bluuebunny/crossref_metadata_2025 huggingface dataset:
Single‐Dose and Steady‐State Pharmacokinetic and Pharmacodynamic Evaluation of Therapeutically Clinically Equivalent Doses of Inhaled Fluticasone Propionate and Budesonide, Given as Diskus® or Turbohaler® Dry‐Powder Inhalers to Healthy Subjects
Authors: Möllmann Helmut , Wagner Melanie , Krishnaswami Sriram , Dimova Hristina , Tang Yufei , Falcoz Christine , Daley‐Yates Peter T. , Krieg Michael , Stöckmann Ricarda , Barth Jürgen , Lawlor Ms. Caroline , Möllmann Anja C. , Derendorf Hartmut , Hochhaus Günther
Published: July 2003

Direct comparisons of the pharmacokinetic (PK) and systemic pharmacodynamic (PD) properties of inhaled corticosteroids after single and multiple dosing in the same subjects are scarce. The objective of this study was to compare the PK/PD properties of clinically equivalent, single, and multiple doses of dry‐powder formulations of inhaled fluticasone propionate (FP, 200 and 500 μg via Diskus®) and budesonide (BUD, 400 and 1000 μg via Turbohaler®). Fourteen healthy subjects completed a double‐blind, doubledummy, randomized, placebo‐controlled, five‐way crossover study consisting of a single dose administered at 8 a.m. on day 1 followed by 4 days of twice‐daily dosing at 8 a.m. and 8 p.m. on days 2 to 5. Serum concentrations of FP and BUD were measured using validated liquid chromatography/mass spectrometry assays. The 24‐hour cumulative cortisol suppression (CCS) in serum was monitored as the pharmacodynamic surrogate marker. Peak serum concentrations following single and multiple dosing were observed 10 to 30 minutes after inhalation for BUD and 30 to 90 minutes after inhalation of FP with no influence of dose or dosing regimen. After a single dose of 1000 vg BUD and 500 Vg FP, the median estimates of terminal half‐life and mean residence time were3.5 and 3.9 hours for BUD and 10.1 and 12.0 hours for FP, respectively. Using previously reported intravenous

data, the mean absorption times (MAT) were calculated to be around 2 hours and 7 hours for BUD and FP, respectively. On average, the area underthe curve (AUC) at steady state (day 5) was up to 30% higher for BUD compared to that over a 12‐hour period following the first dose on day 1, whereas AUC estimates were 50% to 80% higher for FP at steady state, indicating accumulation. However, the steady‐state Cmax values were seven to eight times and AUC values three to four times higher for BUD than for FP Comparison of active treatment data with placebo showed that CCS after a single dose was not pronounced for any of the doses/drugs studied. On day 5, both doses of BUD caused statistically significant suppression (CCS of 19% for the 400 μg dose and 36% for the 1000 μg dose). For FP, only the high dose had a statistically significant effect on serum cortisol (CCS of 14% for the 200 g dose and 27% forthe 500 μg dose). Compared to BUD, FP has slower pulmonary absorption and slower elimination kinetics. However, following inhalation of therapeutically equipotent, multiple twice‐daily doses in healthy subjects, the systemic effects of FP delivered via Diskus® on AUC24 serum cortisol were relatively low and similar to those of BUD delivered via Turbohaler®.
Effect of Modafinil at Steady State on the Single‐Dose Pharmacokinetic Profile of Warfarin in Healthy Volunteers
Authors: Robertson Philmore , Hellriegel Edward T. , Arora Sanjay , Nelson Michael
Published: July 2003

Modafinil has been reported to produce a concentration‐related suppression of CYP2C9 activity in vitro in primary cultures of human hepatocytes. To determine whetherthis effect occurs in vivo, the pharmacokinetics of (S)‐warfarin was investigated after single oral doses of racemic warfarin (5 mg; COUMADIN®) in a placebo‐controlled, single‐blind, single‐period study in 28 volunteers. Subjects received an oral dose of warfarin prior to administration of modafinil (200 mg for 7 days, followed by 400 mg for 21 days) or placebo and they received another after 4 weeks of treatment. Treatment with modafinil did not significantly alter the pharmacokinetics of (S)‐ or (R)‐warfarin relative to placebo. Since (S)‐warfarin is predominantly metabolized via CYP2C9, the results indicate that the marked suppression of CYP2C9 activity in vitro does not translate into a similar effect clinically. However, limitations arising from investigation of single doses of warfarin preclude global conclusions about the potential for more subtle interactions after chronic warfarin administration.
Pharmacokinetic and Pharmacodynamic Assessments of HMG‐CoA Reductase Inhibitors When Coadministered with Everolimus
Authors: Kovarik John M. , Hartmann Stefan , Hubert Martine , Berthier Stephane , Schneider Werner , Rosenkranz Bernd , Rordorf Christiane
Published: July 2003

The authors assessed the mutual influence of the immunosuppressant everolimus (Certican) and the HMG‐CoA reductase inhibitors atorvastatin and pravastatin when coadministered based on pharmacokinetic and pharmacodynamic measures. In this randomized, open‐label, three‐way crossover study, 24 healthy men received three single‐dose oral treatments: 2 mg everolimus, 20 mg atorvastatin (n = 12) or 20 mg pravastatin (n = 12), and the respective statin coadministered with everolimus. Consecutive treatments were separated by a 14‐day washout. The pharmacokinetics of all three drugs and total HMG‐CoA reductase inhibitors were measured. Everolimus Cmax was reduced by 9% and 10% with atorvastatin and pravastatin coadministration; the corresponding decreases in everolimus AUC were 5% and 6%, respectively. Everolimus coadministration increased the Cmax of atorvastatin by 11% but had no influence on atorvastatin AUC. Coadministration of everolimus with pravastatin was associated with a 10% decrease in pravastatin Cmax and a 5% decrease in the AUC. The elimination half‐lives of the two statins were unaffected by everolimus. Changes in total HMG‐CoA reductase inhibitors in plasma exhibited generally similar patterns as for the parent statin exposures. Single‐dose administrations of everolimus with either atorvastatin or pravastatin did not influence the pharmacokinetics of everolimus, atorvastatin, pravastatin, or total HMG‐CoA reductase inhibitors in plasma to a clinically relevant extent.
A Simplified Method for Detecting Isoniazid Compliance in Patients Receiving Antituberculosis Chemotherapy
Authors: Hashiguchi Masayuki , Ohno Keiko , Sakuma Atsuko , Hino Fumio , Tanaka Takanori , Ohtsuji Masahiko , Matsumoto Naoto , Yanase Kumiko , Urae Akinori , Hosogai Yuki , Sato Naomi , Yazaki Asami , Matsuda Kaoru , Yamazaki Katsuji , Rikihisa Tadaaki
Published: July 2003

The objective of this study was to develop a new simplified method using thin‐layer chromatography (TLC) for determining isoniazid (INH) compliance in patients receiving antituberculosis chemotherapy. TLC was performed on silica gel plates using a standard solution of INH and acetylisoniazid (AcINH) and ethyl acetate‐methanol (70:30 v/v) as the developing solvent. The spots of compound were detected by iodine. In the human study, fractional urine samples were collected over 24 hours from 4 healthy human subjects genotyped for NAT2 and to whom 400 mg of INH were administered orally. These samples were used for TLC analysis. The results of TLC were compared with those of high‐performance liquid chromatography (HPLC). This method indicated good separation between INH and AcINH in standard solutions. The detection limits for INH and AcINH (applied volume; 20 μl of standard solution) were 2.2 nmole and 5 nmole, respectively, as detected by iodine. In the human study, the INH spot in urine was not detected on the TLC plate, except in one sample over the 0‐ to 4‐hour period from 1 volunteer. However, the AcINH spot was detected in all urine samples from all volunteers. The total experimental time from application of the urine sample to analysis on TLC was 30 minutes. The results suggest that this method for detecting AcINH on TLC is an excellent, convenient, and simple method for determining INH compliance in patients receiving standard antituberculosis chemotherapy regimen or INH preventative therapy, regardless of the patient's NAT2 genotype.
New Dosing Regimens for Amifostine: A Pilot Study to Compare the Relative Bioavailability of Oral and Subcutaneous Administration with Intravenous Infusion
Authors: Bonner H. S. , Shaw L. M.
Published: July 2003

A phase I clinical trial was conducted to assess the feasibility of a more convenient and safe dosing regime for the cytoprotective drug amifostine. Two alternative routes of administration, oral and subcutaneous (SQ), each with a dose of 500 mg, were compared to a 7.5‐minute intravenous (IV) infusion, with a dose of 200 mg/m2, in normal, healthy volunteers (N =12). Bioavailability of amifostine (parent drug) and its pharmacologically active metabolite, WR‐1065, was evaluated by comparing the area under the concentration‐time curve (AUC) derived from HPLC analysis of amifostine and both protein‐free and protein‐bound WR‐1065 in all three routes of administration. Results showed that SQ (but not oral) administration of amifostine could provide a more effective dosing regimen, in terms of both a reasonable AUC for the bound form of WR‐1065 and decreased toxicity, compared to IV delivery. These data suggest that the protein‐ bound form of WR‐1065 plays an important role in contributing to the bioavailability of this clinically useful cytoprotective drug.
Comparison of the Pharmacokinetics of Oxycodone Administered in Three Percocet® Formulations
Authors: Gammaitoni Arnold R. , Davis Matthew W.
Published: July 2003

This randomized, open‐label, three‐period crossover study compared the single‐dose pharmacokinetics of three dose levels of oxycodone in combination with acetaminophen (5 mg/325 mg, 7.5 mg/500 mg, or 10 mg/650 mg) in healthy volunteers. Serial 24‐hour blood samples were collected from 23 fasting subjects after drug administration. The individual dose levels were evaluated on 3 different days, which were separated by washout periods of at least 7 days, in each subject. Oxycodone AUC0o‐v AUC0o‐∞ and Cmax were dose dependent, whereas tmax and t1/2 were not. The most frequently reported adverse events were dizziness, nausea, headache, pruritus, and vomiting. Most adverse events were mild, and all were self‐limiting. Only dizziness occurred in a doserelated manner. Increasing dose levels of oxycodone/acetaminophen provides proportional increases in oxycodone Cmax and AUC. Adverse events were predictable based on the opioid pharmacologic actions of this agent.
Evaluation of Single‐ and Multiple‐Dose Pharmacokinetics of Synthetic Conjugated Estrogens, A (Cenestin®) Tablets: A Slow‐Release Estrogen Replacement Product
Authors: Stevens R. E. , Roy P. , Phelps K. V.
Published: July 2003

A multiple‐dose, placebo‐controlled, randomized pharmacokinetic study was performed in 15 early (i.e., 1–3 years) postmenopausal women to evaluate the single and steady‐state pharmacokinetics of 0.625 mg Cenestin® (Synthetic Conjugated Estrogens, A) tablets, administered once daily for 90 days. Plasma concentration‐time profiles for both total (conjugated and unconjugated) estrone and equilin, two major estrogens in Cenestin®, were nearly superimposable between Day 1 (single dose) and Day 90 (multiple dose), indicating equivalent drug exposure from one dose to the next. For total estrone, the mean estimates of Cmax and AUC0–24 were 2.5 ng/ml and 35.0 ng·h/ml for Day 1 and 3.0 ng/ml and 39.8 ng·h/ml for Day 90, respectively. Similarly, Cmax and AUC0–24 mean values fortotal equilin were 1.4 ng/ml and 17.4 ng·h/ml after Day 1 and 1.5 ng/ml and 17.3 ng·h/ml after Day 90, respectively. The mean tmax value for total estrone was 8.3 hours on Day 1 and 8.6 hours on Day 90, indicating a slower rate of absorption. The average estimate for observed drug accumulation index forthe 24‐hour dosing interval was calculated to be 1.1 for total estrone and 1.0 for total equilin. These data, taken together, indicate a slow and steady rate of absorption, minimal drug accumulation at steady state, and consistent drug exposure between Cenestin® doses.
Pemoline Ingestion in Children: A Report of Five Cases and Review of the Literature
Authors: Nakamura Hidefumi , Blumer Jeffrey L. , Reed Michael D.
Published: July 2003

The authors describe five pediatric cases of excessive pemoline ingestion. Based on their experience compared with previously reported cases in the literature, they describe the clinical presentation and rational treatment recommendations for acute pemoline ingestion. Overall, patients experienced a relatively benign clinical course following pemoline ingestion. Symptoms of pemoline ingestion appear to be primarily an accentuation of the drug's pharmacological effects on the central nervous and cardiovascular systems with sinus tachycardia, hypertension, hyperactivity, choreoathetoid movements, and hallucinations being most commonly observed. These findings are consistent with previously reported cases. Possible rhabdomyolysis manifested by evaluation of serum CPK was also observed in 3 of 4 patients in whom this laboratory parameter was measured and appears to be a common finding in acute pemoline poisoning. After acute ingestion, symptoms occurred within 6 hours, lasting up to 48 hours in all patients. Gastric lavage and/or activated charcoal would be effective decontamination measures, whereas ipecac‐induced emesis should be avoided after massive ingestion due to the possibility of seizures. Aggressive use of a benzodiazepine appears a reasonable first choice to treat associated involuntary movements, tremor, hyperactivity, irritability, and agitation. Phenothiazines or butyrophenones may also be used especially for serious life‐threatening symptoms, including hypertensive crisis and severe hyperthermia, although these serious complications of stimulant overdose have not been reported after pemoline ingestion. If a patient should experience pemoline‐induced hypertensive crisis, individual dose titration of labetalol or sodium nitroprusside would appear reasonable pharmacologic approaches for rapid stabilization of blood pressure.
Short‐Term Effects of New Synthetic Conjugated Estrogens on Biochemical Markers of Bone Turnover
Authors: Garnero Patrick , Stevens Ruth E. , Ayres Stacey A. , Phelps Kenneth V.
Published: July 2003

Fifty early postmenopausal women completed a double‐blind, placebo‐controlled study evaluating the short‐term effect of a new synthetic conjugated estrogens formulation (Cenestin®) on bone turnover. Subjects were randomized to either 0.625 mg/day synthetic conjugated estrogens (n = 35) or placebo (n = 15) for 3 months. Biochemical markers were evaluated at baseline (three measurements at Days −2, −1, and 0) and Days 30, 60, and 90. Bone resorption assessed by urinary NTX (‐31.4%) and serum CTX (‐34.2%) was significantly (p < 0.01) decreased in the estrogen‐treated group compared to the placebo group within 1 month of treatment. The mean percent decreases for urinary NTX from baseline during estrogen treatment were −58.0% (p < 0.01 vs. placebo) and −34.1% (ns) after 2 and 3 months, respectively. For serum CTX, the percent changes from baseline were −17.6% (p < 0.01) and −16.9% (p < 0.01) at 2 and 3 months, respectively. As expected, the decrease of both bone formation markers (bone ALP and PINP) was delayed compared to that of bone resorption and significant (p < 0.05‐0.01) only after 2 months of treatment in the estrogen‐treated group compared to the placebo group. Synthetic conjugated estrogens significantly decreased bone resorption and bone formation comparable to that previously reported for estrogen treatments proven efficacious in preventing postmenopausal bone loss.
The New Phosphodiesterase 4 Inhibitor Roflumilast Is Efficacious in Exercise‐Induced Asthma and Leads to Suppression of LPS‐Stimulated TNF‐α Ex Vivo
Authors: Timmer Wolfgang , Leclerc Violette , Birraux Guillaume , Neuhauser Markus , Hatzelmann Armin , Bethke Thomas , Wurst Wilhelm
Published: July 2003

Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo‐controlled, randomized, double‐blind, two‐period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise‐induced asthma. The patients received placebo or roflumilast (500 μg/day) for28 days, each according to the randomly determined treatment sequences roflumilast/placebo and placebo/roflumilast. In both study periods, exercise challenge was performed 1 hour after dosing on days 1,14, and 28.FEV1 was measured before exercise challenge, immediately after the end of exercise challenge, and then at 1,3, 5, 7, 9, and 12 minutes after the end of challenge. Blood samples for the determination of lipopolysaccharide (LPS)‐stimulated tumor necrosis factor alpha (TNF‐α) in whole blood ex vivo as a surrogate marker for the inhibition of inflammatory cell activation were taken predose on days 1 and 28. Serial safety measurements were performed during both study periods. Analysis of variance for the crossover design showed a significant superiority of roflumilast over placebo on day 28. The mean percentage fall of FEV1 after exercise was reduced by 41% as compared to placebo (p = 0.021). An improvement of lung function during roflumilast treatment was also observed on days 1 and 14. The median TNF‐α level decreased by 21% (p = 0.009) during roflumilast treatment but remained essentially constant under placebo. It is concluded that roflumilast is effective in the treatment of exercise‐induced asthma. This result was accompanied by a significant reduction of TNF‐α levels ex vivo. Treatment with roflumilast was safe and well tolerated.
Pharmacokinetics of Fluvastatin in Subjects with Renal Impairment and Nephrotic Syndrome
Authors: Appel‐Dingemanse S. , Smith T. , Merz M.
Published: July 2003

The pharmacokinetics (PK) and safety of fluvastatin, a hydroxymethylglutaryl—coenzyme A reductase inhibitor, were assessed in subjects with renal impairment and nephrotic syndrome. In a single‐center, open‐label, parallel‐group study, a single dose of fluvastatin 40 mg was administered to subjects (8 per group, n = 48) with nephrotic syndrome (group II), healthy subjects (group I), and subjects with various degrees of renal impairment (groups III to VI). Subjects undergoing hemodialysis received two doses, one 2 days before and one just prior to hemodialysis. Blood samples to determine the PK parameters of fluvastatin were collected from 0 to 12 hours after drug intake. Noncompartmental PK evaluation and statistical analysis (descriptive and ANOVA) were performed. Safety was evaluated and vital signs were monitored. There was no difference in the PK parameters AUC0‐∞ and Cmax of fluvastatin between healthy subjects and subjects with renal impairment. Fluvastatin was not removed from plasma by hemodialysis. In patients with nephrotic syndrome, the values for AUC0‐∞ and Cmax were less than half of those obtained in the other groups; terminal half‐life values, however, were comparable. Fluvastatin was well tolerated in all study participants. Only few adverse events of mild to moderate intensity were reported. There were no clinically relevant changes in laboratory parameters in the subjects with renal impairment. Renal impairment did not affect the PK of fluvastatin after a single oral dose. Exposure to fluvastatin was lower in subjects with nephrotic syndrome. Fluvastatin also was well tolerated in subjects with nephrotic syndrome.
A Comparison of Methods for Assessing Hypothalamic‐Pituitary‐Adrenal (HPA) Axis Activity in Asthma Patients Treated with Inhaled Corticosteroids
Authors: Nelson Harold S. , Stricker Wes , Casale Thomas B. , Raff Hershel , Fourré Jon A. , Aron David C. , Newman Kenneth B.
Published: July 2003

Suppression of the hypothalamic‐pituitary‐adrenal (HPA) axis is an accepted indicator of potential side effects from inhaled corticosteroids. Although cortisol monitoring is frequently used to detect changes in HPA axis activity, the optimal method for identifying the subset of asthma patients on inhaled steroids who experience severe cortisol suppression of potential clinical significance has not been established. The objective of this study was to compare several methods for assessing HPA axis activity in asthma patients taking inhaled corticosteroids. After screening, 153 patients with mild to moderate asthma were randomly assigned to receive inhaled fluticasone propionate (110, 220, 330, or 440 μg bid), flunisolide (500 μg or 1000 μg bid), or one of two control regimens (prednisone or placebo) for 21 days. Salivary (8 a.m.) and urinary (24‐h) cortisol determinations were compared against 22‐hour area under the serum cortisol concentrationtime curve (AUC0–22 h) measured at baseline and on day 21. Comparisons were also made against 8 a.m. serum cortisol. A significant positive correlation was found between AUC0–22 h of serum cortisol and 8 a.m. serum cortisol level (r = 0.5140; p = 0.0001). The AUC0–22 h of serum cortisol was weakly correlated with 24‐hour urinary cortisol levels, both corrected (r = 0.4388; p = 0.0001) and uncorrected (r = 0.3511; p = 0.0001) for creatinine excretion. The 8 a.m. salivary cortisol level correlated positively with the 8 a.m. serum cortisol level (r = 0.5460; p = 0.0001). Salivary cortisol was both sensitive and specific for the detection of a 50% decline in AUC0–22 h of serum cortisol. Cortisol reductions of this magnitude have been observed following repeated use of inhaled steroids. Because it is noninvasive, salivary cortisol measurement offers distinct advantages as a screening method for detecting pronounced HPA axis suppression in asthma patients receiving corticosteroid therapy.
Is It Really OK to Take This with Food? Old Interactions with a New Twist
Authors: Wallace Allison W , Amsden Guy W
Published: July 2003

In response to consumers' increased interest in preventive health care, the food industry is producing a variety of foods fortified with calcium, iron, and other minerals and vitamins. This well‐meaning idea of food fortification is troubling in the context of clinical pharmacology. The recommended Food and Drug Administration (FDA) meal used in food‐drug interaction studies is a high‐fat, high‐calorie meal with little nutritive value. While some drugs may appear to be safe when taken with food, this may not be true when fortified foods are considered. The mechanisms causing drug‐fortified food interactions are the same well‐known mechanisms that cause other drug‐mineral interactions. Certain drugs may exhibit decreased absorption due to chelation and adsorption. Other drugs may have decreased absorption or increased excretion due to changes in gastric and/or urinary pH. The results of such interactions may be clinically insignificant or severe, including treatment failure, frequent dose changes, antibiotic resistance, and increased morbidity and mortality. Revisions of current regulatory guidelines are necessary to take into account this potentially major source of “new” drug interactions.
The Recruitment of Normal Healthy Volunteers: A Review of The Literature on the Use of Financial Incentives
Authors: Tishler Carl L. , Bartholomae Suzanne
Published: July 2003

Unresolved issues of ethical, methodological, and legal concerns in the use of normal healthy volunteers persist. Financial incentives in their recruitment offer a unique ethical dilemma because of questions surrounding payment. A review of literature was conducted to obtain research systematically examining volunteer motivation and the role of financial incentives. The primary selection criterion was motivation and payment to volunteers; seven studies met the criterion for re view. Studies that have systematically investigated volunteer motivation have found financial rewards to be an important motivator among normal healthy volunteers in their decision to participate in clinical trials. Also evident is that differences based on demographic characteristics exist in the motivation and rates of volunteerism. Ethical issues surrounding the use of normal healthy volunteers are discussed, with attention to the issue of financial incentives (e.g., economically vulnerable volunteers, undue inducements). Regulations, guidelines, and recommendations are discussed with regard to volunteers and financial incentives.
Limited Sampling Strategy to Predict AUC of the CYP3A Phenotyping Probe Midazolam in Adults: Application to Various Assay Techniques
Authors: Kim Jooran S. , Nafziger Anne N. , Tsunoda Shirley M. , Choo Edna F. , Streetman Daniel S. , Kashuba Angela D. M. , Kulawy Robert W. , Beck Debra J. , Rocci Mario L. , Wilkinson Grant R. , Greenblatt David J. , Bertino Joseph S.
Published: July 2003

Midazolam clearance is used to phenotype hepatic CYP3A activity but requires multiple plasma samples following a single intravenous dose. The authors evaluated the use of a limited sampling scheme, using different assay techniques to determine the reproducibility of such a strategy in estimating midazolam AUC. Seventy‐three healthy adults received midazolam as a single intravenous bolus dose. At least eight plasma samples were collected from each subject and were assayed using either LC/MS/MS or electron capture gas chromatography. Eleven subjects were randomly selected for the training set using stepwise linear regression to determine relationships between midazolam plasma concentrations and AUC. Validation of the predictive equations was done using the remaining 62 subjects. Mean percent error (MPE), mean absolute error (MAE), and root mean square error (RMSE) were calculated to determine bias and precision. Based on the training set, five models were generated with coefficients of determination ranging from 0.87 to 0.95. Validation showed that MPE, MAE, and RMSE values were acceptable for three of the models. Int rasubject reproducibility was good. In addition, training set data from one institution were able to predict data from the other two institutions using other assay techniques. Minimized plasma sampling may provide a simpler method for estimating midazolam AUC for CYP3A phenotyping. A limited sampling strategy is more convenient and cost‐effective than standard sampling strategies and is applicable to more than one assay technique.
Effects of Azimilide on Heart Rate and ECG Conduction Intervals during Sinus Rhythm in Patients with a History of Atrial Fibrillation
Authors: Pritchett Edward L. C. , Schulte Marcia C. , Schnell Daniel , Marcello Stephen R. , Wilkinson William E. , Page Richard L. , Connolly Stuart J.
Published: July 2003

The purpose of this study was to assess the effect of azimilide, a Class III antiarrhythmic drug, on ECG conduction intervals recorded during sinus rhythm in patients with a history of symptomatic atrial fibrillation or atrial flutter. In Phase I clinical pharmacology studies, azimilide was associated with prolongation of the QT and QTc intervals on electrocardiograms recorded during sinus rhythm in normal subjects, but the effect of azimilide on the target population of patients with atrial fibrillation has not been reported in detail previously. Patients with a history of atrial fibrillation, atrial flutter, or both were randomly assigned to receive placebo or azimilide twice daily for 3 days and then qd thereafter. Azimilide doses of 50 mg, 100 mg, or 125 mg were tested. The RR, PR, QRS, QT, QTc(Bazett), and QTc(Fridericia) intervals were measured from electrocardiograms recorded at baseline and on Day 4 of test therapy. Increasing azimilide doses were associated with significant increases in the RR, QT, QTc(Bazett), and QTc(Fridericia) compared with changes in the placebo group based on the F‐test for differences among treatment groups and the test for a dose response. In the azimilide 125 mg dose group, the mean change in RR was significantly greater than the mean change in the placebo group (+61.4 ms in the azimilide 125 mg group vs. −14.1 ms in the placebo group). The mean change in QT was significantly greater in the azimilide 125 mg group than the mean change in the placebo group (+44.2 ms in the azimilide 125 mg group vs. −1.0 ms in the placebo group). The mean change in QTc using both correction methods was significantly greater in the azimilide 125 mg group than the mean change in the respective placebo group: QTc(Bazett) +31.6 ms in the azimilide 125 mg group versus +2.1 ms in the placebo group and QTc(Fridericia) +35.8 in the azimilide 125 mg group versus +1.0 ms in the placebo group. It was concluded that in patients with a history of atrial fibrillation or flutter, azimilide was associated with statistically significant increases in RR, QT, QTc(Bazett), and QTc(Fridericia) when patients were in sinus rhythm.
Pharmacokinetic Study of Infusional Valspodar
Authors: Ma Margaret K. , McLeod Howard L. , Westervelt Peter , Fracasso Paula M.
Published: July 2003

The pharmacokinetics of valspodar (PSC 833), a selective second‐generation P‐glycoprotein modulator, was evaluated as part of a Phase I study to modulate paclitaxel therapy in 15 patients with refractory malignancies. Valspodar was given intravenously at 1.42 mg/kg/h for 2 hours, followed by a 27‐hour continuous infusion at 0.42 mg/kg/h. Serial blood samples were obtained after intravenous infusion of valspodar and paclitaxel. Valspodar disposition was best described by a linear two‐compartment model. The median (range) valspodar clearance was 0.40 ml/min/kg (0.07‐1.40 ml/min/kg). The 20‐fold interpatient variability in valspodar clearance was not correlated with age, body weight, or gender but might be associated with coadministered medications that were metabolized via cytochrome P450 3A‐mediated elimination. Valspodar whole‐blood concentrations were maintained above the target threshold of 1000 ng/ml for a median of 32 hours. The pharmacokinetic model generated from this study allows for application in future studies to optimize the use of valspodar.
Contribution of Morphine‐6‐Glucuronide to Antinociception following Intravenous Administration of Morphine to Healthy Volunteers
Authors: Murthy Bindu P. , Pollack Gary M. , Brouwer Kim L. R.
Published: July 2003

This study was performed to develop an integrated pharmacokinetic‐pharmacodynamic model for estimating the contribution of morphine‐6‐glucuronide (M6G) to morphine‐associated antinociception in humans. Healthy volunteers (n = 8) received 10 mg of morphine sulfate as a 5‐minute IV infusion. A Contact Thermode® heat probe was placed on the volar forearm to elicit pain. Thermal threshold, defined as the temperature at which pain was first perceived, was measured at fixed time intervals over 8 hours. Serum concentrations of morphine and M6G were determined by LC/MS. Concentration‐ and effect‐time data were analyzed by stepwise nonlinear least‐squares regression. The pharmacodynamic parameter estimates were recovered with a linear effect‐compartment model and were used to assess the contribution of M6G to morphine‐associated analgesia. The estimates (mean ± SEM) for morphine total clearance and steady‐state volume of distribution were 1.0 ± 0.07 L/h/kg and 1.6 ± 0.1 L/kg, respectively. The AUC ratio of M6G to morphine was 0.73 ± 0.06. The contribution of M6G to an‐algesia ranged from < 0.1% to 66% and was inversely related to the overall effect elicited by the morphine dose (r2 = 0.776). Differences in gender were observed where the contribution (mean ± SEM) of M6G to analgesia was 32% ± 19% in males (n = 3) and 13% ± 8% in females (n = 5). These results suggest that as the overall effect of morphine increases, the fractional contribution of M6G declines and the contribution of M6G to analgesia may differ between males and females. Alterations in the M6G/morphine system may have clinically significant pharmacodynamic consequences.
Pharmacodynamic Modeling of Thrombopoietin, Platelet, and Megakaryocyte Dynamics in Patients with Acute Myeloid Leukemia Undergoing Dose Intensive Chemotherapy
Authors: Bernstein Steven H. , Jusko William J. , Krzyzanski Wojciech , Nichol Janet , Wetzler Meir
Published: July 2003

A proposed model of thrombopoietin (TPO) regulation is that of a constitutive production of TPO with circulating levels being predominately regulated by changes in platelet and megakaryocyte mass. Using a pharmacodynamic (PD) approach, the authors examined the validity of this model for patients with acute myeloid leukemia (AML) undergoing dose‐intensive postinduction chemotherapy (HDT). TPO and platelet values were assayed weekly in AML patients undergoing HDT. A parsimonious dynamic model was then applied to these experimental data. The results (1) support the proposed model of TPO regulation, (2) model and quantify the effects of HDT on the megakaryocyte compartment, (3) characterize variables not amenable to direct measurement, and (4) have clinical utility as this model predicted that TPO given after HDT would not have a significant effect on platelet recovery, a finding borne out in clinical trials. This model provides information relevant to the interpretation of clinical trials of hematopoietic growth factors.
The Pharmacokinetics and Safety of Single Escalating Oral Doses of Eletriptan
Authors: Shah Ajit K. , Harris Stephen C. , Greenhalgh Catherine , Morganroth Joel
Published: July 2003

The pharmacokinetics, safety, and tolerability of the 5‐HT1B/1D agonist eletriptan were characterized in a randomized, double‐blind, placebo‐controlled, dose escalation study. Healthy males received single oral doses of 10 to 120 mg. Following screening and baseline measurements, plasma and saliva eletriptan concentrations were measured at intervals over 48 hours and 24 hours, respectively. Samples were analyzed using high‐performance liquid chromatography with ultraviolet detection. Both the maximum plasma concentration and the area under the plasma eletriptan concentrationtime curve showed an essentially linear relationship to the administered dose. Eletriptan exhibited a median time to maximum plasma concentration of 1 to 1.25 hours and a mean elimination half‐life of 3.6 to 7.0 hours. Mean salivary‐plasma ratios for pharmacokinetic parameters generally remained constant across the 30 to 90 mg dose range. Eletriptan was well tolerated, with mostly mild and transient adverse events. In conclusion, oral doses of eletriptan in the therapeutic range were rapidly absorbed and exhibited essentially linear plasma and saliva pharmacokinetics.
Pharmacokinetics, Pharmacodynamics, and Safety of the 5‐HT1B/1D Agonist Eletriptan following Intravenous and Oral Administration
Authors: Milton K. Ashley , Scott Nicholas R. , Allen Michael J. , Abel Samantha , Jenkins Vivienne C. , James GerryC. , Rance David J. , Eve Malcolm D.
Published: July 2003

Four separate studies were conducted to examine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of eletriptan, a 5‐HT1B/1D receptor agonist being developed for the treatment of migraines, after oral and intravenous administration. Fifty‐five males received oral (1.5–30 mg or 30–120 mg) or intravenous (1.67‐50 μg/kg or 50–102 μg/kg) eletriptan in four double‐ and single‐blind, placebo‐controlled, ascending‐dose crossover studies. The maximum plasma concentration (Cmax) and area under the concentration curve (AUC) appeared linear over all dose ranges, with an apparent terminal half‐life of 4 to 5 hours. Clearance and volume of distribution remained constant with dose. The time to first occurrence of Cmax (tmax) for oral eletriptan was approximately 1 hour and was unaffected by dose. Comparison of AUC values suggested an absolute bioavailability of approximately 50%. A linear PK/PD model, fitted to the data, predicted small, transient elevations in diastolic blood pressure following eletriptan doses ± 60 mg. These effects were considered unlikely to be clinically significant. Eletriptan was well tolerated, and treatment‐related adverse events were mild to moderate and transient. These PK properties should result in eletriptan having a rapid onset and sustained duration of action in terms of migraine efficacy.
Clinical Pharmacokinetics of Verteporfin
Authors: Houle Jean‐Marie , Strong Andrew
Published: July 2003

Verteporfin, a benzoporphyrin derivative, is the first photosensitive (light‐activated) drug to be proven effective in treating certain types of choroidal neovascularization (CNV) secondary to age‐related macular degeneration (AMD). The pharmacokinetics of light‐activated drugs are central to their safety and efficacy. Forty healthy Caucasian volunteers, 24 healthy Japanese volunteers, 9 patients with mild hepatic dysfunction, 69 patients with CNV due to AMD, and 21 patients with skin cancer were infused with verteporfin 3 to 20 mg/m2 of body surface area over 1.5 to 45 minutes. Verteporfin regioisomers and the metabolite benzoporphyrin derivative diacid (BPD‐DA) were quantified by validated methods of liquid chromatography and capillary electrophoresis with laser‐induced fluorescence. Cmax of verteporfin occurred at the end of the infusion and was proportional to the dose and rate of infusion. The extent of formation of the metabolite BPD‐DA was less than 10%, based on the AUC ratio. Renal elimination was minimal (< 0.01% of the dose). All groups studied had similar pharmacokinetics, which were biexponential with distribution in the first 1 to 3 hours and elimination t1/2 of 5 to 6 hours. No significant differences were observed between Japanese and Caucasian volunteers or between men and women. Patients older than 65 years had a slightly higher average Cmax than patients younger than 65 years (1.14 vs. 1.03 μg/ml, p = 0.066), but the ranges of the two age groups overlapped. Verteporfin has a short half‐life and is rapidly eliminated in the bile, mainly as unchanged drug. Based on pharmacokinetic data, dose adjustments are not required for age, gender, race, or mild hepatic or renal impairment. The rapid elimination of verteporfin shows that the period of skin photosensitivity is unlikely to persist after 24 to 48 hours.
Trends of Medication Errors in Hospitalized Children
Authors: Koren Gideon
Published: July 2003

Medication errors are a major cause of morbidity and mortality among hospitalized children. Due to the small volumes of stock solution involved, even a large error may look as an unsuspiciously small dose. Strategies were implemented to reduce medication errors in a large tertiary pediatric hospital in Toronto. Starting in 1993, several initiatives were taken, including a new hospital computer system for medication ordering, a review process to remove hazardous drugs from wards where they are not needed immediately, and in the training of pediatric residents. The rates of reported medication errors were compared before and after these initiatives were taken. Compared to baseline, there was a steady and a statistically significant decrease in medication errors through the decade. Total errors (actual and potential) decreased for nurses and physicians by half and for pharmacists by 75%. Actual incidents decreased by half. Moderate and severe errors decreased by more than 70%. It was concluded that a combination of several initiatives to decrease system and human errors has resulted in more than a 50% reduction of medication errors reaching the pediatric patient.
Educational Issues in Clinical Pharmacology: Who Are Our Audiences and What Are Their Specialized Needs? One Specialized Need: “Understanding the Role of Veterinary Medicine in Public Health”
Authors: Lathers Claire M.
Published: July 2003

When considering educational issues and the need to update the curriculum for clinical pharmacologists for the new millennium, a number of questions must be raised. Who are our audiences? What are the specialized needs? This educational article identifies the audience, which includes those with diverse degrees such as MDs, PhDs, PharmDs, RNs, DVMs, and other non‐MD prescribers working in academia, industry, clinical research organizations, and government in multifaceted disciplines requiring a knowledge base of physiology, pharmacology, biochemistry, anatomy, microbiology, pathology, medicine, and the drug development process of preclinical and clinical studies complete with protocols, pharmacokinetics, and statistics. One specialized current educational issue for clinical pharmacologists to understand is the impact of animal therapeutic and subtherapeutic use of antimicrobials on antibiotic use in human medicine.
Safety, Tolerability, Pharmacokinetics, and Time Course of Pharmacologic Response of the Active Metabolite of Roxifiban, XV459, a Glycoprotein IIb/IIIa Antagonist, following Oral Administration in Healthy Volunteers
Authors: Pieniaszek Henry J. , Sy Sherwin K. B. , Ebling William , Fossler Michael J. , Cain Valerie A. , Mondick John T. , Ma Su , Kornhauser David M.
Published: July 2003

Roxifiban is an ester prodrug that is hydrolyzed, after oral administration, to the active glycoprotein (GP) IIb/IIIa antagonist, XV459. The objectives of the study were to investigate the safety, tolerability, pharmacokinetics, and the time course of the pharmacologic response of XV459 in escalating doses of roxifiban and to assess the effect of age, loading dose of roxifiban, and aspirin pretreatment on XV459 pharmacokinetics, pharmacologic response, and safety profile in a five‐part double‐blind, placebo‐controlled study. Healthy male volunteers (ages 18–46 years) received 7 (0.75‐1.5 mg; n = 20) and 10 (0.75‐1.0 mg; n = 8) multiple, oral, qd doses of roxifiban or placebo (n = 5). Healthy older male and female volunteers (ages 47–75 years) received roxifiban qd doses (0.5‐0.75 mg; n = 8) or placebo (n = 3) for 7 days. Healthy male subjects (ages 18–46 years; n = 16) received a 1.5 or 1.0 mg loading dose either with or without pretreatment of 325 mg aspirin once daily for 3 days followed by single daily doses of 1.0 mg roxifiban for 6 days. Measurable plasma concentrations of XV459 appeared rapidly and were sustained throughout the dosing interval of 24 hours. The pharmacokinetics of XV459 were nonlinear. Systemic exposure of XV459 plateaued at the 1‐mg dose level; plasma concentrations approached steady state in 4 to 6 days for doses greater than 1.0 mg. The time course of pharmacologic response as measured by the inhibition of platelet aggregation in response to an ex vivo 10 μM adenosine 5′‐diphosphate (ADP) agonist correlated closely to the plasma concentration of XV459. Potent inhibition of ADP‐induced platelet aggregation (IPA) persisted over the entire dosing interval. A clear dose response was achieved with roxifiban doses of 0.5 and 1.0 mg. For doses greaterthan 1.0mg, a dose‐proportional increase in IPA was not observed. Both the pharmacokinetics and pharmacologic response of XV459 exhibited low intraindividual variability (coefficient of variation [CV] > 15%) and higher interindividual variability (CV > 30%). Pretreatment with aspirin and/or a loading dose of 1.5 mg roxifiban had no significant effect on the pharmacokinetics and pharmacologic response of XV459. A dose‐related increase in template bleeding time was observed at 1.25‐ and 1.5‐mg doses of roxifiban, as compared to placebo. However, these bleeding time increases in the 1.25‐ and 1.5‐mg dose groups were not significantly different from those at the lower dose groups. Overall, once‐daily oral administration of roxifiban was fairly well tolerated and provided sustained systemic drug exposure and pharmacologic response over the entire administration interval.
Pharmacokinetic and Pharmacodynamic Properties of a New Thromboxane Receptor Antagonist (Z‐335) after Single and Multiple Oral Administrations to Healthy Volunteers
Authors: Matsuno Hiroyuki , Uematsu Toshihiko , Niwa Masayuki , Kozawa Osamu , Nagashima Satoru , Kohno Ken‐Ichi , Kato Hiroki , Kawabata Yoshihiro , Yoshida Yasuhisa , Kanamaru Mitsutaka
Published: July 2003

The pharmacokinetics and pharmacodynamics of a new oral thromboxane (TX) A2 receptor antagonist, Z‐335, were studied in healthy male volunteers following single doses (0.5–40 mg, PO) in a dose‐escalating manner and multiple doses (40 mg, PO, once daily for 7 consecutive days) with a single‐blind, placebo‐controlled design. Serial blood and urine samples were analyzed for Z‐335 and its metabolites to obtain key pharmacokinetic parameters. In the single‐dose (10, 20, and 40 mg) study, the maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) increased in proportion to the dose when administered after fasting, while the mean elimination half‐life (t1/2β) was essentially unchanged (7.79‐7.93 h). Recovery of the unchanged and taurine‐conjugated drugs in the urine within 24 hours was 6.5% to 8.4% and 11.9% to 14.2%, respectively. These parameters essentially remained unchanged when the effect of meal intake was evaluated at the dose of 20 mg with a crossover design. Ex vivo platelet aggregation in the plasma by a TXA2 analogue, U46619, was completely inhibited within 2 hours after all doses, and complete inhibition was maintained for 12 to 14 hours, depending on the dose. The aggregation induced by collagen was also inhibited to a lesser extent, whereas that by adenosine diphosphate was hardly influenced. In themultiple‐dose study, Cmax and AUC0–24 were increased by 34% after the last dose compared with the first dose. Z‐335 afforded extensive inhibition of platelet aggregation by U46619 throughout the administration period, which returned, however, almost to the control level 48 hours after the last dose. The agent was well tolerated without any abnormalities in subjective and objective symptoms, blood biochemistry, hematology, and urinalysis definitely attributable to the agent, except for the changes expected from its TXA2 receptor‐antagonizing actions. Z‐335 was concluded to be safe and to provide long‐lasting blockade of TXA2 receptors on the basis of a once‐daily regimen, promoting further clinical evaluation.
Urinary Excretion and Metabolism of Arbutin after Oral Administration of Arctostaphylos uvae ursi Extract as Film‐Coated Tablets and Aqueous Solution in Healthy Humans
Authors: Schindler Gemot , Patzak Ulrich , Brinkhaus Benno , von Nieciecki Alexander , Wittig Jörg , Krähmer Nils , Glöckl Ingmar , Veit Markus
Published: July 2003

Bearberry leaves and preparations made from them are traditionally used for urinary tract infections. The urinary excretion of arbutin metabolites was examined in a randomized crossover design in 16 healthy volunteers after the application of a single oral dose of bearberry leaves dry extract (BLDE). There were two groups of application using either film‐coated tablets (FCT) or aqueous solution (AS). The urine sample analysis was performed by a validated HPLC cool‐array method (hydroquinone) and a validated capillary electrophoresis method (hydroquinone‐glucuronide, hydroquinone‐sulfate). The total amounts of hydroquinone equivalents excreted in the urine from BLDE were similar in both groups. With FCT, 64.8% of the arbutin dose administered was excreted; with AS, 66.7% was excreted (p = 0.61). The maximum mean urinary concentration of hydroquinone equivalents was a little higher and peaked earlier in the AS group versus the FCT group, although this did not reach statistical significance (Cur max = 1.6893 μmol/ml vs. 1.1250 μmol/ml, p = 0.13; tmax (t midpoint) = 360 h vs. 440 h P = 038). The relative bioavailability of FCT compared to AS was 103.3% for total hydroquinone equivalents. There was substantial intersubject variability. No significant differences between the two groups were found in the metabolite patterns detected (hydroquinone, hydroquinone‐glucuronide, and hydroquinone‐sulfate).