Volume 39, No. 5/2001(May)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Review
Drug treatment in pregnancy
P.A. Thürmann and A. Steioff
Abstract
P.A. Thürmann and A. Steioff
Philipp Klee Institute of Clinical Pharmacology, University of Witten/Herdecke, Germany
When considering drug therapy in pregnancy, the risk of treatment for the embryo/fetus has to be weighed against the risk to the mother and the child of carrying out no treatment. This is of particular relevance in certain conditions like diabetes, epilepsy or AIDS, where the risk of embryopathy is increased when no treatment is carried out and the available drugs are potentially teratogenic. However, carefully selected drugs and close meshed monitoring may even decrease the risk for the child. In many instances, unintentional drug exposure occurs in the period before the pregnancy has been diagnosed. This may lead to additional diagnostic measures or even abortion of an otherwise wanted child. In both situations, planned and unintentional drug exposure during pregnancy, insufficient information is available on the clinical conditions relevant here and the specific drugs involved. Identification of potential teratogenic effects of a new drug takes place during the early development phase. However, animal models may not be representative of specifically human characteristics, e.g. deficiences in enzymes. Since drug treatment is generally best avoided during pregnancy, pharmacokinetic studies in this population are rare. However, physiological changes, known to be relevant for some drugs do occur during pregnancy. In order to improve knowledge on the pharmacokinetics of drugs in pregnancy, population pharmacokinetic approaches may represent a solution. Intensive efforts to investigate the efficacy and safety of drugs during pregnancy are necessary. Since controlled clinical trials are usually not feasible due to ethical reasons, intensified collection of case reports as well as epidemiological studies are warranted to gain sufficient information for the counselling of pregnant women.Correspondence to:
Prof. Dr. P.A. Thürmann; Philipp Klee Institute of Clinical Pharmacology, Hospital Wuppertal GmbH, Heusnerstraße 40, D-42283 Wuppertal, Germany
Email: Petra.Thuermann@klinikum-wuppertal.de
Drug safety
The pharmacokinetics of cerivastatin in patients on chronic hemodialysis
W. Mück, S. Park, W. Jäger, B. Voith, E. Wandel, P.R. Galle and A. Schwarting
Abstract
W. Mück1, S. Park3, W. Jäger3, B. Voith1, E. Wandel2, P.R. Galle2 and A. Schwarting2
1Institute of Clinical Pharmacology, Bayer AG, Wuppertal, 2Nephrology Division, Department of Medicine, University Hospital, Mainz, and 3Department of Medicine, Bayer Vital GmbH, Leverkusen, Germany
Objective: The single-dose and steady-state pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin and its two major metabolites, M-1 and M-23, were evaluated in patients with renal failure on chronic hemodialysis. Methods: After having given their informed consent, 12 end-stage renal disease patients (5 female/7 male; 18 to 63 years) received a single-dose of 0.2 mg cerivastatin sodium followed by a 4-hour dialysis session for pharmacokinetic profiling. Two to four weeks later, all patients received 0.2 mg once-daily as maintenance treatment for a period of 7 days during which PK profiling was carried out on Days 1 and 7/8, both being dialysis-free days. Plasma concentrations of parent drug and active metabolites were measured by HPLC with fluorescence detection. In addition, assessment of lipid parameters, safety and tolerability, and a complete clinical chemistry program were included in the study procedures. Results: Cerivastatin was well-tolerated and no serious adverse events were observed. In spite of the short treatment period, treatment responses with respect to total cholesterol, LDL cholesterol and triglycerides lowering were observed. Mean cerivastatin and metabolite concentrations and thus systemic exposure were slightly higher (up to 50%) in patients on chronic dialysis compared to previous studies carried out in healthy subjects. The unbound fraction of cerivastatin ranged from 0.6 – 1.5% in these patients (normal range: 0.5 – 0.9%). The half-lives of both parent drug (approximately 3 h) and metabolites remained unaffected and, most notably, no accumulation occurred under repeated dosing. In addition, cerivastatin clearance was not increased by concurrent dialysis as would be predicted from the high plasma protein-binding (> 99%), and there were no significant differences in cerivastatin exposure between the dialysis period and the dialysis-free profile days. Conclusion: Cerivastatin can be safely administered in the usual dosages to patients with end-stage renal disease on chronic hemodialysis. Based on the observed moderate increase in cerivastatin mean exposure, patients should be started at the lower end of the recommended dosing range and subsequent titration should be performed with caution.Correspondence to:
Dr. W. Mück; Institute of Clinical Pharmacology, Bayer AG, Pharma Research Center, Aprather Weg, Building 470, D-42096 Wuppertal, Germany
Email: Wolfgang.Mueck.WM@bayer-ag.de
Therapeutics
Long-term administration of the HMG-CoA reductase inhibitor lovastatin in two patients with cholesteryl ester storage disease
F. Rassoul, V. Richter, P. Lohse, A. Naumann, K. Purschwitz and E. Keller
Abstract
F. Rassoul1, V. Richter1, P. Lohse2, A. Naumann1, K. Purschwitz1 and E. Keller3
1Department of Clinical Chemistry and Pathobiochemistry, University Leipzig/Working Group Health Promotion and Prevention of Atherosclerosis (AGA) Leipzig, 2Department of Clinical Chemistry, Großhadern Clinic, Ludwig Maximilians University, München, and 3Clinic of Pediatrics, University Leipzig, Germany
Objective: In order to suppress de novo cholesterol and VLDL biosynthesis, a long-term therapy trial with lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, was initiated in two patients with cholesteryl ester storage disease (CESD), and concentrations of plasma lipids were monitored over a period of 9 years. Methods: We studied two male patients with enzymatically confirmed CESD in whom long-term lovastatin therapy (8 and 9 years) was begun at the age of 7 and 19 years. The diagnosis of CESD was confirmed by the measurement of human lysosomal acid lipase (hLAL) activity in cultured skin fibroblasts and leukocytes. Restriction fragment length polymorphism (RFLP) analysis revealed that both subjects are homozygotes for the common CESD splice site mutation. Levels of serum lipids and lipoproteins were measured yearly. Results: During the first year, total serum cholesterol decreased from 317 to 201 mg/dl in Patient A and from 228 to 120 mg/dl in Patient B, due mainly to the reduction of low-density lipoprotein (LDL) cholesterol from 262 to 151 mg/dl in Patient A and from 166 to 66 mg/dl in Patient B. Accordingly, the LDL cholesterol : high density lipoprotein (HDL) cholesterol ratio was markedly reduced in both patients after one year of therapy. The treatment was continued and, after 9 years of further medication, low total cholesterol and LDL cholesterol levels were still maintained. Conclusions: The study demonstrates that HMG-CoA reductase inhibitors are well tolerated drugs during long-term treatment of CESD patients and may help to prevent the development of premature atherosclerosis.Correspondence to:
Dr. F. Rassoul; Department of Clinical Chemistry and Pathobiochemistry, University Leipzig, Liebigstraße 27, D-04103 Leipzig, Germany
Email: rassf@medizin.uni-leipzig.de
Clinical trials
Does intention-to-treat analysis answer all questions in long-term mortality trials? Considerations on the basis of the ANZ trial
H.C. Tillmann, N. Sharpe, G. Sponer and M. Wehling
Abstract
H.C. Tillmann1, N. Sharpe2, G. Sponer1 and M. Wehling1
1Institute of Clinical Pharmacology Mannheim, University of Heidelberg, Germany, and 2Department of Medicine, University of Auckland School of Medicine, Auckland, New Zealand
Aims: Intention-to-treat (ITT) analyses are the gold standard in endpoint analyses of randomized clinical trials. Valuable information, however, may be lost in this approach as the actual time on trial medication is not accounted for in patients who withdraw early. Since compliance per se can be a prognostic factor and the actual treatment time is a variable likely to influence clinical outcome, this information should be added to an ITT analysis concept. Thus, the aim is to elucidate the influence of actual treatment time on the results of ITT analysis using available data from a well-conducted, large-scale clinical trial. Methods and results: The ANZ trial, a carvedilol study in heart failure, is characterized by a considerable number of early withdrawals in the carvedilol group. Using the ANZ trial database, the percentage of withdrawals was calculated as well as the number of days on treatment. Fourteen out of 21 deaths (67%) in the carvedilol group occurred after discontinuation of carvedilol. At the time of death, 14 out of 29 (48%) patients in the placebo group had withdrawn from treatment. Mean time of patients on medication who withdrew and died later were 301 days for placebo, but only 204 days for carvedilol. We performed a conventional ITT analysis, and an ITT-based Cox-proportional hazards model (modified ITT) in which the actual time on trial medication was entered into the model as an explanatory variable. The risk ratio in conventional ITT analysis was 0.71 (95% confidence interval (CI) 0.41 to 1.24, p = 0.228) and 0.50 (95% CI 0.28 – 0.90, p < 0.001) in modified ITT analysis. Conclusions: Incorporation of the actual treatment time substantially influences the result of this exemplary ITT analysis. The resulting risk ratio is clearly in accordance with clinical implications and in close agreement with those of other b-blocker trials in heart failure. Entering the actual treatment time into a Cox-proportional hazards model as an explanatory variable is reasonable if not necessary from a clinical point of view and thus may strengthen the validity of ITT analysis.Correspondence to:
Prof. Dr. M. Wehling; Institute of Clinical Pharmacology, Faculty of Clinical Medicine, Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany
Email: martin.wehling@kpha.ma.uni-heidelberg.de
Drug disposition
Gender differences in the disposition of metronidazole
A.J. Carcas, P. Guerra, J. Frías, A. Soto, A. Fernandez-Aijón, C. Montuenga and C. Govantes
Abstract
A.J. Carcas1,2, P. Guerra1, J. Frías1,2, A. Soto1, A. Fernandez-Aijón3, C. Montuenga3 and C. Govantes3
1Centro de Farmacología Clínica, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 2Servicio de Farmacología Clínica, Hospital Universitario La Paz, and 3Departamento de Investigación y Desarrollo, Laboratorios Normon, SA, Madrid, Spain
Objective: Gender is usually considered to be one of the factors influencing disposition of drugs, but the evidence available is sometimes conflicting and information for a large number of frequently used drugs is lacking. An evaluation of sex differences in the disposition of metronidazole was carried out during a bioequivalence study. Subjects and methods: Twenty-four volunteers (12 males and 12 females) were included in an open, single-dose, two-sequence, crossover randomized trial with a one-week washout interval. All volunteers received in each period, a single 250 mg dose of one of the two study formulations of metronidazole. Venous blood samples were collected immediately before and at 15 time points in an 48-hour interval after drug administration; metronidazole concentrations were determined by HPLC. Non-compartmental pharmacokinetic analysis was performed and log-transformed AUC0-¥ and Cmax were tested for bioequivalence. Sex differences were evaluated by means of a 4-factor (sex, sequence, treatment and period) ANOVA. Results: The studied formulations were found bioequivalent according to international standards: average 90% confidence interval for AUC0-¥ was 98 to 104 and for Cmax 93 to 115. After correction for the administered dose/kg, AUC was about 12% lower in females than in males (p = 0.0388) and, therefore, a higher calculated oral CI/kg was found in females. Apparent distribution volume, after correction for weight, was significantly higher in males (p = 0.0019). Metronidazole half-life and MRT were shorter in females than in males (p = 0.0014 and p = 0.0002, respectively). Conclusions: Data obtained in this study suggest that metronidazole clearance in females is about 12% higher than in males although these differences are probably of no clinical relevance.Correspondence to:
Dr. A.J. Carcas Sansuán; Farmacología Clínica, Departamento de Farmacología y Terapéutica, Facultad de Medicina, U.A.M., Arzobispo Morcillo s/n, E-28046 Madrid, Spain
Case report
Erythrodermia induced by omeprazole
J. Borrás-Blasco, A. Navarro-Ruiz, F. Navarro-Blasco, J. Tovar-Beltran and M. González-Delgado
Abstract
J. Borrás-Blasco1, A. Navarro-Ruiz1, F. Navarro-Blasco2, J. Tovar-Beltran2 and M. González-Delgado1
1Pharmacy Service, and 2Rheumatology Service, Hospital General Universitario de Elche, Spain
Objective: To report a case of erythrodermia that appears to be related to the intake of omeprazole (OMP) for treatment of gastroesophageal reflux disease. Case summary: We describe a case of erythrodermia associated with OMP therapy in a 58-year-old white woman with no predisposing factors. In 1995, at the Rheumatology Outpatients’ Clinic, she was diagnosed as having scleroderma (CREST subgroup) and Sjögren’s syndrome associated with corticoid osteoporosis and multiple crushed vertebrae, Raynaud’s disease and joint pain. In March 1998, treatment with OMP 20 mg/d p.o. was started for treatment of gastroesophageal reflux disease. She came to our hospital emergency room in October 1999 because of a severe cutaneous reaction and poor general health. The dermatology service diagnosed the erythrodermia as a skin reaction to medication. We suspected that the causative agent was OMP. Examination of a skin biopsy specimen demonstrated that it was compatible with a toxico-dermic reaction to medication. Administration of OMP was suspended and the skin lesions and the patient’s general state of health improved. She was discharged without symptoms. Conclusions: Our case reports, and others from the literature, suggest the importance of recognizing of the possibility of cutaneous adverse drug reactions even with medications, such as OMP, which has a good safety profile. Caution is recommended with the use of OMP, especially in elderly patients, in patients with renal insufficiency or decompensating liver disease and in patients who receive drugs that affect OMP metabolism.Correspondence to:
Dr. A. Navarro-Ruiz; Servicio de Farmacia, Hospital General Universitario de Elche, Partida Huertos y Molinos s/n, E-03202 Elche (Alicante), Spain
Email: anavarroru@nexo.es
Bioavailability studies
Relative bioavailability of two isosorbide dinitrate sublingual tablet formulations administered as single doses in healthy subjects
I. Niopas, A.C. Daftsios and N. Nikolaidis
Abstract
I. Niopas1, A.C. Daftsios2 and N. Nikolaidis2
1Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki, and 2Analyses of Pharmaco-Chemical Products, American Farm School of Thessaloniki, Thessaloniki, Greece
Objective: The purpose of this study was to evaluate the relative bioavailability and bioequivalence of a test and a reference sublingual tablet each containing 5 mg of isosorbide dinitrate in healthy volunteers. Methods: The study was conducted as an open-label, randomized, single-dose, two-period crossover design in 20 healthy volunteers with a washout period of 7 days, under fasting conditions. Plasma concentrations of the major active metabolite isosorbide 5-mononitrate were quantified, using a validated capillary gas chromatographic assay, with electron-capture detection. The pharmacokinetic parameters used to assess the bioequivalence of the two preparations were AUC0-¥ and AUC0-t for the extent of absorption and Cmax and tmax for the rate of absorption. Results: The calculated 90% confidence intervals of the geometric mean values of the test/reference ratios were 98.2% to 103.2% (point estimate; 100.7%) for AUC0-¥, 96.9% to 103.8% (point estimate; 100.3%) for AUC0-t, and 87.9% to 98.2% (point estimate; 92.9%) for Cmax. No statistically significant difference was found for tmax and elimination half-life (t1/2) values. Conclusion: From the results of the present study, it is concluded that the test and reference isosorbide dinitrate sublingual preparations are bioequivalent in both extent and rate of absorption and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice.Correspondence to:
Dr. I. Niopas; Department of Pharmacy, School of Health Sciences, Aristotle University of Thessaloniki, GR-54006 Thessaloniki, Greece
Email: niopas@pharm.auth.gr
