bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and Tolerability of Lornoxicam versus Tramadol in Postoperative Pain
Authors: Staunstrup Henrik , Ovesen Janne , Larsen Ulf Thyge , Elbæk Karsten , Larsen Ulla , Krøner Karsten
Published: July 2003

This randomized double‐blind study compared the analgesic efficacy and tolerability of intramuscular lornoxicam and tramadol in 76 patients with moderate to unbearable pain following arthroscopic reconstruction of the anterior cruciate ligament using the patella bone‐tendon‐bone technique. Patients receiving a single dose of lornoxicam 16 mg experienced significantly greater total pain relief than patients receiving tramadol 100 mg over the following 8 hours. Lornoxicam had greater analgesic efficacy than tramadol in patients with moderate baseline pain but was of equivalent efficacy in those with severe/unbearable baseline pain. Fewer patients in the lornoxicam group required rescue medication (58% vs. 77%, respectively). Patients' global impression of efficacy showed lornoxicam to be superior to tramadol with 82% and 49% of patients, respectively, rating treatment as good, very good, or excellent. Following multiple‐dose administration of lornoxicam (8 mg tid) or tramadol (100 mg tid) for 3 days, efficacy profiles similar to those following a single dose were obtained. Thus, slightly fewer patients in the lornoxicam group required rescue medication, and patients' global impression of efficacy again favored lornoxicam. Adverse events were reported by 38 of the 76 patients and were mainly mild to moderate in severity. Significantly fewer patients reported one or more adverse events with lornoxicam than with tramadol (14 vs. 24, respectively). Thus, intramuscular lornoxicam offers a useful alternative to tramadol for the treatment of moderate to severe postoperative pain.
The Effect of Azithromycin on the Pharmacokinetics of Indinavir
Authors: Foulds George , LaBoy‐Goral Lucia , Wei Greg C. G. , Apseloff Glen
Published: July 2003

This study was performed to examine the effect of the coadministration of azithromycin on the pharmacokinetics of the protease inhibitor indinavir (Crixivan®). In an open‐label, parallel‐design study, 32 healthy male and female volunteers were given indinavir (800 mg tid) for 5 days. One hour prior to the first dose of indinavir on day 5, 18 subjects received 1200 mg azithromycin (Zithromax®), and 14 subjects received matching placebo. Serial samples of plasma were obtained for 8 hours following the morning dose of indinavir on days 4 and 5 and assayed for indinavir by HPLC/UV. Twenty‐seven subjects completed the study. Following coadministration of azithromycin with indinavir, there was no significant change between day 5 and day 4 in AUC (20.7 mg•hr/ml and 23.1 mg•hr/ml; 90% CI on the ratio 81%‐100%) or Cmax (9.88 mg/ml and 10.3 mg/ml; 90% CI 86%‐108%). The day 5 to day 4 difference in indinavir concentrations following coadministration with azithromycin was not significantly different from the day 5 to day 4 difference with placebo (AUC p = 0.68; Cmax p = 0.074). Therefore, azithromycin does not significantly alter the kinetics of indinavir.
Effect of the Endothelin‐Receptor Antagonist Bosentan on the Pharmacokinetics and Pharmacodynamics of Warfarin
Authors: Weber Cornelia , Banken Ludger , Birnboeck Herbert , Schulz Rainer
Published: July 2003

To investigate the effects of bosentan (Ro 47–0203), an endothelin receptor antagonist, on the pharmacokinetics and pharmacodynamics of warfarin, a double‐blind, placebo‐controlled, randomized, two‐way crossover study was performed in 12 healthy male volunteers. All subjects received a single oral dose of 26 mg racemic warfarin twice, once in the morning of the 6th day of treatment with 500 mg bosentan twice daily for 10 days and once at the same time point during treatment with placebo twice daily for 10 days. Both treatments were separated by a 2‐ to 3‐week washout period. Blood samples were collected at intervals up to 120 hours following the warfarin dose for the measurement of prothrombin time and factor VII activity and for determination of plasma concentrations of R‐ and S‐warfarin. Bosentan treatment led to a statistically significant reduction of the maximal prothrombin time (PTmax) and the AUC0‐120h of PT and factor VII activity compared to placebo, on average, by 23% to 38%. This reduction could be explained by an increase in the elimination of the pharmacologically more active S‐enantiomer whose mean AUC0‐∞ was reduced by 29%. The mean AUC0‐∞ of R‐warfarin was also decreased by 38%. Cmax and tmax of both enantiomers did not change. Close monitoring in patients receiving warfarin is recommended at initiation or discontinuation of treatment with bosentan.
The Effect of Low‐Dose Cimetidine (200 mg Twice Daily) on the Pharmacokinetics of Theophylline
Authors: Nix David E. , Di Cicco Robert A. , Miller Ann K. , Boyle Duane A. , Boike Steven C. , Zariffa Nevine , Jorkasky Diane K. , Schentag Jerome J.
Published: July 2003

The potential for nonprescription cimetidine (200 mg twice daily) to affect the pharmacokinetics of sustained‐release (SR) theophylline was assessed in 26 male subjects, 13 smokers and 13 nonsmokers. This was a concentration‐controlled drug interaction study in which the subjects were administered a dose of SR theophylline every 12 hours to provide a mean steady‐state concentration between 8 and 15 μg/ml. To determine individual theophylline dose, a test dose of aminophylline was administered, and baseline theophylline pharmacokinetics were determined. Subjects remained on SR theophylline for 23 days and were treated in the following sequence: run‐in phase (4 days), treatment 1 (7 days), washout (5 days), and treatment 2 (7 days). During the treatment phases, subjects received cimetidine (200 mg at approximately 08:00 and 12:00) or placebo for 7 days in a randomized crossover fashion. Theophylline pharmacokinetics were determined on days 1, 4, and 7 of both treatment phases. A large day‐to‐day variability in the oral clearance of theophylline was evident for the theophylline‐placebo treatment and the theophylline‐cimetidine treatment. Nonprescription strength cimetidine resulted in a mean 5% decrease in theophylline oral clearance on day 1 and a mean 12% decrease on days 4 and 7 combined. There were no significant differences in the cimetidine‐theophylline interaction between smokers and nonsmokers. Oral clearance during the nighttime dosing interval was 13% greater than the daytime oral clearance for nonsmokers and 22% greater for smokers, showing a greater circadian rhythm for smokers. In summary, nonprescription doses of cimetidine (400 mg/day) have the potential to produce small changes in theoophylline concentrations during steady‐state dosing with SR theophylline; however, this effect appears less than changes that occur as a consequence of theophylline's intrasubject variability.
Raloxifene, a New Selective Estrogen Receptor Modulator
Authors: Goldfrank Deborah , Haytoglu Tahir , Frishman William H. , Mohammad Zalt
Published: July 2003

There is evidence from observational studies that estrogen replacement therapy in postmenopausal women can reduce the rates of morbidity and mortality of atherosclerotic heart disease. The mechanism of this cardiovascular protective effect is not yet established, but favorable actions of hormone therapy on plasma lipids and vascular endothelial function have been proposed. Estrogens can also increase the risk of breast and uterine carcinoma. The new selective estrogen receptor modulator (SERM) raloxifene appears to have benefits similar to estrogen on plasma lipids and osteoporosis, but it does not affect the rate of uterine carcinoma as does tamoxifen and estrogen. Animal studies suggest an anti‐atherosclerotic action of raloxifene, but this needs to be confirmed in long‐term human studies.
Lymphocyte Suppression by Rolipram with Other Immunosuppressive Drugs
Authors: Briggs William A. , Wu Qingze , Orgul Onder , Choi Michael , Scheel Paul J. , Burdick James
Published: July 2003

Pentoxifylline, a nonselective phosphodiesterase inhibitor, has immunomodulatory activity in vitro and in vivo and potentiates the suppressive effects of glucocorticoids and cyclosporine on lymphocyte proliferation in vitro. Since phosphodiesterase isotypes 3 and 4 predominate in lymphocytes, the authors measured the suppressive effect of rolipram alone and in combination with low concentrations of methylprednisolone and calcineurin enzyme inhibitors, compared to that of pentoxifylline on mitogen‐stimulated lymphocyte proliferation. The percent inhibition of 3H‐thymidine incorporation by both 10−5 and 10−6 mol/L concentrations of rolipram were significantly greater than that by both 10−4 mol/L pentoxifylline and 10−8 mol/L methylprednisolone. The percent inhibition by the combination of 10−5, but not 10−6, mol/L rolipram and methylprednisolone was significantly greater than that by 10−4 mol/L pentoxifylline and methylprednisolone. Potentiation of the suppressive effects of cyclosporine and tacrolimus by rolipram was less consistent. Measurement of cell culture supernatant concentrations of interferon gamma and interleukin‐10 indicate that one of the mechanisms underlying the immunosuppressive activity of rolipram is a significantly disproportionate inhibition of the proinflammatory cytokine, interferon gamma.
Single‐Dose Pharmacokinetics of Valganciclovir in HIV‐ and CMV‐Seropositive Subjects
Authors: Jung Donald , Dorr Albert
Published: July 2003

As a result of the low oral bioavailability of ganciclovir, a prodrug was developed to improve the bioavailability of ganciclovir. This study was designed to investigate the fasting, single‐dose pharmacokinetics as well as the absolute and relative bioavailability of a valine ester prodrug of ganciclovir, valganciclovir, as compared to oral and intravenous ganciclovir in asymptomatic HIV+ and CMV+ subjects. In this open‐label, randomized, three‐period crossover study, 18 subjects received, in random order, single oral doses of valganciclovir 360 mg and ganciclovir 1000 mg and an intravenous infusion of ganciclovir 5 mg/kg over 1 hour. Valganciclovir was rapidly and extensively hydrolyzed to ganciclovir, resulting in significantly greater bioavailability compared to 1000 mg oral ganciclovir (60.9% vs. 5.6%, respectively). Higher peak serum concentrations were reached earlier following valganciclovir (ganciclovir [2.98 ± 0.77 μg/mL at 1.0 ± 0.3 h]) than following oral ganciclovir (0.47 ± 0.17 μg/mL and 2.2 ± 1.0 h). Mean total ganciclovir AUCs following oral ganciclovir (1000 mg) and 360 mg valganciclovir (3.8 ± 1.2 and 10.8 ± 1.9 μg‐h/mL) were less than that following a standard 5 mg/kg intravenous infusion of ganciclovir (25.1 ± 3.8 μg‐h/mL). In summary, valganciclovir is a prodrug with a favorable safety profile with enhanced bioavailability and significantly higher serum concentrations of ganciclovir than following oral administration of ganciclovir itself.
Moricizine Bioavailability via Simultaneous, Dual, Stable Isotope Administration: Bioequivalence Implications
Authors: Pieniaszek Henry J. , Mayersohn Michael , Adams Michael P. , Reinhart Rosann J. , Barrett Jeffrey S.
Published: July 2003

The relative bioavailability of a 200 mg film‐coated tablet of [12C]moricizine•HCl in comparison toa200 mg [13C6]moricizine•HCl oral solution was determined after simultaneous administration to 8 young healthy male subjects. Concentrations of [12C]moricizine•HCl and [13C6]moricizine•HCl were determined by thermospray liquid chromatography‐mass spectrometry (LC‐MS) using [2H11]moricizine•HCl as the internal standard. The mean absorption and disposition parameters of the tablet versus the solution were the following (% CV): maximum concentration, 0.83 (39%) versus 0.79 (39%) μg/mL; time of maximum concentration, 0.81 (40%) versus 0.65 (28%) hours; area under the concentration‐time curve (AUC), 1.58 (39%) versus 1.49 (37%) μg•h/mL; apparent oral clearance, 150.7 (52%) versus 158.1 (50%) L/h; and t1/2, 1.9 (42%) versus 1.9 (42%) hours. The AUC for the tablet averaged 106% of the solution, which likely reflects a greater first‐pass effect with the oral solution. Partitioning sources of variation confirmed the low (< 6%) intrasubject coefficient of variation (cvε) afforded via the single‐period, dual‐isotope design. In contrast, a previous study using the conventional two‐period crossover design determined the cvε about moricizine metrics to be in excess of 30%, resulting in classification of this drug as having highly variable absorption. The results of this study further illustrate the benefits of dual, stable isotopes to assess bioavailability and bioequivalence. This paradigm results in a reduction in experimental time and subject inconvenience and lower costs in comparison with the standard crossover study. Perhaps most important is the improved statistical power for the evaluation of bioavailability or bioequivalence in the absence of period and sequence effects that confound the assessment of intrasubject variation in the standard crossover design.
Microbial Biofilms: Their Development and Significance for Medical Device—Related Infections
Authors: Habash Marc , Reid Gregor
Published: July 2003

Microbial adhesion and biofilm formation on medical devices represent a common occurrence that can lead to serious illness and death. The process by which bacteria and yeast colonize open and closed implants is fairly complicated and involves a series of steps commencing with deposition of host substances onto the material. Prevention and treatment of established biofilms with antimicrobial agents are difficult because the organisms are encased within a protected microenvironment. Efforts to reduce adhesion using specially developed materials, such as hydrophilic or heparin coated, have had modest success once applied to the patient. The reason, at least for the most part, is the diverse milieu into which devices are placed and the multitude of ways in which organisms can colonize surfaces. A better understanding of the process is required, and the knowledge gained must be used to devise new strategies as alternatives to the traditional employment of antibiotics. These new approaches may still use antibiotics but at different concentrations (low to prevent and high to treat infection) and in a different manner (perhaps spiked therapy in which there is a delay between doses to reduce the risk of drug resistance and impact on normal flora). The possibility of applying functional foods to patient management should also be pursued.
Effect of Meal Timing Not Critical for the Pharmacokinetics of Tegaserod (HTF 919)
Authors: Zhou Honghui , Khalilieh Sauzanne , Lau Henry , Guerret Madeleine , Osborne Stuart , Alladina Latifa , Laurent Aziz L. , McLeod James F.
Published: July 2003

This study assessed the pharmacokinetic profiles of administering tegaserod (HTF 919) at different time intervals with respect to a meal. It was a randomized, open‐label, two‐phase, five‐period crossover study. In the first phase, 18 healthy subjects received a single 12 mg oral dose of tegaserod administered either 30 or 15 minutes prior to the start of the 600‐calorie, fat‐rich breakfast. In the second phase, subjects received a single 12 mg oral dose of tegaserod 1 minute before, 2.5 hours after the start of meal, or with a continued 4‐hour postdose fast. Safety assessment and plasma samples for the determination of drug concentration were obtained for 24 hours postdose. Noncompartmental analysis results indicated that the AUC of tegaserod was reduced by almost half under fed conditions compared to the fasted condition. Exploratory analyses were implemented to further investigate the absorption characteristics of tegaserod under different fed conditions. A numerical deconvolution approach was used to obtain the tegaserod oral absorption versus time profiles under both fasted and fed conditions. The tegaserod oral absorption versus time profiles were then fitted by NONMEM to a model containing two absorption phases. Based on the absorption analyses, we found that the reduction in the bioavailability of tegaserod under fed conditions was primarily due to a decrease in the extent of absorption and less so to a decrease in the absorption rate(s). Therefore, although the timing of administration of food does not appear to significantly alter the pharmacokinetics of tegaserod, the administration of food reduces the AUC by approximately 50%.
Rabeprazole: Pharmacokinetics and Tolerability in Patients with Stable, End‐Stage Renal Failure
Authors: Keane William F. , Swan Suzanne K. , Grimes Imogene , Humphries Thomas J.
Published: July 2003

The authors compare the pharmacokinetic profiles, safety, and tolerability of rabeprazole, a new proton pump inhibitor (PPI), in healthy volunteers and in subjects with stable, end‐stage renal failure. This single‐center, open‐label trial included two groups of subjects: 10 healthy males with 24‐hour creatinine clearance 90 mL/min/m2 and 10 males with renal failure (24‐hour creatinine clearance ∼ 5 mL/min/m2) receiving hemodialytic therapy. Normal subjects received a single, oral 20 mg rabeprazole dose. Those with renal failure received a 20 mg dose of rabeprazole on the day after hemodialysis and a second dose after a 2‐week washout period during dialysis. Blood samples were drawn before and up to 24 hours after rabeprazole administration for determination of plasma rabeprazole concentrations by high‐performance liquid chromatography. Safety and tolerability of rabeprazole were determined by reporting adverse events and comparing vital signs, ECG, physical examinations, and clinical laboratory tests before and during treatment. Comparison of pharmacokinetic results from healthy volunteers with those from subjects with renal failure indicated no clinically significant differences between groups. In addition, there were no statistically significant differences between any pharmacokinetic parameters recorded during or after hemodialysis. Rabeprazole was well tolerated by both groups. Only two drug‐related adverse events were reported, and there were no significant treatment‐emergent changes in vital signs or ECG. Treatment‐emergent changes in hematologic and clinical chemistry parameters were observed for a few subjects in each group and generally represented only slight deviations from the normal range. These results indicate that no dosage adjustment of rabeprazole is required in patients with renal dysfunction. These findings and the well‐documented clinical efficacy of this new PPI in patients with gastric ulcers, duodenal ulcers, or gastroesophageal reflux disease support rabeprazole's use in the treatment of patients with acid peptic disorders.
Gabapentin Does Not Affect Antipyrine Clearance
Authors: Allen Elizabeth , Tsanaclis Lolita M. , Wroe Steven J. , Reece Phillip A. , Sedman Allen J.
Published: July 2003

The effect of gabapentin on antipyrine clearance was assessed in 12 healthy male volunteers, using a known enzyme inducer, phenytoin, as control. Subjects received gabapentin 400 mg or phenytoin 100 mg three times daily for 2 weeks. Antipyrine tests were performed before, during, and after treatment with gabapentin or phenytoin. In contrast to phenytoin, chronic administration of gabapentin did not affect antipyrine clearance. Gabapentin appears to have little potential for drug interactions.
Lack of Pharmacokinetic Interaction between Oral Pantoprazole and Cisapride in Healthy Adults
Authors: Ferron Geraldine M. , Paul Jeffrey C. , Fruncillo Richard J. , Martin Patrick T. , Yacoub Lena , Mayer Philip R.
Published: July 2003

Pantoprazole, an irreversible proton pump inhibitor, may be administered with cisapride, a prokinetic agent. As increased cisapride concentrations may result in longer electrocardiogram (ECG) QTc intervals, a crossover study was conducted in healthy subjects to evaluate the oral pharmacokinetic interaction between cisapride (20 mg) and pantoprazole (40 mg). After dosing, serial blood samples and 12‐lead ECGs were collected, and cisapride plasma concentrations were quantitated. For cisapride alone, mean parameter values were the following: peak concentration (Cmax), 56 ng/mL; time to Cmax (tmax), 1.7 hours; area under the concentration‐time curve (AUC), 426 ng•h/mL; and terminal half‐life (t1/2), 5.8 hours. Pantoprazole coadministration did not alter cisapride AUC or other pharmacokinetic parameters except for a slight 17% decrease in Cmax, resulting in 90% confidence limits of 79% to 88%, which were marginally outside strict bioequivalence limits. In addition, cisapride did not affect ECG QTc intervals, with or without pantoprazole. Therefore, no dosage adjustment is needed when pantoprazole and cisapride are coadministered.
No Effect of Gender or Age on Binding Characteristics of Valproic Acid to Serum Proteins in Pediatric Patients with Epilepsy
Authors: Kodama Yasuo , Kodama Hirofumi , Kuranari Masae , Tsutsumi Kimiko , Ono Shunsuke , Fujimura Akio
Published: July 2003

The gender‐ and age‐related binding characteristics of valproic acid to serum proteins were determined in the pediatric population. Serum samples examined in the study were obtained from 61 pediatric patients (28 males, 33 females) with epilepsy on valproic acid monotherapy. Their ages ranged from 1to 15 years (mean age with [SD]: 7.8 [3.9] years; < 10 years, n = 41; /10 years, n = 20). The in vivo population binding parameters of valproic acid to serum proteins and theoretical minimal unbound serum fraction (fu) of valproic acid were determined in (1) all, (2) male and female subgroups, and (3) prepubescent (< 10 years) and pubescent (/10 years) subgroups. The association constant (K) was approximately 1.4 times higher in male (0.018 L/μmol) than in female (0.013 L/μmol) patients, while the total concentration of binding sites (n(Pt)) was 1.2 times greater in female (1235 μmol/L) than in male (997 mmol/L) patients. The fu was 0.053 and 0.059 for male and female patients, respectively. The value of K was approximately 1.6 times higher in the pubescent (0.019 L/μmol) than in the prepubescent (0.012 L/μmol) patients, while the n(Pt) was 1.2 times higher in the prepubescent (1244 μmol/L) than in the pubescent (1057 μmol/L) patients. The fu was 0.063 for the prepubescent and 0.047 for the pubescent patients. No significant differences were observed in binding characteristics of valproic acid to serum proteins between male and female or younger and older patients. However, the differences in valproic acid binding to serum proteins appear to be relatively larger in binding affinity than in binding capacity between the two groups. Because no significant differences were observed in serum concentrations of total and unbound valproic acid, albumin, or free fatty acids between any subgroups (male and female, younger and older), the results suggest that gender or age may not be factors for the determination of the binding characteristics of valproic acid to serum proteins in pediatric patients.
Altered Pharmacokinetics of Indinavir by a Novel Nonnucleoside Reverse Transcriptase Inhibitor (HBY‐097): A Pharmacokinetic Evaluation in HIV‐Positive Patients
Authors: Hayashi Sandra , Jayesekera Deepthi , Jayewardene Anura , Shah Anita , Thevanayagam Lourdes , Aweeka Francesca
Published: July 2003

HBY‐097 (HBY), an investigational nonnucleoside reverse transcriptase inhibitor (NNRTI), and indinavir (IDV) share a common metabolic pathway, cytochrome P4503A4 (CYP3A4), and may clinically be used together as well as with zidovudine (ZDV). Thus, the potential pharmacokinetic (PK) interaction between these drugs was evaluated. HBY (500 mg Q8H), IDV (800 mg Q8H), and ZDV (200 mg Q8H) were given to 8 HIV‐infected subjects. Serial plasma samples were collected at baseline (ZDV and IDV alone) and day 11 (all 3drugs) to determine PK parameters using noncompartmental analysis. PK parameters for ZDV in the presence and absence of HBY were not appreciably different. However, both the maximum (Cmax) and minimum (Cmin) concentrations of IDV were significantly reduced, from a mean of 7514 ⌖ 1636 and 146 ⌖ 81 mcg/L to 4725 ⌖ 2494 mcg/L and 54 ⌖ 24 mcg/L (p < .05) after addition of HBY. Furthermore, apparent clearance (CL/F) of IDV before and after 11 days of concomitant HBY administration was significantly higher, from 0.69 ⌖ 0.14 to 1.94 ⌖ 0.63 L/h/kg (p < .05) with an associated reduction in area under the curve (AUC0–8) from 16,034 ⌖ 4903 to 6134 ⌖ 2701 mg/L/h (p < .05). The increase in IDV CL/F is consistent with the observed metabolic induction effects of other NNRTIs. The results of this trial showed that HBY significantly alters the pharmacokinetic parameters of IDV at the dose studied.
P‐glycoprotein and Drug Therapy in Organ Transplantation
Authors: Lo Agnes , Burckart Gilbert J.
Published: July 2003

The role of multidrug resistance and P‐glycoprotein (P‐gp) in the development of drug‐resistant tumor cells has been extensively studied. As more knowledge on the physiological functions of P‐gp has accumulated, the effects of P‐gp modulation on the pharmacokinetics and the pharmacodynamics of many drugs have become apparent. Solid organ transplant recipients receive numerous medications that are substrates for P‐gp. The objective of this review is to discuss the effects of P‐gp modulation on the pharmacokinetics and the pharmacodynamics of immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus, and corticosteroids. Pharmacokinetic alterations may occur in drug absorption since P‐gp is in the small bowel, in drug distribution since P‐gp functions in the blood‐brain barrier, in drug metabolism since P‐gp and cytochrome P450 3A have linked functions, and in drug elimination since P‐gp is in the bile canaliculi and renal tubules. A link between P‐gp and organ rejection has been speculated since upregulation of the P‐gp pump may restrict immunosuppressant drug entry into immunocompetent cells. A further understanding of P‐gp regulation upon chronic exposure to P‐gp substrates and inhibitors and the potential administration of selective P‐gp inhibitors will enhance our ability to use potent immunosuppressive drugs in organ transplant patients.
Assessment of the Quality and Quantity of Drug‐Drug Interaction Studies in Recent NDA Submissions: Study Design and Data Analysis Issues
Authors: Huang Shiew‐Mei , Lesko Lawrence J. , Williams Roger L.
Published: July 2003

This report investigates the quality and quantity of drug‐drug interaction studies in recent new drug applications (NDAs). Eighty‐nine studies contained in 14 NDAs submitted between December 1995 and November 1996 to the U.S. Food and Drug Administration (FDA) were reviewed. The results indicated that the median number of clinical drug‐drug interaction studies per NDA was 6, almost double that of a 1994–1995 survey. In vitro metabolism data were present in 70% of the submissions. More than 50% of the submissions contained interaction studies using a battery of drugs (cimetidine, digoxin, or warfarin) without optimal use of the in vitro metabolism or in vivo mass balance data. Various study designs using a median number of 12 subjects were employed in the evaluation of drug‐drug interactions. Some of the important study design factors such as dose size, dosing regimen, dosing duration, and timing of coadministration were considered, although not consistently, by the sponsors in their study design. Seventy‐five percent of the studies used normal, healthy male subjects, and 25% used patients for whom the new molecular entities were intended. In 33% of the studies, female subjects were also recruited. Although the majority (80%) of the submissions still used p‐values to determine the significance of drug interactions, 30% used a more relevant equivalence approach with 90% confidence intervals for key pharmacokinetic and/or pharmacodynamic parameter ratios to assess the extent of drug interactions. Overall, 82% of the studies concluded no interaction. Although population pharmacokinetic analysis can be a useful tool in studying drug‐drug interactions, only 21% of the submissions used this approach. In summary, this assessment reveals that the quantity and quality of drug‐drug interaction studies in NDAs have improved over the years. These improvements, as well as others that can be implemented, should result in more informative labeling and better patient care. FDA guidance for industry dealing with the design, analysis, and labeling language of in vivo metabolic drug‐drug interactions has been developed to assist sponsors and FDA reviewers with these issues.
The Pharmacokinetics of Extended‐Release Formulations of Calcium Antagonists and of Amlodipine in Subjects with Different Gastrointestinal Transit Times
Authors: Zimmermann Torsten , Laufen Heinrich , Yeates Rodney , Scharpf Friedrich , Riedel Klaus‐Dieter , Schumacher Tilo
Published: July 2003

The influence of gastrointestinal (GI) transit times on the pharmacokinetics (PK) of three calcium channel blockers (CCBs), recommended for once‐daily dosing, was investigated. In a three‐way crossover design, the single‐dose PK of a controlled‐delivery formulation of 240 mg diltiazem (DIL), an extended‐release formulation of 10 mg felodipine (FEL), and 5 mg amlodipine (AML) were compared in two groups of healthy subjects, with either slow (> 35 h) or rapid (< 15 h) GI transit, as assessed by the metal detector method (EAS II). GI transit significantly affected the PK of DIL. Mean PK parameters in the rapid versus slow transit group were the following: trough levels (C24h): 22.8 ± 8.3 versus 49.5 ± 35.7 ng/ml, p <0.05; AUC 1135.2 ± 510.9 versus 1704.7 ± 1185.6 hng/ml, p <0.05 (one‐sided). Neither AUC nor trough levels of FEL and AML were significantly influenced by transit times, nor was Cmaxafter any of the three treatments. Variations in PK parameters, as indicated by coefficients of variation, were about twofold higher for both DIL and FEL, compared to AML. Variations in mean residence times were significantly lower for AML compared to DIL and FEL (7% vs. 30% and 17%, p <0.001 andp <0.002, respectively). Peak‐to‐trough ratios (Cmax/C24hmean) were 1.8 ± 0.9 for DIL, 7.6 ± 3.5 for FEL, and 1.7 ± 0.2 for AML. In conclusion, the predictability of pharmacokinetic behavior both in conditions of rapid or slow GI transit is optimized in drugs with intrinsically slow elimination such as amlodipine. The pharmacokinetics of the CCBs with formulation‐based once‐a‐day characteristics are sensitive to GI transit if these processes are rapid enough to interfere with the formulation‐specific release profile.
Bioequivalence of 1 and 5 mg Tacrolimus Capsules Using a Replicate Study Design
Authors: Bekersky Ihor , Dressler Dawna , Colburn Wayne , Mekki Qais
Published: July 2003

Tacrolimus (FK506, Prograf®) is marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation. A previously conducted, randomized, 24‐subject, crossover bioavailability study of 1 and 5 mg capsules (one period each) failed to demonstrate bioequivalence. A single‐dose, four‐period, four‐sequence, randomized, crossover, replicate study (N = 32) was therefore used to evaluate the bioequivalence of the marketed 1 and 5 mg capsules in healthy volunteers. Tacrolimus blood concentrations were measured serially over 72 hours using a commercially available ELISA assay. Noncompartmental pharmacokinetic parameters were determined. Ninety percent CIs of log‐transformed parameter ratios were 90.5–101.9, 87.1–101.7, and 89.7–103.8 for Cmax, AUC0‐t, and AUC0‐∞ respectively. Since all values were within 80% to 125%, the capsules are bioequivalent. Based on %CVs, intersubject variability was approximately two to three times greater than intrasubject variability. The safety of single 5 mg oral tacrolimus doses administered to healthy volunteers at 7‐day intervals was also ascertained.
The Effect of Pharmacokinetically Guided Acute Intravenous Testosterone Administration on Electrocardiographic and Blood Pressure Variables
Authors: White C. Michael , Ferraro‐Borgida Melissa J. , Moyna Niall M. , McGill Carol C. , Ahlberg Alan W. , Thompson Paul D. , Heller Gary V.
Published: July 2003

Previous studies have demonstrated that intravenous testosterone can dilate coronary arteries and increase exercise treadmill time, but the electrocardiographic and hemodynamic effects are unknown. This trial determined the hemodynamic and electrocardiographic effects of dosing intravenous testosterone to achieve a physiologic and a superphysiologic serum testosterone concentration. Twenty men (70.6 ⌖ 6.2 years) had individualized testosterone bolus and continuous infusions designed to increase the serum testosterone concentration by two (physiologic) and six times baseline (superphysiologic). The men were studied on three occasions when they were randomly allocated to received a placebo, physiologic testosterone regimen, or superphysiologic testosterone regimen. Blood pressures and 12‐lead electrocardiograms (ECGs) were taken preinfusion and 28 minutes after initiating the infusion on each visit. The blood pressure (systolic and diastolic) and ECG variables (PR, QRS, QT, QTc, and RR intervals) preinfusion and during the infusion were compared, and the delta changes in the variables were compared between groups. The physiologic testosterone regimen increased the serum testosterone concentration by 2.39 ⌖ 0.48 times the preinfusion concentration, while the superphysiologic regimen increased it by 6.22 ⌖ 0.99 times. No significant changes occurred in the blood pressure or ECG variables in any group versus preinfusion values or between the three groups. Exogenously administered intravenous testosterone does not significantly affect the blood pressure or ECG variables when given to achieve physiologic or superphysiologic concentrations.
Fluoxetine Bioequivalence Study: Quantification of Fluoxetine and Norfluoxetine by Liquid Chromatography Coupled to Mass Spectrometry
Authors: Moraes M. O. , Lerner F. E. , Corso G. , Bezerra F. A. Frota , Moraes M.E.A. , De Nucci G.
Published: July 2003

In this study, the authors assessed the bioequivalence of two fluoxetine tablet formulations in 24 healthy volunteers of both sexes who received a single 20 mg dose of each fluoxetine formulation, and anew sensitive method for the quantification of fluoxetine and norfluoxetine in human plasma was developed. The study was conducted using an open, randomized, two‐period crossover design with a 4‐week washout interval. Plasma samples were obtained over a 672‐hour period. Plasma fluoxetine and norfluoxetine concentrations were analyzed by combined liquid chromatography coupled to mass spectrometry (LC‐MS) with positive ion electrospray ionization using selected ion recording (SIR). Kolmogorov‐Smirnov's test, histograms, probit plots, and the correlation between norfluoxetine AUC(0‐∞) and fluoxetine AUC(0‐∞) were used to analyze the population distribution. The limit of quantification was 0.15 ng•ml−1 and 0.50 ng•ml−1 for both fluoxetine and norfluoxetine, respectively. Within‐ and between‐run imprecision was less than 13% and 17%, respectively. The pharmacokinetic parameters obtained for fluoxetine and norfluoxetine after the administration of each formulation included AUC(0‐672h), AUC(0‐∞), Cmax, Cmax/AUC(0‐672h),tmax,t1/2, and Ke. The AUC values for fluoxetine were not consistent with a normal distribution, reflecting the existence of two different populations (poor and extensive metabolizers). The mean pharmacokinetic parameters for extensive fluoxetine metabolizers were 27.0 ng ml−1 for Cmax, 2064.0 ng h ml−1 for AUC(0‐∞), and 85.4 h t1/2. The mean pharmacokinetic parameters for norfluoxetine (in extensive metabolizers only) were 2532.0 ng h ml−1 for AUC(0‐∞) and 8.4 ng ml−1 for Cmax. For fluoxetine bioequivalence, the 90% CI of the individual ratio geometric mean for Psiquial®/Prozac® (including both extensive and poor metabolizers) was 101.6% to 121.1% for AUC(0‐672h) and 86.1% to 102.6% for Cmax. For norfluoxetine, the 90% CI of the individual ratio geometric mean for Psiquial®/Prozac® (including both extensive and poor metabolizers) was 90.3% to 108.3% for AUC(0‐672h) and 84.5% to 106.3% for Cmax. The new method developed (LC‐MS) presented high sensitivity, specificity, and short chromatographic run for the quantification of both fluoxetine and norfluoxetine in human plasma. Since both 90% CI for AUC and Cmax geometric mean ratios were included in the 80% to 125% interval proposed by the U.S. Food and Drug Administration, Psiquial® was considered bioequivalent to Prozac® according to both the rate and extent of absorption. The finding that there were no significant differences in the bioequivalence assessed by either fluoxetine or norfluoxetine pharmacokinetic parameters indicates that future bioequivalence trials may be performed by quantifying fluoxetine only.
The New Topical Steroid Ciclesonide Is Effective in the Treatment of Allergic Rhinitis
Authors: Schmidt Bernhard M. W. , Timmer Wolfgang , Georgens Anette C. , Hilt Monika , Mattinger Catherine , Wurst Wilhelm , Hörmann Karl , Wehling Martin
Published: July 2003

A randomized, placebo‐controlled, double‐blind crossover study was performed to investigate the efficacy of ciclesonide nasal spray in allergic rhinitis at the dose level of 200 μg per nostril. Twenty‐four subjects (13 males, 11 females; median age: 28 years) with a history of allergic rhinitis but free of symptoms at screening entered the study. Ciclesonide and placebo were given for 7 days each with a washout period of at least 14 days in between. In both treatment periods, controlled intranasal allergen provocation with pollen extracts was performed on the 2 days before start of treatment (days −2 and −1) and on all treatment days (days 1 to 7) about 2 hours after administration of the study medication. At 5 and 30 minutes after each allergen provocation, rhinal airflow was measured by anterior rhinomanometry, and the subjective symptoms of obstruction, itching, and rhinorrhea were assessed by means of a standardized visual analog scale. Rhinal airflow improved significantly from day 5, while the subjective symptom of obstruction improved from day 2. Itching and rhinorrhea also improved significantly. The local and systemic tolerability of ciclesonide nasal spray was excellent. The results of this study clearly indicate that the new topical steroid ciclesonide is effective in the treatment of allergic rhinitis without producing local or systemic side effects.
Concurrent Administration of the Erythromycin Breath Test (EBT) and Oral Midazolam as In Vivo Probes for CYP3A Activity
Authors: McCrea Jacqueline , Prueksaritanont Thomayant , Gertz Barry J. , Carides Alexandra , Gillen Lisa , Antonello Suzanne , Brucker Mary Jo , Miller‐Stein Cynthia , Osborne Barbara , Waldman S.
Published: July 2003

Given the prominent role of CYP3A in the metabolism of drugs, it is important to identify whether new chemical entities will affect this enzyme system and produce clinically relevant drug interactions. This study evaluated concomitant administration of intravenous [14C N‐methyl] erythromycin (3μCi) (erythromycin breath test; EBT) and 2 mg oral midazolam as probes of systemic and of systemic plus presystemic CYP3A activity, respectively Twelve males received the probes in a two‐period crossover fashion: one period included the probes on two occasions, 5 days apart; in the second period, 200 mg ketoconazole was given orally 2 hours prior to the probes. The within‐subject CV for EBT (%14CO2/h) and midazolam AUC0‐last was 4.9% and 16.9%, respectively. Ketoconazole reduced %14CO2/h by 43% and increased midazolam AUC0‐last by approximately fivefold. In a nonrandomized third period (N = 5), ketoconazole was given simultaneously with midazolam (no EBT); midazolam AUC0‐last was similar whether ketoconazole was given 2 hours prior to or simultaneously with the midazolam. The low midazolam dose was generally well tolerated; mild sedation was occasionally seen. Concurrent administration of the EBT and oral midazolam is a sensitive and reproducible tool to screen new chemical entities for potentially important CYP3A interactions.
Limits of Confidence in Tracer Compounds as a Means of Measuring Patient Compliance with Medication
Authors: Shine Daniel , McDonald Joseph
Published: July 2003

Chemical tracers are thought to be a desirable means of measuring patient compliance with medication. However, no compound has emerged as a standard. To explain this observation, the authors explored the mathematics of simulated tracers with half‐lives 5 to 140 days over a month of daily dosing. To model assay variability, they added random “noise” to calculated tracer serum levels. They then fitted those altered levels to the dosing pattern most likely to have produced them, given known kinetics of the tracers. The large number of possible dosing patterns over a month (268,435,456) magnified uncertainty in interpreting noise‐altered levels. At best, with an assay variability of 5%, compliance could be estimated only within 4 to 8 doses per month. The tracer with a half‐life of 30 days performed best. Pairing tracers did not improve uncertainty. The authors found that even a model neglecting many real‐world variables suggests a limited role for tracers in measuring compliance.
Clinical Pharmacokinetics of the CD19 Receptor‐Directed Tyrosine Kinase Inhibitor B43‐Genistein in Patients with B‐Lineage Lymphoid Malignancies
Authors: Chen Chun‐Lin , Levine Alexandra , Rao Asha , O'Neill Karen , Messinger Yoav , Myers Dorothea E. , Goldman Frederick , Hurvitz Carole , Casper James T. , Uckun Fatih M.
Published: July 2003

The authors examined the pharmacokinetics of the CD 19 receptor‐directed tyrosine kinase inhibitor B43‐Genistein in 17 patients (4 children, 13 adults) with B‐lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5patients with non‐Hodgkin's lymphoma (NHL). The immune conjugate was administered intravenously as a 1‐hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration‐time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half‐life of 19 ± 4 hours, mean residence time of 22 ± 4 hours, and a systemic clearance of 18 ± 2 mL/h/kg. The average (mean ± SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 ± 225ng/ml, 291 ± 37mL/kg, and 9987 ± 2021 μg × h/L, respectively The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 ± 5118 μg × h/L vs. 7128 ± 1156 μg × h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 ± 47 mL/kg vs. 191 ± 12 mL/kg, p = 0.04), faster clearance (21 ± 3 mL/h/kg vs. 11 ± 2 mL/h/kg, p = 0.03), and lower dose‐corrected AUC than patients with NHL (6010 ± 836 μg × h/L vs. 12,044 ± 2707 μg × h/L, p = 0.006). There was a trend toward faster clearance rates (23 ± 4 mL/h/kg vs. 16 ± 3 mL/h/kg, p = 0.1), shorter elimination half‐lives (5.7 ± 3.6 hours vs. 13 ± 8.8 hours, p = 0.1), and shorter mean residence times (11 ± 3 hours vs. 25 ± 5 hours, p = 0.08) for non‐Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 ± 82 mL/kg vs. 252 ± 34 mL/kg, p = 0.02) and a longer elimination half‐lives (18.4 ± 13.6 hours vs. 8.7 ± 6.7 hours, p = 0.04). The pharmacokinetics of B43‐Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43‐Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.
Pharmacokinetic Changes of Theophylline and Amikacin through the Menstrual Cycle in Healthy Women
Authors: Matsuki Shunji , Kotegawa Tsutomu , Tsutsumi Kimiko , Nakamura Koichi , Nakano Shigeyuki
Published: July 2003

The objective of this open‐label, single‐dose study was to clarify the influence of the menstrual cycle on the pharmacokinetics of theophylline (n = 10) and amikacin (n = 8) in young healthy Japanese women with regular menstrual cycles. Each subject received an intravenous infusion of theophylline or amikacin sulfate at four different phases—mid‐follicular (phase I), periovulatory (phase II), mid‐luteal (phase III), and premenstrual days (phase IV). In the theophylline study, there were no significant differences in the pharmacokinetic parameters among the four phases studied. In the amikacin study, CLtot was 15% higher in phase III than in phase I (p < 0.01). Vdβ was 35% higher in phase III than in phase I (p < 0.05). The other pharmacokinetic parameters of amikacin were not significantly altered during the menstrual cycle. Evidence suggests that the phase of the menstrual cycle maybe a factor in determining the pharmacokinetics of amikacin.
Pharmacokinetics and Pharmacodynamics following Intravenous Doses of Azimilide Dihydrochloride
Authors: Corey Alfred , Agnew Jeffrey , Brum Jose , Parekh Nikhil , Valentine Suzanne , Williams Melanie
Published: July 2003

Azimilide pharmacokinetics and pharmacodynamics were characterized in a safety and tolerance study of intravenously administered azimilide dihydrochloride. This was a parallel‐group design (seven treatments), and 68 healthy volunteers received the drug. Single intravenous infusion doses (4.5 to 9 mg/kg) were administered over 60 minutes, and single 4.5 mg/kg intravenous infusion doses were also given over 15 or 30 minutes. Blood and urine specimens were collected and analyzed for azimilide and metabolites. QTC was measured as a marker of class III antiarrhythmic activity. Azimilide pharmacokinetics were dose proportional and did not differ among infusion rates. Azimilide pharmacodynamics did not differ among treatments. Mean Emax ranged from 23 to 28%ΔQTC, with mean EC50 of 509 to 566 ng/mL. Peak circadian variation in QTC was equivalent to 14% of Emax. Rapid equilibration occurred between blood and the biophase. Unconfounded pharmacodynamic estimates required inclusion of circadian QTc variation in the pharmacodynamic model.
Azimilide Pharmacokinetics following Intravenous and Oral Administration of a Solution and Capsule Formulation
Authors: Corey Alfred E. , Agnew Jeffrey R. , Valentine Suzanne N. , Nesbitt John D. , Wagner Dan L. , Powell James H. , Thompson Gary A.
Published: July 2003

Azimilide dihydrochloride (NE‐10064) is a novel class III antiarrhythmic agent that blocks both the slowly and rapidly acting components of the delayed rectifier potassium current of human atrial and ventricular myocytes. In clinical studies, azimilide reduced the frequency of symptomatic episodes of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. This study was conducted to characterize azimilide pharmacokinetics following single‐dose administration of a 1 mg/kg intravenous infusion (18 min), 2 mg/kg oral solution, and a 150 mg orally administered capsule. This was a three‐period, randomized, crossover study in 27 healthy, drug‐free (including caffeine and alcohol), nonsmoking male volunteers (mean [SD]; age, 25.9 [1.0] years; weight 74.3 [0.7] kg; 23 Caucasians and 4 Hispanics). Blood and urine samples were collected for 2 7 days and analyzed for azimilide using HPLC with UV detection. Subjects were monitored for adverse events and abnormalities in clinical laboratory tests, vital signs, and electrocardiography (including Holter monitoring). Mean (%CV) azimilide parameters were total clearance = 0.143 L/h/kg (38%), renal clearance = 0.014 L/h/kg (35%), steady‐state volume of distribution = 13.2 L/kg(23%), and terminal exponential half‐life = 78.8h (44%). Similar parameter estimates were obtained following oral administration. Both the oral solution and capsule formulations were completely absorbed. In addition, the rate (Cmax) and extent of absorption (AUC) following oral administration of the capsule dosage form were bioequivalent to the oral solution with means for times of maximum blood concentration of 7.08 and 7.18 hours for the oral solution and capsule, respectively. Azimilide dihydrochloride was generally well tolerated in all subjects.