bluuebunny/crossref_metadata_2025 huggingface dataset:
Minimal Interaction between Gatifloxacin and Oxycodone
Authors: Grant Edward M. , Nicolau David P. , Nightingale Charles , Quintiliani Richard
Published: July 2003

Previous studies have demonstrated a significant reduction in the oral bioavailability of trovafloxacin and ciprofloxacin when administered concomitantly with an intravenous opiate, such as morphine. This decrease in absorption results in a 36% and 50% lower AUC for trovafloxacin and ciprofloxacin, respectively, which could cause clinical failures. The authors investigated the possibility of a similar interaction between oxycodone and gatifloxacin. Twelve healthy volunteers were randomized in an open‐label, two‐way crossover study to receive oxycodone (5 mg po Q4H) and gatifloxacin (400 mgpo 1 h) after starting the oxycodone or gatifloxacin 4UU mg po alone. Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdosing. No significant difference was noted (p > 0.05) in AUC (31.6 +− 7.3 vs. 31.7 +− 7.1) and Cmax (3.2 +− 0.6 vs. 3.0 +− 0.6) for gatifloxacin versus gatifloxacin/oxycodone regimens; however, the tmax (1.8 +− 0.8 vs. 4.3 +− 1.5) was significantly delayed (p < 0.001). It was concluded that oral oxycodone and gatifloxacin can be administered concomitantly without a significant decrease in bioavailability.
Risk Assessment in Regulatory Policy Making for Human and Veterinary Public Health
Authors: Lathers Claire M.
Published: July 2003

Risk assessment is the method of systematically identifying and assessing factors that influence the probability and consequences of a negative event occurring. One responsibility of veterinary medicine is to protect animal and human health. Food animal production uses antibiotics to enhance production. Regulators evaluate new production technology to ensure animal safety and safe, edible products and to make public policy decisions by assessing risks/benefits. The U.S. Food and Drug Administration, Center for Veterinary Medicine's (CVM's) first risk assessment addressed the potential human health impact of campylobacter effects associated with the use of fluoroquinolines in food‐producing animals. CVM used the Monte Carlo method to estimate risk by probability distributions that reflect the uncertainty and variability in the data used for the assessment. Enterococci faecium is a species more likely to be resistant to antibiotics of last resort. Effective control of multidrug‐resistant enterococci will require a better understanding of the transfer of E. faecium from animals to humans and the interaction between E. faecium, the hospital environment, and humans; prudent antibiotic use; better contact isolation in hospitals; and better surveillance. CVM will model these factors in a second, more complex risk assessment designed to examine the indirect transfer of resistance from animals to humans. Use of risk assessments allows researchers, the industry, regulatory authorities, and educators to make better policy decisions regarding antimicrobial use in food animals and humans and the development of resistance. Today the question of whether the use of antimicrobials for growth enhancement in food animals should or should not be terminated for the benefit of human health remains unresolved.
A Controlled Comparative Study of Ibuprofen Arginate versus Conventional Ibuprofen in the Treatment of Postoperative Dental Pain
Authors: Mehlisch Donald R. , Ardia Alfredo , Pallotta Teresa
Published: July 2003

The analgesic efficacy of an arginine salt of ibuprofen was compared to one of the commercially available forms of conventional ibuprofen in a 500‐patient clinical trial in postoperative dental pain. Patients were administered a single dose of ibuprofen arginate (200 mg or 400 mg), conventional ibuprofen (200 mg or 400 mg), or placebo in this double‐blind, randomized, parallel‐group trial. Results demonstrated that ibuprofen arginate was a safe and effective analgesia that was superior to conventional ibuprofen in both the amount of pain relief achieved and the time to onset of pain relief. Onset of analgesia, assessed as the median amount of time to achieve meaningful pain relief, was reached after 32 and 31 minutes with ibuprofen arginate 200 and 400 mg, respectively, and 64 and 58 minutes with conventional ibuprofen 200 and 400 mg, respectively (p < 0.05). Patients treated with ibuprofen arginate rated its overall effectiveness higher than those patients treated with conventional ibuprofen. Adverse event profiles were similar across all treatment groups.
Efficacy and Tolerability of Nonprescription Ibuprofen versus Celecoxib for Dental Pain
Authors: Doyle Geraldine , Jayawardena Shyamalie , Ashraf Elizabeth , Cooper Stephen A.
Published: July 2003

Many clinicians appear confused about the purported clinical advantages of the new generation COX‐2 inhibitors compared to both over‐the‐counter and prescription nonsteroidal anti‐inflammatory analgesic agents (NSAIDs). In fact, there is a paucity of published information comparing the safety and efficacy of these two classes of drugs when used to treat acute pain. This study was designed to compare the safety and analgesic efficacy of an over‐the‐counter (OTC) analgesic, ibuprofen (Advil Liqui‐Gels®), to the leading prescription COX‐2 inhibitor celecoxib (Celebrex®). Ibuprofen liquigel is an encapsulated, solubilized potassium salt of ibuprofen that has a higher Cmax and shorter tmax than traditional ibuprofen solid‐dosage formulations. This trial evaluated the maximum approved OTC dosing regimen (400 mg × 3, q4‐6h) of ibuprofen liquigels compared to a single dose of celecoxib (200 mg) and placebo in 174 patients with moderate or severe pain following surgical extraction of impacted third molars. The study design was multiple dose, randomized (stratified by baseline pain and gender), placebo controlled, double blind, double dummy, and parallel group. The onset of pain relief was determined using a two‐stopwatch procedure. Treatments were also compared using standard indices of pain intensity and pain relief. The study demonstrated assay sensitivity in that both active medications were significantly more effective than placebo for all efficacy measures. In comparing the two active medications, the time to meaningful relief was significantly shorter, and the mean 4‐, 8‐, and 12‐ hour summed pain relief combined with pain intensity difference scores were significantly higher for ibuprofen liquigels compared with celecoxib (p < 0.001). Analyses of other key efficacy variables, including the time to rescue medication and the patients' overall assessment of study medication, confirmed the superior efficacy of ibuprofen liquigels over celecoxib. Both active treatments were well tolerated, with no differences in incidence or severity of adverse events. Of particular interest, there were no differences in gastrointestinal‐related side effects when comparing these doses of ibuprofen liquigels to celecoxib. In conclusion, ibuprofen liquigels were a significantly more effective analgesic and provided relief significantly faster compared with celecoxib in the treatment of postsurgical pain.
Effect of Potent CYP2D6 Inhibition by Paroxetine on Atomoxetine Pharmacokinetics
Authors: Belle Donna J. , Ernest C. Steven , Sauer John‐Michael , Smith Brian P. , Thomasson Holly R. , Witcher Jennifer W.
Published: July 2003

The purpose of this study was to characterize the effect of potent CYP2D6 inhibition by paroxetine on atomoxetine disposition in extensive metabolizers. This was a single‐blind, two‐period, sequential study in 22 healthy individuals. In period 1, 20 mg atomoxetine bid was administered to steady state. In period 2, 20 mg paroxetine was administered qd for 17 days. On days 12 through 17, 20 mg atomoxetine bid were coadministered. Plasma pharmacokinetics of atomoxetine, 4‐hydroxyatomoxetine, and N‐desmethylatomoxetine was determined at steady state in each treatment period. Plasma pharmacokinetics of paroxetine were determined after the 11th and 17th doses. Paroxetine increased Css,max, AUC0–12, and t1/2 of atomoxetine by approximately 3.5‐, 6.5‐, and 2.5‐fold, respectively. After coadministration with paroxetine, increases in N‐desmethylatomoxetine and decreases in 4‐hydroxyatomoxetine concentrations were observed. No changes in paroxetine pharmacokinetics were observed after coadministration with atomoxetine. It was concluded that inhibition of CYP2D6 by paroxetine markedly affected atomoxetine disposition, resulting in pharmacokinetics similar to poor metabolizers of CYP2D6 substrates.
Pharmacokinetics and Pharmacodynamics of Zoledronic Acid in Cancer Patients with Bone Metastases
Authors: Chen Tianling , Berenson James , Vescio Robert , Swift Regina , Gilchick Alicia , Goodin Susan , LoRusso Patricia , Ma Peiming , Ravera Christina , Deckert Fabienne , Schran Horst , Seaman John , Skerjanec Andrej
Published: July 2003

The pharmacokinetics, pharmacodynamics, and safety of zoledronic acid (Zometa®), a new‐generation bisphosphonate, were evaluated in 36 patients with cancer and bone metastases. Zoledronic acid (by specific radioimmunoassay) and markers of bone turnover were determined in plasma and urine after three consecutive infusions (qx28 days) of 4 mg/5 min (n = 5), 4 mg/15 min (n = 7), 8 mg/15 min (n = 12), or 16 mg/15 min (n = 12). Zoledronic plasma disposition was multiphasic, with half‐lives of 0.2 and 1.4 hours representing an early, rapid decline of concentrations from the end‐of‐infusion Cmax to < 1% of Cmax at 24 hours postdose and half‐lives of 39 and 4526 hours describing subsequent phases of very low concentrations between days 2 and 28 postdose. AUC0‐24h and Cmax were dose proportional and showed little accumulation (AUC0_24h ratio between the third and first dose was 1.28). Prolonging the infusion from 5 to 15 minutes lowered Cmax by 34%, with no effect on AUC0‐24h. Urinary excretion of zoledronic acid was independent of infusion duration, dose, or number of doses, showing average Ae0‐24h of 38% ± 13%, 41% ± 14%, and 37% ± 17%, respectively, after 4, 8, and 16 mg. Only trace amounts of drug were detectable in post 24‐hour urines. Renal clearance (Ae0‐24h)/(AUC0‐24h) was on average 69 ± 28, 81 ± 40, and 54 ± 34 ml/min after 4, 8, and 16 mg, respectively, and showed a moderate correlation (r = 0.5; p < 0.001) with creatinine clearance, which was 84 ± 23, 82 ± 25, and 80 ± 40 ml/min for the dose groups at baseline. Adverse events and changes from baseline in vital signs and clinical laboratory variables showed no relationship in terms of type, frequency, or severity with zoledronic acid dose or pharmacokinetic parameters. Zoledronic acid produced significant declines from baseline in serum and/or creatinine‐corrected urine C‐telopeptide (by 74%), N‐telopeptide (69%), pyridinium cross‐links (19–33%), and calcium (62%), with an increasing trend (by 12%) in bone alkaline phosphatase. There was no relationship of the magnitude and duration of these changes with zoledronic acid dose, Ae0‐24j, AUC0‐24h, or Cmax. The antiresorptive effects were evident within 1 day postdose and were maintained over 28 days across all dose levels, supporting monthly dosing with 4 mg zoledronic acid.
Preliminary Studies of the Pharmacokinetics and Tolerability of Zolmitriptan Nasal Spray in Healthy Volunteers
Authors: Yates Roger , Nairn Kevin , Dixon Ruth , Seaber Emma
Published: July 2003

Two preliminary studies of the pharmacokinetics and tolerability of zolmitriptan nasal spray were conducted, each involving 12 healthy volunteers. In study 1, an initial double‐blind, dose escalation phase (placebo or 2.5, 5.0, or 10 mg zolmitriptan intranasally) was followed by an open crossover phase in which all subjects received 10 mg zolmitriptan as a nasal spray, tablet, and oral solution. In study 2, subjects received, on three separate occasions, zolmitriptan 2.5 mg as an intranasal solution at pH7.4, at pH 5.0, and as an oral tablet. In study 1, plasma concentrations of zolmitriptan and its active metabolite, 183C91, were broadly dose proportional. Plasma concentrations of zolmitriptan were detected earlier following nasal spray administration than after either tablet or oral solution. Similarly, in study 2, zolmitriptan was absorbed more rapidly following nasal spray administration with detectable plasma concentrations 5 minutes after dosing. Plasma levels were maintained at a plateau between 1 and 6 hours postdose, then decreased with a half‐life of approximately 3 hours. There was no statistically significant difference for AUC or Cmax values between the two nasal spray solutions or between nasal spray and oral formulations. Other pharmacokinetic parameters for zolmitriptan were similar between the formulations. Plasma concentrations of 183C91 were higher for the first 2 hours after oral than after nasal spray administration. All formulations of zolmitriptan were well tolerated.
Effects of Rifampin on Tacrolimus Pharmacokinetics in Healthy Volunteers
Authors: Hebert Mary F. , Fisher Richard M. , Marsh Christopher L. , Dressler Dawna , Bekersky Ihor
Published: July 2003

Tacrolimus is a marketed immunosuppressant used in liver and kidney transplantation. It is subject to extensive metabolism by CYP3A4 and is a substrate for P‐glycoprotein‐mediated transport. A pharmacokinetic interaction with rifampin, an antituberculosis agent and potent inducer of CYP3A4 and P‐glycoprotein, and tacrolimus was evaluated in six healthy male volunteers. Tacrolimus was administered at doses of 0.1 mg/kg orally and 0.025 mg/kg/4 hours intravenously. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected over 96 hours, after single oral and intravenous administration prior to and during an 18‐day concomitant rifampin dosing phase. Coadministration of rifampin significantly increased tacrolimus clearance (36.0 ± 8.1 ml/hr/kg vs. 52.8 ± 9.6 ml/hr/kg; p = 0.03) and decreased tacrolimus bioavailability (14.4% ± 5.7% vs. 7.0% ± 2.7%; p = 0.03). Rifampin appears to induce both intestinal and hepatic metabolism of tacrolimus, most likely through induction of CYP3A and P‐glycoprotein in the liver and small bowel.
A Clozapine Overdose with Markedly Elevated Serum Levels
Authors: Mahoney Martin C. , Connolly Brian F. , Smith Cedric M.
Published: July 2003

Clozapine (Clozaril®) is an atypical antipsychotic agent used to treat schizophrenia refractory to other pharmacological agents. This report describes an accidental clozapine overdose. The half‐life of clozapine in this patient was determined from two blood levels, one obtained on admission and the second 10.5 hours later. The calculated half‐life of 8.11 hours is consistent with published levels for single doses and suggests an apparent stability in clozapine elimination half‐life in the face of overdose. The maximum clozapine blood level attained was probably among the highest nonfatal levels reported. The patient recovered fully following hospital admission for monitoring and supportive care. This case report illustrates the usefulness of following the time course of the changes in blood level at selected time intervals, as well as the importance of entertaining a diagnosis of drug overdose in patients presenting with acute mental status changes.
Alpha‐Adrenergic Blocking Drugs in Clinical Medicine
Authors: Frishman William H. , Kotob Fayez
Published: July 2003

The α‐adrenergic blockers have played an important role in the treatment of vascular diseases. Nonselective α blockers have been used as treatments for patients with severe hypertension, including pheochromocytoma. Selective α1 blockers have been used in the treatment of hypertension and prostatic obstruction, and these drugs have also been considered in the treatment of other vascular and nonvascular conditions. They have unique metabolic actions, specifically on plasma lipids and lipoproteins, which could be of clinical benefit.
The Pharmacodynamics of Sumatriptan in Nitroglycerin‐Induced Headache
Authors: Fullerton Terence , Komorowski‐Swiatek Denise , Forrest Alan , Gengo Fran M.
Published: July 2003

Migraine is a common disorder that causes significant morbidity in those afflicted. Many novel antimigraine compounds are in clinical development, yet full characterization of each one's pharmacodynamic behavior is a formidable task due to the difficulty in studying a migraineur during an attack. Nitroglycerin (NTG) administration commonly causes a headache with some features similar to those of a migraine. As such, NTG has been used as a model of vascular headaches, including migraine. The pharmacodynamic effects of nitroglycerin and sumatriptan on middle cerebral artery blood flow velocity (MCAv) and headache scores were studied in 10 healthy male volunteers. An intravenous infusion of NTG titrated to 0.5 mcg/kg/min over 30 minutes resulted in a median reduction from baseline in MCAv of 27% (range: 16.4%‐37.3%). Nine of the subjects developed a headache with a median verbal score of 3.5 of 10 (range: 0–5). Subjects received sumatriptan either 2 mg intravenously or 6 mg subcutaneously, which abated clinical headache in 9 of the 10 subjects (p = 0.030). A median sumatriptan‐induced increase in MCAv of 21% (p = 0.054) suggested a constricting effect on the NTG‐induced dilated MCA. A two‐compartment pharmacokinetic/indirect‐effects pharmacodynamic model was fit to the sumatriptan concentration and MCAv data using iterative two‐stage analysis. This model was unbiased and fit the concentration (r2 = 0.98) and the MCAv (r2 = 0.79) data well. These results suggest that NTG‐induced headache and the development of pharmacokinetic/pharmacodynamic models could serve as a useful method for exploring the mechanisms of abortive migraine drugs.
The Effect of Converting from Pravastatin to Simvastatin on the Pharmacodynamics of Warfarin
Authors: Lin Jennifer C. , Ito Matthew K. , Stolley Stephen N. , Morreale Anthony P. , Marcus David B.
Published: July 2003

Forty‐six adult patients maintained on warfarin therapy were converted from pravastatin to simvastatin. Mean international normalized ratio (INR) significantly increased from 2.42 to 2.74, p = 0.002. Although warfarin doses were reduced in 7 patients and increased in 4 patients following the postconversion INR measurements, the pre‐ and postconversion median weekly warfarin dose of all 46 patients did not differ significantly. The number of patients with an INR > 3.0 increased significantly from 6 to 16 following the conversion. There was no report of unusual episodes of bleeding. The results indicate that antihyperlipidemic therapy can be changed safely from pravastatin to simvastatin in patients who are taking warfarin concomitantly. Additional anticoagulation monitoring is not necessary in institutions where patients are followed in formal anticoagulation clinics.
Lack of Pharmacokinetic and Pharmacodynamic Interaction between Rizatriptan and Paroxetine
Authors: Goldberg Michael R. , Lowry Richard C. , Musson Donald G. , Birk Kimberly L. , Fisher Allison , DePuy M. Elizabeth , Shadle Craig R.
Published: July 2003

Rizatriptan is a potent, oral 5‐HT1B/1D agonist with a rapid onset of action being investigated for the acute treatment of migraine. This study examined the clinical and pharmacokinetic interaction between rizatriptan and the selective serotonin reuptake inhibitor, paroxetine. In this two‐period crossover study, 12 healthy young subjects (6 males and 6 females) received 10 mg rizatriptan following 14 days of treatment with placebo or paroxetine (20 mg once daily). Plasma was sampled for rizatriptan and N‐monodesmethyl rizatriptan, a minor but active metabolite of rizatriptan. Safety evaluations included monitoring for adverse events, vital signs, and visual analog scale assessment of mood. Plasma levels of rizatriptan and N‐monodesmethyl rizatriptan were not altered when rizatriptan was administered with paroxetine compared to the placebo. Clinically, coadministration of rizatriptan with paroxetine was well tolerated. Blood pressure, heart rate, and temperature changes during the observation period did not differ to a clinically significant degree when rizatriptan was administered with paroxetine compared to the placebo. No effects on mood occurred following treatment with the combination compared to rizatriptan alone. Adverse events following rizatriptan administration with paroxetine were similar to those reported when rizatriptan was given with the placebo.
Analgesic Efficacy and Pharmacokinetics of Ketoprofen Administered into a Surgical Site
Authors: Dionne Raymond A. , Gordon Sharon M. , Tahara Martin , Rowan Janet , Troullos Emanuel
Published: July 2003

A series of three clinical trials in the oral surgery model evaluated the analgesic efficacy and pharmacokinetics of ketoprofen administered locally as a strategy for decreasing systemic exposure to nonsteroidal anti‐inflammatory drugs (NSAIDs). A gel formulation was administered directly into extraction sites 1 hour following oral surgery, and pain intensity was evaluated for 6 hours. Significantly less pain was seen following peripheral administration of both 10 and 30 mg ketoprofen in comparison to the placebo. In a second study, peripheral administration of the 10 mg dose resulted in greater analgesia than oral administration of the same dose formulation or the placebo. The third study demonstrated lower plasma drug levels following the peripheral route of administration in comparison to oral administration of the same dose or ingestion of a 25 mg oral capsule. These data indicate that administration of an NSAID to a peripheral site of tissue injury results in greater analgesia than oral administration and suggests the potential for less drug toxicity through lower circulating drug levels.
Effect of Food on High‐Dose Oral Ganciclovir Disposition in HIV‐Positive Subjects
Authors: Jung Donald , Griffy Kay , Dorr Albert
Published: July 2003

The effect of food on the steady‐state pharmacokinetics of ganciclovir following high‐dose oral ganciclovir in HIV‐ and CMV‐seropositive subjects was investigated in an open‐label, randomized, two‐treatment crossover study. Over 2 consecutive weeks, subjects received in random order multiple oral doses of ganciclovir 2000 mg tid for 3 consecutive days either on an “empty stomach” (i.e., at least 1 hour before or 2 hours after a meal or snack) or within 30 minutes of finishing a meal. For the 3 days of dosing each week, the breakfast consisted of a standardized 602 calorie, high‐fat (46.5%) meal, while the contents of lunch, dinner, and snacks met American Dietetic Association recommendations (25%–35% fat). Serial blood samples over 24 hours were obtained on day 3 of each regimen over the first dosing interval. When ganciclovir was administered within 30 minutes following the breakfast, there was a mean increase of 110.6% ± 79.0% and 114.1% ± 81.7% in Cmax0‐5 and AUC0–5, respectively, with a prolongation of mean Tmax from 1.8 to 2.7 hours. Over the total day of dosing, there was a mean increase of 47.6% ± 12.3% and 97.2% ± 30.9% in Cmax0‐24 and AUC0–24, respectively, and a 36.0% ± 18.0% decrease in half‐life when doses were taken following a meal as compared to when taken on an empty stomach. Since food increases the systemic availability of ganciclovir, it is recommended that patients be instructed to take each dose of ganciclovir with food.
A Limited Sampling Strategy for the Estimation of 12‐Hour SangCya and Neoral AUCs in Renal Transplant Recipients
Authors: Meier‐Kriesche Herwig‐Ulf , Alloway Rita , Osama A. , Gaber A , Canafax Daniel M , Kaplan Bruce
Published: July 2003

Neoral and SangCya are new cyclosporine formulations with more consistent pharmacokinetic profiles than the older formulation of cyclosporine, Sandimmune. Limited sampling strategies have been derived to estimate the full area under the curve (AUC) for both Neoral and Sandimmune. In addition, no limited sampling strategy has been derived for SangCya, and no rigorous prospective testing has been done on any of these formulas. The authors studied 32 renal transplant patients who received Neoral and then SangCya during a formulation conversion study. Full AUCs were drawn on all patients (twice while on Neoral, once while on SangCya). Abbreviated formulas were derived using linear regression models and then tested for the prediction error. The authors found that several abbreviated formulas offer excellent estimations of the full AUC for both SangCya and Neoral. The generated formulas worked equally well with either formulation. In addition, the authors found that limited sampling strategies using a 1.5‐hour sample may predict a full AUC more accurately than those that use a 2‐hour sample. The use of these abbreviated formulas allows for a convenient and accurate estimate of CsA exposure.
The Effects of Fluvastatin, a CYP2C9 Inhibitor, on Losartan Pharmacokinetics in Healthy Volunteers
Authors: Meadowcroft Amy M. , Williamson Kristin M. , Patterson J. Herbert , Hinderliter Alan L. , Pieper John A.
Published: July 2003

Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady‐state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A prospective, open‐label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phase was 7 days of losartan (50 mg QAM), and the inhibition phase was 14 total days of fluvastatin (40 mg QHS), with the final 7 days including losartan. The authors found that flvastatin did not significantly change the steady‐state AUC0–24 or half‐life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolism appears to require both CYP2C9 and CYP3A4 inhibition.
Pharmacokinetics of Intrvenous Alendronate
Authors: Cocquyt Veronique , Kline Walter F. , Gertz Barry J. , Van Belle Simon J. P. , Holland Sherry D. , DeSmet Marina , Quan Hui , Vyas Kamlesh P. , Zhang Kanying E. , De Grève Jacques , Porras Arturo G.
Published: July 2003

Alendronate is a potent bisphosphonate that has been studied for the treatment of osteoporosis and Paget's disease of the bone. To examine the pharmacokinetics of this drug, several groups of postmenopausal women were dosed intravenously in several studies. Twelve patients with metastatic bone disease were administered an intravenous dose of 10 mg of 14C‐labeled alendronate (∼26 μCi), and plasma, feces, and urine samples were collected for 72 hours. Radioactivity was excreted almost exclusively in urine, and all of it was accounted for by alendronate. Overall recovery accounted for 47% of dose, with the remainder presumed to be retained in bone. Metabolism of alendronate was not observed. Renal clearance of alendronate was 71 mL/min. An additional 10 subjects were given repeated IV administrations of alendronate to demonstrate that previous exposure does not alter the pharmacokinetic behavior of the drug. Examination of the findings from these and other studies in which alendronate was administered intravenously revealed that disposition of single doses is linear in the range of 0.125 to 10 mg. With the possible exception of a somewhat greater skeletal retention of a systemically administered dose, the pharmacokinetics of IV alendronate were found to be similar to those of other bisphosphonates.
Pharmacokinetic and Adrenal Interactions of IL‐10 and Prednisone in Healthy Volunteers
Authors: Chakraborty Abhijit , Blum Robert A. , Mis Suzette M. , Cutler David L. , Jusko William J.
Published: July 2003

The pharmacokinetic and adrenal interactions of recombinant human interleukin‐10 and prednisolone were examined in this open‐label, randomized, four‐way crossover study in 12 healthy adult male volunteers. Single doses of IL‐10 (8 μg/kg SC), IL‐10 with prednisone (15 mg PO), placebo with prednisone, or placebo were administered on four separate occasions with at least 3‐week interceding washout periods. Measurements included plasma prednisone, prednisolone and cortisol, unbound prednisolone, and serum IL‐10 concentrations. Pharmacokinetic parameters were determined using noncompartmental and model‐fitting analysis, while area analysis and an indirect response model were used to assess cortisol dynamics. IL‐10 exhibited prolonged serum concentrations owing to dual‐absorption processes that were largely unaffected by prednisone. The Cmax values were about 3 ng/mL, while the tmax occurred at 7 to 9 hours. Prednisolone exhibited rapid systemic kinetics with a Cmax of 235 ng/mL, tmax at 1.11 hours, and t1/2 of 2.54 hours with no significant alterations owing to IL‐10. Both prednisolone and prednisolone/IL‐10 caused marked suppression of cortisol concentrations with similar magnitude and IC50 values; however, IL‐10 alone significantly increased the 24‐hour AUC of cortisol by 20%. Thus, IL‐10 and prednisolone do not interact in disposition or adrenal suppression to a clinically significant degree.
Effect of Indinavir on the Single‐Dose Pharmacokinetics of Theophylline in Healthy Subjects
Authors: Mistry Goutam C. , Laurent Aziz , Sterrett Andrew T. , Deutsch Paul J.
Published: July 2003

The effect of multiple doses of indinavir on the pharmacokinetics of a single dose of theophylline was investigated in 16 healthy male subjects using a randomized, double‐blind, placebo‐controlled, parallel‐group study design. On days 1 and 7, all of the subjects received a single oral 250 mg dose of theophylline. From days 2 to 7, the subjects received orally administered 800 mg doses of indinavir or a matched placebo every 8 hours. On day 7, theophylline and indinavir (or a placebo) were coadministered. The geometric mean AUC(0–24 h) of theophylline increased 18% when coadministered with indinavir compared to when theophylline was administered alone. This small increase in AUC(0–24 h), although considered statistically significant, did not meet the prespecified criterion for clinical significance. The geometric mean Cmax of theophylline, when coadministered with indinavir, was within 8% of theophylline when administered alone. The mean tmax (± SD) value for theophylline, when coadministered with indinavir (0.9 ± 0.5 h), was comparable to that observed for theophylline alone (1.0 ± 0.5 h). In conclusion, the administration of multiple doses of indinavir followed by a single dose of theophylline did not appear to result in a clinically significant pharmacokinetic interaction for theophylline.
Practical Considerations of the Pharmacology of Angiotensin Receptor Blockers
Authors: McConnaughey Mona M. , McConnaughey J. Scott , Ingenito Alphonse J.
Published: July 2003

A review of the drug class of angiotensin receptor blockers (ARBs) as well as the ARBs currently available by prescription in the United States is presented. The importance of angiotensin II production by non‐angiotensin‐converting enzyme (non‐ACE) pathways, particularly human chymase, is discussed. Emphasis is placed on the mechanism of action of ARBs and the different binding kinetics of these agents. Although all ARBs, as a group, block the AT1 receptor, they may differ in the pharmacological characteristics of their binding and be classified as either surmountable or insurmountable antagonists. Mechanisms of surmountable and insurmountable antagonism as well as possible benefits of these blocking characteristics are discussed in relation to the various ARBs. The cardiovascular effects of activation of the two main subtypes of angiotensin receptors (AT1 and AT2) are presented. In addition to their treatment of hypertension, ACE inhibitors are recognized as being effective in the management of heart failure, left ventricular hypertrophy, recurrent myocardial infarctions, and renal disease. ARBs are currently indicated only for the treatment of hypertension; however, in vitro and in vivo pharmacological studies as well as preliminary clinical data suggest that ARBs, like ACE inhibitors, may also provide effective protection against end‐organ damage in these conditions.
Lamivudine/Zidovudine as a Combined Formulation Tablet: Bioequivalence Compared with Lamivudine and Zidovudine Administered Concurrently and the Effect of Food on Absorption
Authors: Moore Katy H. P. , Shaw Shuching , Laurent Aziz L. , Lloyd Peggy , Duncan Benjamin , Morris David M. , O'Mara Michael J. , Pakes Gary E.
Published: July 2003

A single‐center, open‐label, three‐way crossover study was conducted in 24 healthy subjects to assess (1) the bioequivalence of a combined lamivudine 150 mg/zidovudine 300 mg tablet relative to the separate brand‐name components administered concurrently and (2) the effect of food on the bioavailability of the drugs from the combination tablet. The subjects were randomly assigned to receive each of the following three treatments, separated by a 5‐ to 7‐day washout period: one lamivudine/zidovudine combination tablet after an overnight fast, one lamivudine 150 mg tablet and one zidovudine 300 mg tablet simultaneously after an overnight fast, or one lamivudine/zidovudine combination tablet 5 minutes after completing a standardized high‐fat breakfast (67 g fat, 58 g carbohydrate, and 33 g protein). Serial blood samples were collected up to 24 hours postdose for the determination of lamivudine and zidovudine plasma concentrations. Standard pharmacokinetic parameters were estimated. Treatments were considered bioequivalent if 90% confidence intervals for the ratio of least squares (LS) means for the lamivudine and zidovudine area under the plasma concentration‐time curve (AUC∞) and maximum observed plasma concentration (Cmax) fell entirely within 0.80 to 1.25 for log‐transformed parameters. The combined lamivudine/zidovudine tablet was bioequivalent in the extent (AUC∞) and rate of absorption (Cmax and time of Cmax [tmax]) to the individual brand‐name drug components administered concurrently under fasted conditions. Geometric LS mean ratios and 90% confidence intervals for AUC∞ and Cmax were 0.97 (0.92, 1.03) and 0.94 (0.84, 1.06), respectively, for lamivudine and 0.99 (0.91, 1.07) and 0.97 (0.82, 1.15), respectively, for zidovudine. The extent of absorption of lamivudine and zidovudine from the combination tablet was not altered by administration with meals, indicating that this formulation may be administered with or without food. However, food slowed the rate of absorption, delayed the tmax, and reduced the Cmax of lamivudine and zidovudine. These changes were not considered clinically important. All formulations were well tolerated under fasted and fed conditions.
Single Oral Dose Escalation Pharmacokinetics of Pleconaril (VP 63843) Capsules in Adults
Authors: Abdel‐Rahman Susan M. , Kearns Gregory L.
Published: July 2003

Pleconaril is an orally active broad‐spectrum antipicornaviral agent with excellent penetration into the central nervous system and nasal epithelium. The authors report the results of a randomized, placebo‐controlled, dose escalation study of pleconaril oral capsules following single‐dose administration of 50 to 1000 mg. Fifty‐six healthy adults (ages 19–55) participated in the study. Each subject received a single dose of pleconaril oral capsule(s) or an identically matched placebo. Blood samples (n = 19) were obtained over 36 hours postdose, and pleconaril was quantified from plasma by gas chromatography. Pleconaril disposition was best characterized using a two‐compartment open‐model with first‐order absorption. Fifty‐five subjects completed the study (31 ± 10 years, 77.6 ± 11 kg). The administration of pleconaril was well tolerated. There was no difference in tmax, lz, ka, t1/2elim, Cl/F, or Vdss/F among the various dose groups. A significant difference in both Cmax and AUC was observed between study groups; however, this difference became insignificant when the parameters were corrected for dose. Cmax and AUC were dose proportional between 50 and 1000 mg (r2 > 0.97 and 0.90, respectively). Pleconaril demonstrates a favorable safety and pharmacokinetic profile following single‐dose administration.
Buprenorphine Pharmacokinetics: Relative Bioavailability of Sublingual Tablet and Liquid Formulations
Authors: Nath Rajneesh P. , Upton Robert A. , Everhart E. Thomas , Cheung Polly , Shwonek Peter , Jones Reese T. , Mendelson John E.
Published: July 2003

Buprenorphine is an effective new treatment for opiate dependence. This study compared the bioavailability of buprenorphine from a tablet to that from a reference solution. Six men experienced with, but not dependent on, opiates (DSM‐III‐R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in tablet form 1 week apart in a balanced crossover design. Plasma levels were measured by electron capture capillary gas chromatography (GC), and concentration‐time curves were constructed. Pharmacokinetic data were analyzed by analysis of variance. The bioavailability from the tablet was approximately 50% that from the liquid and was not affected by saliva pH. Lower bioavailability from the tablet may be due to slow dissolution.
Combination of Calcium Channel Blockers and Beta‐Blockers for Patients with Exercise‐Induced Angina Pectoris: Beneficial Effect of Calcium Channel Blockers Largely Determined by Their Effect on Heart Rate
Authors: Cleophas Ton J. , van der Sluijs Johan , van der Vring Jan A. , Daniëls Marcel C. , Holwerda Klaas J. , Withagen Adrie J. , Schelling Adri , Hendriks Maarten G. , Zwinderman Aeilko H.
Published: July 2003

The combination of calcium channel blockers and beta‐blockers is more effective for the treatment of exercise‐induced angina pectoris than beta‐blocker monotherapy. As ischemia in exercise‐induced angina is essentially preceded by an increase in heart rate, calcium channel blockers with a negative chronotropic property may perform better for this purpose than nonchronotropic compounds. A 335‐patient, 10‐week, double‐blind, parallel‐group comparison of amlodipine 5 mg and 10 mg, diltiazem 200 mg and 300 mg, and mibefradil 50 mg and 100 mg treatment added to baseline beta‐blocker treatment was performed. Exercise testing (ETT) was performed by bicycle ergometry. All of the calcium channels blockers significantly delayed the onset of 1 mm ST‐segment depression on ETT (p < 0.001 for any treatment vs. baseline). In addition, mibefradil, in both low‐ and high‐dose treatments, produced the largest delays (low dose: different from diltiazem and amlodipine by 24.1 and 29.8 seconds, respectively, p < 0.003 and < 0.001; high dose: different from diltiazem and amlodipine by 33.7 and 37.0 seconds, respectively, p < 0.001 and < 0.001). A stepwise logistic regression analysis revealed that this beneficial effect of calcium channel blockers was largely dependent on their effect on heart rate. Serious symptoms of dizziness likewise occurred significantly more frequently on mibefradil (p < 0.05 vs. diltiazem) and urged no fewer than 19 patients on mibefradil to withdraw from the trial. The authors conclude that calcium channel blockers with a negative chronotropic property provide a better delay of ischemia in patients with exercise‐induced angina, but the concomitant risk of intolerable dizziness may reduce this benefit.
Pharmacokinetics and Pharmacodynamics of Sibrafiban, an Orally Administered IIb/IIIa Antagonist, in Patients with Acute Coronary Syndrome
Authors: Modi Nishit B. , Novotny William , Reimann James D. , Cannon Christopher P. , Braunwauld Eugene
Published: July 2003

Sibrafiban is a double prodrug that is converted to the inactive single prodrug and to the active IIb/IIIa antagonist following oral administration. Pharmacokinetics (PK) and pharmacodynamics (PD) of oral sibrafiban and its metabolites were evaluated in patients postacute coronary syndrome receiving once‐ or twice‐daily sibrafiban for up to 28 days at several dose levels. Mean peak concentrations of sibrafiban were < 5 ng/mL. Peak single prodrug concentrations occurred 1.7 1.0 (mean SD) hours after sibrafiban dosing. Total apparent plasma clearance of the single prodrug was 40 15 L/h, and the elimination half‐life was 2.3 0.8 hours. Mean values of the steady‐state pharmacokinetics for total concentrations of the active drug over all doses were: time to peak plasma concentration, 5.0 1.7 hours; apparent clearance, 13.9 3.9 L/h; and half‐life, 11.0 2.8 hours. Once‐daily dosing resulted in high peak‐trough excursions in active drug concentrations: trough concentrations were 21% 6% of peak. Twice‐daily dosing resulted in an AUC for the active drug on Day 28 that was 168% 36% of that on Day 1, and steady‐state trough concentrations were 54% 10% of peak with sustained inhibition of platelet aggregation. Dose‐adjusted steady‐state active drug concentrations increased with increasing age and with decreasing renal function and body weight.
Pharmacokinetics and Pharmacodynamics of Avitriptan during Intravenous Administration in Healthy Subjects
Authors: Sharma Amarnath , Jusko William J. , Fulmor I. Edgar , Norton Jean , Uderman Howard D. , Salazar Daniel E.
Published: July 2003

Avitriptan, a selective 5‐HT1‐like receptor agonist, is an effective compound for the treatment of migraine headaches with a prolonged duration of response. A double‐blind, placebo‐controlled, parallel‐group, ascending‐dose study in 24 healthy subjects was designed to assess the safety, tolerance, pharmacokinetics, and pharmacodynamics of avitriptan. This antimigraine drug was administered as two consecutive constant‐rate IV infusions at three dose levels (12.7, 25.3, and 38.0 mg), which were targeted to produce plasma concentrations in and above the therapeutic range. The best fitting of the plasma concentration‐time data was obtained by using a triexponential function yielding a terminal t1/2 of 8 hours. The areas under the plasma concentration versus time curves were proportional to dose, indicating linear pharmacokinetics. Moreover, the clearance and steady‐state volume of distribution values were independent of the dose. The change in pulse rate and supine systolic and diastolic blood pressure was determined as pharmacodynamic effects of avitriptan. A “threshold log‐linear” model, which accounts for the linear increase in pharmacodynamic effect with the log of plasma concentrations when the latter was higher than a certain threshold value, adequately described the pharmacodynamic data. The threshold plasma drug concentrations for the pulse rate and the diastolic and systolic blood pressure were 14, 74, and 161 ng/ml, respectively. Overall, avitriptan has consistent, linear pharmacokinetics and increases systolic and diastolic blood pressure in a predictable manner at a higher plasma concentration. However, this drug does not produce a significant change in pulse rate at the dose levels (12.7–38 mg) evaluated in this study.
A Pharmacokinetic Study to Evaluate the Absolute Bioavailability of Triamcinolone Acetonide following Inhalation Administration
Authors: Argenti Domenick , Shah Bharti , Heald Donald
Published: July 2003

Triamcinolone acetonide is a glucocorticoid administered by oral inhalation in the management of asthma. With oral inhalation of glucocorticoids, systemic absorption can come from oropharyngeal, gastrointestinal, or airway deposition of the drug. The objectives of this study were to determine the absolute bioavailability of triamcinolone acetonide following inhalation administration and to delineate the airway contribution of triamcinolone acetonide absorption relative to the absolute bioavailability. All subjects received a 5‐minute 400 mcg intravenous infusion of triamcinolone acetonide and a single 800 mcg dose of inhaled triamcinolone acetonide with and without oral charcoal administration in a randomized three‐way crossover fashion. The oral charcoal allowed for isolating the pulmonary component of absorption by adsorbing the oropharyngeal and gastrointestinal deposited drug. The mean (± SD) absolute bioavailability value for inhaled triamcinolone acetonide was 25% (8.75%). Delineation of the airway contribution of triamcinolone acetonide absorption showed that 10.4% of an inhaled dose is absorbed as triamcinolone acetonide from the lungs. Mean (± SD) total body clearance was rapid at 0.57 (0.12) L/hr/kg. The mean (± SD) apparent volume of distribution following the intravenous dose was a low 1.96 (0.31) L/kg. No significant differences were noted in the apparent terminal elimination half‐life of triamcinolone acetonide (∼2.4 hr) between treatments.
Population Pharmacokinetics of Methylphenidate in Children with Attention‐Deficit Hyperactivity Disorder
Authors: Shader Richard I. , Harmatz Jerold S. , Oesterheld Jessica R. , Parmelee Dean X. , Sallee Floyd R. , Greenblatt David J.
Published: July 2003

Sources of individual variation in plasma methylphenidate (MP) concentrations during usual clinical use are not established. This was evaluated in a series of patients receiving clinical treatment with MP. A single plasma MP concentration was determined in each of 273 children and adolescents ages 5 to 18 years (mean: 11.1 years) who were clinically good responders to MP for the treatment of attention‐deficit hyperactivity disorder. MP was given on a twice‐daily schedule (mean dose: 25 mg/day) in 40% of patients and three times daily (mean dose: 39.3 mg/day) in 60%. A nonlinear regression model was applied to estimate overall population values of MP clearance and elimination half‐life (t1/2), assuming a one‐component model with first‐order absorption and elimination, and further assuming that clearance is linearly related to body weight. The model incorporated each patient's dosage size and schedule, body weight, and time of the plasma sample. Iterated solutions of best fit were: t1/2, 4.5 hours (95% confidence interval [CI]: 3.1–8.1 hours), and apparent clearance, 90.7 ml/min/kg (95% CI: 74.6–106.7 ml/min/kg). The model explained 43% of the overall variance in MP concentrations (r2 = 0.43, p < .001). In a small subsample (N = 16), a second plasma sample was drawn at the same time of day and at the same dose; the correlation between the two concentration values was 0.83. The relatively noninvasive approach used in this study allows the assessment of pharmacokinetic properties of medications under conditions of appropriate clinical use in special populations such as children, adolescents, and the elderly.
Systemic Absorption of Clindamycin after Intravaginal Administration of Clindamycin Phosphate Ovule or Cream
Authors: Borin Marie T. , Ryan Kristi K. , Hopkins Nancy K.
Published: July 2003

The absolute bioavailability of clindamycin phosphate vaginal ovule with comparison to a reference treatment of clindamycin phosphate sterile solution, as well as the relative bioavailability of the ovule compared to clindamycin phosphate vaginal cream, was evaluated in 12 healthy adult female volunteers. Subjects were randomly assigned to receive either the ovule or cream formulation intravaginally for 3 consecutive days during the two‐way crossover portion of the study. During a third treatment period, all subjects received 100 mg of clindamycin as a 4‐minute intravenous infusion of clindamycin phosphate sterile solution (10 mg/mL). Clindamycin concentrations in serum were assayed by a high‐performance liquid chromatography method with detection by mass spectrometry. Pharmacokinetic analyses of the serum data indicated low systemic absorption of clindamycin from the vaginal cream (about 4%), consistent with results of previous bioavailability studies. Following intravaginal administration of the clindamycin phosphate ovule, systemic absorption averaged 30%, which was approximately sevenfold greater than after dosing with the vaginal cream. The higher drug absorption for the ovule may be related to differences in formulation effects on the vaginal membrane. Nevertheless, systemic exposure to clindamycin from the ovule is still considerably lower than from a therapeutic oral dose.