bluuebunny/crossref_metadata_2025 huggingface dataset:
The Single‐Dose Pharmacokinetics of Midazolam and Its Primary Metabolite in Pediatric Patients after Oral and Intravenous Administration
Authors: Reed Michael D. , Rodarte Alexander , Blumer Jeffrey L. , Khoo Ko‐Chin , Akbari Bardia , Pou Sovitj , Kearns Gregory L.
Published: July 2003

The first‐dose pharmacokinetics of midazolam and its primary α‐hydroxy metabolite were studied after single‐dose administration. Eligible study patients were enrolled into one of three study arms: Arm I (midazolam/metabolite pharmacokinetic evaluation after oral administration of a syrup formulation), Arm II (the absolute bioavailability of midazolam syrup), and Arm III (midazolam and metabolite pharmacokinetics after IV administration). Complete blood sampling for pharmacokinetic analysis was available in 87 subjects. Midazolam absorption after administration of the oral syrup formulation was rapid, with adolescents absorbing the drug at approximately half the rate observed in younger children (ages 2 to < 12 years). Furthermore, midazolam t1/2 was prolonged and CL/F reduced in adolescents as compared with younger children. Although the midazolam Vd/F appeared larger in the youngest age group after oral administration, this observation was not apparent after IV dosing, suggesting subject differences in bioavailability rather than distribution. Like midazolam, the disposition characteristics for α‐hydroxymidazolam were also highly variable, with the greatest formation of metabolite (reflected by the AUC ratio) observed in children ages 2 to < 12 years. The AUC ratios of α‐hydroxymidazolam to midazolam after IV dosing were similar across all age groups and were smaller than corresponding values following oral administration. The absolute bioavailability of midazolam averaged 36% with a very broad range (9%‐71%). No relationship between midazolam bioavailability and age was observed. Overall, the disposition characteristics of midazolam and its α‐hydroxy metabolite were highly variable, appeared independent of age and dose administered, and were linear over the dose range studied (0.25 to 1 mg/kg). These data suggest that an initial oral dose of 0.2 to 0.3 mg/kg should be adequate for successful sedation of most pediatric patients. The inherent variability in midazolam bioavailability and metabolism underscores the importance of titrating midazolam dose to desired effect.
Evaluation of Student Achievement and Educational Outcomes
Authors: Williams Patricia B. , Lathers Claire M. , Smith Cedric M. , Payer Andrew , Volle Robert L.
Published: July 2003

Development of problem‐solving skills is vital to professional education as is factual recall. Student mastery must be measured to document student achievement required for completion of educational requirements and professional certification. These measurements also help determine if the educational process is meeting its goal of helping students develop critical cognitive skills fortherapeutic problem solving. Testing student growth in the ability to solve problems is less understood. Stressing integration of information across disciplines to derive answers is also important. Test items should resemble the real‐world task that students are expected to master. That is really the essence of content validity, which means faculty should be biased toward presenting information that way. This article is based on a symposium presented at the annual meeting of the American College of Clinical Pharmacology in September 1996. Symposium goals were to define purposes and uses of student evaluations by type and format, including application of techniques that improve evaluation, precision, and validity. Technical applications of computer‐based learningand evaluation of problem‐solving skills are described. Actual experience with evaluation of problem solving in the curriculum is discussed. The process by which a medical school developed and implemented an evaluation system for a new problem‐based curriculum is presented, followed by a critique of the successes and problems encountered duringthe first year of implementation. Criteria that a well‐constructed evaluation program must meet are explored. The approach and philosophy of national standardized testing centers are explained.
Pharmacodynamics and Pharmacokinetics of Omapatrilat in Heart Failure
Authors: Kostis John B. , Klapholz Marc , Delaney Ms. Carol , Vesterqvist Ole , Cohen Marvin , Manning James A. , Jemal Mohammed , Kollia Georgia D. , Liao Wei‐Chi
Published: July 2003

The purpose of this study was to determine the pharmacodynamics and pharmacokinetics of omapatrilat, administered orally (25 mg) or intravenously (10 mg) in 19 New York Heart Association class II and class III congestive heart failure (CHF) patients versus 17 healthy controls matched for age, race, gender, and weight. The plasma concentrations of atrial natriuretic peptide (ANP) increased by approximately 20% and 30% in CHF and control subjects, respectively, at 4 hours after intravenous or oral omapatrilat administration. Similar elevation in the cyclic guanosine monophosphate concentration (25% to 35%) and ANP urinary excretion (21 ng/24 h to 22 ng/24 h) was seen in all treatment groups after omapatrilat administration. Angiotensin‐converting enzyme activity was > 90% inhibited at 4 hours after dosing and remained approximately 60% to 70% inhibited at 24 hours after dosing. The levels of endothelin‐1 and endothelin‐2 remained unchanged after oral or intravenous administration of omapatrilat. The maximal reduction in seated blood pressure compared with baseline was similar for CHF and control subjects. Clinical pharmacokinetic parameters were similar in both groups after intravenous dosing, but maximum concentration and area underthe concentration‐time curve were elevated in CHF patients compared with controls after oral dosing. Omapatrilat was well tolerated; differences in systemic exposure and metabolism between CHF patients and controls did not appear to be clinically significant.
Pharmacokinetics of Norelgestromin and Ethinyl Estradiol Delivered by a Contraceptive Patch (Ortho Evra™/Evra™) under Conditions of Heat, Humidity, and Exercise
Authors: Abrams Larry S. , Skee Ms. Donna M. , Natarajan Jaya , Wong Frankie A. , Leese Philip T. , Creasy George W. , Shangold Mona M.
Published: July 2003

The objectives of this randomized, open‐label, three‐period, incomplete block design study were to evaluate the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE) delivered by the contraceptive patch, Ortho EvraTM/EvraTM, and to evaluate patch adhesion under conditions of heat, humidity, and exercise. During each treatment period, 30 healthy women wore Ortho EvraTM on the abdomen for 7 days under one of six conditions (normal activity, sauna, whirlpool, treadmill, cool water immersion, ora combination of activities). Blood samples were collected before and several times to 240 hours after patch application. Mean serum concentrations of NGMN and EE generally remained within the reference ranges, 0.6 to 1.2 ng/ml and 25 to 75 pg/ml, respectively, duringthe 7‐day wear period for all activities. Only 1 (1.1%) of 87 patches completely detached spontaneously. Peel force measurements were comparable for all activities. Ortho EvraTM was well tolerated. In conclusion, Ortho EvraTM delivers efficacious concentrations of NGMN and EE and maintains adhesive reliability through 7 days of wear even under conditions of heat, humidity, and exercise.
The Effect of Intravenous Haloperidol on QT Interval Dispersion in Critically Ill Patients: Comparison with QT Interval Prolongation for Assessment of Risk of Torsades de Pointes
Authors: Tisdale James E. , Rasty Saeed , Padhi I. Desmond , Sharma Nagaraja D. , Rosman Howard
Published: July 2003

The objective of this study was to determine the effect of intravenous haloperidol on QT interval dispersion in critically ill patients and to compare increases in QT interval dispersion and QTc intervals in patients who developed haloperidol‐induced Torsades de Pointes versus those in patients who did not. This was a case‐controlled study of 30 critically ill patients who received intravenous haloperidol for delusional agitation. Cases were patients (n = 6) who developed Torsades de Pointes during haloperidol therapy. Controls were patients (n = 24) who did not experience haloperidol‐induced Torsades de Pointes. QTc intervals were measured and QT interval dispersion was calculated. Haloperidol prolonged QTc interval compared to pretreatment values in Torsades de Pointes patients (606 ± 61 ms vs. 501 ± 44 ms, p = 0.007) by a greater magnitude than in patients who did not experience Torsades de Pointes (507 ± 60 ms vs. 466 ± 44, p = 0.01). Twelve‐lead analysis revealed that QTinterval dispersion increased in patients who experienced Torsades de Pointes (from 63 ± 11 to 95 ± 22 ms, p = 0.03) but not in those who did not (62 ± 18 vs. 60 ± 26 ms, p = 0.66). Analysis of precordial leads only showed no significant haloperidol‐associated increases in QT interval dispersion in either group. The odds of developing haloperidol‐induced Torsades de Pointes were highest in patients with QTc interval > 521 ms during haloperidol therapy (odds ratio = 12.0). It was concluded that intravenous haloperidol prolongs QTc intervals in critically ill patients. The degree of prolongation is greater in patients who experience Torsades de Pointes. QT interval dispersion may be increased in patients who develop haloperidol‐induced Torsades de Pointes compared with those who do not. However, these effects are dependent on the method of measurement (12 leads vs. precordial leads). In addition, the odds of haloperidol‐induced Torsades de Pointes are higher in patients with QTc interval prolongation compared with increased QTinterval dispersion. Therefore, QTc inter‐val determination remains preferable to QT interval dispersion as a means assessment of risk for haloperidol‐induced Torsades de Pointes.
Pharmacokinetics of Intravenous Itraconazole followed by Itraconazole Oral Solution in Patients with Human Immunodeficiency Virus Infection
Authors: Zhao Qinying , Zhou Honghui , Pesco‐Koplowitz Luana
Published: July 2003

This randomized, open‐label, comparative study assessed the pharmacokinetics and safety of intravenous and oral hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) solutions of itraconazole in patients with advanced human immunodeficiency virus (HIV) infection. All patients received 1‐hour intravenous infusions of itraconazole 200 mg twice daily for 2 days, then once daily for 5 days. Patients were then randomized to receive itraconazole oral solution, 200 mg twice daily or 200 mg once daily, for a further 28 days. Itraconazole was solubilized by HP‐β‐CD in both intravenous and oral solutions, so HP‐β‐CD concentration in plasma was measured. Thirty‐two patients were enrolled and analyzed (n = 32 for intravenous treatment, 32 completed; n = 16 for oral once daily, 15 completed; n = 16 for oral twice daily, 12 completed). Steady‐state plasma concentrations of itraconazole and hydroxyitraconazole were reached by days 3 and 6, respectively. After intravenous dosing, mean trough plasma concentrations of itraconazole and hydroxyitraconazole were 906 ng/ml and 1690 ng/ml, respectively. During oral dosing, mean trough plasma concentrations of itraconazole and hydroxyitraconazole were maintained or increased in the 200 mg twice‐daily group but fell with the 200 mg once‐daily oral dose. Itraconazole was generally well tolerated and had a favorable safety profile; minor changes in hematology variables werenoted duringthe intravenous phase, and HP‐β‐CD was cleared rapidly, mostly in urine. Twenty‐eight patients (88%) experienced at least one adverse event; no adverse event was severe, and only seven were definitely related to itraconazole. In conclusion, itraconazole 200 mg given intravenously twice daily for 2 days, then once daily for 5 days, rapidly achieves a mean steady‐state trough concentration of itraconazole of over 250 ng/ml, which is associated with clinic outcome and is effectively maintained with itraconazole oral solution 200 mg twice daily in patients with advanced HIV infection.
Pharmacokinetics and Safety of Oral Eletriptan during Different Phases of the Menstrual Cycle in Healthy Volunteers
Authors: Shah Ajit K. , LaBoy‐Goral Ms. Lucia , Scott Nicholas , Morse Ms. Theresa , Apseloff Glen
Published: July 2003

The purpose of this study was to determine the pharmacokinetics and safety of eletriptan in different phases of the menstrual cycle. Female volunteers (n = 16) with a regular menstrual cycle (28 ± 4 days) received a single oral dose of 80 mg eletriptan during each of the four cycle phases: phase 1 (menses), days 1 to 4; phase 2 (follicular), days 6 to 10; phase 3 (ovulatory), days 11 to 13; and phase 4 (luteal), days 21 to 24. Eletriptan plasma concentrations were determined from serial plasma samples taken during a 24‐hour period after dosing. Blood pressure, pulse rate, and ECG measurements were performed at baseline, 1 and 24 hours after dosing. No significant differences between phases were observed for maximum plasma concentration (Cmax, range of means = 188–234 ng/ml), time to maximum concentration (tmsx, range of means = 1.8‐2.5 h), or systemic exposure (area underthe curve [AUC], range of means = 1194–1514 ng·h/ml). Although there was a statistically significant difference in the terminal phase elimination rate constant (kel) between phases 1and 2 (0.175/h vs. 0.158/h, p = 0.044), the corresponding difference in terminal phase half‐life (t1/2) (4.0 h vs. 4.4 h) was not considered to be clinicallyrelevant. No clinicallyrelevant differences in blood pressure, pulse rate, or ECG were observed, and the incidence, nature, and severity of adverse events were similar in all phases. The different phases of the menstrual cycle had no clinically significant effect on the pharmacokinetics, safety, or tolerability of oral 80 mg eletriptan in healthy females.
Comparative Pharmacokinetics of Lovastatin Extended‐Release Tablets and Lovastatin Immediate‐Release Tablets in Humans
Authors: Sun Jim X. , Niecestro Robert , Phillips Gale , Shen Jason , Lukacsko Peter , Friedhoff Lawrence
Published: July 2003

The pharmacokinetics of lovastatin and its active metabolite lovastatin acid was evaluated in 9 healthy subjects in a three‐period crossover study following a single oral dose of lovastatin extended‐release (ER) tablets and lovastatin immediate‐release (IR) tablets. Participants were dosed with lovastatin IR 40 mg tablets following a standard breakfast, lovastatin ER 40 mg tablets following a standard breakfast, and lovastatin ER 40 mg tablets under fasting conditions. Serial plasma samples were collected for up to 48 hours postdose and assayed for lovastatin and lovastatin acid using a liquid chromatography/mass spectroscopy/mass spectroscopy method. Lovastatin ER tablets, unlike lovastatin IR tablets, exhibited delayed‐ and extended‐release characteristics. The relative bioavailabilitv, in terms of area under the curve values, of lovastatin (156%) and lovastatin acid (124%) was greater from lovastatin ER tablets as compared with lovastatin IR tablets when given with breakfast. An even greater increase in the bioavailability of lovastatin (261%) and lovastatin acid (231%) was observed when the lovastatin ER tablets were administered under fasting conditions. Thus, greater gastrointestinal tract drug absorption of lovastatin from lovastatin ER tablets was demonstrated. Ingestion of a standard breakfast prior to administration of lovastatin ER tablets decreased absorption of lovastatin by approximately 40%, relative to lovastatin ER tablets under fasting conditions.
Oral Hormone Replacement Therapy: Factors That Influence the Estradiol Concentrations Achieved in a Multiracial Study Population
Authors: Gavaler Judith S.
Published: July 2003

The assumption that estradiol (E2) concentrations are reliably increased to therapeutic levels in postmenopausal women receiving hormone replacement therapy (HRT) has not been explicitly tested. Nor have factors that may modulate the E2 levels achieved been evaluated. The author examined E2 concentrations in a multiracial study population of 309 postmenopausal women treated with oral HRT and observed that 51.1% had achieved estradiol levels of at least 45 pg/ml (achievers). The odds of being an achiever were significantly elevated among non‐Caucasian women by a HRT dose greater than 0.625 mg, current moderate drinking, and increasing duration of HRT use. The odds were significantly decreased by having a high school education or less and increasing time since last HRT dose. White postmenopausal women had significantly reduced odds of being an achiever, and both a dose of less than 0.625 mg and a dose equal to 0.625 mg significantly reduced the odds of being an achiever. Increasing body mass index and menopause duration were both associated with lower odds. This report demonstrates not only that women treated with HRT do not all achieve therapeutic levels of estradiol but also that factors can be identified that modulate the E2 concentration achieved in response to HRT administration.
Increased Sensitivity to Warfarin in Elderly Hispanics
Authors: Casner Paul R. , Sandoval Eduardo
Published: July 2003

It has been suggested that aging enhances the pharmacologic effect of warfarin, but there is little information about the effects of warfarin in aging minority populations. The authors examine the response of an aging Hispanic population to warfarin. Charts in their anticoagulation clinic were retrospectively examined for the following information: age, sex, weight, duration of anticoagulant therapy, number of medical problems, number of medications, number of minor or major bleeding episodes, prothrombin time, warfarin dose, and international normalized ratio (INR). The dose‐adjusted prothrombin time ratio (PTR) and dose‐adjusted INR were calculated by dividing the PTR and INR by the mean warfarin dose. Four groups were compared by age: <50, 50 to 59, 60 to 69, and ≥70. A total of243 charts were reviewed: 113 female, 130 male; 90% were Hispanic. The most common indication for anticoagulation was atrial fibrillation. Elderly patients had more medical problems (3.1 vs. 2.4) and took more medications (3.4 vs. 2.4) than younger patients. The dose‐adjusted PTR and dose‐adjusted INR increased with aging (0.59 vs. 0.38 and 0.85 vs. 0.59, p > .05 ANOVA). In a multiple linear regression analysis, only age remained significantly associated with the anticoagulant effect. These results are consistent with previous reports on the effect of warfarin in aging patients and extend these data to the Hispanic population.
Multiple‐Dose, Safety, Pharmacokinetics, and Pharmacodynamics of a New Selective Estrogen Receptor Modulator, ERA‐923, in Healthy Postmenopausal Women
Authors: Cotreau Monette M. , Stonis Lucille , Dykstra Kevin H. , Gandhi Thimma , Gutierrez Maria , Xu Jing , Park Young , Burghart Peter H. , Schwertschlag Ullrich S.
Published: July 2003

ERA‐923 is a new selective estrogen receptor modulator under clinical investigation for use in tamoxifen refractory metastatic breast cancer. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of once‐daily oral ERA‐923 (10–200 mg) for 28 days in healthy postmenopausal females. ERA‐923 was well tolerated, and adverse events were mild and reversible. No clinically significant changes in laboratory values were found with ERA‐923 versus placebo. ERA‐923 appeared to undergo extensive metabolism and enterohepatic recirculation. In addition, pharmacokinetic analysis showed that a high‐fat breakfast increased the extent of absorption. ERA‐923‐dosed subjects had no uterine or ovarian changes when evaluated with transvaginal ultrasound and compared to placebo subjects. Overall, ERA‐923 was safe and well tolerated in postmenopausal women dosed for 28 days.
Multiple‐Dose, Linear, Dose‐Proportional Pharmacokinetics of Retigabine in Healthy Volunteers
Authors: Ferron Geraldine M. , Paul Jeffrey , Fruncillo Richard , Richards Lyette , Knebel Norbert , Getsy John , Troy Steven
Published: July 2003

Retigabine, a first‐in‐class selective M‐current potassium channel opener, is a novel antiepileptic compound currently in clinical development. The purpose of this randomized placebo‐controlled study was to assess retigabine oral safety and pharmacokinetics in healthy male volunteers (N = 45). Subjects received one dose on day 1 and doses every 12 hours for the next 14 days. Fixed doses were given to the first four groups (200, 400, 500, and 600 mg per day). Titrated doses were given to group 5 in 100 mg increases every 4 days, achieving 700 mg per day on day 15. Serial blood samples were collected on days 1 and 15. Pharmacokinetic parameters were compared between days and among dose groups. After administration of a single dose, retigabine was rapidly absorbed, with maximum concentrations of 387 ng/ml (normalized to a 100 mg dose) occurring within 1.5 hours. Retigabine was eliminated with a mean terminal half‐life of 8.0 hours and an apparent oral clearance of 0.70 L/h/kg in white subjects. In black subjects, retigabine clearance and volume of distribution were 25% and 30% lower, respectively, after normalizing by body weight, leading to higher exposure in this population. Retigabine's pharmacokinetics was linearly dose proportional. Steady‐state pharmacokinetics was in agreement with single‐dose pharmacokinetics, and the accumulation ratio was about 1.5. Retigabine and AWD21‐360 trough evening concentrations were significantly lower (about 30% to 35%) than morning values. The titration regimen allowed for higher doses to be tolerated compared to the fixed‐dose regimen. In conclusion, the pharmacokinetics of retigabine is linearly dose proportional for daily doses of 100 to 700 mg and is not modified on multiple administrations.
Effect of Fluconazole on the Pharmacokinetics and Pharmacodynamics of Oral and Rectal Bromazepam: An Application of Electroencephalography as the Pharmacodynamic Method
Authors: Ohtani Yasukiyo , Kotegawa Tsutomu , Tsutsumi Kimiko , Morimoto Takuya , Hirose Yumiko , Nakano Shigeyuki
Published: July 2003

Quantitative analysis of electroencephalography (EEG) is used increasingly to evaluate the pharmacodynamics of benzodiazepines. The present study aimed to apply the EEG method as well as more traditional approaches to an interaction study of bromazepam and fluconazole. Twelve healthy male volunteers participated in a randomized, double‐blind, four‐way crossover study. The subjects received single oral or rectal doses of bromazepam (3 mg) after 4‐day pretreatment of oral fluconazole (100 mg daily) or its placebo. Plasma bromazepam concentrations were measured before and 0.5, 1,2,3,4, 6,12,22,46, and 70 hours after bromazepam administration. Pharmacodynamic effects of bromazepam were assessed using self‐rated drowsiness, continuous number addition test, and EEG. Fluconazole caused no significant changes in pharmacokinetics and pharmacodynamics of oral or rectal bromazepam. Rectal administration significantly increased AUC (1.7‐fold, p < 0.0001) and Cmax (1.6‐fold, p < 0.0001) of bromazepam. These changes following rectal dose may be due to avoidance of degradation occurringin the gastrointestinal tract. Rectal bromazepam also increased the area under the effect curves assessed by EEG (p < 0.05) and subjective drowsiness (p < 0.05). EEG effects were closely correlated with mean plasma bromazepam concentrations (r = 0.92, p < 0.001 for placebo; r = 0.89, p < 0.0001 for fluconazole). Thus, the EEG method provided pharmacodynamic data that clearly reflected the pharmacokinetics of bromazepam.
Pharmacokinetics of Diethylcarbamazine after Single Oral Dose at Two Different Times of Day in Human Subjects
Authors: Bolla Sambamoorthy , Boinpally Ramesh R. , Poondru Srinivasu , Devaraj Rambhau , Jasti Bhaskara R.
Published: July 2003

In most Wuchereria bancrofti and Brugia malayi infections, the microfilaria are found in the blood in greatest number between 10 p.m. and 2 a.m., indicating that chronotherapy may be beneficial in treating such infections. This study reports the influence of time of administration on the pharmacokinetics of diethylcarbamazine (DEC) in healthy volunteers. The study was conducted in 12 healthy volunteers by administering a 150 mg single oral dose of diethylcarbamazine citrate at 0600 or 1800 h in a balanced crossover design with the approval of an institutional ethics committee. The subjects fasted for about 10 hours before and 3 hours after drug treatment. Blood samples were collected at predetermined time intervals, and the drug content in the serum was estimated using HPLC with an electrochemical detector. Pharmacokinetic analysis was performed using noncompartmental methods employing WinNonlin (version 3.1), and the means of various pharmacokinetic parameters were compared for any dosing time‐related changes using a paired t‐test at a probability level of 95%. The mean ± SD values of pharmacokinetic parameters of DEC for the treatments at 0600 versus 1800 h were as follows: Cmax, 500 ± 227 versus 637 ± 401 ng/ml; tmax, 2.3 ± 0.7 versus 2.7 ± 1 h; Ka, 2.23 ± 0.72 versus 1.96 ± 0.97 h−1; t1/2, 14.6 ± 6.7 versus 11.4 ± 4.9 h; AUC0‐t, 5,334 ± 1,853 versus 6,901 ± 4,203 ng·h/ml; AUC0‐∞, 5,840 ± 1,922 versus 7,220 ± 4,205 ng·h/ml; CL/F, 36,058 ± 19,011 versus 32,189 ± 25,293 ml/h/kg; Vd/F, 570 ± 225 versus 533 ± 447 L; and MRT, 17.7 ± 5.9 versus 15.3 ± 5.2 h. None of the parameters was significantly changed (p > 0.05)as a function of time of administration.
Lack of Interaction between Amiodarone and Mexiletine in Cardiac Arrhythmia Patients
Authors: Yonezawa Emi , Matsumoto Kana , Ueno Kazuyuki , Tachibana Miho , Hashimoto Hiroshi , Komamura Kazuo , Kamakura Shiro , Miyatake Kunio , Tanaka Kazuhiko
Published: July 2003

Amiodarone has pharmacokinetic interactions with various therapeutic agents, including phenytoin, flecainide, and cyclosporine. Mexiletine is metabolized by CYP2D6 and CYP1A2. The objective of this study is to evaluate the effect of amiodarone on the pharmacokinetics of mexiletine through its inhibition of various cytochrome P450 (CYP) subtypes. In a series of 181 inpatients with supraventricular tachyarrhythmias, 26 inpatients received mexiletine and amiodarone therapy (MEX + AMD group), and the others received mexiletine therapy (MEX group). In 10 inpatients of the MEX + AMD group, the mexiletine clearance (CLMEX/F) before and after coadministration of amiodarone was compared. CLMEX/F was also compared in the MEX and MEX + AMD groups after the start of amiodarone therapy. Serum mexiletine, amiodarone, and desethylamiodarone concentrations were measured by an HPLC method. The CLMEX/F was estimated by the Bayesian method using population pharmacokinetic analysis. There was no significant difference in CLMEX/F before and after 1‐month coadministration of amiodarone in 10 inpatients of the MEX + AMD group. Although serum amiodarone and desethylamiodarone concentrations gradually increased with time after the start of amiodarone therapy in these patients, CLmex/F showed no change at 3 and 5 months after the start of amiodarone therapy. There was no significant difference in CLMEX/F of the MEX group and the MEX + AMD group. The results suggest that the pharmacokinetics of mexiletine is not affected by amiodarone in patients with cardiac arrhythmias.
The Influence of Hormones and Pharmaceutical Agents on DHEA and DHEA‐S Concentrations: A Review of Clinical Studies
Authors: Salek Firoozeh S. , Bigos Kristin L. , Kroboth Patricia Dowley
Published: July 2003

Low endogenous levels of dehydroepiandrosterone (DHEA) and/or its sulfoconjugated derivative DHEA‐S have been associated with diseases such as lupus, cancer, and diabetes. Circulating concentrations of DHEA and DHEA‐S resulting from endogenous production or hormone supplementation may also be relevant in psychiatric illness. Drugs may significantly increase or decrease circulating concentrations of these adrenal androgens by various mechanisms. Some agents, such as dexamethasone, affect the HPA axis by inhibiting ACTH and therefore decrease DHEA and DHEA‐S concentrations. Central nervous system agents, including carbamazepine and phenytoin, induce the P450 enzymes that metabolize DHEA and DHEA‐S and therefore decrease circulating concentrations of these hormones. Danazol alters the ratio between DHEA and DHEA‐S by inhibiting sulfatase. As research moves forward to better understand the relationships of these adrenal androgens with health and disease, it is essential that studies be designed to control for the influence of administered pharmaceuticals on DHEA and DHEA‐S.
Serum Concentrations, Efficacy, and Safety of a New, Intravenously Administered Varicella Zoster Immune Globulin in Pregnant Women
Authors: Koren Gideon , Money Deborah , Boucher Marc , Aoki Fred , Petric Martin , Innocencion Gilda , Woloski Michael , Remple Valencia , Pelland Francine , Geist Ruth , Ho Tommy , Bar‐Oz Benny , Loebstein Ronen
Published: July 2003

Chickenpox is teratogenic in humans, and varicella zoster immune globulin (VZIG) is given to pregnant women believed to be susceptible to the virus after contact with chickenpox. Available VZIG is given as intramuscular injections. The objective of this study was to evaluate the efficacy, safety, and serum concentrations of a new VZIG that can be given intravenously. The new VZIG (Cangene Pharm, Inc.) was compared to the standard VZIG (Massachusetts Public Health Biologic Laboratories) in a randomized protocol in 57 pregnant women seronegative to varicella zoster virus (VZV). Pregnant women received 125 units per 10 kg body weight to a maximal dose of 625 units. Women were evaluated on days 2, 7, 14, and 28 and at other times if symptoms developed into clinical varicella, which was scored by the Constitutional Illness Score. The new VZIG was comparable to the standard VZIG on all parameters of efficacy and safety. Levels of VZV antibodies at day 2 postinjection were significantly higher among those receiving the new preparation intravenously. The authors concluded that the new intravenous form of VZIG confers higher initial levels of VZV antibodies and is comparable in terms of its maternal efficacy and safety to the standard form of VZIG.
Influence of Food Intake and Formulation on the Pharmacokinetics and Metabolism of Bosentan, a Dual Endothelin Receptor Antagonist
Authors: Dingemanse Jasper , Bodin Frederic , Weidekamm Erhard , Kutz Klaus , van Giersbergen Paul
Published: July 2003

The purpose of the study was to investigate the effect of food intake on the pharmacokinetics and metabolism as well as the relative bioavailability of bosentan. Sixteen healthy male subjects were treated in a randomized, four‐way, crossover design with single oral doses of 125 mg bosentan, given as one tablet (with or without food), two tablets of 62.5 mg (with food), and a suspension (without food). The pharmacokinetic parameters of bosentan (and also three of its metabolites) were very similar after the four treatments: geometric means for Cmax and AUC0‐∞ ranged from 1.3 to 1.6 μg/ml and from 7.8 to 8.9 μg·h/ml, respectively, and median tmax from 3.0 to 4.0 hours. The bioavailability of the 125 mg tablet relative to that of the suspension, both given fasted, was 102%. In the presence of food, Cmax and AUC0‐∞ increased by 22% and 10%, respectively, whereas the two 62.5 mg tablets were bioequivalent to the 125 mg tablet, both underfed conditions. The pharmacokinetics of the metabolites was independent of the treatment administered. In conclusion, bosentan bioavailability from the newly developed 125 mg tablet formulation is similar to that of the suspension, and food intake does not influence its pharmacokinetics to a clinically relevant extent.
A Study of the Interaction Potential of Azithromycin and Clarithromycin with Atorvastatin in Healthy Volunteers
Authors: Amsden Guy W. , Kuye Olatunde , Wei Greg C. G.
Published: July 2003

Atorvastatin is a common option among the HMG‐CoA reductase inhibitors for the treatment of lipid disorders because of its excellent lipid‐lowering efficacy and overall safety profile. Although these agents can rarely cause rhabdomyolysis by themselves, macrolides, among other agents, have been demonstrated to increase the likelihood of this via inhibition of CYP metabolism of the lipid agent. This study investigated the potential for azithromycin and clarithromycin to inhibit the metabolism of atorvastatin. Although there was no interaction between azithromycin and atorvastatin, clarithromycin did have a significant effect on atorvastatin pharmacokinetic parameters. When coadministered, clarithromycin raised subject exposure (AUC24) by 82% and peak plasma concentrations by 56%. These data suggest that while azithromycin appears to be safe to coadminister with atorvastatin, clarithromycin should be avoided in patients taking this and similarly metabolized HMG‐CoA inhibitors.
Lack of Bioequivalence of Ciprofloxacin When Administered with Calcium‐Fortified Orange Juice: A New Twist on an Old Interaction
Authors: Neuhofel Ashley L , Wilton John H. , Victory Jennifer M. , Hejmanowski Linda G. , Amsden Guy W.
Published: July 2003

Fluoroquinolones are known to interact with drugs containing multivalent ions. Current Food and Drug Administration (FDA) labeling states that ciprofloxacin and most other fluoroquinolones are safe to be given with food and dietary calcium but not calcium supplements. Although many of the currently marketed calcium fortified foods have calcium contents that usually exceed those in dietary calcium sources, it is unclear whether they represent a risk for less than optimal absorption of fluoroquinolones, which may result in subsequent clinical failures due to lack of bacterial eradication and antibiotic resistance. The purpose of this three‐way, randomized, crossover study was to characterize and compare the bioequivalence of single doses of oral ciprofloxacin in 15 healthy volunteers when administered with water, concurrently with orange juice, and concurrently with calcium‐fortified orange juice. Compared to the control arm, the Cmax of ciprofloxacin significantly decreased when it was given with orange juice (23%, p = 0.001) and with calcium‐fortified orange juice (41%, p < 0.001). Twenty‐four‐hour ciprofloxacin AUCs were also decreased for both forms of the orange juice (22% [p < 0.001] and 38% [p < 0.001], respectively). When compared to each other, neither of the orange juice regimens were bioequivalent to each other, with the Cmax and AUC for the fortified form being 22% (p = 0.005) and 21% (p = 0.015) lower than those of the nonfortified form. By FDA standards, although ciprofloxacin is marginally bioequivalent when administered with orange juice, it is not when it is administered with calcium‐fortified orange juice. The changes in Cmax and AUC have the potential to significantly decrease clinical efficacy and promote antibiotic resistance. Not warning patients about potential food‐drug interactions with fortified foods may be a major unrealized and unstudied inadvertent source of clinical failures and resistance trends with fluoroquinolones.
Bioavailability and Metabolism of Mometasone Furoate: Pharmacology versus Methodology
Authors: PhD Hartmut Derendorf , Daley‐Yates Peter T. , Pierre Lisa N. , Efthimiou John
Published: July 2003

The degree of systemic exposure after inhalation of corticosteroids is of great clinical concern. For optimum outcome, the pulmonary deposition should be sufficiently high to produce the desired anti‐inflammatory effect in the lungs, whereas the plasma concentrations due to the absorption of the corticosteroid from the lung and the gut should be minimal. Recently, it has been reported that inhaled mometasone furoate has a systemic bioavailability of less than 1%, which is much lower than other corticosteroids currently available. However, critical evaluation of the study methodology and results does not support this finding. A major shortfall of the study was an insufficient analytical sensitivity, resulting in a calculated average plasma concentration profile that was entirely below the limit of quantification. These numbers were generated by replacing all concentrations below the limit of quantification by zero and then calculating an average value. This procedure can lead to erroneous results and misinterpretation. Furthermore, the potential contribution of active metabolites needs to be adequately addressed in comparisons of inhaled corticosteroids. Reliable estimates of systemic drug exposure are critical in evaluating the real safety profiles and therapeutic index for inhaled corticosteroids that are effective in treating chronic asthma.
Safety and Pharmacokinetics of Oral Voriconazole in Patients at Risk of Fungal Infection: A Dose Escalation Study
Authors: Lazarus Hillard M. , Blumer Jeffrey L. , Yanovich Saul , Schlamm Haran , Romero Alain
Published: July 2003

The objective of this study was to investigate the safety, tolembility, and pharmacokinetics of oral voriconazole in subjects at high risk of developing fungal infections. This was a multicenter, randomized, double‐blind, double‐dummy, parallel‐group, dose escalation study with a fluconazole active control. Twenty‐four subjects with hematological malignancies, solid tumors, or autologous bone marrow transplants were randomized to receive voriconazole 200 mg q 12 h (n = 9), voriconazole 300 mgq 12 h (n = 9), or fluconazole 400 mg OD(n = 6) for a period of 14 days. Blood samples were taken for the assessment of voriconazole pharmacokinetics in plasma on Days 1 and 14. Using a 200 mgq 12 h dosing regimen, geometric mean voriconazole peak plasma concentrations (Cmsx) were 904 ng/ml on Day 1 and 2996 ng/ml on Day 14. Geometric mean voriconazole exposure, as measured by the area under the curve within a dosing interval (AUCπ, was 4044 and 20308 ng·h/ml on Days 1 and 14, respectively. On Day 1, geometric mean Cmax and AUC were 1.80‐ and 1.94‐fold higher in subjects receiving voriconazole 300 mg q 12 h than in those receiving 200 mg q 12 h. Similarly, on Day 14, geometric mean Cmax and AUC were 1.56‐ and 1.80‐fold greater in the high‐dose group. Although the confidence intervals are large, this trend suggests nonlinearity in pharmacokinetics with respect to dose as seen in healthy volunteers. The absorption of orally administered voriconazole was relatively rapid, with tmax achieved in 1.7 to 3.0 hours. There was a mean 5.4‐ and 5.0‐fold accumulation of voriconazole over the 14‐day study period in the 200 mg and 300 mg q 12 h dose groups, respectively. Voriconazole was generally safe and well tolerated. Mild, reversible visual disturbances were the most commonly reported adverse event but were not associated with treatment discontinuation. No patient developed a breakthrough fungal infection. It was concluded that in thisgroup of patients at risk of fungal infection, voriconazole pharmacokinetics was consistent with that reported in healthy volunteers.
Comparative Target Site Pharmacokinetics of Immediate‐ and Modified‐Release Formulations of Cefaclor in Humans
Authors: de la Peña Amparo , Brunner Martin , Eichler Hans‐Georg , Rehak Edelgard , Gross Jens , Thyroff‐Friesinger Ursula , Müller Markus , Derendorf Hartmut
Published: July 2003

Optimal dosing of beta‐lactam antibiotics aims at maximizing the time at which drug levels in the interstitial space fluid (ISF)—the fluid that surrounds the causative microorganisms at the target site—exceed the minimal inhibitory concentration (MIC). One potentially attractive strategy to achieve this goal is to administer antibiotics as oral sustained‐release formulations. The present study was designed to test the hypothesis that sustained‐release formulations could lead to a more suitable pharmacokinetic profile in the ISF at the relevant target site. For this purpose, time versus cefaclor concentration profiles attained in the ISF were measured following administration of two formulations, an immediate‐ (500 mg IR) and a modified‐release formulation in two different doses (500 mg MR and 750mgMR)in a three‐way crossover study of healthy male volunteers (n = 12). For the measurement of unbound cefaclor concentrations in the ISF of human skeletal muscle, the in vivo microdialysis technique was employed. For all three formulations, unbound cefaclor concentration in the ISF closely followed individual plasma concentration profiles in a dose‐dependent pattern, with ISF to unbound plasma ratios ranging from 0.67 to 0.73. The mean residence time was found to be significantly longer for the MR formulations versus the IR formulation. The data of the present study indicate that time above MIC values at the target site can be substantially prolonged if an antibiotic is administered as a sustained‐release product.
Effect of Food on the Oral Bioavailability of Didanosine from Encapsulated Enteric‐Coated Beads
Authors: Damle Bharat D. , Yan Jing‐He , Behr Douglas , O'Mara Edward , Nichola Peter , Kaul Sanjeev , Knupp Catherine
Published: July 2003

The objective of this study was to assess the effect of food and timing of meals on the bioavailability of didanosine from encapsulated enteric‐coated beads. Four different independent, open‐label, single‐dose, randomized, crossover studies were conducted in healthy subjects (n = 20–30). Didanosine (400 mg) was given concomitantly with a high‐fat meal, light meal, yogurt, and applesauce. In addition, didanosine was given 1, 1.5, 2, and 3 hours before and 2 hours after a light meal. Statistical comparison with fasting conditions was made using the equivalence approach for Cmax (70%‐143%) and AUC (80%‐125%). The high‐fat meal, light meal, yogurt, and applesauce decreased the Cmax by 46%, 22%, 30%, and 24%, respectively, and lowered the AUC by 19%, 27%, 20%, and 18%, respectively; statistical analyses indicated an indeterminate food effect, except for the Cmax for the high‐fat meal. For 1 hour before meal, Cmax and AUC were lower by 15% and 24% and, for 2 hours after meal, were lower by 15% and 10%, respectively. There was an indeterminate food effect for 1 hour before the meal treatment; in addition, 2 hours after the meal, treatment approached statistical equivalence, missing narrowly on the lower bounds. For 1.5, 2, and 3 hours before meal treatments, Cmax values were unchanged, but AUC was lower by 10%, 4%, and 0%, respectively; lack of food effect was observed for all three treatments. Across studies, median time to Cmax ranged from 1.67 to 2.67 hours but was delayed by 2.5 to 3 hours with high‐fat and light meals compared to fasting conditions. The half‐life of didanosine was 1.5 to 2 hours. It was concluded that the bioavailability of didanosine from encapsulated enteric‐coated beads was reduced by approximately 20% to 25% with food, which can be circumvented by taking didanosine on an empty stomach. The clinical significance of such moderate reductions in didanosine exposure with food, especially as part of a highly active antiretroviral therapy, is not clear.
Pharmacokinetics and Safety of Galantamine in Subjects with Hepatic Impairment and Healthy Volunteers
Authors: Zhao Qinying , Iyer Ganesh R. , Verhaeghe Tom , Truyen Luc
Published: July 2003

The objective of this study was to compare the pharmacokinetics and safety of galantamine in subjects with hepatic impairment with those in healthy subjects. This was an open‐label study in which a single oral 4‐mg dose of galantamine was administered to volunteers with mild (Child‐Pugh score of 5–6, n = 8), moderate (Child‐Pugh score of 7–9, n = 8), or severe hepatic impairment (Child‐Pugh score of 10–15, n = 1) and to healthy, matched control subjects (n = 8). Galantamine pharmacokinetics and safety (adverse events, laboratory test results, electrocardiograms, vital signs, and cardiac events) were assessed over 6 days after administration of galantamine. The pharmacokinetic parameters of galantamine were similar in subjects with mild hepatic impairment compared with healthy controls. Compared with the healthy control group, subjects with moderate hepatic impairment showed relative increases in the area under the plasma‐concentration curve from zero to infinity (AUC0∞_J (+33%) and terminal half‐life (t1/2) (+30%) (p = 0.051 and p = 0.003, respectively), a 23% relative decrease in total plasma clearance (p = 0.061), and a small but significant relative increase in the fraction of free plasma galantamine (p = 0.009). Galantamine was well tolerated by all subjects. There were no serious adverse events (AEs) or premature withdrawals from the study because of AEs. Reported AEs were headache (three cases), nausea (one case), and paresthesia (one case). There were no clinically relevant changes in clinical laboratory findings, vital signs, and electrocardiograms. Low patient recruitment (n = 1) precluded statistical analysis of galantamine pharmacokinetics and safety in severe hepatic impairment. It was concluded that the pharmacokinetics of galantamine in subjects with mild hepatic impairment was similar to those in healthy subjects. In subjects with moderate hepatic impairment, galantamine clearance was decreased by approximately 23% compared with normal volunteers. Galantamine was also well tolerated and appeared to be safe in subjects with mild or moderate hepatic impairment. Based on the study results, it appears that it would not be necessary to adjust doses of galantamine during administration to subjects with mild hepatic impairment. In subjects with moderately impaired hepatic function, dose titration should proceed cautiously. Unfortunately, difficulties with patient recruitment did not allow adequate assessment of the safety of galantamine in subjects with severe hepatic impairment in this study. Therefore, the use of galantamine in subjects with severe hepatic impairment is not recommended.
Electrocardiographic Effects of Rivastigmine
Authors: Morganroth Joel , Graham Stephen , Hartman Richard , Anand Ravi
Published: July 2003

The electrocardiographic (ECG) effects of rivastigmine treatment were assessed in mild to moderately severe Alzheimer's disease (AD) by analysis of four 26‐week, double‐blind, multicenter, placebo‐controlled, phase III clinical trials. Of an initial 2791 patients, 77% completed treatment. Seventy‐one percent required at least one concomitant medication for conditions other than AD, with 34% requiring cardiovascular medications. Safety assessments included ECGs, adverse events, vital signs, and clinical laboratory parameters. Pooled 12‐lead ECG data were analyzed by an independent cardiologist blinded to treatment group and clinical information. Heart rate, PR, QTc, and QRS intervals did not differ significantly between treatment and placebo groups. Percentage change from baseline for PR, QTc, and QRS intervals was also no different. In conclusion, rivastigmine appears not to produce adverse effects on cardiac function assessed by ECG.
The Effects of Concomitant Administration of Theophylline and Toborinone on the Pharmacokinetics of Both Compounds in Poor and Extensive Metabolizers via CYP2D6
Authors: Tammara Brinda , Trang John M. , Miyamoto Gohachiro , Kitani Mami , Brisson Jerry , Bramer Steven L.
Published: July 2003

This study investigated the effects of the concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6. In period 1, a single dose of 3.5 mg/kg theophylline was administered orally. In period 2, a single dose of 1.0 μg/kg/min toborinone was infused over 6 hours. In period 3, 3.5 mg/kg theophylline was coadministered with 1.0 μg/kg/min toborinone. Serial blood and pooled urine samples were collected before and after toborinone administration for the quantification of toborinone and its metabolites in plasma and urine. Serial blood samples were collected before and after theophylline administration for the quantification of theophylline and its metabolites in plasma. No significant differences were observed in toborinone pharmacokinetics between poor and extensive metabolizers via CYP2D6. Toborinone coadministration with theophylline did not result in a substantive effect on the disposition of theophylline and vice versa.