Volume 44, No. 2/2006(February)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Drug Safety
Antidiabetic medications in overdose: a comparison of the inquiries made to a regional poisons unit regarding sulfonylureas, biguanides and insulin
Abstract
M.-A. von Mach, M. Gauer, S. Meyer, B. Omogbehin, H. Schinzel, P.H. Kann and L.S. Weilemann
1II. Medical Department, Division of Clinical Toxicology, University Hospital, Mainz, 2Department of Internal Medicine, Division of Endocrinology and Diabetology, Philipps University Hospital, Marburg, Germany
Objective: The drugs most commonly used to treat diabetes mellitus are sulfonylureas, biguanides and insulin. The most serious effects seen in overdose with these agents are hypoglycemia or lactic acidosis which may be fatal or cause cerebral defects. The present investigation analyzes inquiries made to a regional poisons unit involving overdoses with sulfonylureas, biguanides and insulin. Patients and methods: A total of 218,070 made inquiries between 1995 and 2004 were evaluated. The inquiries were received by telephone and a standardized questionnaire was sent subsequently to the physicians calling for follow-up information. The cases were analyzed with regard to gender, age, etiology, symptoms and clinical outcome. Results: 263 inquiries concerning sulfonylureas (48.3% female, 49.4% male, 2.3% sex unknown, average age 39.1 ± 26.8 years), 172 concerning biguanides (60.5% female, 37.2% male, 2.3% sex unknown, average age 41.5 ± 24.1 years), and 191 concerning insulin (53.9% female, 41.9% male, 4.2% sex unknown, average age 44.6 ± 16.7) were made. In cases involving sulfonylureas, the etiology was deliberate self-poisoning in 62.7% and accidental in 31.9% (biguanides 60.5% and 29.1%, insulin 85.3% and 9.4%). Using the Poisoning Severity Score, no symptoms were observed in 41.4% of the patients with sulfonylurea overdose (biguanides 40.1%, insulin 22.5%), minor symptoms in 37.6% (biguanides 32.6%, insulin 33.5%), major symptoms in 14.4% (biguanides 13.4%, insulin 26.2%) and serious symptoms in 4.6% (biguanides 12.2%, insulin 14.7%). Returned questionnaires reporting clinical outcomes showed that a full recovery occurred in most patients (sulfonylureas 97.4%, biguanides 93.0%, insulin 94.4%), cerebral defects persisted in 1.8% of the cases involving sulfonylureas (biguanides 1.5%, insulin 2.4%), and that 0.9% of the patients with sulfonylurea overdose died (biguanides 6.1%, insulin 3.6%). Conclusions: Sulfonylureas were the most frequently observed medication in cases of overdose with antidiabetic agents. Insulin overdose caused the highest number of major and serious symptoms. Overdose with biguanides led to the most deaths.Correspondence to:
Dr. M.-A. von Mach
II. Medical Department
Division of Clinical Toxicology
University Hospital
Langenbeckstraße 1
55131 Mainz, Germany
Email: marcm@giftinfo.uni-mainz.de
Pharmacokinetics
Placental transfer of antibiotics administered to the mother: a review
Abstract
G.M. Pacifici
Department of Neurosciences, Section of Pharmacology, Medical School, Pisa, Italy
Background: The purpose of antibiotic treatment in pregnant women is to treat the mother and/or the fetus since it is known that antibiotics administered to the mother cross the placenta and reach the fetus. A comparison of the drug concentration in maternal and fetal plasma gives an indication of the exposure of the fetus to the maternally administered antibiotics. Aim: The aim of this study was to review the literature pertaining to the placental transfer of antibiotics in man and to classify the antibiotics according to the type of transfer involved. A table has been developed for use by physicians that lists the name of the antibiotic, the drug concentration in the cord and maternal plasma at delivery and the type of transfer involved. Methods: An initial medline search was performed with the key words “placental transfer of antibiotics” with the limit of “human”. A second medline search was performed with the key words “placental transfer of ...” followed by the class names of the antibiotic such as penicillins, cephalosporins, aminoglycosides, tetracyclines and macrolides. The bibliographic search on the placental transfer of antibiotics covered the period up to July 2005. Results: 3 types of placental transfers were identified. A few antibiotics cross the placenta rapidly and equilibrate in the maternal and cord plasma; this type of transfer is termed “complete” and include the antibiotics ampicillin, methicillin, cefmenoxime and cefotiam. Antibiotics which show incomplete transfer to the placenta where concentrations are lower in the cord than maternal plasma are said to have “incomplete” transfer and these include azlocillin, dicloxacillin, piperacillin, sulbenicillin, cefoxitin, amikacin, gentamicin, kanamycin, streptomycin, fosfomycin, thiamphenicol, griseofulvin, vancomycin and colistimethate. Ceftizoxime is the only antibiotic so far known whose concentrations are higher in the cord than maternal plasma. This type of transfer is called “exceeding” transfer. Conclusion: All examined antibiotics cross the human placenta including those with a molecular weight greater than 1000 kDa such as vancomycin and colistimethate but there are 3 distinct types of placental transfer: complete, incomplete and exceeding and most antibiotics exhibit incomplete transfer.Correspondence to:
G.M. Pacifici
Associate Professor in Pharmacology
Department of Neurosciences
Section of Pharmacology
Medical School
Via Roma 55
56126 Pisa, Italy
Email: pacifici@biomed.unipi.it
Pharmacokinetics
Absence of a food effect with a 145 mg nanoparticle fenofibrate tablet formulation
Abstract
R. Sauron, M. Wilkins, V. Jessent, A. Dubois, C. Maillot and A. Weil
1Department of Clinical Pharmacokinetics, Department of Biometrics, Laboratoires Fournier S.A., Daix, France, 2Department of Pharmaceutical Sciences, Fournier Laboratories Ireland Ltd., Anngrove, Carrigtwohill, Cork, Ireland, and 3AVOGADRO, Fontenilles, France
Objectives: The present study was conducted to assess the effect of food on the bioavailability of fenofibric acid from a new tablet formulation containing fenofibrate nanoparticles. Methods: In this 3-way crossover study, 45 subjects received in a random order one 145 mg fenofibrate tablet under high-fat fed (HFF), low-fat fed (LFF) or fasting (reference) conditions. Plasma concentrations of fenofibric acid were determined up to 120 hours post-dose. Comparisons were made between test (HFF and LFF) and reference conditions (fasting). Results: Very close values of pharmacokinetic parameters were obtained following the three different regimens. The 90% confidence intervals (CI) for the ratio of geometric means of HFF versus fasting condition were (1.018 – 1.088) for AUC¥, (1.020 – 1.090) for AUCt and (0.963 – 1.054) for Cmax with point estimates of 1.052, 1.054 and 1.007, respectively. The 90% CI for the geometric means of LFF versus fasting condition were (0.978 – 1.046) for AUC¥, (0.981 – 1.047) for AUCt and (0.964 – 1.055) for Cmax with point estimates of 1.012, 1.013 and 1.009, respectively. They all fall within the required limits for bioequivalence (0.80 – 1.25). A slightly prolonged tmax was observed following HFF conditions (4.3 ± 1.9 hours, versus 3.6 ± 1.2 hours and 2.3 ± 0.7 hours under LFF and fasting conditions, respectively), without any effect on mean Cmax. Conclusion: The peak and overall exposures from the new 145 mg fenofibrate tablet were not affected by food. Therefore, this new fenofibrate tablet may be taken without regard to the timing of meals.Correspondence to:
R. Sauron, PharmD
Department of Clinical Pharmacokinetics
Laboratoires Fournier S.A.
50, Rue de Dijon
21121 Daix, France
Email: r.sauron@fr.fournierpharma.com
Drug Interactions
Effect of erythromycin on the absorption of fexofenadine in the jejunum, ileum and colon determined using local intubation in healthy volunteers
Abstract
N. Petri, O. Borga, L. Nyberg, M. Hedeland, U. Bondesson and H. Lennernas
1Department of Pharmacy, Biopharmaceutics Research Group, Uppsala University, 2Bioperm AB, Lund, 3Department of Chemistry, National Veterinary Institute, and 4Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
Objective: To investigate the in vivo intestinal absorption mechanism(s) and systemic availability of fexofenadine in the jejunum, ileum and colon in humans. Method: A single dose of fexofenadine hydrochloride (60 mg as solution) was applied under fasting conditions, either alone or directly after a solution of erythromycin lactobionate (corresponding to a dose of 250 mg erythromycin), to the jejunum, ileum and colon in 6 healthy volunteers (3 male and 3 female) using a regional intubation dosing technology (Bioperm AB, Lund, Sweden). A total of 36 fexofenadine administrations were performed. The administration of fexofenadine to the specified location either alone or in combination with erythromycin was conducted in a randomized manner on 2 consecutive days with a 5-day washout period between doses. Results: The plasma AUC for fexofenadine (mean ± SEM) was higher (2.7- to 2.3-fold, p < 0.001) after application to the jejunum (1,090 ± 134 h × ng/ml) than to the ileum (404 ± 102 h × ng/ml) or colon (476 ± 212 h × ng/ml). No significant differences were found between application to the ileum and colon. The administration of erythromycin affected the absorption rate after jejunal application with a prolonged tmax from a median of 40 min (range 10 – 90 min) to a median of 3 hours (range 10 – 180 min) (p = 0.009). A change in tmax was not observed with application to the ileum and colon. The concomitant administration of erythromycin in the jejunum tended to increase the plasma AUC of fexofenadine from 1,090 ± 134 to 1,750 ± 305 h × ng/ml (p = 0.069). Conclusions: The systemic availability of fexofenadine was significantly higher after jejunal administration in accordance with a low permeability compound. The effects of erythromycin suggest that absorption of fexofenadine involves an uptake transport in addition to passive diffusion in the jejunum and predominantly passive diffusion in the ileum and colon.
Correspondence to:
Prof. H. Lennernäs, PhD
Head of the Biopharmaceutics Research Group
Department of Pharmacy
Uppsala University
Box 580
75123 Uppsala, Sweden
Email: Hans.Lennernas@farmaci.uu.se
Drug Interactions
Drug interaction between capecitabine and warfarin: a case report and review of the literature
Abstract
Y. Yildirim, O. Ozyilkan, Z. Akcali and B. Basturk
Departments of Medical Oncology and Immunology, Baskent University Faculty of Medicine, Bahcelievler, Ankara, Turkey
Objective: To report on possible adverse interaction between capecitabine and warfarin in a patient with cancer, who developed subconjunctival and nose bleeding during treatment with these drugs and review of the previously reported five cases in the literature. Case summary: In the second week of capecitabine treatment the patient was hospitalized owing to subconjunctival hemorrhage and nose bleeding. Her international normalized ratio (INR) level was found to have increased, and both drugs were discontinued. Fresh frozen plasma replacement was administered. Warfarin and capecitabine treatment were restarted again but the warfarin dose was decreased. The patients INR was kept between 2.5 – 3 with the reduced dose of warfarin. Discussion: Capecitabine is an orally active prodrug of fluorouracil (FU) and is extensively used as an antineoplastic agent. It is converted to 5-FU in the liver and tumor tissues. Warfarin is an antithrombolytic agent and is metabolized by liver cytochorom P450 (CYP) isoenzymes in liver. Preclinical in vitro studies using human liver microsomes report no inhibitory effects between capecitabine and substrates of CYP. However, the concomitant administration of capecitabine and warfarin resulted in gastrointestinal, retroperitoneal bleeding and hemorrhagic blisters in the five cases previously reported. The exact mechanism of this interaction is unknown; however, a significant pharmacokinetic interaction between capecitabine and S-warfarin resulting in exaggerated anticoagulant activity has recently been demonstrated. Here, we describe another case and use of the Naranjo adverse drug reaction (ADR) probability scale, which indicated a probable relationship between subconjunctival bleeding and epistaxis in this patient after concomitant warfarin and capecitabine use. Conclusion: Capecitabine is extensively used in outpatient clinics, and physicians should be aware of ADRs arising from combined used of capecitabine and warfarin. In the light of the current data, INR levels should be closely monitored in patients using this medication regimen.Correspondence to:
Yesim Yildirim, MD
Department of Medical Oncology
Baskent University
Faculty of Medicine
Fevzi Cakmak Caddesi 12. Sokak 7/5
06490 Bahcelievler, Ankara, Turkey
Email: dryesimyildirim@yahoo.com
Biavailability Section
Bioequivalence of an ezetimibe/simvastatin combination tablet and coadministration of ezetimibe and simvastatin as separate tablets in healthy subjects
Abstract
E.M. Migoya, A. Bergman, D. Hreniuk, N. Matthews, B. Yi, B. Roadcap, R. Valesky, L. Liu, K. Riffel, M. Groff, J.J. Zhao, D.G. Musson, J. Gambale, T. Kosoglou, P. Statkevich, K.C. Lasseter, A. Laurent, A.O. Johnson-Levonas, G. Murphy, K. Gottesdiener and J
1Merck Research Laboratories, Rahway, NJ, Blue Bell, PA, and West Point, PA, 2Solid Tumor Service, Division of Hematology and Medical Oncology, Weill Medical College, Cornell University, New York, NY, 3Schering-Plough Research Institute, Kenilworth, NJ, 4SFBC International, Miami, FL, and 5PPD Development, Austin, TX, USA
Objective: To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA). Methods: In this open-label, randomized, 2-part, 2-period crossover study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within pre-specified bounds of (0.80, 1.25). Results: The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/ SIMVA and EZE + SIMVA were generally well tolerated. Conclusions: The lowest and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dosages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tablet across the clinical dose range.
Correspondence to:
E.M. Migoya, PharmD
Merck & Co., Inc.
RY34-A544, 126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065-0900, USA
Email: elizabeth_migoya@merck.com
Biavailability Section
Comparative bioavailability of two ramipril formulations after single-dose administration in healthy volunteers
Abstract
G. Duarte Mendes1,3, A.T. Dantas Sanfelice1, N.C. do Carmo Borges2, L.E. Cavedal2, C. Sverdloff3, M. Prado Galuppo3, J.H. Módolo3 and G. De Nucci1,2,3
1Department of Internal Medicine, 2Department of Pharmacology, State University of Campinas, and 3Cartesius Development of Clinical Research, Campinas, SP, Brazil
Objective: To assess the bioequivalence of a ramipril 5 mg tablet formulation (ramipril test formulation from Laboratórios Biosintética Ltda (Sao Paulo, Brazil) and Triatec® from Aventis Pharma (Sueano, Brazil) standard reference formulation) in 26 healthy volunteers of both sexes. Methods: The study was conducted using an open, randomized, 2-period crossover design with a 2-week washout interval. Plasma samples were obtained over a 36-hour period. Plasma ramipril and ramiprilat concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM). From the ramipril and ramiprilat plasma concentration vs. time curves, the following pharmacokinetic parameters were obtained: AUClast, AUCinf and Cmax. Results: The limit of quantification was 0.2 ng × ml–1 and 1.0 ng × ml–1 for ramipril and ramiprilat, respectively. The geometric means and 90% confidence intervals (CI) for Ramipril/Triatec® and Ramiprilat/Triatec® percent ratios were: 104.69% (90% CI = 93.21 – 117.59%) for Cmax, 102.49% (90% CI = 92.76 – 113.24%) for AUClast, 103.60% (90% CI = 93.56 – 114.73%) for AUCinf, 108.48% (90% CI = 98.86 – 119.03%) for Cmax, 105.88% (90% CI = 101.55 – 110.39%) for AUClast, 97.30% (90% CI = 90.17 – 104.99%) for AUCinf, respectively. Conclusion: Since the 90% CI for AUClast, AUCinf and Cmax ratios were within the 80 – 125% interval proposed by the US FDA, it was concluded that the ramipril formulation produced by Laboratórios Biosintética Ltda is bioequivalent to the Triatec® formulation in both rate and extent of absorption.Correspondence to:
G. De Nucci, MD, PhD
415 Jesuino Marcondes Machado Ave.
Campinas, SP 13092-320, Brazil
Email: denucci@dglnet.com.br
