Volume 42, No. 3/2004(March)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Bioavailability section
Pharmacokinetics and bioequivalence evaluation of 2 levosulpiride preparations after a single oral dose in healthy male Korean volunteers
H.Y. Cho, J.D. Moon and Y.B. Lee
Abstract
H.Y. Cho, J.D. Moon and Y.B. Lee
1College of Pharmacy and Institute of Bioequivalence and Bridging Study, and 2Medical School and CNU Hospital, Chonnam National University, Gwangju, Korea
Objective: To evaluate the bioequivalence of a single oral 25 mg dose of 2 levosulpiride preparations in healthy male Korean volunteers. Subjects, materials and methods: The study was conducted as a randomized, 2-period crossover design in 28 healthy male Korean volunteers who received a single oral dose of 25 mg levosulpiride tablet in each study period. There was a 6-day washout period between the doses. Serum concentrations of levosulpiride up to 36 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 similar by calculating similarity factor (f2 = 67.73). There were no significant differences between the 2 preparations in AUC0-t, AUC0-¥ and Cmax. The point estimates (90% confidence intervals) for AUC0-t, AUC0-¥ and Cmax were 1.085 (1.003 – 1.173), 1.069 (0.991 – 1.153) and 1.075 (0.954 to 1.210), 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 2 preparations of levosulpiride are bioequivalent and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice.
Pharmacogenetics
Single-step identification of all length polymorphisms in the UGT1A1 gene promoter
C. Skarke, S. Grösch, G. Geisslinger and J. Lötsch
Abstract
C. Skarke, S. Grösch, G. Geisslinger and J. Lötsch
Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Johann Wolfgang Goethe University, Frankfurt, Germany
Aim: To provide a sensitive genetic screening method for rapid identification of all known length polymorphisms in the promoter region of the uridine 5’-diphosphoglucose glucuronosyltransferase (UGT) 1A1 gene comprising (TA)5, (TA)7 and (TA)8 repeats as opposed to the non-mutated (TA)6 allele. Methods: The UGT1A1 promoter genotype was assessed in 115 subjects by means of a newly developed pyrosequencing method. PCR-generated DNA templates of heterozygous (TA)5 and (TA)7 carriers were cloned into a TOPO TA vector and verified by sequencing. In addition, a (TA)8 segment was produced by cloning to demonstrate the ability of the method to detect this mutation. Results: All length polymorphisms of the UGT1A1 promoter described in the literature were clearly identified. Fifteen subjects had Gilbert’s syndrome with elevated serum bilirubin associated with a homozygous (TA)7TAA/(TA)7TAA genotype. Two subjects with the rare genotypes (TA)5TAA/(TA)6TAA and (TA)5TAA/(TA)7TAA were found, where only the latter one displayed elevated serum bilirubin levels. Allelic frequencies were 0.9%, 66.1% and 33% for the (TA)5TAA, (TA)6TAA and (TA)7TAA allele, respectively. Conclusion: Our method enables reliable genetic single-step screening for all known length polymorphisms in the UGT1A1 gene promoter that cause Gilbert’s syndrome. This facilitates pharmacogenetic-guided dosing of drugs with known toxicity metabolized by UGT1A1.
Drug Interactions
Drug interactions with St. John’s Wort (Hypericum perforatum): a review of the clinical evidence
A.A. Izzo
Abstract
A.A. Izzo
Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy
St. John’s Wort (SJW, Hypericum perforatum) is effective in mild-to-moderate depression. As a monotherapy, SJW has an encouraging safety profile. However, numerous reports indicate the possibility of important interactions with prescribed drugs. SJW has been shown to lower the plasma concentration (and/or the pharmacological effect) of a number of drugs including alprazolam, amitriptyline, cyclosporine, digoxin, fexofenadine, indinavir, irinotecan, methadone, nevirapine, simvastatin, tacrolimus, theophylline, warfarin, phenprocoumon and oral contraceptives. Induction of P-glycoprotein and/or cytochrome P450 (CYP) enzymes (particularly CYP 3A4) by SJW could explain such pharmacokinetic interactions. When combined with serotonin reuptake inhibitor, antidepressants (e.g. sertaline, paroxetine, nefazodone) or buspirone, SJW can cause serotonergic syndrome. SJW represents a herbal medicine with a high potential for drug interactions. Some of such interactions may have serious clinical consequences.
Drug Interactions
Investigation on interaction between tacrolimus and sildenafil in kidney-transplanted patients with erectile dysfunction
B. Christ, D. Brockmeier, E.W. Hauck and S. Kamali-Ernst
Abstract
B. Christ, D. Brockmeier, E.W. Hauck and S. Kamali-Ernst
1Department of Internal Medicine, 2Rudolf Buchheim Institute of Pharmacology, 3Department of Urology, Justus Liebig University of Gießen, and 4Center for Hemodialysis, Wetzlar, Germany
Objective: Sildenafil may provide an effective treatment for erectile dysfunction, frequently observed in uremic patients and after kidney transplantation. Pharmacokinetic interactions between sildenafil and tacrolimus are to be expected due to a common elimination pathway via cytochrome P450 3A4. Therefore, the pharmacokinetics during combined use of these agents were studied over 9 days. Material and methods: Nine male patients (age 29 – 52 years) were included, who had previously participated in a recent interaction study with sildenafil given as a single dose. Comedication remained unchanged in order to avoid introducing confounding factors. In the previous study in the patients, tacrolimus blood levels with and without sildenafil were measured for pharmacokinetic analysis. In the present study, 25 mg sildenafil were coadministered daily over 9 days and tacrolimus levels were assessed at sampling times optimized using simulation. In addition, laboratory parameters and blood pressure changes were measured and adverse effects monitored. Results: Terminal half-lives of tacrolimus did not differ significantly and trough levels did not change when sildenafil was coadministered daily over 9 days. Mean arterial blood pressure was lower after sildenafil intake. Two patients had to reduce their antihypertensive treatment, 6 patients reported mild side effects. In 1 case, there was an asymptomatic, temporary increase in the serum concentration of g-GT. Conclusions: There was no evidence obtained for a change in elimination half-life or average concentration of tacrolimus during repeated coadministration of sildenafil. Since blood pressure decreased, a starting dose of 25 mg sildenafil and, if necessary, adjustment of the dose of antihypertensive drugs on days when sildenafil is given has to be considered. With respect to the observed blood pressure changes, pharmacokinetic/pharmacodynamic interaction studies with other antihypertensive drugs are of critical importance in these patients.
Complementary and alternative medicine
Are herbal medicines effective?
E. Ernst
Abstract
E. Ernst
Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, Exeter, UK
Herbal medicine is again popular and its widespread use demands that we assess its effectiveness objectively. The evidence in this area has grown considerably in recent years, not least due to the endeavors of the Cochrane Collaboration. They show amongst other things that it is possible to evaluate herbal medicines in much the same way as conventional drugs. By far the biggest hindrance to research into herbal medicine is the lack of funds available for this line of scientific investigation. In view of the present popularity of herbal medicine it seems necessary to overcome obstacles to rigorous research and establish which herbal medicines do more good than harm for which conditions.
Endocrinology
Endogenous estradiol metabolism during treatment with oral contraceptives
A.O. Mueck, H. Seeger and D. Wallwiener
Abstract
A.O. Mueck, H. Seeger and D. Wallwiener
Section of Endocrinology and Menopause, University Women’s Hospital, Tübingen, Germany
Objective: Recent clinical studies indicate that an increase in D-ring estradiol metabolites over A-ring metabolites may be a risk factor for breast cancer. The present work was aimed to investigate the effect of oral contraceptives (OC) on the endogenous estradiol metabolism in premenopausal women. Methods: Two studies were conducted, firstly comparing 2 different progestins, i.e. norethisterone and dienogest, each in combination with a constant ethinyl estradiol dosage (study A) and secondly comparing a single progestin, i.e. levonorgestrel in 2 ethinyl estradiol/progestin dosage combinations (study B). The main A- and D-ring metabolites, i.e. 2-OHE1 and 16-OHE1, were measured by enzyme immunoassay in 8-h night-urine collected before and after 3 cycles of OC administration. Results: In study A, i.e. ethinyl estradiol plus dienogest or norethisterone acetate, the ratios of 16-OHE1 to 2-OHE1 before administration were 0.62 and 0.68, and after 3 months 0.31 and 0.54, respectively. The ratio after ethinyl estradiol and dienogest was significantly lower after treatment. In study B, i.e. ethinyl estradiol plus levonorgestrel (0.03 mg/0.15 mg and 0.02 mg/0.1 mg), the ratios before treatment were 0.71 and 0.75 for the higher and the lower dosages, respectively, which changed not significantly to 0.73 and 0.71 after 3 cycles. Conclusion: OCs containing norethisterone acetate, dienogest or levonorgestrel did not have a negative effect on estradiol metabolism, i.e. they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.
Bioavailability section
Amoxicillin/clavulanic acid (875/125): bioequivalence of a novel Solutab tablet and rationale for a twice-daily dosing regimen
H. Sourgens, M.A. Bertola, J.S.C. Verschoor, M. Kuipers and B. Rayer
Abstract
H. Sourgens, M.A. Bertola, J.S.C. Verschoor, M. Kuipers and B. Rayer
1University of Münster, Germany, 2Medical Affairs, 3Biometrics Department, 4Clinical Pharmacology Research Department, Yamanouchi Europe, Leiderdorp, The Netherlands, and 5Medical Department, Dr. Jung Gruppe, Planegg, Germany
A new amoxicillin/clavulanic acid tablet formulation (Solutab® tablet, Forcid Solutab®) containing amoxicillin/clavulanic acid (875/125) has been developed. The aim of the present study was to demonstrate bioequivalence between the new tablet formulation (test), taken as an intact tablet and after prior dispersal, versus the originator product viz. Augmentan® film-coated tablet (875/125) used as reference. The study was performed in 48 healthy volunteers according to an open, single-dose, crossover design. Bioequivalence was demonstrated using Cmax and AUC0-¥ as primary parameters of evaluation for both amoxicillin and clavulanic acid with 90% confidence intervals of the ratios Solutab® tablet/Augmentan® within the range of 0.8 – 1.25. The duration of the plasma concentration exceeding the amoxicillin minimal inhibitory concentration (MICs) was calculated using individual plasma concentration-time curves and compartmental analysis. The data showed that the bioavailability characteristics of the test tablet, taken intact or in dispersed form, and the reference tablets were very similar. The analysis, moreover, also confirmed the appropriateness of using a b.i.d. dosage regimen for both formulations, taking into account the pharmacodynamic breakpoint values for some major pathogens.
Workshop Proceedings
Organizers and time table
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Workshop Proceedings
Overview
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Workshop Proceedings
Individual dose optimization: why and how
R. Jelliffe
Workshop Proceedings
Non-parametric mixed effects modeling with NPAG: hematopoietic response to erythropoietin in children
R.E. Port
Workshop Proceedings
Covariate selection in population pharmacokinetics/ pharmacodynamics
H. Mager
Workshop Proceedings
A Linux cluster for population pharmacokinetic analyses
H. Speth, responsible for the UNIX Systems in Aventis FFM
Abstract
H. Speth, responsible for the UNIX Systems in Aventis FFM
