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Abstract

A.-R. van Troostenburg, D. Lee, T.R. Jones, J.A. Dyck-Jones, M.H. Silverman, G.N. Lam and S.J. Warrington

¹HMR, Central Middlesex Hospital, London, UK, ²Ångstrom Pharmaceuticals, San Diego, CA, ³BioStrategics Consulting, Marblehead, MA, and ⁴MicroConstants, San Diego, CA, USA
Aims: To assess the safety, tolerability and pharmacokinetics of subcutaneous Å6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men. Methods: Double-blind, placebo-controlled, parallel-group, dose-rising, phase I study of single and repeated doses. In the single dose phase, successive groups of 5 subjects received Å6 15, 35, 75, 150, 300 mg, or placebo, as subcutaneous injections in the upper thigh. In the repeat dose phase, 2 groups of 6 subjects received repeat doses of Å6 35 mg and 75 mg, or placebo, and 1 group of 5 subjects received 150 mg, or placebo, 12-hourly for 6 days (11 doses in total). In each group, 4 subjects received active treatment, the remainder placebo. Pharmacokinetics of Å6 were assessed up to 24 h after single doses, for 12 h after the first of the repeated doses, and up to 24 h after the last of the repeated doses. Materials: Å6 for subcutaneous injection in phosphate buffer, pH 5.6 – 6.0. Phosphate-buffered saline was used as placebo. Results: All dose regimens of Å6 were safe and well-tolerated, both systemically and locally. Time to peak plasma concentration was similar (0.5 – 2.1 h) in all dosage groups. Cmax and AUC(0-inf) were linearly proportional to dose. Mean Cmax ranged from 454 – 10,333 ng/ml and mean AUC(0-inf) from 1,690 – 43,371 ng×h/ml after the 15 and 300 mg single doses, respectively. Terminal t1/2 was 1.4 – 1.8 h, and there was no evidence of unexpected drug accumulation. Urinary excretion of unchanged Å6 was 94.6% (SD 20.7) after the 300 mg single dose (0 – 24 h collection), and 78.4% (SD 13.0) after the 150 mg repeated dose (0 – 12 h collection). Å6 did not trigger production of anti-Å6 IgG antibodies within 14 days of the first dose. Conclusion: Single doses of Å6 up to 300 mg, and repeated doses up to 150 mg, were well-tolerated and safe in healthy young men. Å6 was rapidly absorbed; it was eliminated, mainly unchanged, in urine. Plasma concentrations were dose-proportional. Å6 did not trigger an early immunogenic response.

Abstract

M.J.S. Langman, H.-G. Eichler, P. Mavros, D.J. Watson and S.X. Kong

¹Department of Medicine, Queen Elizabeth Hospital, The University of Birmingham, Birmingham, UK, ²Outcomes Research, Merck and Co., Inc., Whitehouse Station, NJ, USA, ³Department of Clinical Pharmacology, Vienna University School of Medicine, Vienna, Austria, and ⁴Epidemiology, Merck and Co., Inc., Blue Bell, PA, USA
Background: The comparative effects of cyclooxygenase-2- (COX-2) selective inhibitors and nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) on blood pressure are debated. Clinicians have been concerned about the need for antihypertensive treatment following therapy with these agents. Objective: To compare initiation of antihypertensive treatment among new users of the COX-2-selective inhibitor rofecoxib and of nonselective NSAIDs in clinical practice. Methods: Retrospective cohort study using the MediPlus (UK) database that covers 1.8 million patients throughout the UK. Patients included were at least 50 years of age, had at least 1 prescription for either diclofenac, ibuprofen, naproxen or rofecoxib (drugs of interest, DOIs), and had no prescription for any NSAID, COX-2 inhibitor, or antihypertensive treatment during the 6 months prior to their first/index prescription date. A subset of patients, classified as chronic and persistent new users, had at least 3 prescriptions of the index prescription DOI and did not switch to another DOI during the 6-month follow-up period. Logistic regression analysis, adjusted for potential predictors, was used to assess initiation of new antihypertensive treatment. Results: 18,737 suitable patients were identified (diclofenac 7,861, ibuprofen 8,423, naproxen 1,556 and rofecoxib 897). Those using rofecoxib were older and more likely to be female than those using NSAIDs. During the 6 months following the index prescription, 7.0% of all new users and 11.5% of chronic and persistent new users initiated antihypertensive treatment. After adjusting for potential predictors there were no statistically significant differences in the risk of initiating antihypertensive treatment between new or chronic and persistent new users of rofecoxib, diclofenac, ibuprofen and naproxen (p > 0.05). Conclusion: The results of this study did not indicate any significant differences in the initiation of antihypertensive therapy among patients who were prescribed rofecoxib and NSAIDs, even after multiple prescriptions.

Abstract

H. Zhou, M. Buckwalter, J. Boni, P. Mayer, D. Raible, J. Wajdula, S. Fatenejad and M. Sanda

¹Clinical Pharmacology and ²Clinical R & D, Wyeth Research, Collegeville, PA, USA
Objective: The purpose of this study was to evaluate the pharmacokinetics of etanercept in patients with ankylosing spondylitis (AS) in a phase 3 study. Methods: Serum etanercept concentrations were analyzed from samples obtained at weeks 4 and 12 from 43 patients with AS (median age: 45 years; median body weight: 75 kg; white/nonwhite: 40/3; male/female: 34/9) receiving 25 mg subcutaneously twice weekly for 12 weeks. A population pharmacokinetics analysis using NONMEM was conducted to estimate individual etanercept pharmacokinetic parameters. Initially, appropriate base and covariate population pharmacokinetic models were built based on data from 10 prior clinical studies of etanercept administered subcutaneously or intravenously to healthy subjects (n = 53) and to patients with rheumatoid arthritis (RA) (n = 212). The influence of demographic characteristics on the pharmacokinetics of etanercept was thoroughly evaluated. The stability of the final model was evaluated using both internal (bootstrapping) and external (data splitting) validation approaches. Finally, the selected final population covariate model was used to estimate the Bayesian pharmacokinetic parameters for the patients with AS. Results: The data from the 10 prior clinical studies were optimally fitted to a 2-compartment linear population covariate model. Both age (< 17 years) and body weight (< 60 kg) were found to be important covariates on clearance. Both bootstrapping and data splitting validated the population model. The mean Bayesian-predicted etanercept clearance and steady-state trough concentration were 0.072 l/h and 2,004 ng/ml, respectively. The pharmacokinetic parameters of etanercept in the patients with AS were similar to those observed in the patients with RA. Conclusions: The pharmacokinetics of etanercept in patients with AS were similar to those in patients with RA. The AS disease state does not appear to alter the disposition of etanercept.

Abstract

M.-A. von Mach, S. Meyer, B. Omogbehin, P.H. Kann and L.S. Weilemann

¹II. Medical Department, Division of Clinical Toxicology, University Hospitals, Mainz, and ²Department of Internal Medicine, Division of Endocrinology and Diabetology, Philipps University Hospital, Marburg, Germany
Objective: Overdoses with insulin are common, and cases of hypoglycemic coma can be fatal and cause cerebral defects. However, data published on this topic are rare, consisting mostly of case reports or reports in a small number of patients. The present investigation analyzes inquiries made to a regional poisons unit involving overdoses with insulin. Patients and methods: A total of 175,890 inquiries for the years 1995 – 2003 (until September) were evaluated. 160 inquiries were received by telephone concerning insulin overdoses, and a standardized questionnaire was sent to the physicians asking for follow-up information. The cases were analyzed in regard to etiology, type of insulin used, concomitant substances being taken by the patient, symptoms and clinical outcome. Results: Of the 160 inquiries investigated, 53.1% of the patients were female, 43.1% male and in 3.8% the sex of the patient was unknown. The average age was 44.7 years. 89.4% involved suicidal or parasuicidal cases, 5.0% were accidental overdoses and 1.9% involved cases of criminal overdose (3.7% were for other reasons). Rapidly acting insulins (57.8%) were used more commonly than long-acting formulations (42.8%). Benzodiazepines were the most frequently ingested concomitant medication (37.5%) with ethanol 15.6%, antihypertensive drugs 12.5% and antidepressants 10.0%. Most patients presented with a delay of 2 – 3 hours after insulin administration (15.0%). Almost 50% of the patients presented within the first 6 hours. According to the Poisoning Severity Score, no symptoms were observed in 16.8% of the patients, minor symptoms in 36.8%, major symptoms in 25.2% and serious symptoms in 21.3%. Information concerning the clinical outcome (75 cases) showed that a full recovery occurred in most patients (94.7%), but in 2.7% there were cerebral defects and 2.7% of the patients died. Conclusions: The etiology of overdoses with insulin was mainly deliberate self-poisoning. Physicians should take into account that long-acting insulin formulations and concomitant substances were frequently used. For overdoses with insulin, relatively high rates of serious symptoms and deaths were observed.

Abstract

P.A. Thürmann¹, A. Neff¹ and J. Fleisch²

¹Philipp Klee Institute of Clinical Pharmacology, Helios Hospital Wuppertal, University of Witten/Herdecke, and ²Kliniken St. Antonius, Wuppertal, Germany
Objective: Presentation of a case report and pharmacokinetic investigation in healthy volunteers on the potential interference between cardiac glycosides and glycosides of Uzara, a herbal antidiarrheal preparation. Methods: Pharmacokinetic pilot investigation of apparent digitoxin and digoxin serum concentrations in 4 healthy volunteers after single-dose administration of 30 drops Uzara (approximately 1.5 ml @ 22 mg glycosides). Results: Maximal apparent serum concentrations of digitoxin between 198.0 mg/l and 919.8 mg/l (therapeutic range: 10 – 25 mg/l) occurred at 4 – 8 hours after administration. The terminal half-life of the glycosides was 8.87 ± 2.20 hours. For digoxin, maximal apparent serum concentrations ranged between 1.4 mg/l and 6.34 mg/l (therapeutic range: 0.9 – 2.0 mg/l) at 6 hours post dosing. Conclusions: Administration of a single dose of an Uzara preparation, an over-the-counter product, results in false high serum concentrations of digitoxin and digoxin. As described in the manufacturers Summary of Product Characteristics, this preparation should not be given to patients with cardiac failure or arrhythmia who require treatment with cardiac glycosides because of the demonstrated pharmacological actions of uzara glycosides.

Abstract

M. Rochdi¹, M.A. González² and S.J. Hirshey Dirksen³

¹GloboMax, The Strategic Pharmaceutical Development Division of ICON plc, Hanover, MD, ²P’Kinetics International, Pembroke Pines, FL, and ³Celltech Americas, Rochester, NY, USA
Objective: To assess the dose-proportionality of the 10 mg, 20 mg and 30 mg methylphenidate extended-release (MPH ER) capsule formulations in healthy adults. Materials: Metadate® CD (methylphenidate HCl, USP) extended-release capsules (10, 20 and 30 mg) were obtained from Celltech Manufacturing Inc. (Rochester, NY, USA). Methods: This was a single-center, single-dose, fasted, randomized, open-label, 3-way crossover study with a 1-week washout period between doses, in 24 healthy male and female subjects, aged 21 – 40 years. MPH plasma concentration-time data were used to calculate the pharmacokinetic parameters for each treatment. The 20 mg capsule, the first FDA-approved dosage strength, was used as reference treatment. Results: Twenty-three subjects completed all 3 study periods. Regardless of the dose, MPH ER capsules exhibited similar PK profiles as evidenced by a biphasic absorption profile, consisting of a sharp initial increase followed by a second increase in MPH plasma levels, all occurring at the same times. All 90% confidence intervals for the 10 : 20 mg and 30 : 20 mg dose-normalized geometric mean ratios were within the 80 – 125% FDA limits for bioequivalence. This was true for Cmax (maximum observed concentration), AUC0-last (area under the plasma concentration curve from time 0 to the last measurable time point) and AUC0-inf (area under the plasma concentration curve from time 0 to infinity). Adverse events were mild and the number and types of adverse events experienced by subjects did not differ among the 3 dosages. Conclusion: Data collected from this study demonstrate the dose proportionality of the new 10 mg and 30 mg dosage strengths of MPH ER capsules with the 20 mg capsule. The availability and predictability of these dosage strengths should facilitate dose titration of ADHD patients.

Abstract

I. Bitsch¹, M. Janßen¹, M. Netzel², G. Straß² and T. Frank³

¹Institute of Nutrition, Justus Liebig University, Gießen,
²Institute of Nutrition, Friedrich Schiller University, Jena, and
³IMFORM GmbH, Darmstadt, Germany
Pharmacokinetic parameters and the bioavailability of several dietary anthocyanins following consumption of blackcurrant juice and elderberry extract were compared exploratorily in 6 healthy volunteers. They were given a single oral dose of either 137 ml of blackcurrant juice (144.8 mg total anthocyanins) or 30 ml of elderberry extract (147.3 mg total anthocyanins). Within 7 hours, the urinary excretion of total anthocyanins (i.e. the sum of all assayed anthocyanidin glycosides) was 0.04% and 0.37% of the administered dose following blackcurrant juice and elderberry extract ingestion, respectively. Pharmacokinetic parameters based on non-compartmental methods for plasma and urine concentrations exhibited higher variability in urinary excretion after ingestion of elderberry extract. Anthocyanin absorption was significantly greater following the intake of elderberry extract than after the intake of blackcurrant juice as shown by the 5.3- and 6.2-fold higher estimates of dose-normalized C_max and AUC_(0-tz) of total anthocyanins, respectively. The geometric means of t_1/2 were not significantly different following elderberry extract (1.74 h) and blackcurrant juice ingestion (1.73 h, p > 0.05). The urinary excretion rate of intact anthocyanins was fast, appeared to be monoexponential for both blackcurrant juice and elderberry extract. However, in order to evaluate the contribution of anthocyanins to the health-protecting effects of blackcurrant juice and elderberry extract it will be necessary to perform further studies on the unchanged glycosides and their in vivo metabolites in human plasma and urine.

Abstract

S.K. Bae, E.J. Kim, C.H. Lim, J.S. Lee, Y.G. Kim and M.G. Lee

¹College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, ²Sam Chun Dang Pharmaceutical Company, Ltd., and ³Department of Pharmacology, College of Medicine, Dankook University, Korea
Aim: Determination of the bioequivalence of 2 pravastatin tablet formulations manufactured in Korea. Patients and methods: Twenty-three healthy male Korean volunteers received each of the 2 pravastatin formulations at a dose of 20 mg in a 2 × 2 crossover study. There was a 1-week washout period between doses. Plasma concentrations of pravastatin were monitored using high-performance liquid chromatography over a period of 8 hours after administration. AUC0-8h (the area under the plasma concentration-time curve from time zero to the last measured time in plasma, 8 h) was calculated using the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC0-8h and Cmax and untransformed tmax. Results: The point estimates and 90% confidence intervals for AUC0-8h (parametric) and Cmax (parametric) were 1.067 (0.968 ~ 1.176) and 1.074 (0.999 ~ 1.155), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. The corresponding value of tmax was 0.000 (–0.250 ~ 0.250). Conclusion: These results indicate that the 2 medications of pravastatin are bioequivalent and, thus, may be prescribed interchangeably.

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Volume 42, No. 5/2004(May)