapeutic window for the dose of viral vector administered. Isolated pancreatic rat islets were incubated with an adenovirus expressing a beta-galactosidase gene (AdHCMVsp1LacZ) at different viral concentrations [multiplicity of infection (MOI) 1:10, 1:100, and 1:1000]. Transfection rate, in vitro and in vivo islet viability, and occurrence of programmed cell death were determined 1, 3, and 7 days after transfection. Islets, transfected at MOI 1:10 and 1:100, demonstrated apoptosis not significantly different from nontransfected controls. Islets, transfected at MOI 1:1000, demonstrated a significant increase in apoptosis at 24 hr, which decreased over 7 days of culture. The increase in apoptosis was not reflected by a significant decrease in in vitro GSIS of surviving islet cells, as assessed by stimulation index following in vitro perifusion. SCID or nude mice transplanted with AdlacZ-transfected islets (MOI 1:100 and 1:1000) remained normoglycemic for > or = 30 days. These results demonstrate that transfection of islets using adenoviral vectors can be manipulated such that efficient expression of the gene product encoded by the transfected gene (beta-galactosidase) can be achieved at lower transfecting concentrations of the adenoviral vector (MOI 1:10, 20.2%; MOI 1:100, 30.7%) while preserving islet function. This efficiency of transfection may allow pretransplant manipulation of isolated islet cells without vector-specific alteration of islet function. In cases where high virus concentrations are required for efficient gene transfer (adequate expression of the transgene product), a deleterious effect of the vector on islet cell function, with increased cell loss due to increased apoptotic events, is predicted. Using the AdlacZ vector, cell loss by apoptotic mechanisms appears limited to the first days following coculture with high viral concentrations, and does not appear to influence in vitro or in vivo cell function of the surviving islet cells.

Adenoviridae↗