Volume 41, No. 11/2003(November)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Reviews
Determination of the pharmacokinetics of cerivastatin when administered in combination with sirolimus and cyclosporin A in patients with kidney transplant, and review of the relevant literature
Abstract
L. Renders1, D. Czock2, H. Schöcklmann1 and U. Kunzendorf1
1Division of Nephrology, University Hospital Schleswig-Holstein, Campus Kiel, and 2Division of Nephrology, University Hospital Ulm, Germany
Objective: Therapy of elevated cholesterol serum concentrations is often necessary in patients with kidney transplants. However, the pharmacokinetics of HMG-CoA reductase inhibitors when administered in combination with sirolimus and cyclosporin A (CsA) have not been determined. The aim of this study was to investigate the pharmacokinetics of cerivastatin when administered in combination with sirolimus in patients with kidney transplants, and to review the literature with regard to the differences in pharmacological behavior between sirolimus, CsA and tacrolimus. Methods: Patients (n = 7) with a stable and functioning kidney transplant and elevated LDL cholesterol serum concentrations were included in the study. After an observation period of 3 months, and whilst receiving sirolimus and CsA, cerivastatin (0.2 mg daily) was administered for a period of 3 months. Pharmacokinetic parameters were calculated on Day 1 and 3 months after initiation of cerivastatin therapy. Routine laboratory parameters and clinical adverse events were monitored throughout the study period. Results: Single-dose cerivastatin AUC was 2 to 3-fold higher in comparison to published values obtained in healthy subjects. The accumulation ratio of cerivastatin (after 3 months/ Day 1) was 1.6. Sirolimus and CsA trough levels, and the sirolimus AUC did not differ after single dose and multiple doses of cerivastatin. Conclusions: The combination therapy of cerivastatin with sirolimus and CsA leads to a significant increase in cerivastatin exposure. Additional drug monitoring of sirolimus and CsA is not necessary.
Reviews
A review of the effects of chronic exercise and physical fitness level on resting pharmacokinetics
Abstract
A.M. Persky, N.D. Eddington and H. Derendorf
1Department of Pharmaceutics, College of Pharmacy, University of Florida, J.H.M.H.C., Gainesville, Florida, and 2Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA
Pharmacological intervention in cooperation with physical activity is currently being used in the prevention and treatment of diseases like cardiovascular disease and obesity. Physical activity, both acute and chronic, can cause changes in physiology that can alter the observed pharmacokinetics of drugs. Objective: The purpose of this paper is to focus on how chronic exercise can change pharmacokinetics. Results: Chronic exercise can affect drug absorption by the increase in collateral blood flow and absorption may also be affected by changes in gastrointestinal transit times. Chronic exercise may affect volume of distribution of drugs by the increases in lean body mass, decreased fat mass, increased plasma protein and increased plasma volume that occurs with physical conditioning. Changes in hepatic clearance of drugs may explain the differences in systemic clearance seen when comparing physically trained subjects to sedentary ones. Some studies have shown that hepatic enzymes are increased with training but other studies have found no change or lower activities. Finally, renal elimination of drugs may be altered by changes in protein binding but there is little evidence that renal elimination of drugs changes with long-term exercise. Conclusion: Therefore, changes in pharmacokinetics associated with chronic exercise can differ from those during acute exercise and in sedentary subjects. The differences between the physically active and sedentary individuals may require individualization of dosing regimens. It should be noted that there are no standardized protocols to evaluate the influence of exercise on drug disposition.
Pharmacokinetic modeling
Center specificity in the limited sampling model (LSM): can the LSM developed from healthy subjects be extended to disease states?
Abstract
I. Mahmood
Office of Therapeutic Research and Review, Division of Clinical Trial Design and Analysis, Clinical Pharmacology and Toxicology Branch, Center for Biologics Evaluation and Research, Food and Drug Administration, Woodmont Office Center, Rockville, MD, USA
Background and objectives: Area under the curve (AUC) can be related to the therapeutic or toxic effect of a drug. In order to accurately measure AUC, multiple blood samples are required, but in a clinical setting, frequent blood sampling from the patients is time-consuming and expensive. The limited sampling model (LSM) is one of the approaches that is gaining popularity due to its simplicity for the estimation of AUC using 1 – 3 samples. Despite its simplicity, the LSM has some shortcomings. One of the major drawbacks of the LSM is that the LSM developed under a given condition may not be extended to other conditions. For example, the LSM developed from healthy subjects may not be extended to disease states such as renal or hepatic impairment or vice versa. This characteristic of the LSM can be referred to as “center-specific”. In this investigation, the LSM developed from the healthy subjects was used to predict AUC in patients with renal or hepatic impairment. Methods: Two sets of simulated plasma concentration versus time data for 2 antihypertensive drugs and measured plasma concentration versus time data for 2 representative drugs (A and B) were used in the analysis. Results and conclusion: The results of the study indicate that the LSM developed from healthy subjects is inadequate to predict AUC in patients with hepatic or renal impairment, indicating center specificity of the LSM.
Pharmacodynamics and lipoprotein(a)
Long-term administration of pravastatin reduces serum lipoprotein(a) levels
Abstract
M. Horimoto, A. Hasegawa, T. Takenaka, M. Fujiwara, H. Inoue and K. Igarashi
1Division of Cardiovascular Disease, Chitose City Hospital, Hokkaido, Japan, and 2Division of Cardiology, National Sapporo Hospital, Hokkaido, Japan
Background: The long-term effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum lipoprotein(a) (Lp(a)) levels has been poorly investigated. Objective: This study sought to examine the effect of 24 months’ administration of pravastatin on serum Lp(a) levels. Subjects: 23 patients with coronary artery disease and serum low-density lipoprotein (LDL) cholesterol levels of 120 mg/dl or above were included. Method: Serum levels of lipids and Lp(a) were serially determined after the administration of pravastatin for 24 months. Results: Serum LDL-cholesterol (LDL-C) levels significantly decreased from 1 month after the drug administration and the reduction persisted for 24 months, whereas Lp(a) levels did not decrease at 3 months after the administration but significantly decreased at 12 months or more. The reduction in the Lp(a) levels was not related to the dose of pravastatin. Conclusions: The results indicated that long-term administration of pravastatin for 12 months or more significantly reduced serum Lp(a) levels and the reduction of Lp(a) levels occurred much later than that of LDL-C levels. The delayed reduction in serum Lp(a) levels after the administration of pravastatin may be associated with a retarded inhibition of Lp(a) synthesis by the drug.
Abstracts
Oral Presentations
Abstract
Poster Session I
Abstracts
Poster Session II
