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Abstract

I. Os*

Department of Nephrology, Ulleval University Hospital, Oslo, Norway
Objective: To examine (1) the relative therapeutic equivalence of 4 mg doxazosin gastrointestinal therapeutic system (DOX GITS) and 4 mg doxazosin standard (DOX-S4) and (2) the efficacy and safety of 4 mg DOX GITS versus 2 mg doxazosin standard (DOX-S2). Patients: Male or female patients aged 18 – 80 diagnosed with mild-to-moderate essential hypertension (sitting diastolic blood pressure (DBP) 95 – 110 mmHg and systolic blood pressure (SBP) < 180 mmHg) were randomized into the study. Methods: This double-blind, parallel, 9-week trial compared DOX-GITS with doxazosin standard (DOX-S) in 310 hypertensive patients. Following a 2-week placebo run-in phase, patients were randomized to receive DOX-GITS at 4 mg/d or DOX-S at 2 or 4 mg/d. DOX GITS dosage remained unchanged at 4 mg throughout the study. Titration in the DOX-S groups was initiated at Week 0 with 1 mg DOX-S and increased to 2 mg DOX-S at Week 1. Dosage in the DOX-S4 group was increased to 4 mg DOX-S at Week 3. Therapeutic equivalence was measured by the change from baseline in sitting diastolic BP (DBP). Efficacy was assessed using the change from baseline for all blood pressure measures. Safety analysis included evaluation of laboratory tests at clinic visits and adverse events (AEs). Results: Therapeutic equivalences between DOX GITS and DOX-S4 and DOX-S2 were established at all study visits except for a significant difference in favor of DOX GITS at Week 1 (p = 0.019) when the dose of DOX-S was 1 mg. All groups had a significant decrease in BP at all study visits compared with baseline. The proportion of patients who reached goal sitting DBP (< 90 mmHg) was similar among the three treatment groups, except at Week 1, when more patients in the DOX GITS group had obtained the goal compared with those in the DOX-S2 group (40.6% vs. 22.3%; p = 0.005). The proportion of patients who reached sitting SBP (< 140 mmHg) goal was similar among groups. AE profiles among the groups were similar. Conclusion: DOX GITS was as effective as DOX-S in patients with mild-to-moderate hypertension. The improved pharmacokinetic profile of the GITS formulation compared with the standard formulation allows a therapeutic dose to be delivered earlier and without dose titration. Both formulations of doxazosin were well tolerated.

*for the Doxazosin Study Group Correspondence to:
I. Os, MD, PhD
Department of Nephrology
Ulleval University Hospital
0407 Oslo, Norway
Email: ingrid.os@medisin.uio.no

Abstract

M. Burian, T. Neumann, M. Weber, R. Brandt, G. Geisslinger, V. Mitrovic and C. Hamm

¹Department of Clinical Pharmacology, University Clinic of Johann Wolfgang Goethe University, Frankfurt/Main, ²Department of Cardiology, Kerckhoff Heart Center, Bad Nauheim, Germany
The present study was undertaken to evaluate the safety and release of nickel after implantation of a nickel device (Amplatzer occluder) in patients with an atrial septal defect (ASD) receiving antiplatelet therapy. Methods: Blood and urine samples were obtained from 24 patients with ASD before occluder implantation (baseline) and during a 12-month post closure period. Antiplatelet drugs were administered for the initial 6-month period post implantation. The nickel content in the specimens was determined using electrothermal atomic absorption spectroscopy. The clinical, sonographic and magnetic resonance imaging follow-ups were carried out 1 week, 1 month, 6 months and 12 months post implantation. Results: Mean baseline concentrations of nickel in serum and urine were within normal range with values of 0.6 ± 0.2 mg/l and 3.1 ± 1.2 mg/l, respectively. During the 6-week post closure period, the time needed for the formation of neointima on the surface of the graft, nickel levels in serum increased up to 5-fold (p < 0.01 versus baseline). Mean concentrations in serum and urine returned to baseline levels within 4 – 6 months post implantation. All patients showed satisfactory clinical improvements and there was no sonographic evidence of complications. Conclusions: The initial dissolution of nickel from the Amplatzer occluder is not a specific cardiovascular risk and is temporarily linked to the formation of the non-thrombogenic neointima on the surface of the graft. The antiplatelet drug regimen used (300 mg aspirin + 75 mg clopidogrel daily for 3 months in the initial phase and 100 mg aspirin daily for a further 3 months) appears to cover the period of neointima formation on the nickel device when nickel levels are significantly elevated. However, further studies in a larger number of patients and over a period greater than 12 months are needed to confirm the validity of these conclusions and to formulate definitive recommendations on the duration of the antiplatelet treatment. Correspondence to:
Dr. V. Mitrovic
Department of Cardiology
Kerckhoff Heart Center
61321 Bad Nauheim, Germany
Email: v.mitrovic@kerckhoff-klinik.de

Abstract

P.L.M. van Giersbergen, A. Halabi and J. Dingemanse

¹Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland, ²Institut für klinische Pharmakologie, Kiel, Germany
Objective: Bosentan has been shown in vitro and in vivo to induce the cytochrome P450 enzymes CYP2C9 and CYP3A4. The present study was conducted to investigate the effect of bosentan on the pharmacokinetics of a combined oral contraceptive. Subjects and methods: In a randomized, 2-way crossover study, 20 healthy female subjects received Treatments A and B. Treatment A consisted of a single dose of Ortho-Novum containing 1 mg norethisterone (norethindrone) and 35 mg ethinyl estradiol. Treatment B consisted of bosentan, 125 mg b.i.d. for 7 days plus concomitant norethisterone and ethinyl estradiol on Day 7. Plasma concentrations of norethisterone and ethinyl estradiol were measured on days of oral contraceptive administration. Results: In the absence of bosentan, the pharmacokinetics of norethisterone and ethinyl estradiol were characterized by Cmax and AUC0-¥ values (95% CI) of 9.8 (8.1, 11.9) ng/ml and 72.9 (57.0, 93.1) ng ´ h/ml, and 53.0 (47.0, 59.9) pg/ml and 758 (655, 878) pg × h/ml, respectively. Concomitant bosentan did not affect the Cmax but significantly decreased the AUC of norethisterone and ethinyl estradiol by 13.7% (–23.5, –2.6) and 31.0% (–40.5, –20.2), respectively. The maximum decrease in AUC of norethisterone and ethinyl estradiol in an individual subject was 56% and 66%, respectively. Conclusions: Bosentan decreases the AUC of norethisterone and ethinyl estradiol in healthy female subjects. In patients treated with bosentan, reduced efficacy of hormonal contraceptives should be considered.Correspondence to:
Dr. P.L.M. van Giersbergen
Actelion Pharmaceuticals Ltd.
Department of Clinical Pharmacology
Gewerbestraße 18
4123 Allschwil, Switzerland
Email: paul.vangiersbergen@actelion.com

Abstract

M. Hassan-Alin¹, T. Andersson², M. Niazi¹, M. Liljeblad³, B.-A. Persson³ and K. Röhss¹

¹Clinical Pharmacology, AstraZeneca Research and Development, Mölndal, Sweden, ²Clinical Pharmacology, AstraZeneca LP, Wilmington, DE, USA, ³DMPK and Bioanalytical Chemistry, AstraZeneca Research and Development, Mölndal, Sweden
Objective: A combination of esomeprazole, amoxicillin and clarithromycin may be used for Helicobacter pylori eradication. We explored the potential for interactions between these drugs. Methods: In 2 randomized, 4-way crossover studies, healthy CYP2C19 extensive metabolizers (EMs) received esomeprazole 40 mg once daily (n = 20) or 20 mg twice daily (b.i.d.) (n = 20), clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d. or the combination of the 3 drugs for 7 days. In a third randomized, 2-way, crossover study, 6 healthy CYP2C19 poor metabolizers (PMs) received esomeprazole 40 mg once daily with and without clarithromycin 500 mg b.i.d. for 1 week. Results: Triple therapy with esomeprazole 40 mg increased the area under the plasma concentration-time curve during the dosing interval (AUCt) from 13.31 mmol × h/l (11.12 – 15.93) for esomeprazole alone to 22.69 mmol × h/l (18.94 – 27.17) for triple treatment. Respective AUCt values with esomeprazole 20 mg b.i.d. were 4.97 mmol.h/l (3.97 – 6.21) and 11.29 mmol × h/l (9.03 – 14.12). Clarithromycin and amoxicillin plasma levels were largely unchanged by combination therapy. In PMs, the esomeprazole AUC also approximately doubled when administered in combination with clarithromycin. All treatments were well tolerated. Conclusion: Clarithromycin decreases the metabolism rate of esomeprazole, leading to approximately doubled AUC values, both in EMs and PMs.Correspondence to:
Dr. M. Hassan-Alin
Clinical Pharmacology
AstraZeneca R & D
431 83 Mölndal, Sweden
Email: mohammed.hassan-alin@astrazeneca.com

Abstract

U. Merkel¹, K. Farker¹, U. Wedding², M. Roskos³, M. Hippius¹, K. Höffken² and A. Hoffmann¹

¹Institute of Clinical Pharmacology, ²Clinic of Internal Medicine, ³Department of Clinical Chemistry and Laboratory Diagnostics, Friedrich Schiller University, Jena, Germany
Objective: To analyze in a pilot study the association between the pharmacokinetics of chronomodulated administered oxaliplatin and non-hematological toxicity in patients with metastatic gastrointestinal cancer. Methods: 16 patients received a 4-day chemotherapeutic regimen consisting of a 12-h chronomodulated infusion of oxaliplatin (25 mg/m2) followed by a 12-h chronomodulated infusion of 5-fluorouracil (750 mg/m2) and sodium folinate (150 mg/m2) daily. Plasma pharmacokinetics of oxaliplatin, measured as ultrafiltrable platinum, were determined. Results: Pharmacokinetics and non-hematological adverse events could be assessed in all patients included in the study. Pharmacokinetic parameters showed moderate interpatient variability. The occurrence of nausea and vomiting, but not diarrhea, was significantly associated with the pharmacokinetics of ultrafiltrable platinum. Thus, increased AUC values were observed in patients who experienced nausea or vomiting. No differences in pharmacokinetic parameters were found between patients with and without oxaliplatin-induced neurotoxicity or the other selected non-hematological toxicities. Conclusion: The preliminary results in this pilot study suggest an association between pharmacokinetics of ultrafiltrable platinum and non-hematological toxicity such as nausea and vomiting. Furthermore, although the sample size is limited, systemic exposure to ultrafiltrable platinum appears to predict the risk of non-hematological toxicity in patients treated with chronomodulated oxaliplatin combined with 5-FU and FS.

*Supported by Deutsche Krebshilfe(AZ 70-2445-Hö3)Correspondence to:
Dr. U. Merkel
Institute of Clinical Pharmacology
Friedrich Schiller University
Dornburger Straße 159
07740 Jena, Germany
Email: ute.merkel@med.uni-jena.de

Abstract

R. Fischer¹, H. Schütz², M. Grossmann³, H.J. Leis⁴ and R. Ammer¹

¹Medice, Iserlohn, Germany, ²BEBAC, Vienna, Austria, ³IKP, Mannheim, Germany, ⁴BPA, Graz, Austria
Objective: To assess bioequivalence between an intact capsule and the content of a capsule sprinkled on applesauce. Materials: Medikinet retard 20 mg capsules were obtained from Medice (Iserlohn, Germany). Methods: This was a single-center, completely randomized, open, 2-period, 2-sequence, balanced crossover study with a washout period of 1 week between administrations, in 12 healthy male and female subjects, aged 18 – 45 years. Blood samples were collected over 24 hours and methylphenidate plasma concentration-time data were used to calculate pharmacokinetic parameters for both administrations. The main parameters were (confirmatory) AUC0-tz (extent of BA), Cmax, tmax (rate of BA) and (descriptively) AUC0-¥ and t1/2. Equivalence was concluded if the 90% confidence interval (CI) for the ratio between test and reference was 0.80 – 1.25 (AUC0-tz). Results: All 12 dosed subjects finished both treatment periods and were included in pharmacokinetic and safety analyses. 90% geometric confidence intervals for AUC0-tz and Cmax data were well within accepted bioequivalence limits. The study has shown that both treatment modes lead to similar pattern of absorption and elimination following single-dose administration in the fed state. The test treatment (content of capsule sprinkled over 15 ml applesauce) is bioequivalent to the reference treatment (intact capsule) in terms of extent and rate of absorption. Conclusion: Data collected from this study demonstrate that Medikinet retard capsules can be opened and the content sprinkled on a tablespoon of applesauce without influencing the rate and extent of bioavailability. Correspondence to:
Dr. R. Fischer
MEDICE Arzneimittel
Pütter GmbH & Co. KG
Kuhloweg 37
58638 Iserlohn, Germany
Email: r.fischer@medice.de

Abstract

C.H. Oliveira¹, R. Medeiros Silva¹, V. Santagada³, G. Caliendo³, E. Perissutti³, M. Prado Galuppo¹, V. Marcondes Rezende¹, R.E. Barrientos-Astigarraga¹, G. Duarte Mendes¹,² and G. De Nucci¹,²

¹Cartesius Development of Clinical Research, Caminas, ²Department of Internal Medicine, State University of Campinas, Campinas/SP, Brazil, and ³Dipartamento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli “Federico II”, Napoli, Italy
Objective: To compare the bioavailability of two potassic losartan immediate release tablet (50 mg) formulations (Losartan from Laboratórios Cristália Ltd., Brazil, as a test formulation and Cozaar® from Merck Sharp & Dohme Farmacêutica Ltd., Brazil, as a reference formulation) in 25 volunteers of both sexes. Material and methods: The study was conducted in an open, randomized, 2-period crossover design and a 1-week washout period. Plasma samples were obtained over a 24-hour interval. The concentrations of losartan and its active metabolite losartan acid were analyzed by combined reversed phase liquid chromatography and tandem mass spectrometry (LC-MS-MS) with negative ion electrospray ionization using a selected ion monitoring method. From the losartan and losartan acid plasma concentrations vs. time curves the following pharmacokinetic parameters were obtained: AUClast, AUC0-inf and Cmax. Results: The geometric mean and respective 90% confidence interval (CI) of Losartan/Cozaar® losartan percent ratios were 92.9% (82.2 – 105.0%) for Cmax, 99.0% (92.5 – 105.9%) for AUClast, and 99.1% (92.7 – 105.8%) for AUC0-inf. Furthermore, the geometric mean and respective 90% CI of Losartan/Cozaar® losartan acid percent ratios were 98.5% (91.5 – 106.0%) for Cmax, 97.9% (93.3 – 102.7%) for AUClast, and 98.1% (93.6 – 102.9%) for AUC0-inf. Conclusion: Since the 90% CI for Cmax, AUClast and AUC0-inf were within the 80 – 125% interval proposed by the US Food and Drug Administration, it was concluded that the potassic losartan immediate release 50 mg tablet was bioequivalent to the Cozaar® immediate release 50 mg tablet, according to both the rate and extent of absorption. While there were no significant differences in the bioequivalence assessed by either losartan or losartan acid, future bioequivalence studies on losartan may be performed by quantifying losartan alone as the parent compounds are more discriminative. Correspondence to:
G. De Nucci, MD, PhD
415 Jesuino Marcondes Machado Ave.
Campinas, SP 13092-320, Brazil
Email: denucci@dglnet.com.br

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Volume 44, No. 3/2006(March)