Volume 40, No. 10/2002(October)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Review
Pharmacokinetics of pravastatin in heart-transplant patients taking cyclosporin A*
J.-W. Park, R. Siekmeier, M. Merz, B. Krell, S. Harder, W. März, D. Seidel, S. Schüler and W. Groß
Abstract
J.-W. Park1, R. Siekmeier2,3, M. Merz4, B. Krell4, S. Harder5, W. März6, D. Seidel7, S. Schüler8 and W. Groß9
1Medizinische Klinik I, Krankenhaus Hoyerswerda, Hoyerswerda, 2Institut für Klinische Chemie und Laboratoriumsmedizin, Klinikum Carl-Gustav-Carus der Technischen Universität, Dresden, 3Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Bonn, 4Herzzentrum Duisburg, Kaiser-Wilhelm-Krankenhaus, Duisburg, 5Institut für Klinische Pharmakologie, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt/Main, 6Institut für Klinische Chemie – Zentrallabor, Medizinische Klinik der Albert-Ludwigs-Universität, Freiburg, 7Institut für Klinische Chemie, Klinikum Großhadern der Universität, München, 8Herzzentrum der Universitätsklinik Dresden e.V., Dresden, and 9Labor für Angewandte Biochemie, Gustav-Embden-Zentrum für Biologische Chemie der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main
Background: Heart transplantation is an established tool for the treatment of terminal heart failure. Hyperlipidemia is a common problem following heart transplantation and has been implicated as an additional risk factor in the development of transplant coronary artery disease (TxCAD). Therefore, heart recipients are commonly treated with inhibitors of cholesterol synthesis (HMG-CoA reductase inhibitors). However, these patients have an increased risk of developing rhabdomyolysis due to elevated concentrations of HMG-CoA reductase inhibitors under co-administration with the immunosuppressive cyclosporin A (CsA). Aim of the study: Aim of our study was to obtain pharmacokinetic data on pravastatin whilst monitoring the safety and efficiency of the lipid lowering therapy in heart-transplant recipients under immunosuppression with CsA and to compare these data to those of a healthy control group. Subjects, materials and methods: Eleven patients (30.2 ± 12.3 months after transplantation) receiving immunosuppressive therapy consisting of cyclosporin A, prednisone and azathioprine with LDL cholesterol (LDL-C) concentrations exceeding 3.9 mmol/l and 8 control subjects were included into the study. In addition to the immunosuppressive therapy, the patients received a daily dose of 40 mg/day pravastatin for the first 8 days which was then reduced to 10 mg/day administered until Day 29. Blood was sampled for pharmacokinetic profiling (maximum concentration of the drug (Cmax), time to reach Cmax (tmax), area under the concentration vs. time curve (AUC0-24h), elimination half-life time (tel)) and measurement of the parameters of clinical chemistry on Days 1, 8 and 29. The control group received a single dose of 60 mg pravastatin and the values of Cmax and AUC0-24h were normalized for a dose of 10 mg. Results: Pravastatin 40 mg/day for 1 week in the patient group caused a significant reduction in total cholesterol (C) and LDL-C from 8.11 ± 1.20 mmol/l and 5.88 ± 1.15 mmol/l to 6.91 ± 1.01 mmol/l and 4.72 ± 1.05 mmol/l, respectively (p = 0.005 and p = 0.003). Triglycerides and HDL cholesterol (HDL-C) concentrations did not change significantly. Mean values for Cmax of pravastatin were 384.2 ng/ml, 392.0 ng/ml and 115.1 ng/ml in patients on Days 1, 8 and 29, respectively. After normalization for a dose of 10 mg, the corresponding values of Cmax-DN10mg and Cmax were 96.0 ng/ml, 98.0 ng/ml and 115.1 ng/ml on study Days 1, 8 and 29. These values were 7 – 8 times higher than the normalized value of Cmax-DN10mg for the control group (13.7 ng/ml). The corresponding values of AUC0-24h were 1228.2 ng/ml´h, 1214.1 ng/ml´h and 345.9 ng/ml´h in the patient group on study Days 1, 8 and 29 as well as 157.5 ng/ml´h in the control group prior to normalization. After normalization for a dose of 10 mg, the values of AUC0-24h-DN10mg in the patient group were approximately 12 times higher than those of the control group. However, no significant differences between the 2 groups were observed in tmax and tel. Within the patient group, no significant increase in Cmax or AUC was found on Day 1 to Day 8. The results of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) showed also no significant increase during the observation period. Conclusion: Heart-transplant recipients treated with the HMG-CoA reductase inhibitor pravastatin generally show higher plasma concentrations of this drug than control subjects. However, our data suggest that the HMG-CoA reductase inhibitor pravastatin can be used effectively in these patients receiving the immunosuppressive cyclosporin A. The pharmacokinetic data obtained indicate that there is no significant cumulation of the drug following multiple dosages in spite of increased drug concentrations after a single oral dosage.Correspondence to:
Dr. R. Siekmeier; Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Kurt-Georg-Kiesinger-Allee 3, D-53175 Bonn
Email: r.siekmeier@bfarm.de
Drug interactions
Intake of grapefruit juice alters the metabolic pattern of cyclosporin A in renal transplant recipients
M. Hermann, A. Åsberg, J.L.E. Reubsaet, S. Sæther, K.J. Berg and H. Christensen
Abstract
M. Hermann1, A. Åsberg3, J.L.E. Reubsaet2, S. Sæther3, K.J. Berg3 and H. Christensen1
1Department of Pharmacology, 2Department of Pharmaceutical Analysis, School of Pharmacy, University of Oslo, and 3Laboratory for Renal Physiology, Medical Department, The National Hospital, Oslo, Norway
Objective: The aim of the present study was to investigate the effect of grapefruit juice on the pharmacokinetics of cyclosporin A (CsA), as Sandimmun Neoral, and its main metabolites, M1, M9 and M4N, in renal transplant recipients. Methods: Ten renal transplant recipients, on CsA-based immunosuppressive therapy, were included in this open, randomized crossover study. Patients were given their individualized morning dose of CsA, administered with either 250 ml water or 250 ml grapefruit juice and 12-hour CsA pharmacokinetic investigations were performed. The 2 investigation days were separated by at least 7 days. Results: Administration of CsA with grapefruit juice compared with water significantly increased the area under the whole blood concentration versus time curve in the interval from 0 – 12 hours (AUC0-12) of CsA, by an average of 25 ± 19% (p = 0.002). Intake of grapefruit juice did not have any significant influence on maximum whole blood concentration (Cmax) or time to Cmax (tmax) of CsA. AUC(0-12) and Cmax of M9 decreased significantly with intake of grapefruit juice, on average 22 ± 11% (p = 0.0007) and 36 ± 6% (p = 0.0001), respectively. AUC(0-12) of M1, however, was on average 13 ± 14% (p = 0.02) higher upon co-administration of CsA with grapefruit juice as compared with water. The level of M4N was below the limit of quantification in most samples, and an effect of co-administration of CsA with grapefruit juice could not be determined for this metabolite. Conclusion: The present study shows that co-administration of grapefruit juice with CsA compared with water affects the formation and/or elimination of the 2 metabolites M1 and M9 differently. In addition, administration of CsA with grapefruit juice compared with water induced a moderate, but significant increase in systemic exposure of CsA in renal transplant recipients.Correspondence to:
M. Hermann; Department of Pharmacology, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway
Email: monicahe@farmasi.uio.no
Drug interactions
A 3-way crossover study to evaluate the pharmacokinetic interaction between nateglinide and diclofenac in healthy volunteers
D.M. Anderson, S. Shelley, N. Crick and M. Buraglio
Abstract
D.M. Anderson1, S. Shelley2, N. Crick1 and M. Buraglio3
1Ajinomoto Pharmaceuticals Europe Limited, Surrey, 2GCP Management Services Limited, Hampshire, and 3LCG Bioscience, Bourn, Cambridge, United Kingdom
Objective: To assess in healthy male volunteers (n = 18) the effect of diclofenac, a non-steroidal anti-inflammatory analgesic drug used for treatment of rheumatic diseases, on the pharmacokinetics of nateglinide, a new oral hypoglycemic agent that acts by a novel therapeutic mechanism to stimulate insulin release. The effects of nateglinide on the pharmacokinetics of diclofenac were also investigated. Methods: This open-label study was conducted as a randomized, 3-period, 6-sequence, crossover investigation consisting of 2 reference treatment periods (diclofenac 75 mg or nateglinide 120 mg, alone) and 1 test period (concomitant nateglinide and diclofenac). On the days when nateglinide was administered, subjects received a 120 mg dose at the start of the study day and a second 120 mg dose 4 h after the first. A 2 to 7-day washout interval separated each of the study periods. Nateglinide and diclofenac plasma concentrations were determined up to 12 and 24 h, respectively. Results: Administration of diclofenac did not alter the pharmacokinetics of nateglinide in healthy subjects. Similarly, concurrent administration of nateglinide with diclofenac did not alter the pharmacokinetics of diclofenac in these subjects. All treatments were considered to have been both safe and well tolerated. Conclusions: These data indicate that concomitant administration of diclofenac with nateglinide does not significantly alter the pharmacokinetic profile of either drug.Correspondence to:
Ms. S. Shelley; GCP Management Services Limited, 21 Westering, Romsey, Hampshire, SO51 7LX, United Kingdom
Email: shelley.sarah@talk21. com
Pharmacocinetics
Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure
M. Kivikko, S. Antila, J. Eha, L. Lehtonen and P.J. Pentikäinen
Abstract
M. Kivikko1,3, S. Antila1, J. Eha2, L. Lehtonen3 and P.J. Pentikäinen4
1Orion Pharma, Clinical Research, Cardiovascular Projects, Espoo, Finland, 2Mustamäe Hospital, Tallinn, Estonia, 3Department of Clinical Pharmacology, University of Helsinki, and 4Department of Internal Medicine, Helsinki University Central Hospital, Helsinki, Finland
Objective: Levosimendan is a new calcium sensitizer with additional vasodilatory properties developed for the short-term intravenous treatment of congestive heart failure. The aims of the present study were to determine the pharmacokinetics and hemodynamic effects of levosimendan and its metabolites during and after a 24-hour levosimendan infusion. Methods: The study was an open-label, non-randomized, phase II study in 2 centers. Twelve patients with NYHA III – IV heart failure received 0.2 mg/ kg/min continuous infusion of levosimendan for 24 hours. Blood samples for the determination of plasma concentrations of the parent drug and the metabolites were drawn repeatedly during the infusion and the 2-week follow-up period. Heart rate from Holter recordings and blood pressure were measured. Results: The elimination half-life of levosimendan was 1.3 hours and that of the metabolites 75 – 78 hours. The mean maximum increase in heart rate of 10 bpm (p < 0.005) and the mean maximum decreases in systolic and diastolic blood pressure of 12 mmHg and 8 mmHg (p < 0.05 for both), respectively, were observed during the first day after stopping levosimendan infusion. The hemodynamic effects slowly declined during the follow-up, and after 1 week no statistically significant differences compared with baseline were observed. No increase in ventricular arrhythmias was seen. Conclusion: A 24-hour infusion of levosimendan induces hemodynamic effects lasting several days after stopping the infusion. The prolongation of the effects beyond the infusion period is most likely due to an active metabolite with a long half-life.Correspondence to:
Dr. M. Kivikko; Orion Pharma, Clinical Research, Cardiovascular Projects, P.O. Box 65, FIN-02101 Espoo, Finland
Email: matti.kivikko@orionpharma.com
Education
Skills of Bulgarian students in choosing a rational drug therapy
N. Bakracheva, A. Beltcheva and E. Gatchev
Abstract
N. Bakracheva1, A. Beltcheva2 and E. Gatchev1
1Department of Clinical Pharmacology and Therapeutics, Medical University of Sofia, Bulgaria, and 2Department of Preclinical and Clinical Pharmacology an Biochemistry, Medical University of Varna, Bulgaria
109 medical students in their 5th year of study in Sofia and 37 medical students in their 5th year of study in Varna, Bulgaria, participated in a study comparing the therapeutic skills of a total of 1,234 students from various EU countries. The students were required to determine a drug or non-drug treatment for 4 written patient cases within 30 minutes. They then had to complete a questionnaire regarding their education in therapeutics. For preliminary results see Table 1. Conclusion: Medical students in Sofia and Varna, Bulgaria, receive problem-oriented teaching comparable with the WHO-accepted model. The results indicate that the therapeutic skills they develop during the 5th and 6th year of study are similar to the therapeutic skills of students from EU countries.Correspondence to:
Prof. N. Bakracheva, MD, PhD, DSc; Head of the Department of Clinical Pharmacology and Therapeutics, Medical Faculty, Medical University of Sofia, University Hospital Queen Giovanna, 8, Belo More Street, 1504 Sofia, Bulgaria
Bioavailability section
Bioequivalence assessment of rifampicin, isoniazid and pyrazinamide in a fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol vs. separate formulations
S. Agrawal, I. Singh, K.J. Kaur, S.R. Bhade, C.L. Kaul and R. Panchagnula
Abstract
S. Agrawal, I. Singh, K.J. Kaur, S.R. Bhade, C.L. Kaul and R. Panchagnula
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab, India
Depending on the patient category, tuberculosis requires treatment with 3 to 5 drugs which means that patient’s compliance to therapy may not be optimal. To increase patient’s adherence to treatment schedules, these drugs can be given as single drug preparations or fixed dose combinations (FDCs) of 2 or more drugs in a single formulation. However, an important issue associated with a rifampicin-containing FDC is its quality. Hence, to avoid spurious formulations entering the market, the World Health Organization and the International Union Against Tuberculosis and Lung Disease have recommended FDCs only of proven bioavailability. In this study, the relative bioavailability of rifampicin, isoniazid and pyrazinamide was assessed in a group of 14 healthy male subjects using the FDC tablet containing 4 drugs versus separate formulations at the same dose levels. The study was designed as an open, crossover trial. A total of 9 blood samples were collected over a period of 24 h. The concentration of rifampicin, its main metabolite desacetyl rifampicin, isoniazid and pyrazinamide in plasma were assessed using HPLC analysis. The pharmacokinetic parameters AUC0-24 and Cmax were subjected to parametric and non-parametric statistical tests at 90% confidence interval. In addition, time to reach peak concentration (tmax), elimination rate constant (Kel) and terminal elimination half-life (t1/2) for each drug were also calculated. It was concluded that the FDC tablet containing 4 drugs is bioequivalent to separate rifampicin, isoniazid and pyrazinamide formulations at the same dose levels.Correspondence to:
Dr. R. Panchagnula; Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), sector 67, S.A.S. Nagar, 160 062 Punjab, India
Email: panchagnula@ yahoo.com
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9th Annual Meeting American Academy of Pharmaceutical Physicians: Navigating the Biotechnology Revolution
