bluuebunny/crossref_metadata_2025 huggingface dataset:
Antioxidant Effects of Chinese Traditional Medicine: Focus on Trilinolein Isolated from the Chinese Herb Sanchi (Panax pseudoginseng)
Authors: Chan Paul , Tomlinson Brian
Published: July 2003

It is thought that oxygen‐derived free radicals (OFR) cause lipid peroxidation, which contributes to the process of atherosclerosis, and they are also involved in the myocardial damage seen with ischemia and reperfusion. Antioxidants could potentially ameliorate such harmful effects. Many natural plant products have been shown to have antioxidant effects. Trilinolein, a triacylglycerol purified from Panax pseudoginseng, which is commonly used in Chinese traditional medicine, has been found to have pharmacological effects, including antioxidant activity that may explain the benefits in treating circulatory disorders perceived from the use of the herb over the centuries.
The Absolute Bioavailability of Oral Melatonin
Authors: DeMuro Rob L. , Nafziger Anne N. , Blask David E. , Menhinick Anne M. , Bertino Joseph S.
Published: July 2003

The absolute bioavailability of oral melatonin tablets was studied in 12 normal healthy volunteers. Subjects were administered, in a randomized crossover fashion, melatonin 2 mg intravenously and 2 and 4 mg orally. Blood was sampled over approximately eight (estimated) half‐lives. Both the 2 and the 4 mg oral dosages showed an absolute bioavailability of approximately 15%. No difference in serum half‐life was seen in any of the study phases. Oral melatonin tablets in dosages of 2 and 4 mg show poor absolute bioavailability, either due to poor oral absorption, large first‐pass metabolism, or a combination of both. Further studies examining larger doses, in an attempt to saturate first‐pass metabolism if it occurs, may be warranted.
Modeling of Circadian Testosterone in Healthy Men and Hypogonadal Men
Authors: Gupta Suneel K. , Lindemulder Elizabeth A. , Sathyan Gayatri
Published: July 2003

The testosterone circadian rhythm has been reported extensively in the literature and has been described by a cosine function. Typically, these data are measured at frequent and regular (e.g., hourly) intervals. However, modeling circadian rhythm with data collected sparsely at irregular intervals and/or data that are not collected at the same time in all individuals has not been reported. The population nonlinear mixed‐effects approach can handle such data and also allows covariates to be incorporated into the model. Frequent hourly testosterone concentration data available in the literature for young and elderly healthy volunteers were analyzed first. In the elderly, blunted or completely absent circadian rhythm has been reported, but a full circadian model was significantly better than a model containing one or no circadian component. Therefore, data from both the elderly and young were modeled together, and age was included as a categorical variable (young or elderly). Consistent with literature, the rhythm‐adjusted mean testosterone concentrations was lower, and the deviation from the mean, especially to the maximum daily value, was less than half in the elderly (7%) compared to young subjects (16%). The testosterone concentration data measured infrequently and at varying intervals in young normal men and hypogonadal men were evaluated next. Although not measured at regular frequency in each individual, the data were obtained at different clock times for different subjects. Since for population mixed‐effects analysis, data from all subjects are pooled, there was enough information to profile the 24‐hour circadian cycle. In healthy young subjects, the mean Cnadir, Cpeak, Tnadir, and Tpeak values estimated from the model were 420 ng/dL, 577 ng/dL, 21:42 hours, and 0600 hours, respectively, and were similar to the parameters obtained for the frequently sampled young subjects. In hypogonadal men (testosterone concentrations < 300 ng/dL), the mean testosterone concentrations were much lower than the healthy young or elderly men, and a straight‐line model was the best descriptor (i.e., no circadian rhythm was detected). It was also shown that with the application of a transdermal testosterone system, the mean testosterone concentrations in the treated men were within the 95% confidence interval for healthy young men. The results presented here suggest that the advantages of the analysis approach—namely, handling of covariates and handling of sparse, infrequently collected data—can be used in characterizing testosterone circadian rhythm or the lack of it.
The Influence of the Menstrual Cycle on Triazolam and Indocyanine Green Pharmacokinetics
Authors: Kamimori Gary H. , Sirisuth Nattee , Greenblatt David J. , Eddington Natalie D.
Published: July 2003

The aim of this study was to investigate the effects of the menstrual cycle phase on the pharmacokinetics of two high‐clearance agents, triazolam and indocyanine green (ICG). Eleven nonsmoking, healthy, eumenorrheic women were enrolled in this study. Triazolam (0.25 mg) was administered orally, and indocyanine green was administered as an i.v. bolus (0.5 mg/kg) during the follicular, ovulatory, and luteal phases of a single menstrual cycle. Blood samples were collected over 10 hours for triazolam and over 30 minutes for ICG. Triazolam and indocyanine green concentrations were quantitated by electron capture gas chromatography and spectrophotometry, respectively. Noncompartmental analysis was used to determine relevant pharmacokinetics parameters, which were statistically assessed using two‐way ANOVA (p < 0.05). No statistical differences for triazolam were observed. Vd/F was lower in the luteal phase (107 L) as compared to the follicular (138 L) and ovulatory (133 L) phases. Clearance of triazolam was comparable in the follicular (583 ml/min), ovulatory (565 ml/min), and luteal (538 ml/min) phases. ICG also revealed no significant differences across the phases. These results suggest that the phases of the menstrual cycle do not influence triazolam or ICG pharmacokinetics.
Pharmacokinetics and Safety of Single Intravenous Infusions of the Adenosine Agonist, AMP 579, in Patients with End‐Stage Renal Insufficiency
Authors: Zannikos Peter N. , Jensen Bradford K. , Boutouyrie Bruno X. , Tripp Lisa , Yongyi Luo , McGowan Tracy , Waldman Scott A. , Greenberg Howard E.
Published: July 2003

The pharmacokinetics of an adenosine agonist (AMP 579) were characterized in patients with end‐stage renal disease compared to sex‐ and age‐matched healthy volunteers. All study participants were administered single AMP 579 doses of 50 μg/kg as a 6‐hour, constant‐rate intravenous infusion. Serial blood samples were obtained for measurement of plasma AMP 579 concentration, and predose samples were collected for determination of AMP 579 plasma protein binding. The safety of AMP 579 administration in renally impaired patients also was evaluated. AMP 579 was rapidly cleared from the systemic circulation in all subjects as plasma concentrations were below the limit of detection by 2 to 4 hours after terminating the infusion. Noncompartmental analysis yielded mean values for the plasma AMP 579 concentration at the end of the 6‐hour infusion (C6h) of 9.6 and 10.5 ng/mL and for systemic clearances (Cl) of 0.91 and 0.72 L/h/kg in renally impaired patients and healthy volunteers, respectively. Mean volumes of distribution (Vss) in the renally impaired and healthy volunteers were 0.92 and 0.84 L/kg, and terminal elimination half‐life values (t1/2) were 1.61 and 1.33 hours, respectively. The extent to which AMP 579 is bound to plasma protein was not altered in renally impaired patients since the free fractions were 4.0% and 3.4% for renally impaired and healthy volunteers, respectively. It was concluded that the pharmacokinetic parameters of AMP 579 were similar in both groups. The 6‐hour AMP 579 infusion was generally well tolerated by both renal patients and healthy volunteers. There were no serious adverse events, and there were only two mild adverse events in 1 renally impaired patient judged possibly related to the study drug that quickly resolved. There were no clinically significant changes in laboratory values or clinical evaluations during the study. There was a slight increase in heart rate during the infusion of similar magnitude for both the renal patients and healthy volunteers. These data suggest that AMP 579 may be administered to renally impaired patients with minimal cardiovascular effects and adverse events. These results in end‐stage renal patients (worst‐case scenario) indicate that dose adjustment in patients with renal insufficiency of any degree is not indicated in future studies of AMP 579.
Mechanism and Amelioration of Recombinant Human Interleukin‐11 (rhIL‐11)–Induced Anemia in Healthy Subjects
Authors: Dykstra Kevin H. , Rogge Holly , Stone Anne , Loewy John , Keith James C. , Schwertschlag Ullrich S.
Published: July 2003

Recombinant human interleukin‐11 (rhIL‐11), or Neumega® rhIL‐11 Growth Factor, is a recombinant cytokine that stimulates megakaryocytopoiesis, increases platelet production, and also has shown anti‐inflammatory and immune‐modulating activity. Mild, reversible anemia was the most common adverse event observed in clinical studies and was demonstrated to be related to hemodilution. The purpose of this study was to examine the renal mechanisms of the rhIL‐11‐induced volume retention and devise a possible therapeutic intervention to ameliorate this effect. Eighteen healthy volunteers (9 male and 9 female) on a controlled sodium (180 mEq/day) and potassium (120 mEq/day) diet were randomized to one of six treatment sequences in a three‐period crossover design. Each subject received 25 μg/kg IL‐11 SC once daily, 25 μg/kg IL‐11 SC once daily + Maxzide‐25® twice daily, or placebo for 7 days in a crossover design. There was a 14‐day washout period between treatment periods. Renal clearance parameters indicated that mean sodium excretion was decreased compared to placebo within 8 hours after dosing with rhIL‐11, with these results reaching statistical significance 8 to 16hourspostdose (p < 0.01). The cumulative sodium excretion (mEq ± SD) over the 7‐day treatment period for each respective treatment group was the following: rhIL‐11 = 833 ± 154, rhIL‐11 + Maxzide‐25® twice daily = 1114 ± 178, and placebo = 982 ± 193 (p < 0.01). Hemoglobin concentration and hematocrit values, used as indicators of hemodilution, decreased in the rhIL‐11‐treated group as compared to the baseline and placebo groups (p < 0.01). Concurrent dosing with Maxzide‐25® twice daily reduced the rhIL‐11‐associated hemodilution by about 50%.
The Pharmacokinetics and Tolerability of the Oral Neuraminidase Inhibitor Oseltamivir (Ro 64–0796/GS4104) in Healthy Adult and Elderly Volunteers
Authors: Massarella Joseph W. , He George Z. , Dorr Albert , Nieforth Keith , Ward Penelope , Brown Andy
Published: July 2003

The tolerability and pharmacokinetics of Ro 64–0802, a potent, selective inhibitor of influenza neuraminidase, and its oral prodrug oseltamivir were investigated in three double‐blind, placebo‐controlled studies. Two studies involved healthy adult volunteers (18–55 years) (n = 48) who received single (20–1000 mg) or bid doses (50–500 mg) (n = 32) of oseltamivir or placebo for 7 days. Healthy elderly volunteers (≥65 years) (n = 24) received oseltamivir 100 to 200 mg bid or placebo for 7 days in a third study. Measurable plasma concentrations of the active metabolite appeared rapidly in plasma and were significantly higher and longer lasting than those of oseltamivir. Pharmacokinetics of both compounds were linear. Multiple‐dose exposure was predictable from single‐dose data, and steady‐state plasma concentrations were achieved within 3 days of bid drug administration. Oseltamivir was well tolerated at single doses of up to 1000 mg and twice‐daily doses of up to 500 mg. Adverse events were mild in intensity. Exposure to both prodrug and active metabolite was increased in elderly patients by approximately 25%. However, due to the wide safety margin of both compounds, no dose adjustment is necessary for elderly patients.
Pharmacokinetics of Ofloxacin Enantiomers after Intravenous Administration for Antibiotic Prophylaxis in Biliary Surgery
Authors: Gascón A. R. , Campo E. , Hernández R. M. , Calvo B. , Errasti J. , Muñoz J. L. Pedraz
Published: July 2003

The pharmacokinetics of S‐(−)‐ and R‐(+)‐ofloxacin, enantiomers of the fluoroquinolone ofloxacin, were characterized after prophylactic administration in 15 patients undergoing elective biliary surgery. A single dose of ofloxacin 400 mg given intravenously as an infusion was administered 1 hour before surgery. Plasma levels of S‐(−)‐ and R‐(+)‐ofloxacin showed very small differences between both enantiomers, although the ratio of S‐(−)‐ to R‐(+)‐enantiomer concentration in plasma showed significant differences (p < 0.05) at 4 and 12 hours. Adequate S‐(−)‐ofloxacin (levofloxacin, the active enantiomer) plasma levels (≥ minimum inhibitory concentration [MIC90] for Escherichia coli) were found throughout the procedure. For pharmacokinetic parameters, the authors found small but statistically significant differences (p < 0.05) in the area under the concentration‐time curve, AUC0‐0‐∞ (22.30 ± 2.72 mgh/L for S‐(−)‐ofloxacin vs. 20.50 ± 2.06 mgh/L for R‐(+)‐ofloxacin), and in the clearance (0.15 ± 0.04 L/h/Kg for S‐(−)‐ofloxacin vs. 0.16 ± 0.04 L/h/Kg for R‐(+)‐ofloxacin). To test the penetration of ofloxacin enantiomers into tissues, the authors measured levels in subcutaneous cell tissue and gallbladder cell tissue. They did not observe statistical differences between the two isomers, which means that distribution is not an estereoselective process. Enantiomer levels in these two tissues decreased rapidly, but the highest concentrations were reached during the 4 first hours (i.e., when the surgical procedure was being performed). In conclusion, with the prophylactic treatment used, levofloxacin plasma and tissue levels are high enough to prevent surgical infections.
Effect of Fluoxetine on Carvedilol Pharmacokinetics, CYP2D6 Activity, and Autonomic Balance in Heart Failure Patients
Authors: Graff Donald W. , Williamson Kristin M. , Pieper John A. , Carson Stanley W. , Adams Kirkwood F. , Cascio Wayne E. , Patterson J. Herbert
Published: July 2003

The objective of this study was to examine the pharmacokinetic and pharmacodynamic consequences of concomitant administration of fluoxetine and carvedilol in heart failure patients. Fluoxetine (20 mg) or matching placebo was administered in a randomized, double‐blind, two‐period crossover study to 10 patients previously identified as extensive metabolizers of CYP2D6 substrates. Patients were maintained on a carvedilol dose of 25 or 50 mg bid and given fluoxetine/placebo for a minimum of 28 days. Plasma was collected over the 12‐hour carvedilol dosing interval, and the concentrations of the R(+) and S(−) enantiomers of carvedilol were measured. CYP2D6 phenotype was assessed during each study period using dextromethorphan (30 mg). Changes in autonomic modulation between study periods were measured by heart rate variability in the time and frequency domains using ambulatory electrocardiographic monitoring. Compared to placebo, fluoxetine coadministration resulted in a 77% increase in mean (± SD) R(+) enantiomer AUC0–12 (522 ± 413 vs. 927 ± 506 ng•h/mL, p = 0.01) and a nonsignificant increase in S(−) enantiomer AUC (244 ± 185 vs. 330 ±179 ng•h/mL, p = 0.17). Mean apparent oral clearance for both enantiomers decreased significantly with fluoxetine administration (R(+): 10.3 ± 7.2 vs. 4.5 ± 2.2 mL/min/kg; S(−): 22.5 ± 12.3 vs. 12.6 ± 7.4 mL/min/kg; p = 0.004 and 0.03, respectively). No differences in adverse effects, blood pressure, or heart rate were noted between treatment groups, and there were no consistent changes in heart rate variability parameters. In conclusion, fluoxetine administration resulted in a stereospecific inhibition of carvedilol metabolism, with the R(+) enantiomer increasing to a greater extent than the S(−) enantiomer. However, this interaction was of little clinical significance in our sample population.
In Vitro and In Vivo Techniques Used in Drug Development for Evaluation of Dose Delivery of Inhaled Corticosteroids
Authors: Rhodes Gerald R. , Rohatagi Shashank , Gillen Michael S. , Deluccia Frank , Banerji Donald D. , Chaikin Philip
Published: July 2003

Oral inhaled corticosteroids are important in the treatment of asthma since their delivery is targeted directly to the lung, which is the site of action. Triamcinolone acetonide (TAA) is an effective and safe corticosteroid that is marketed as a metered‐dose inhaler (MDI) with an integrated spacer (Azmacort®) for the treatment of asthma. Due to the phasing out of chlorofluorocarbon (CFC) propellants, Azmacort® has been reformulated with a non‐CFC propellant. Due to the complexities of oral inhaled formulations and the topical nature of drug delivery to the lung for efficacy, the reformulation of oral inhaled MDIs requires careful consideration and support throughout their development, using a combination of in vitro and in vivo studies to ensure clinical comparability for both efficacy and safety. This paper describes a chronological series of studies designed to support the reformulation of Azmacort®. These included in vitro studies to estimate respirable fraction, in vivo pulmonary deposition studies, in vivo pharmacokinetic‐pharmacodynamic studies to estimate the systemic effects of each formulation, and final clinical studies in adult and pediatric patients to confirm the clinical comparability of the new formulation of Azmacort®. The results of these studies, performed at various stages during the development of new formulations, were critical in guiding the reformulation efforts for Azmacort®.
Application of Preclinical Data to Initiate the Modified Continual Reassessment Method for Maximum Tolerated Dose—Finding Trials
Authors: Mahmood Iftekhar
Published: July 2003

This study was conducted to evaluate whether the allometric approach can be used to predict maximum tolerated dose (MTD) in humans from animal data. Twenty‐five anticancer drugs were taken from the literature and used in this analysis. The results of the study indicate that MTD can be predicted with reasonable accuracy using interspecies scaling. The predicted MTD can then be applied to the modified continual reassessment method retrospectively for the selection of initial and subsequent doses of anticancer drugs in the patient population. This approach can save time and avoid many unnecessary steps to attain MTD in humans if it could be applied prospectively.
Reduction of LDL Cholesterol in Patients with Primary Hypercholesterolemia by SCH 48461: Results of a Multicenter Dose‐Ranging Study
Authors: Dujovne Carlos A. , Bays Harold , Davidson Michael H. , Knopp Robert , Hunninghake Donald B. , Stein Evan A. , Goldberg Anne C. , Jones Peter , Lipka Leslie J. , Cuffie‐Jackson Cynthia
Published: July 2003

SCH 48461, an inhibitor of gastrointestinal absorption of cholesterol, was evaluated for its effects on lipid parameters in patients with primary hypercholesterolemia in a multicenter, double‐blind, randomized, parallel‐group study. Following the baseline phase, which consisted of a 2‐ to 10‐week drug washout and dietary stabilization phase and a 4‐week placebo lead‐in (placebo baseline phase), 190 patients were randomized to an 8‐week double‐blind active drug (SCH 48461 1, 6.25, 25, 100, 200, or 400 mg) or 40 mg lovastatin once daily each morning or placebo treatment phase. By week 2, patients who received SCH 48461 6.25 to 400 mg or lovastatin demonstrated greater reduction from baseline in directly measured low‐density lipoprotein cholesterol (LDL‐C) levels than patients in the placebo group (p ≤ 0.03). Overall, the percent reductions in LDL‐C from baseline increased as the dose of SCH 48461 increased, with 0.6% to 15.5% reductions from the minimum dose of 1 mg to the maximum dose of 400 mg. Lovastatin 40 mg/day reduced LDL‐C by 30.7% (p < 0.01). Statistically significant decreases were also seen for total cholesterol and apolipoprotein B (apo B) with doses of 25 mg to 400 mg of SCH 48461 and lovastatin. SCH 48461 was well tolerated. There was a similar incidence of adverse events in each SCH 48461‐ or lovastatin‐treated group compared to placebo. This study demonstrated a clinically and statistically significant cholesterol‐lowering effect of SCH 48461 in patients with primary hypercholesterolemia.
Evaluation of the Potential Pharmacokinetic Interaction between Almotriptan and Fluoxetine in Healthy Volunteers
Authors: Fleishaker Joseph C. , Ryan Kristi K. , Carel Barbara J. , Azie Nkechi E.
Published: July 2003

This study was designed to assess the pharmacokinetics of almotriptan, a 5HT1B/1D agonist used to treat migraine attacks, when administered in the presence and absence of fluoxetine. Healthy male (n = 3) and female (n = 11) volunteers received (1) 60 mg fluoxetine daily for 8 days and 12.5 mg almotriptan on Day 8 and (2) 12.5 mg almotriptan on Day 8, according to a two‐way crossover design. Plasma and uri‐nary almotriptan concentrations were measured by HPLC methods. Treatment effects on pharmacokinetic parameters were assessed by analysis of variance. Mean almotriptan Cmax was significantly higher following combination treatment with fluoxetine (52.5 ± 11.9 ng/ml vs. 44.3 ± 10.9 ng/ml,p = 0.023). Mean AUC0 was not significantly affected by fluoxetine coadministration (353 ± 55.7ngh/ml vs. 333 ± 33.6 ng*h/ml, p = 0.059). Confidence interval analysis (90%) of log‐transformed pharmacokinetic parameters showed that the confidence interval for AUC0 was within the 80% to 125% limit for equivalence, but Cmax was not (90% CI 106%‐134% of the reference mean). Adverse events were mild to moderate in intensity, and no clinically significant treatment effects on vital signs or ECGs were observed. The results show that fluoxetine has only a modest effect on almotriptan Cmax. Concomitant administration of the two drugs is well tolerated, and no adjustment of the almotriptan dose is warranted.
Theophylline Metabolism after Cardiac Surgery
Authors: Hirooka Kazunobu , Shimizu Masato , Mineshita Satoru
Published: July 2003

The effect and metabolism of theophylline administration after cardiac surgery has never been reported. Two series of 2‐hour intravenous aminophylline administrations (3 mg/kg/h) were conducted in 10 adult patients on the operative day (acute phase) and on the 4th or 5th postoperative day (recovery phase). Both blood and urine samples were collected for 24 hours after dosing. Heart rate increased in both phases, but the cardiac index increased with the decrease of diastolic blood pressure only in the acute phase (p < 0.05). Plasma concentration levels of theophylline tended to be slightly higher in the acute phase, and renal clearance increased in the recovery phase (p < 0.05). The urinary ratio of 3‐methylxanthine to theophylline was significantly higher in the acute phase (p < 0.05). This suggests that cytochrome P4501A2 is partially activated rather than depressed and that N‐demethylation is promoted more than hydroxylation immediately after surgery.
Pharmacokinetics of Naratriptan in Adolescent Subjects with a History of Migraine
Authors: Christensen Michael L. , Eades Shannan K. , Fuseau Eliane , Kempsford Rodger D. , Phelps Stephanie J. , Hak Lawrence J.
Published: July 2003

Naratriptan is a novel 5‐HT1 agonist developed to treat acute migraine. The study objective was to characterize the pharmacokinetics of oral naratriptan in adolescent migraine patients outside a migraine attack. Subjects received a single 2.5 mg naratriptan tablet. Serial serum samples for naratriptan concentrations were collected over 24 hours. Blood pressure, pulse rate, and 12‐lead ECG were recorded at baseline and at regular intervals after dosing. Seven patients—3 males and 4 females, 12 to 16 years of age—received drug and completed the study. The geometric mean and 95% confidence interval maximum concentration (Cmax) was 8.0 ng/mL (5.9–10.7), elimination half‐life (t1/2) was 4.9 hours (4.5‐5.4), area under the concentration‐time curve (AUC) was 74.6 ng•h/mL (56.6–98.2), and apparent total clearance (Cl/F) was 558.8 mL/min (424.3–735.9). The median time to maximal concentration (tmax) was 4 hours, with a range of 1.5 to 4. Blood pressure, pulse rate, and ECG parameters did not change significantly from baseline. No serious adverse events or subject withdrawal after drug administration occurred. Oral naratriptan pharmacokinetic parameters in adolescents were similar to values reported in adults. Naratriptan doses for adolescents older than 12 years of age would be expected to be similar to adult doses.
Lack of Effect of Food on the Pharmacokinetics of an Extended‐Release Oxybutynin Formulation
Authors: Sathyan Gayatri , Hu Weiting , Gupta Suneel K.
Published: July 2003

The effect of food on the pharmacokinetics of 15 mg oxybutynin XL was evaluated in a single‐dose, randomized, crossover, open‐label study in healthy volunteers. A validated, stereospecific, high‐performance liquid chromatography assay was used to simultaneously determine the plasma concentrations of R‐ and S‐oxybutynin and active metabolite R‐ and S‐desethyloxybutynin. The mean AUC and Cmax values for each of the four analytes in the fed treatment were within ±20% of the fasting treatment values. The 90% confidence intervals for the treatment ratios (fed/fasted) for logtransformed Cmax and AUCinf values for the drugisomers and AUCinf values for the metabolite isomers were all within the 80% to 125% range. Only the ranges for the Cmax values for Rand S‐desethyloxybutynin were slightly wider but were well within the 70% to 143% criteria recommended for Cmax when comparing effect of food. Lack of effect of food on oxybutynin XL is consistent with the previous observation that the osmotically controlled formulations are nearly insensitive to the gastrointestinal environment, including food. Oxybutynin XL was well tolerated, and the safety results were comparable whether administered alone or with food. In conclusion, oxybutynin XL administration does not require any caution to be exercised regarding food
Pharmacokinetics, Safety, and Tolerability of BAY 12–9566 and Nonsteroidal Anti‐inflammatory Agents (Naproxen, Ibuprofen) during Coadministration in Patients with Osteoarthritis
Authors: Shah Anita , Woodruff Marilyn , Agarwal Vipin , Liu Patrick , Sundaresan Pavur
Published: July 2003

The pharmacokinetic interactions between BAY 12–9566 and two nonsteroidal anti‐inflammatory drugs (NSAIDs), naproxen and ibuprofen, were investigated in osteoarthritis (OA) patients. The study comprised six groups: two NSAID groups with three levels of treatment (BAY 12–9566 400 mg, BAY 12–9566 100 mg, and placebo). Plasma pharmacokinetic parameters (AUCτ’ Cmax’, and tmax) were determined for each treatment group following 5 days of NSAID administration, 14 days of BAY 12–9566 administration, and 14 days of concurrent NSAID and BAY 12–9566 administration. For most conditions, the total plasma drug concentrations of both NSAID and BAY 12–9566 were diminished by coadministration; total plasma BAY 12–9566 was not affected by ibuprofen treatment. Importantly, the free drug concentrations were largely unaffected by coadministration. Most side effects were mild or moderate in intensity, and all events, with the exception of headache, were reported in both NSAID groups and in both placebo and BAY 12–9566 groups.
Lack of Citalopram Effect on Oral Digoxin Pharmacokinetics
Authors: Larsen Frank , Priskorn Morten , Overø Kerstin Fredricson
Published: July 2003

The effect of chronic administration of citalopram on the single oral dose pharmacokinetics of digoxin was evaluated in 11 healthy adult subjects in an open, one‐way crossover study. Subjects received 1 mg digoxin on day 1. Serial blood samples and total urine were collected over 192 hours, followed by an 11‐day washout period. On days 22 through 50, subjects received 40 mg citalopram once daily. On day 43, a single dose of1 mg digoxin was coadministered; again, serial blood samples and total urine were collected over 192 hours after the digoxin dose. There were no statistically significant differences in any of the digoxin pharmacokinetic parameters (AUC→,∞’ AUC→ Cmax’ tmax’ t1/2’CL/F CL/renal’ and Ae→∞, and the 90% confidence intervals for treatment differences for the parameters (except for tmax) were all within 80% to 125%. Concomitant digoxin administration did not significantly affect citalopram pharmacokinetics. The treatment was well tolerated by all subjects; no serious adverse events and no clinically significant ECG changes were observed. These data suggest that it is unlikely that concomitantly administered citalopram would have any significant effect on serum digoxin concentrations in patients who are receiving chronic digoxin therapy.
Comparative Safety of Bone Remodeling Agents with a Focus on Osteoporosis Therapies
Authors: Kleerekoper Michael , Schein Jeffrey R.
Published: July 2003

This article reviews the different treatments currently available for osteoporosis and examines the benefits and adverse events that are associated with each. While emphasizing safety considerations, this review summarizes the following treatments for osteoporosis: calcium supplements, fluoride, hormone replacement therapy, raloxifene, bisphosphonates, salmon calcitonin, and calcitriol. Before prescribing any of these agents, the clinician should review the risk/benefit profile of each drug in the context of the individual patient's history, concomitant diseases, concurrent medications, and general physical condition.
Effect of Time of Meal Consumption on Bioavailability of a Single Oral 5 mg Tacrolimus Dose
Authors: Bekersky Ihor , Dressler Dawna , Mekki Qais
Published: July 2003

Tacrolimus (FK506, Prograf ®) is marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation. This study investigated the effect of timing of a standardized breakfast meal on both the rate and extent of tacrolimus absorption following a single 5 mg oral dose. The protocol used a randomized, open‐label, four‐period, four‐treatment, four‐sequence crossover design in 16 healthy, nonsmoking, drug‐free male subjects between the ages of 22 and 45 years who were within 15% of their ideal body weight. The four treatments were the following: (A) fasting for 10 hours, (B) ingestion 1 hour before breakfast, (C) ingestion immediately following consumption of the breakfast, and (D) ingestion 1.5 hours after beginning consumption of the breakfast. The breakfast, which was consumed over 15 minutes, contained 848 kcal, with 30%, 16%, and 54% of calories derived from fat, protein, and carbohydrate, respectively. Tacrolimus absorption in the fasting state provided the greatest relative bioavailability (p < 0.05 compared with all other three treatments). AUC(0∞) averaged 312, 276, 205, and 203 ng•h/mL for treatments A, B, C and D, respectively. In contradistinction to taking the drug 1 hour prior to a meal, which had a relatively minor impact on the relative extent of absorption (∼12%) compared to the fasting state, ingestion of tacrolimus immediately after a meal (treatment C) or 1.5 hours subsequent to a meal (treatment D) had a more pronounced influence. Mean AUC(∞) ratios (fasting to either postmeal treatments) were ∼1.5, indicating that absorption extent was considerably reduced by ingesting tacrolimus capsules immediately after eating or 1.5 hours thereafter. Absorption was also prolonged following drug ingestion after a meal, as indicated by a mean tmax value in the fasting state of 1.84 hours, relative to 3.41 hours (immediately after meal, p = 0.0035) and 3.22 hours (1.5 hours postmeal, p = 0.0094). The only discernable difference in parameters between treatments C and D was with Cmax, with values of 7.19 and 9.04 ng/mL, respectively, but was not statistically significantly different (p = 0.231). Based on these results and those from a prior study, it is recommended that under therapeutic conditions, oral tacrolimus be administered in a consistent manner, both with respect to the type of meal as well as timing of ingestion relative to consumption of the meal.
Food Increases the Bioavailability of Tolterodine but Not Effective Exposure
Authors: Olsson Birgitta , Brynne Niclas , Johansson Christina , Arnberg Henrik
Published: July 2003

The objective of this study was to investigate the influence of food on the pharmacokinetics of tolterodine, its active 5‐hydroxymethyl metabolite (5‐HM), and exposure to the active moiety (sum of unbound tolterodine + 5‐HM) in healthy volunteers. Serum concentrations of tolterodine and 5‐HM were measured for up to 12 hours after a single oral dose (2 mg) of tolterodine L‐tartrate, administered either on an empty stomach or with a standardized medium‐fat breakfast. All 23 subjects completing the study were classified as extensive metabolizers (phenotyped with debrisoquine). Pharmacokinetic data on tolterodine and the active moiety were evaluable for 22 subjects; all completing subjects were evaluable for 5‐HM pharmacokinetics. Based on Cmax and AUC∞ ratios, relative bioavailability of tolterodine in the presence of food was 1.49 (90% confidence interval [CI], 1.35‐1.71) and 1.53 (1.35‐1.72), respectively. The pharmacokinetics of 5‐HM and the active moiety were unaffected by food, as were the rates of drug absorption and terminal half‐lives of tolterodine and 5‐HM. Given that bioequivalence was observed for the active moiety underfed and fasting conditions, the authors concluded that coadministration of tolterodine with food is not expected to have any clinically relevant effects.
Lack of Correlation between In Vitro Inhibition of CYP3A‐Mediated Metabolism by a PPAR‐γ Agonist and Its Effect on the Clinical Pharmacokinetics of Midazolam, an In Vivo Probe of CYP3A Activity
Authors: Fayer Jessica L. , Zannikos Peter N. , Stevens Jeffrey C. , Luo Yongqi , Sidhu Rajinder , Kirkesseli Stephane
Published: July 2003

RG 12525 (2‐[[4‐[[2‐(1H‐tetrazole‐5‐ylmethyl)phenyl]meth‐oxy]phenoxy]methyl] quinolone) is a novel peroxisome proliferator‐activated receptor gamma (PPAR‐γ) agonist. In vitro microsomal inhibition assays indicated that RG 12525 is a potent inhibitor of CYP3A4, with a Ki value of 0.5 μM. With the conservative assumption that the total plasma concentration of drug was available to metabolic enzymes following RG 12525 oral administration, marked inhibition of CYP3A4 was expected to substantially reduce the systemic clearance of compounds metabolized by this enzyme. The possibility also existed for inhibition of intestinal and hepatic CYP3A4 by RG 12525 to reduce “first‐pass” metabolism and increase absolute bioavailability of CYP3A4 substrates orally coadministered. Consequently, an in vivo drug‐drug interaction study was performed to evaluate the effects of orally administered RG 12525 on in vivo CYP3A4 activity in healthy male subjects. The pharmacokinetics of oral midazolam, a probe for intestinal and hepatic CYP3A activity, was not influenced by either the low (100 mg qd for 4 days) or high (600 mg qd for 4 days)RG 12525 dosing regimen despite the resulting total plasma concentrations of inhibitor that were well above in vitro Ki values. The point estimates and 90% confidence intervals for the ratios of mean midazolam AUC for subjects administered 100 mg RG 12525 (110.6; 98.7–124.1) and 600 mg RG 12525 (98.4; 84.4–114.7) versus midazolam alone were within 80% to 125%. To explain these results, factors that could limit the accuracy of in vitro models in predicting metabolic drug interactions, mainly the high degree of RG 12525 protein binding (> 99.9%), were considered. The lack of correlation between the in vitro inhibition of CYP3A4 by RG 12525 and the inconsequential effects of this compound on midazolam pharmacokinetics accentuate the need to recognize factors other than plasma drug concentrations and potency of in vitro enzyme inhibition when extrapolating in vitro data to predict in vivo drug‐drug interactions.
Effects of Grapefruit Juice on Pharmacokinetic Exposure to Indinavir in HIV‐Positive Subjects
Authors: Shelton Mark J. , Wynn Heather E. , Hewitt Ross G. , DiFrancesco Robin
Published: July 2003

The objective of this study was to determine the effects of double‐strength grapefruit juice on gastric pH and systemic bioavailability of indinavir in HIV‐infected subjects receiving indinavir. Fourteen HIV‐infected subjects took 800 mg of indinavir with 6 ounces (180 ml) of water or double‐strength grapefruit juice. Gastric pH was measured and blood samples were collected for 5 hours after indinavir dosing. Grapefruit juice increased the mean gastric pH (from 1.39 ± 0.4 to 3.20 ± 0.3; p < 0.05) and slightly delayed the absorption of indinavir (tmax increased from 1.12 ± 0.8hto 1.56± 0.6 h; p < 0.05). However, there were no significant differences in indinavir exposure. Cmax was 16.7 ± 7.3 μ with water versus 13.9 ± 4.2 μ with grapefruit juice (p = NS), and AUC0–8 was 37.5 ± 19 with water versus 36.9 ± 15 with grapefruit juice (p = NS). The authors concluded that concomitant administration of grapefruit juice increases gastric pH and delays indinavir absorption but does not uniformly affect the systemic bioavailability of indinavir in HIV‐infected subjects.
Effect of Venlafaxine versus Fluoxetine on Metabolism of Dextromethorphan, a CYP2D6 Probe
Authors: Amchin Jess , Ereshefsky Larry , Zarycranski William , Taylor Karen , Albano Dominick , Klockowski Patricia M.
Published: July 2003

Two antidepressants, venlafaxine and fluoxetine, were evaluated in vivo for their effect on cytochrome P450 2D6 (CYP2D6) activity, measured by the ratio of dextromethorphan, a sensitive CYP2D6 marker, to its metabolite dextrorphan (i.e., DM:DT) excreted in urine after DM coadministration. Twenty‐eight healthy extensive metabolizers of CYP2D6 received either venlafaxine (37.5 mg bid for 7 days, then 75 mg bid until Day 28) or fluoxetine (20 mg daily for 28 days); 26 completed the study. Plasma concentrations of both drugs and their active metabolites were determined. DM:DTs were evaluated at baseline (Day0), on Days 7 and 28 of dosing, and 2 weeks after drug discontinuation (Day 42). Steady‐state drug and metabolite levels were achieved in both groups by Day 28. Mean DM:DTs for venlafaxine and fluoxetine differed statistically significantly (p < 0.001) on Days 7,28, and 42. Comparisons of DM:DT as a percentage of baseline values showed that DM:DT increased 1.2‐fold for venlafaxine and 9.1‐fold for fluoxetine on Day 7 (p < 0.001) and increased 2.1‐fold for venlafaxine and 17.1‐fold for fluoxetine on Day 28 (p < 0.001). Inhibition of CYP2D6 metabolism persisted for 2 weeks after discontinuation of fluoxetine, unlike the case with venlafaxine. These in vivo results confirm in vitro data demonstrating significantly weaker inhibition of CYP2D6 with venlafaxine than with fluoxetine. This suggests that clinically significant interactions involving CYP2D6 inhibition could occur between fluoxetine and drugs metabolized by CYP2D6 but may be less likely to occur with venlafaxine.
The Stereoselective Effects of Bucolome on the Pharmacokinetics and Pharmacodynamics of Racemic Warfarin
Authors: Matsumoto Kana , Ishida Shigenobu , Ueno Kazuyuki , Hashimoto Hiroshi , Takada Mitsutaka , Tanaka Kazuhiko , Kamakura Shiro , Miyatake Kunio , Shibakawa Masahiko
Published: July 2003

The objective of this study was to investigate the stereoselective influence of bucolome on the pharmacokinetics and pharmacodynamics of warfarin in Japanese inpatients with heart disease. Thirty patients were administered a fixed‐maintenance dose of warfarin alone once a day for at least 7 days. The other 25 patients were concomitantly administered warfarin and a 300 mg dose of bucolome once a day, and blood samples were collected on days 1, 4, 7, 14, or 21 after administration of bucolome. Serum concentration of warfarin enantiomers was measured by a chiral reversed‐phase HPLC‐ultraviolet detection method. The PT‐INR was used as a measure of the pharmacodynamic effect of warfarin. Coadministration of bucolome and warfarin had no effect on serum (R)‐warfarin concentration and significantly increased serum (S)‐warfarin concentration compared with warfarin alone. The PT‐INR of warfarin alone was significantly lower with bucolome cotreatment. These results indicate that the augmented anticoagulant effect of warfarin by bucolome is due to inhibition of (S)‐warfarin metabolism in vivo. When bucolome is added to a stabilized regimen of warfarin therapy, the dose of warfarin should be reduced by about 30% to 60%, and caution should be exercised during the first 7 days after coadministration of bucolome.
Use of In Vitro Drug Metabolism Data to Evaluate Metabolic Drug‐Drug Interactions in Man: The Need for Quantitative Databases
Authors: Rodrigues A. David , Winchell Gregory A. , Dobrinska Michael R.
Published: July 2003

It has become widely accepted that metabolic drug‐drug interactions can be forecast using in vitro cytochrome P450 (CYP) data. For any CYP form‐inhibitor pair, the magnitude of the interaction will depend on the potency of the inhibitor (inhibition constant, Ki), the concentration of the inhibitor available for inhibition ([I]), the fraction of the substrate dose metabolized by CYP (fm), and the fraction of the CYP‐dependent metabolism catalyzed by the inhibited CYP form (e.g., fm,CYP3A4). While progress is being made toward our understanding of the factors necessary for predictions of [I]/Ki in vivo, it is evident that there is a need for quantitative databases that contain in vitro (e.g., Ki, fm,CYP3A4) and in vivo pharmacokinetic/absorption‐distribution‐metabolism‐excretion (PK/ADME) data (e.g., fm) for a large number of marketed drugs. Ultimately, such databases would allow one to integrate all of the data necessary for the prediction of drug‐drug interactions and permit the rational evaluation of new drug entities.
A Dose‐Ranging Study of Gentamicin Pharmacokinetics: Implications for Extended Interval Aminoglycoside Therapy
Authors: McNamara David R. , Nafziger Anne N. , Menhinick Anne M. , Bertino Joseph S.
Published: July 2003

Prolonged distribution time has been noted for high‐dose (7 mg/kg) gentamicin. Higher doses are used for extended‐interval aminoglycoside therapy (EIA). The authors investigated whether the increase in distribution time was proportional to the dose of gentamicin. Twelve healthy volunteers were given low (LD, 2 mg/kg), medium (MD, 4.5 mg/kg), and high (HD, 7 mg/kg) doses of gentamicin in a randomized, crossover fashion. Gentamicin was infused over 30 minutes, with 15 concentrations obtained over 8 hours aftereach dose. Data were fit to a two‐compartment pharmacokinetic model. Distribution half‐life for HD (31.1 ± 5.7 min) differed significantly (p < 0.05) from LD (22.4 ± 6.1 min) and MD (23.8 ± 5.1 min) with no significant difference being seen between LD and MD. This study verifies that when using EIA dosing with HD gentamicin, sampling within 90 minutes after the beginning of the infusion provides information that leads to overestimation of peak serum concentration/minimum inhibitory concentration and inaccurate calculation of pharmacokinetic parameters.
Pharmacokinetics and Pharmacodynamics of Recombinant FGF‐2 in a Phase I Trial in Coronary Artery Disease
Authors: Bush Mark A. , Samara Emil , Whitehouse M. J. , Yoshizawa Carl , Novicki Deborah L. , Pike Marilyn , Laham Roger J. , Simons Michael , Chronos Nicolas A.
Published: July 2003

Fibroblast growth factor‐2 (FGF‐2) is a heparin‐binding protein capable of inducing angiogenesis in multiple animal models of chronic ischemia. The pharmacokinetics and pharmacodynamics of a single dose of recombinant FGF‐2 (rFGF‐2) administered by intracoronary or intravenous infusion were evaluated in a Phase I trial in 66 patients with severe coronary artery disease. rFGF‐2 displayed biphasic elimination with a mean studywide distribution t1/2 of 21 minutes and a mean apparent terminal elimination t1/2 of 7.6 hours. Systemic exposure to rFGF‐2 was comparable following intracoronary or intravenous administration. Peak plasma concentration and area under the concentration‐time curve increased proportionally with dose, indicating linear pharmacokinetics over the dose range examined (0.33 to 48.0 μg/kg). Greater systemic exposure was observed when heparin was administered closer to rFGF‐2 infusion, consistent with slower clearance of heparin/rFGF‐2 complexes. Infusion of rFGF‐2 was associated with changes in acute hemodynamics. While a clear PK/PD dose‐response relationship was not established, a trend toward hypotension and tachycardia with higher rFGF‐2 doses was observed.
Metabolic Disposition and Pharmacokinetics of [14C]‐Amprenavir, a Human Immunodeficiency Virus Type 1 (HIV‐1) Protease Inhibitor, Administered As a Single Oral Dose to Healthy Male Subjects
Authors: Sadler Brian M. , Chittick Gregory E. , Polk Ronald E. , Slain Douglas , Kerkering Thomas M. , Studenberg Scott D. , Lou Yu , Moore Katy H. P. , Woolley Joseph L. , Stein Daniel S.
Published: July 2003

The objective of this study was to determine the metabolic profile, routes of elimination, and total recovery of amprenavir and its metabolites after a single oral dose of [14C]‐amprenavir. Six healthy male subjects each received a single oral 630 mg dose of amprenavir containing 95.76 μCi of [14C]‐amprenavir in this Phase I mass balance study. The metabolic disposition of amprenavir was determined through analyses of radiocarbon in whole blood, plasma, urine, and stool samples, collected for a period of 10 to 17 days postdosing. Cerebral spinal fluid (CSF) sampling was conducted on day 1. The ratio of unchanged amprenavir AUC0→∞ to plasma radiocarbon was 27%, suggesting that most of the radiocarbon was metabolites. The median total recovery of the administered dose of radiocarbon was 89% (range: 66%‐93%), with 75% (range: 56%‐80%) recovered in the feces and 14% (range: 10%‐17%) in the urine. Most of the recovered radiocarbon in the feces and urine was excreted within 240 and 48 hours postdose, respectively. Of the 75% of the radiocarbon dose recovered in the feces, 62% wasidentified as a metabolite resulting from dioxidation of the tetrahydrofuran ring (GW549445X) and 32% as a metabolite resulting from subsequent oxidation of the p‐aniline sulfonate group (GW549444X). Unchanged amprenavir was below the limit of quantitation in feces and urine. Therefore, approximately 94% of the dose excreted in the feces was accounted for by these two metabolites. Concentrations of radiocarbon in the CSF were below the limit of quantitation in 5 of 6 subjects sampled. In summary, oral amprenavir is extensively metabolized in humans, with concentrations of unchanged drug below the limits of quantitation in urine and feces. The majority (75%) of administered radiocarbon was excreted in feces.
Single‐Dose Pharmacokinetics of Atrasentan, an Endothelin‐A Receptor Antagonist
Authors: Samara Emil , Dutta Sandeep , Cao Guoliang , Granneman G. R. , Dordal Margaret S. , MD R. J. Padley
Published: July 2003

The pharmacokinetics of 1, 10, 23.25, and 139.5 mg doses of atrasentan was assessed in a placebo‐controlled, double‐blind, single oral dose study in 24 healthy male subjects. Atrasentan was well tolerated. Atrasentan pharmacokinetics was linear in the 1 to 23.25 mg dose range, with some dose dependency in the highest dose group. Harmonic mean terminal half‐life was similar across all dose groups (20–25 h). Apparent oral clearance was low (12 L/h) for the highest dose group compared with the other three dose groups (21–27 L/h). The apparent volume of distribution was large (∼6 L/kg), consistent with extensive tissue distribution.