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Abstract

F. Keller, U. Ludwig and D. Czock

Nephropharmacology is becoming a branch of its own within clinical pharmacology and in recent years has been the subject of several symposia. The background of these developments is interesting both clinically and pharmacokinetically. Indeed renal pharmacokinetics has been a driving force in clinical pharmacokinetics as a whole.

Kunin et al. [1959] were the first to demonstrate the dependence of drug elimination half-life (t1/2) on renal function. Luzius Dettli [1974] had the enlightening idea that the elimination rate constant (Ke) or the drug clearance (CL) could be linearly correlated to the renal function as measured by the creatinine clearance (CreaCL).

CL = CLnonren + A × CreaCL
A = (CLnorm – CLnonren)/CreaCLnorm

The most reliable estimate of the nonrenal clearance (CLnonren) corresponds to the drug clearance in patients with renal failure. By linear interpolation, drug dose can be adjusted to the individual renal function based on the specific pharmacokinetic parameters of each drug [Bennett et al. 1977]. Hallmark studies have demonstrated an improvement in survival after individually adjusting dosage according to renal function [Evans et al. 1998].

Pharmacokinetics is an essential requirement for individual dosage adjustment. However, it has to be used in combination with pharmacodynamics [Holford 1999] and the mathematical correlation between pharmacokinetic and pharmacodynamic parameters must be explicitly defined.

After repetitive administration with interval (t), the area under the effect time curve (AUETC) is a function of the specific kinetic (t1/2, Cpeak, Ctrough) and dynamic (H, CE50) parameters of the respective drug [Czock and Giehl 1995].

AUETCt = n (1.44 Emax t1/2/H)
ln[(CpeakH + CE50H)/(CtroughH + CE50H)]

Using such correlations the expert will be able to apply calculation algorithms in specialized computer systems [Proost and Punt 2003]. Such algorithms use parameters that can be retrieved from scientific publications and recorded in a structured database [Keller et al. 1998].
Looking to the future, the new subject of pharmacogenetics will need to be translated into pharmacokinetic and pharmacodynamic parameters before it can be applied to drug dose individualization. At the present time, of most practical interest for the nephropharmacologist are the fields of renal drug toxicity, toxicity prevention [Haeussler et al. 2004] and the specific drug therapy of renal disease.
During the next few months several articles, on aspects of this editorial, and which were presented at the 9th NephroPharmacology meeting in Ulm, Germany 2005, will be published in this journal.

References

Bennett WM, Singer I, Golper T, Feig P, Coggins CJ. Guidelines for drug therapy in renal failure. Ann Intern Med. 1977; 86: 754-783.
Czock D, Giehl M. Aminoglycoside pharmacokinetics and -dynamics: a nonlinear approach. Int J Clin Pharmacol Ther. 1995; 33: 537-539.
Dettli LC. Drug dosage in patients with renal disease. Clin Pharmacol Ther. 1974; 16: 274-280.
Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med. 1998; 338: 499-505.
Haeussler U, Riedel M, Keller F. Free reactive oxygen species and nephrotoxicity of contrast agents. Kidney Blood Press Res. 2004; 27: 167-171.
Holford NH. Target concentration intervention: beyond Y2K. Br J Clin Pharmacol. 1999; 48: 9-13.
Keller F, Frankewitsch T, Zellner D, Simon S, Czock D, Giehl M. Standardized structure and modular design of a pharmacokinetic database. Comput Methods Programs Biomed. 1998; 55: 107-115.
Kunin CM, Rees SB, Merrill JP, Finland M. Persistence of antibiotics in blood of patients with acute renal failure. I. Tetracycline and chlortetracycline. J Clin Invest. 1959; 38: 1487-1497.
Proost JH, Punt NC. Dose individualization in PharmDIS-e+. Int J Clin Pharmacol Ther. 2003; 41: 451-458.

Abstract

W. Gielen, T.J. Cleophas and R. Agrawal

¹European College of Pharmaceutical Medicine, Lyon, France, ²Department of Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands, ³Berlin-Chemie AG, Berlin, Germany
Nebivolol is a cardioselective lipophilic b-blocker devoid of intrinsic sympathomimetic and membrane-stabilizing actions. The pharmacological profile differs from that of conventional cardioselective b-blockers in that it displays nitric oxide- (NO) mediated vasodilator activity. The net hemodynamic effect of nebivolol is the result of a balance between the depressant effects of b-blockade and an action that tends to maintain cardiac output, presumably connected with its afterload reducing vasodilator effect. Recent studies suggest that nebivolol may also restore endothelial dysfunction. Long-term follow-up studies indicate that the compound is efficacious and safe both in patients with mild hypertension and those with stable angina. An interesting effect of chronic nebivolol therapy in elderly patients with mild hypertension is the reversal of a depressor effect into a pressor effect on standing. This action indicates that nebivolol has advantages over other antihypertensive drugs and that it may protect elderly hypertensive patients from orthostatic complaints. The observation that nebivolol improves exercise capacity in non-claudicant hypertensives is also of clinical interest. Nebivolol resembles serotonin reuptake inhibitors in that it is metabolized by CYP450 2D6 and, therefore, concomitant treatment with serotonin uptake inhibitors may lead to overdosing. Nebivolol compared to placebo does not significantly reduce the mortality risk in elderly subjects. The effects of biological age and comorbidities may be responsible for this finding. In conclusion, clinical studies suggest that nebivolol is effective and safe in patients with hypertension, angina pectoris and heart failure. The beneficial effects on endothelial function, autonomic control and exercise capacity are of considerable clinical interest.Correspondence to:
T.J. Cleophas, MD, PhD, Associate Professor Department of Medicine Albert Schweitzer Hospital Box 444 3300 AK K Dordrecht, The Netherlands
Email: ajm.cleophas@wxs.nl

Abstract

K. Chandra¹, N. Shafiq¹, P. Pandhi¹, S. Gupta² and S. Malhotra²

¹Department of Pharmacology, ²Department of Dermatology, Pgimer, Chandigarh, India
Background: Gabapentin and nortriptyline have not been compared in a randomized trial in post-herpetic neuralgia (PHN). The present study was, therefore, undertaken to determine their comparative efficacy and tolerability in the treatment of post-herpetic neuralgia. Patients and methods: The study was a randomized, double-blind, parallel-group trial of 9 weeks duration. Adult PHN patients with history of > 8 weeks of PHN pain after healing of rash, a pain intensity of at least 40 mm on a 100 mm visual analog scale at screening and at randomization, and average pain score of at least 4 on the Likert scale during the baseline week were included in the study. Gabapentin and nortriptyline were given in incremental doses at 2-weekly intervals till a maximum tolerated dose was obtained. The primary efficacy parameter was change in pain score (11-point Likert scale) from baseline to the end of the study period. Results: 70 patients were available for intention-to-treat analysis. The average pain scores on the Likert scale were significantly reduced at the end of study in both the treatment groups with 47.6% and 42.8% reduction in pain scores in nortriptyline and gabapentin groups, respectively. Patients showed significant improvement in sleep scores in both the treatment groups nortriptyline (46.0%) and gabapentin (52.0%). The VAS and the SF-MPQ scores for pain were significantly reduced in both the groups. Gabapentin was, however, better tolerated as compared to nortriptyline. Conclusion: Gabapentin was shown to be equally efficacious but was better tolerated compared to nortriptyline and can be considered a suitable alternative for the treatment of PHN. Correspondence to:
S. Malhotra
Department of Dermatology
PGIME, Chandigarh, India
Email: samirmalhotra345@yahoo.com

Abstract

C.A. Böger¹, T. Haak², A.K. Götz¹, J. Christ¹, E. Ruff², U. Hoffmann¹, G.A.J. Riegger¹ and B.K. Krämer¹

¹Klinik und Poliklinik für Innere Medizin II, University of Regensburg, Regensburg, and ²Diabetesklinik Bad Mergentheim, Bad Mergentheim, Germany
Introduction: There is an established role of clinical risk factors such as arterial hypertension and smoking in causing cardiovascular morbidity and diabetic nephropathy (DNP). Genetic factors increase the risk for DNP. To examine the genetic risk, we initiated a case-control study with predefined follow-up examinations. We describe the study design and baseline characteristics under special consideration of comedication, and give preliminary results of the 4-year follow-up. Methods: We enrolled all 477 patients with DNP receiving maintenance hemodialysis in 30 centers in Southern Germany between August 1999 and January 2000. As controls, we enrolled all 482 diabetes mellitus type 2 patients without urinary microalbuminuria in two examinations on consecutive days and without other signs of renal disease in a large diabetes clinic from September 2000 to September 2001. Follow-up examinations are performed 4 and 6 years after inclusion by questionnaire and telephone interview to determine mortality and new morbidity. Controls progressing to novel DNP at follow-up, as defined by semiquantitative dipstick urinary albumin/creatinine ratio > 30 mg/g, are defined as cases in the study’s nested case control component. Results: At study inclusion in cases and controls, respectively, mean age was 67.3 ± 8.2 and 58.1 ± 11.2 years and duration of diabetes mellitus was 15.6 ± 9.6 (at dialysis initiation) and 11.0 ± 8.6 years. 328 controls (of which 25 had died and 14 did not perform urinalysis) were subjected to follow-up at 4 years, at a mean of 3.5 ± 0.8 years after inclusion. 51.2% (n = 148) of living controls remained normalbuminuric, 33.9% (n = 98) had micro- or macroalbuminuria, and in 14.9% (n = 43) the dipstick test was inconclusive. There was no significant difference in progression to micro- or macroalbuminuria between controls treated with ACE or AT-2 inhibitors at baseline or not. Renal function as estimated by the abbreviated MDRD formula declined from 86.8 ± 21.0 to 82.5 ± 22.3 ml/min/1.73 m2 (p < 0.001). The decline was significant in patients on ACE or AT-2 inhibitors at baseline and not in patients without such medication at baseline. Discussion: GENDIAN is a large case-control study designed to evaluate clinical and genetic determinants of DNP and other complications of long-standing diabetes mellitus type 2. We observed an association of ACE or AT-2 inhibitor therapy with cardiovascular comorbidity and a significant decline in renal function after a 4-year follow-up.

*Presented at the 9th NephroPharmacology Meeting in Ulm, Germany 2005Correspondence to:
Dr. C.A. Böger
Klinik und Poliklinik für Innere Medizin II
Clinic of the University of Regensburg
Franz-Josef-Strauß-Allee 11
93053 Regensburg, Germany
Email: carsten.boeger@klinik.uni-regensburg.de

Abstract

W. Arns¹, M. Gies¹, L. Choi², W. Zhu², P. Cooper², C.-M. Yeh², P. Prasad², P. Graf² and R. Schmouder²

¹Kliniken der Stadt Köln gGmbH, Clinic Merheim, Medical Clinic I, Cologne, Germany, and ²Novartis Pharma Corp., Basle, Switzerland
Enteric-coated mycophenolate sodium is an advanced formulation delivering mycophenolic acid (MPA), designed to improve MPA-related upper gastrointestinal adverse events by delaying MPA release until the small intestine. Objective: Two studies were undertaken to identify the absolute bioavailability and dose-proportionality of enteric-coated mycophenolate sodium in stable renal transplant patients receiving cyclosporine. Methods: Study 1: The mean MPA AUC0–t was shown to be greater after MPA infusion than after oral enteric-coated mycophenolate sodium (42.1 vs. 28.9 µg × h/ml). Mean absolute bioavailability was 0.71 ± 0.21 (SD). Study 2: The AUC0–t and Cmax for MPA were proportional to the dose of enteric-coated mycophenolate sodium, similarly mean AUC0–¥ and Cmax for MPA glucuronide were proportional to dose administered. Results and conclusions: In patients receiving cyclosporine the absolute bioavailability of MPA provided by enteric-coated mycophenolate sodium is equivalent to that provided by mycophenolate mofetil when administered in combination with cyclosporine, and exhibits dose-proportionality. Enteric-coated mycophenolate sodium was well tolerated from 180 – 2,160 mg with no serious adverse events reported.Correspondence to:
Dr. W. Arns
Kliniken der Stadt Köln gGmbH
Clinic Merheim, Medical Clinic I
Ostmerheimer Straße 200
51109 Cologne, Germany
Email: wolfgang.arns@uni-koeln.de

Abstract

H.Y. Cho, H.A. Kang and Y.B. Lee

¹College of Pharmacy and Institute of Bioequivalence and Hospital Bridging Study, ²Clinical Trial Center, CNUH, Chonnam National University, Gwangju, Korea
Objective: To evaluate the bioequivalence of a single oral 400 mg dose of 2 gabapentin preparations in healthy male Korean volunteers. Subjects, materials and methods: The study was conducted as a randomized, 2-period crossover design in 26 healthy male Korean volunteers who received a single oral dose of 400 mg gabapentin capsule in each study period. There was a 7-day washout period between the doses. Serum concentrations of gabapentin up to 24 hours after the administration were determined using a validated HPLC method with fluorescence detection. In addition, in vitro dissolution profiles of both preparations were examined. The pharmacokinetic parameters such as AUC0-t (the area under the curve from zero to the time), AUC0-¥ (the area under the curve from zero to infinity), Cmax (maximum serum concentration), tmax (time to reach Cmax) and t1/2 (terminal half-life) were analyzed by non-compartmental analysis, and the analysis of variance (ANOVA) was carried out using logarithmically transformed AUC0-t, AUC0-¥ and Cmax and untransformed tmax. Results: In vitro dissolution profiles were very similar at all media. There were no significant differences between the two preparations in AUC0-t, AUC0-¥ and Cmax. The point estimates (90% confidence intervals) for AUC0-t, AUC0-¥ and Cmax were 1.0319 (0.9142 – 1.1647), 1.0127 (0.8458 – 1.2127) and 0.9796 (0.8670 – 1.1069), respectively, satisfying the bioequivalence criteria of 0.80 – 1.25 as proposed by the US FDA and the Korean legislation. No statistically significant difference was found for tmax and t1/2 values. Conclusion: From the results of the present study, it is indicated that the two preparations of gabapentin are bioequivalent and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice.Correspondence to:
Dr. Y.B. Lee
College of Pharmacy and Institute of Bioequivalence and Bridging Study
Chonnam National University
300 Yongbong-Dong, Buk-Gu, Gwangju 500-757, Korea
Email: leeyb@chonnam.chonnam.ac.kr

Abstract

K.A.J. Al Khaja, T.M. Al-Ansari, R.P. Sequeira and A.H.H. Damanhori

Abstract

M. Lohitnavy, Y. Lu and O. Lohitnavy

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Volume 44, No. 8/2006(August)