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Abstract

H.-W.M. Breuer

St.-Carolus-Krankenhaus, Medical Department, Görlitz, Germany
Acarbose – the most extensively investigated and widely prescribed a-glucosidase inhibitor – reduces postprandial plasma glucose excursions by delaying the absorption of carbohydrate from the small intestine. Acarbose is an effective first-line therapy for patients with newly diagnosed type 2 diabetes, and induces a further improvement in glycemic control when used in combination with other antidiabetes agents. By decreasing postprandial hyperglycemia and improving insulin sensitivity, acarbose therapy also reduces fasting and postprandial serum insulin, fasting plasma glucose, and hemoglobin A1c levels. As the burden of type 2 diabetes continues to grow, there is a great need for an oral antidiabetes agent with a proven ability to prevent the development of micro- and macrovascular complications, and maintain long-term glycemic control. More than 15 years of clinical investigation have confirmed the sustained efficacy, tolerability, and excellent safety profile of acarbose in a wide range of patient types. Furthermore, the results of the recent Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) showed that acarbose therapy significantly decreased the risk of cardiovascular events in high-risk individuals with glucose intolerance. Acarbose is therefore a convenient and effective long-term option for the treatment of type 2 diabetes, with the added benefit of reducing cardiovascular risk.

Abstract

K.L. Valentino, M. Gutierrez, R. Sanchez, M.J. Winship and D.A. Shapiro

¹Idun Pharmaceuticals, San Diego, CA, ²Comprehensive Phase One, Ft. Lauderdale, FL, and ³Light Sciences Corporation, Issaquah, WA, USA
Objective: To evaluate the safety of IDN-6556, a novel anti-apoptotic pan-caspase inhibitor, administered in single and multiple ascending doses in normal volunteers and patients with hepatic dysfunction. Materials and methods: IDN-6556 was administered as a 30-minute intravenous infusion in rising doses to 3 groups: Group A, normal volunteers, given as a single infusion, Group B, normal volunteers, given q.i.d. for 7 days, Group C, patients with hepatic impairment (elevated transaminases, alanine transaminase, ALT and aspartate transaminase, AST), given q.i.d. for 7 days. Results: The drug was well tolerated up to 10 mg/kg/infusion for a single dose, and 1.5 mg/kg/infusion q.i.d. for 7 days, with the dose-limiting adverse event of phlebitis or inflammation at the site of the infusion. This toxicity was predicted from animal studies. Clinically and statistically meaningful dose-related falls in transaminases were seen in all but 1 of the hepatic impaired patients. Two-way ANOVA analyses of the changes for all the IDN-6556 groups combined versus placebo were: ALT absolute change: p < 0.0001 and % change: p = 0.012, AST absolute and % changes: p < 0.0001. After discontinuation of the drug (after 7 days of dosing), the transaminases rapidly returned to the pre-treatment levels. Conclusions: Following intravenous administration of a novel anti-apoptotic caspase inhibitor, adverse events were mild-to-moderate in severity, resolved in a few days and did not result in any subject terminating treatment prematurely. The effects in hepatic impaired patients appear to be consistent with both the administration and subsequent abrupt withdrawal of an effective hepatoprotective drug that delays cell death in hepatocytes.

Abstract

F. Keller

Frieder Keller, Ulm Johannes H. Proost, Groningen George R. Aronoff, Louisville
On October 4, 2002, the 6th NephroPharmacology meeting was held in Ulm, Germany. Selected papers of earlier meetings have been published previously: Nieren-Hochdruckkrankheiten 1990, 19; Eur. J. Clin. Pharmacol. 1993, 44 Suppl. 1; Int. J. Clin. Pharmacol. Ther. 1998, 36; Nephrol. Dial. Transplant. 1999, 14 Suppl. 4.

NephroPharmacology started with measuring pharmacokinetics in patients with renal impairment. A debate followed on which parameters, drug clearance, half-life, drug levels or AUC were most suitable for use in individualized dose adjustment. The mechanisms of nephrotoxicity were addressed to support preventive measures including drug level monitoring and modified dosing regimens. We present here manuscripts from the latest meeting illustrating the wide spectrum of work covered by the term NephroPharmacology.

Recently, pharmacodynamics has emerged as the link between drug dosing and therapeutic effect. The PK-PD correlation between pharmacokinetics and pharmacodynamics must be specified, and new but, general principles must be derived to help determine the individual dose required in each patient. The availability of reliable measures for the determination of renal function provides a sound basis for PK-PD-based drug dosing in individual patients with renal impairment. Moreover, the severe consequences of inappropriate dosing in renal impairment are a challenge in applying PK-PD-based drug dosing in this group of patients.

In the future, computer-assisted drug dose individualization might be made possible using integrated database systems. The PharmDIS system, which is supported by the European Commission (IST Craft-2001-52107), was presented at the 2002 meeting in Ulm. Further details on the PharmDIS system have been demonstrated on a Satellite meeting at the World Congress of Nephrology 2003 in Berlin.

Abstract

J.H. Proost and N.C. Punt

¹Department of Pharmacokinetics and Drug Delivery, Groningen
University Institute for Drug Exploration, University of Groningen, and ²Medimatics, Maastricht, The Netherlands
Individualized dosage regimen calculations require knowledge on the pharmacokinetic and pharmacodynamic properties of the drug and the characteristics of the patient. A PK-PD-based dosage regimen is not easily and generally applicable, mainly because the combination of available PK parameters and therapeutic target levels may be inappropriate for the purpose of predicting a plausible dosage regimen. Within the project PharmDIS-e+, an alternative approach was chosen, and this “PK and standard dose”-based principle is well suited for computerized dosing advice. PharmDIS-e+ aims at the development of several applications for dosing regimen advice for general practitioners, hospital physicians and pharmacists.

Abstract

J.E. Scherberich

Second Medical Department, Hospital Munich-Harlaching, Academic Educational Hospital, Ludwig-Maximilians-University, Munich, Germany
Although peripheral blood monocytes are heterogeneous, they all express the CD14 molecule, a multifunctional receptor, and part of the toll-like membrane receptor complex. In healthy persons, a minor subset (8%) coexpresses CD14 and CD16, a low affinity Fc-g type III receptor. This subpopulation shows characteristics of tissue macrophages and expands greatly in acute and chronic infections, systemic inflammatory syndromes, hyperlipidedemia, AIDS and renal failure. CD14+/CD16+ monocytes (Mo) exhibit higher phagocytosis activity than CD14++/CD16-negative monocytes and synthesize high levels of interleukin-1, TNF-a and HLA-DR, -DP and -DQ antigens. Glucocorticoids (and interleukin-4), and successful therapy in patients with inflammatory and septic complications lead to a down-regulation in the expression of CD14 and deplete CD14+/CD16+-proinflammatory Mo. Recovery of low monocytic HLA-DR expression parallels clinical improvement. Serial analyses of Mo phenotypes may be useful tools for monitoring patients receiving immunosuppressive and anti-inflammatory therapy respectively.

Abstract

C. Morath and M. Zeier

Department of Nephrology, University of Heidelberg, Germany
Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is a selective, non-competitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) and of the type II isoform in particular. IMPDH is the rate-limiting enzyme in the de novo biosynthesis of guanosine nucleotides. MMF strongly inhibits both T- and B lymphocyte proliferation and has been used in the prevention of acute and chronic allograft rejection since the mid 1990s. Recent evidence, however, suggests that MMF is also capable of inhibiting the proliferation of non-immune cells. In various cell lines, i.e. smooth muscle cells, renal tubular cells and mesangial cells, MPA reduced or even abrogated proliferation in response to proliferative stimuli. Furthermore, data from our own laboratory demonstrate a dose-dependent inhibition of dermal fibroblast proliferation by MPA. In animal studies, MMF ameliorated renal lesions in immune-mediated disease, i.e. in the anti-thy 1.1 model and experimental lupus nephritis, but was also effective in non-immune-mediated renal damage in the rat remnant-kidney model. These observations prompted several investigators to study the effects of MMF in proliferating (renal) disease of non-immune origin in humans. MMF significantly reduced proteinuria in minimal-change disease and focal segmental glomerulosclerosis. In addition, MMF showed beneficial effects in the treatment of chronic allograft nephropathy and calcineurin inhibitor toxicity through reduction of immune- and non-immune-mediated renal damage. MMF is well tolerated and has proven to be a relatively safe drug causing only minor bone marrow suppression. Taken together, there is a growing body of evidence pointing to therapeutic applications of MMF other than immunosuppression, in particular the prevention of fibrosis.

Abstract

P. Glander, P. Hambach, K.-P. Braun, L. Fritsche, J. Waiser, I. Mai, H.-H. Neumayer and K. Budde

¹Department of Internal Medicine, Nephrology, and ²Department of Clinical Pharmacology, Charité Campus Mitte, Humboldt University, Berlin, Germany
Objective: Mycophenolate mofetil (MMF) is routinely used as an immunosuppressant in a fixed daily dose regimen although it shows marked fluctuations in pharmacokinetics, and despite the fact that in regard to the active metabolite, mycophenolic acid (MPA), there is a well-known association between the pharmacokinetic parameters and clinical outcome. Method: In order to determine the time course and the variability in cellular target of MPA after renal transplantation, we investigated the pharmacodynamic response in 8 patients receiving 1 g MMF for the first time prior to renal transplantation and in 8 stable renal transplant patients maintained on long-term MMF therapy (1 g b.i.d.) for more than 1 year. The pharmacodynamic response was measured using inosine 5’-monophosphate dehydrogenase (IMPDH) activity in peripheral mononuclear cells. MPA plasma concentrations were measured in parallel, IMPDH activity in 89 healthy blood donors was used as a control. Results: We observed a high interindividual variability in IMPDH activity in the 89 untreated healthy volunteers (4.0 – 32.9 nmol/h/mg protein), in 8 patients on dialysis (5.3 – 18.9 nmol/h/mg protein) and in 8 renal transplant patients under long-term MMF treatment (2.3 – 14.4 nmol/h/mg protein). The mean AUC0-12h for mycophenolic acid was 2-fold higher in patients receiving long-term treatment with MMF (62.2 ± 16.6 mg x h/ml) compared to dialysis patients receiving 1 g MMF for the first time (31.5 ± 15.6 mg x h/ml). Despite this pharmacokinetic difference there were no statistically significant differences in the cellular pharmacodynamic response. Minimal IMPDH activity (1.62 ± 1.23 vs. 1.77 ± 1.49 nmol/h/mg protein) and maximal IMPDH inhibition (87.5 ± 0.08 vs. 77.4 ± 18.8%) during the dosing interval were similar. Conclusions: The considerable interindividual variability in the pharmacokinetics of MMF as well as in the drug target support the use of pharmacodynamic drug monitoring to optimize MMF dosing and to reduce the risk of graft rejection and side effects.

Abstract

G. Einecke¹, I. Mai², L. Fritsche¹, T. Slowinski¹, J. Waiser¹, P. Glander¹, T. Böhler¹, H.H. Neumayer¹ and K. Budde¹

¹Medizinische Klinik mit Schwerpunkt Nephrologie, and ²Institut für Klinische Pharmakologie, Charité, Humboldt-Universität, Berlin, Germany
Therapeutic drug monitoring of cyclosporin A (CsA) is essential because of its variable pharmacokinetics in individual patients and its narrow therapeutic window. In the past, standard trough level (C0) monitoring has been used, and although this method is currently the routine strategy, it has been shown that a single blood concentration measurement 2 hours after CsA administration (C2hour) is a significantly more accurate predictor of drug exposure and clinical events than trough concentrations. The CsA absorption profiling, in particular the measurement of C2hour, is a much more sensitive approach to assessing the pharmacokinetics and predicting the clinical effect in the individual patient. However, there are limited prospective data available examining the risks and benefits of C2hour monitoring in renal transplant recipients. Most studies focus on the early post-transplant phase, but there is little experience with C2hour monitoring in maintenance patients. Our experience in 127 stable long-term renal allograft recipients suggests that the therapeutic window for C2hour levels in patients during maintenance is lower than previously anticipated. Repeat determinations of both C0 and C2hour levels in 46 patients to determine precision of C2hour monitoring showed a high intrapatient variability. We observed only a slightly better coefficient of variation for C2hour than for C0 in repeat determinations. This suggests that drug monitoring using C2hour levels in transplant patients may provide a more accurate and reliable measure of drug exposure in the individual patient. However, CsA absorption showed only a weak correlation with dose during repeated measurements, suggesting high variability in absorption in these stable patients. We conclude that an adequate C2hour level soon after transplantation is associated with a reduced risk of acute rejection in adult renal transplant recipients. It is important to identify slow and poor absorbers in the initial phase after transplantation in order to avoid inappropriate increases in CsA dose. In maintenance patients, C2hour values between 500 and 600 ng/ml are effective and safe for providing effective rejection prophylaxis. Although mean C2hour levels do not seem to identify patients at risk of rejection, they may help to identify excessive immunosuppression and to improve long-term survival by reducing CsA toxicity.

Abstract

T. Böhler, J. Waiser, M. Schütz, B. Schumann, H.-H. Neumayer and K. Budde

Department of Internal Medicine, Nephrology, Charité, Campus Mitte, Humboldt University, Berlin, Germany
FTY is a novel immunomodulator currently undergoing clinical investigation and has the potential of improving immunosuppressive therapy after organ transplantation. Previous experimental studies in animals have shown that FTY has a unique mechanism of action. We have studied the pharmacodynamic effects of FTY in stable renal allograft recipients taking part in a phase I clinical trial. As in various animal models including non-human primates, a single oral dose of FTY (0.25 – 3.5 mg) significantly reduced peripheral lymphocyte count by 30 – 70%. The peripheral lymphocyte count returned to baseline within 24 hours. Only in those patients treated with the highest dose of FTY (3.5 mg), did peripheral lymphopenia persist for more than 96 hours. FTY reduced all lymphocyte subsets, T cells more than B cells and CD4+ cells more than CD8+ cells. The reduction in CD3+CD62L+ cell counts was more pronounced, whereas CD3+CCR5+ cell counts were less affected in comparison to the total number of CD3+ lymphocytes. We found only slightly increased apoptosis rates (< 5%) in peripheral lymphocytes, and this change does not explain the marked reduction in lymphocyte count. In cultured human lymphocytes only suprapharmacological doses of 10 mM FTY induced apoptosis (20.6 ± 2.8%) after a 4-h incubation. More important, clinically relevant doses of 0.1 mM FTY increased lymphocyte mobility 2-fold. No effect of FTY on anti-CD3mAb-stimulated lymphocyte proliferation was detected and there was no change in phagocytosis rates in whole-blood cultures incubated with FTY. Further studies are necessary to investigate the mechanism of action of FTY in detail.

Abstract

L. Fritsche, K. Budde, P. Glander, G. Einecke, F. Diekmann, R. Schötschel and H.-H. Neumayer

Department of Nephrology, Charité Campus Mitte, Berlin, Germany
The advent of new antidiabetic drugs is of special importance for diabetic patients with already impaired renal function since renal insufficiency is a relative or absolute contraindication for several of the established hypoglycemic drugs. Pioglitazone is a novel oral hypoglycemic agent that increases insulin responsiveness in target tissues. Pioglitazone and its active metabolites are excreted mainly via the liver. Drug exposure remains almost constant across a wide range of renal function since there is no accumulation of the drug or its active metabolites during repeated dosing in renal insufficiency. The pharmacokinetic properties of pioglitazone are ideally suited for patients with renal insufficiency. Although there are possible side effects (mainly fluid retention and weight gain and – very rarely – hepatotoxicity). Pioglitazone has a good safety profile in diabetic patients with impaired renal function.

Abstract

D. Czock, U. Aisenpreis, F.M. Rasche and P.M. Jehle and P.M. Jehle

¹Nephrology Division, University Hospital, Ulm, and ²Hospital for Internal Medicine, Hospital of the Paul-Gerhardt-Stiftung, Lutherstadt Wittenberg, Germany
Objective: Lispro-insulin, after subcutaneous injection in patients with normal renal function, is absorbed faster and has a faster onset of action when compared to regular insulin. However, the pharmacokinetics and pharmacodynamics of lispro-insulin in renal failure have not yet been investigated. Patients and methods: Eight patients with diabetes mellitus on long-term hemodialysis received an individualized dose of regular insulin or lispro-insulin in a crossover design. Blood glucose and insulin concentrations were measured before and after the subcutaneous insulin injections. Results: Plasma insulin concentrations increased faster (time of maximum concentration t_max 20 vs 40 minutes, p = 0.01) and were higher (standardized maximum concentration C_max/ D 13.6 vs 6.1 mU/ml/U, p = 0.01) after lispro-insulin compared to regular insulin. The area under the curve, clearance and parameters of the hypoglycemic action for the 2 insulin products did not differ significantly, but there was a trend to minimum blood glucose level (time of the blood glucose minimum, Gt_min) to occur earlier with lispro-insulin (120 vs 210 minutes, p > 0.05). Differences in elimination half-life and volume of distribution were explained by flip-flop pharmacokinetics in the case of regular insulin. Conclusions: In hemodialysis patients with diabetes mellitus, lispro-insulin is absorbed faster than regular insulin. Differences in the effects of lispro- and regular insulin can be explained by the differences in pharmacokinetics.

Abstract

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Volume 41, No. 10/2003(October)