bluuebunny/crossref_metadata_2025 huggingface dataset:
Antihypertensive Effect of Low‐Dose Hydrochlorothiazide Alone or in Combination with Quinapril in Black Patients with Mild to Moderate Hypertension
Authors: Radevski I. V. , Valtchanova Z. P. , Candy G. P. , Hlatswayo M. N. , Sareli P.
Published: July 2003

In this study, using 24‐hour ambulatory blood pressure (BP) monitoring, the authors assessed the potential for BP control using hydrochlorothiazide (HCTZ, 12.5 mg daily), given as a monotherapy over 12 months to 49 black South African patients with mild to moderate hypertension (mean day diastolic blood pressure [DBP] ≥ 90 and < 115 mmHg). Uncontrolled patients received fixed combination of quinapril/HCTZ 10/12.5,20/12.5, and 20/25 mg, with dose titration at 3 monthly intervals if BP control was not achieved (day DBP < 90 mmHg). Overall, profound and sustained BP reduction was observed at the end of the study. The 24‐hour BP decreased from 151 ± 14/98 ± 7 to 136 ± 15/87 ± 9mmHg (p < 0.0001 at end of study vs. baseline); the mean day BP decreased from 155 ± 14/104 ± 7 to 140 ± 15/91 ± 10 mmHg (p < 0.0001 at end of study vs. baseline). The overall control (mean day DBP < 90 mmHg) and response (decrease in day DBP ≥ 10 mmHg) rates were 49% and 61%, respectively. At the end of the study, only 2 patients (4%) remained on treatment with HCTZ. Out of the initial 12 patients controlled on HCTZ at 3 months (12/49, 24%), 5 patients remained controlled at 6 months and only 1 patient at 12 months. In contrast, quinapril/HCTZ combinations maintained their antihypertensive effect up to 9 months, with a significant number of patients (22/49, 45%) requiring the highest dose of the combination (20/25 mg daily). In conclusion, low‐dose HCTZ should not be recommended as monotherapy in black patients with mild to moderate hypertension due to the fact that the BP‐lowering effect is attenuated already at 6 months of treatment, with most patients requiring the addition of the ACE inhibitor.
Product Equivalence Study Comparing the Tolerability, Pharmacokinetics, and Pharmacodynamics of Various Human Immunoglobulin‐G Formulations
Authors: Andresen Irmgard , Kovarik John M. , Spycher Martin , Bolli Reinhard
Published: July 2003

In this randomized, double‐blind, parallel‐group study, a commercially available human immunoglobulin‐G product, IVIG, was compared with two test formulations: (1) IVIG‐N, which is a nanofiltered formulation of IVIG, and (2) IVIG‐L, which is a nanofiltered, liquid, ready‐for‐use IgG formulation containing nicotinamide, L‐proline, and L‐isoleucine as stabilizers. Three groups of 10 healthy subjects each received a single 0.6 g/kg dose of one of the formulations infused over 3.5 to 6.8 hours, depending on the total volume to be infused. Blood samples were obtained over a 6‐week period to assess pharmacokinetics, immunogenicity and the pharmacodynamic effects on leukocytes and TNF‐α. A blood sample was taken at 6 months for a viral safety check. Administrations were generally well tolerated with only one reference IVIG infusion stopped prematurely due to headache. The IgG Cmax and AUC over the 6‐week blood sampling period from both test formulations satisfied equivalence criteria compared with the reference formulation. In subjects receiving IVIG‐L, peak concentrations of the stabilizer nicotinamide ranged from 0.34 to 0.47 mmol/L and of nicotinamide‐N‐oxide from 0.03 to 0.04 mmol/L, which are below those reported to cause adverse events. During the infusion of IVIG, leukocyte counts initially declined from a baseline of 5.7 ± 1.1 × 109/L to 3.7 ± 0.8 × 109/L at 2 to 4 hours and returned to baseline by 24 hours. TNF‐α levels, reflecting activation of the monocyte‐macrophage system by the infused IVIG, rose from a baseline of13± 4 pg/mL to a peak of 272 ± 324 pg/mL at 2 to 4 hours and returned to baseline by 24 hours. These patterns were generally similar for the test formulations, with the exception that the increase in TNF‐α levels was dampened for IVIG‐N, although this was not statistically significant. There was no evidence of immunogenicity or viral transmission from any of the formulations. Hence, these three formulations were generally well tolerated, yielded similar systemic exposure to IgG over a 6‐week period after administration, and did not give rise to immunogenicity or viral safety concerns.
Pharmacokinetic/Pharmacodynamic Evaluation of a Novel Potassium Channel Opener, SKP‐450, in Healthy Volunteers
Authors: Jang In‐Jin , Yu Kyung‐Sang , Shon Ji‐Hong , Bae Kyun‐Seop , Cho Joo‐Youn , Yi So‐Young , Shin Sang‐Goo , Ryu Keun Ho , Cho Yong‐Baik , Kim Dae‐Kee , Yoo Sung Eun
Published: July 2003

To evaluate the pharmacokinetic/pharmacodynamic characteristics of SKP‐450, a novel K+ channel opener, a single blind, randomized, placebo‐controlled, dose‐rising, parallel‐group study was conducted in 28 healthy volunteers. The volunteers were randomly allocated to dosage groups of 50 μg, 100 μg, 200 μg, and 300 μg. Single doses of SKP‐450 were administered orally, after overnight fasting, and serial blood sampling and pharmacodynamic measurements were performed up to 48 hours after the drug was administered. The 200 μg group was further studied for food interactions in a crossover fashion. Drug concentrations in plasma were determined by HPLC. Hemodynamic changes after drug administration were evaluated by serial measurements of blood pressure (BP), pulse rate (PR), cardiac index (CI), and total peripheral resistance (TPR), using computerized impedance cardiography. Changes in plasma renin activity (PRA) and aldosterone concentrations (PAC) were determined 4 and 24 hours after drug administration. Both SKP‐450 and SKP‐818, an active metabolite, showed linear pharmacokinetic characteristics, and food intake did not significantly affect the pharmacokinetic characteristics of either compound. Dose‐related pharmacological effects were obvious for both the 200 μg and 300 μg groups. Hemodynamic parameters related to vasodilation and reflex tachycardia, such as maximum changes in diastolic BP, PR, CI, and TPR, showed significant dose‐dependent changes. The area under the time‐effect curve (AUEC) of the parameters also showed a similar dose‐dependent pattern. The PRA and PAC exhibited significant changes 4 hours after drug administration in the 300 μg group. Adverse effects, such as headaches, were more frequently observed at the higher dose levels. SKP‐450 was generally well tolerated by these normotensive subjects. The antihypertensive efficacy of SKP‐450 needs to be evaluated in hypertensive patients after multiple dosing.
Optimizing the Science of Drug Development: Opportunities for Better Candidate Selection and Accelerated Evaluation in Humans
Authors: Lesko Lawrence J. , Rowland Malcolm , Peck Carl C. , Blaschke Terrence F.
Published: July 2003

Two international meetings were convened in 1998 to review the current science of drug development and the potential opportunities to optimize the evaluation of new drugs in humans. This report represents a synopsis of these meetings, and focuses on the current state of knowledge pertaining to drug development, future scientific and technical needs, and the relative merits of various strategies intended to accelerate the clinical development of drugs.
The Future of Clinical Trials in Chronic Renal Disease: Outcome of an NIH/FDA/Physician Specialist Conference
Authors: Bakris George L. , Whelton Paul , Weir Matthew , Mimran Albert , Keane William , Schiffrin Ernesto ,   For the Evaluation of Clinical Trial Endpoints in Chronic Renal Disease Study Group
Published: July 2003

For people with chronic renal insufficiency, the therapeutic goal is to prevent progression to end‐stage renal disease, a serious condition that can only be treated with dialysis and kidney transplantation. Although restriction of dietary protein slows the progression of renal disease somewhat, the principal treatment to slow chronic renal disease is appropriate reduction of blood pressure. Antihypertensive agents, particularly those that produce sustained, long‐term reductions in proteinuria, such as angiotensin‐converting enzyme inhibitors, not only decrease blood pressure but also preserve renal function. Clinical trials to evaluate these and other drug therapies in renal disease progression have used both “hard end points” (e.g., dialysis, transplantation, death) and intermediate end points of renal disease progression (e.g., doubling of serum creatinine concentration, reductions in proteinuria). Trials that have used hard end points typically recruited patients with advanced renal disease to demonstrate a difference in therapies within a period of 2 to 5 years. However, proteinuria reduction, along with a decrease in the time to doubling of serum creatinine in very early diabetic renal disease, could demonstrate an altered natural history of renal disease. Although hard end points are indicators of a drug's efficacy in reducing cardiovascular events or preserving renal function, they do not assess the impact of a treatment on altering the natural history of early renal disease. For clinical trials of people with all but the most advanced renal disease, use of intermediate end points of renal disease progression is the only practical option for assessment of treatment efficacy and effectiveness. Given the available data on proteinuria reduction and doubling of serum creatinine from clinical trials, these end points, taken together, appear to provide an acceptable means of assessing a treatment's impact on slowing renal disease progression.
Who Needs Individual Bioequivalence Studies for Narrow Therapeutic Index Drugs? A Case for Warfarin
Authors: Yacobi Avraham , Masson Eric , Moros Daniel , Ganes Derek , MSc Claude Lapointe , Abolfathi Zohreh , LeBel Marc , Golander Yechiel , Doepner Darlene , Blumberg Tamar , Cohen Yoram , Levitt Barrie
Published: July 2003

Warfarin is, among drugs, considered to have a narrow therapeutic index for which individual bioequivalence has been suggested. To establish the propriety of “switching,” an individual bioequivalence study involving a replicate‐design study and three “switchings” in healthy subjects was undertaken using the U.S.‐brand warfarin sodium tablet and a generic product. A randomized, single‐center, open‐label, single‐dose, four‐way crossover replicate bioequivalence study was performed in 24 healthy male volunteers in which each subject received the same 5 mg warfarin test and reference tablets twice on different occasions under fasting conditions. Concentrations of warfarin in plasma were measured by a validated specific HPLC method. The individual pharmacokinetic parameters obtained with test and reference products were compared using pooled data and Liu's method. Bioequivalence was shown with both average and individual bioequivalence methods. The individual bioequivalence assessment did not show a subject‐by‐formulation interaction, nor did it add value to the bioequivalence assessment of warfarin.
Steady‐State Pharmacokinetics of Carvedilol and Its Enantiomers in Patients with Congestive Heart Failure
Authors: Tenero David , Boike Steven , Boyle Duane , Ilson Bernard , Fesniak Henry F. , Brozena Susan , Jorkasky Diane
Published: July 2003

Carvedilol is a relatively new drug with β‐and α1‐receptor blocking activity and antioxidant effects recently approved for the treatment of congestive heart failure (CHF). An ascending, multiple‐dose study was completed in 20 male patients with stable New York Heart Association (NYHA) Class III or IV CHF. The pharmacokinetics of carvedilol, S(−)‐carvedilol, R(+)‐carvedilol, and the active metabolites of carvedilol was assessed at steady state after twice‐daily oral administration of carvedilol for 7 days at 6.25, 12.5, 25, and 50 mg doses. Carvedilol exhibited stereoselective pharmacokinetics in CHF patients with dose‐proportional increases in steady‐state plasma concentrations of carvedilol and its enantiomers. Mean AUC and Cmax values for carvedilol were up to twofold higher in patients with Class IV CHF as compared to those with Class III CHF. Steady‐state plasma concentrations of the active metabolites also increased in a dose‐proportional manner and were typically 10% or less of that observed for carvedilol. In general, carvedilol was adequately tolerated by adult male CHF patients at the dose levels (6.25–50 mg) evaluated in this study as adverse events were consistent with those frequently observed in patients with CHF.
Variable Absorption of Carbidopa Affects Both Peripheral and Central Levodopa Metabolism
Authors: Durso R. , Evans J. E. , Josephs E. , Szabo G. , Evans B. , Fernandez H. H. , Browne T. R.
Published: July 2003

Carbidopa (CD), a competitive inhibitor of aromatic l‐amino acid decarboxylase that does not cross the blood‐brain barrier, is routinely administered with levodopa (LD) to patients with Parkinson disease (PD) to reduce the peripheral decarboxylation of LD to dopamine. Using a stable isotope‐labeled form of LD, the authors examined in 9 PD patients the effects of variable CD absorption on peripheral and central LD metabolism. Subjects were administered orally 50 mg of CD followed in 1 hour by a slow bolus intravenous infusion of 150 mg stable isotope‐labeled LD (ring 1′,2′,3′,4′,5′,6′‐13C). Eight patients underwent a lumbar puncture 6 hours following the infusion. Blood and cerebrospinal fluid (CSF) samples were analyzed for labeled and unlabeled metabolites using a combination of high‐performance liquid chromatography and mass spectrometry. When patients were divided into “slow” and “rapid” CD absorption groups, significantly greater peripheral LD decarboxylation (as measured by area under the curve [AUC]‐labeled serum HVA) was noted in the poor absorbers (p = 0.05, Mann‐Whitney U test). Elimination half‐lives for serum LD did not differ between groups, suggesting a further capacity for decarboxylation inhibition in the “rapid” absorbers. A significant correlation between AUC serum CD and percent‐labeled HVA in CSF was found for all patients (R = 0.786, p = 0.02). “Rapid” as compared to “slow” CD absorbers had significantly more percent‐labeled CSF HVA (60 vs. 49, p = 0.02, Mann‐Whitney U test), indicating greater central‐labeled DA production in the better CD absorbers. The data suggest that peripheral aromatic l‐amino acid decarboxylase activity is not saturated at CD doses used in current practice. The authors believe that future studies to better examine a dose dependence of CD on peripheral LD decarboxylation and LD brain uptake are warranted.
Pharmacokinetics of Ibuprofen Enantiomers in Children with Cystic Fibrosis
Authors: Dong Jennifer Q. , Ni Liyun , Scott Christy S. , Retsch‐Bogart George Z. , Smith Philip C.
Published: July 2003

Chiral inversion of R(−)‐ to S(+)‐ibuprofen in children with cystic fibrosis was investigated. Children with cystic fibrosis (n = 38, ages 2–13 years) were administered a single oral dose of racemic ibuprofen (20 mg/kg), and the pharmacokinetics of ibuprofen was found to be stereoselective. Mean Cmax, AUC, apparent CL/F, and Varea/F of S‐ibuprofen were significantly different from those of R‐ibuprofen. The enantiomeric ratio of plasma AUC (S:R = 2.09:1) and of free and conjugated ibuprofen in urine (S:R = 13.9:1) of children with cystic fibrosis was not different from reported values for healthy children and adults. No significant gender difference was observed for any of the pharmacokinetic parameters determined. However, there was an inverse linear relationship between the CL/F of R‐ibuprofen and age in children with cystic fibrosis. Apparent CL/F was higher in children with cystic fibrosis than previously reported for healthy children; therefore, higher doses of ibuprofen would be necessary for children with cystic fibrosis.
Irbesartan Does Not Affect the Pharmacokinetics of Simvastatin in Healthy Subjects
Authors: Marino Maria R. , Vachharajani Nimish N. , Hadjilambris Ophelia W.
Published: July 2003

This open‐label, single‐dose, crossover study was conducted to assess the effect of irbesartan on the pharmacokinetics of total simvastatin acid in 14 healthy subjects. Subjects were randomized to receive one simvastatin 40 mg tablet or one simvastatin 40 mg tablet + one irbesartan 300 mg tablet. Subjects were crossed over to the other treatment after a 7‐ to 10‐day washout period. Serum samples were collected at specified times before and over a 24‐hour period after dosing. Safety was assessed by monitoring vital signs, laboratory tests, and adverse events. Irbesartan did not exhibit a clinically significant effect on the peak serum concentration and area under the concentration versus time curve to infinity (AUC0‐∞) of total simvastatin acid. The mean AUC0‐∞ of total simvastatin acid was 74.55 ng × h/mL when simvastatin was given alone and 67.55 ng × h/mL when simvastatin and irbesartan were given concomitantly. The time to peak serum concentration for both treatments was 3 hours. No serious adverse events occurred during the study, and both agents were well tolerated. In summary, irbesartan had no significant effect on the single‐dose pharmacokinetics of total simvastatin acid.
Advances in Pharmacogenetics and Pharmacogenomics
Authors: Vesell Elliot S.
Published: July 2003

Large differences among normal human subjects in the efficacy and safety of many therapeutic agents are caused by genetically controlled polymorphisms of drug‐metabolizing enzymes, drug transporters, and drug receptors. Development of pharmacogenomics as a new field has accelerated progress in pharmacogenetics by elucidating at the level of the human genome the inherited basis for those large interindividual variations. Examples discussed in this review illustrate how this approach can be used not only to guide new drug discovery but also to individualize therapy. Adverse drug reactions, often attributable to large differences among subjects in drug response, constitute a leading cause of death in the USA. Such high morbidity and mortality could be reduced by application of the principles of pharmacogenetics and pharmacogenomics, defined broadly as the study of genetically caused variability in drug response.
Observation and Experiment on the Cusp of Collaboration: A Parallel Examination of Clinical Pharmacology and Pharmacoepidemiology
Authors: Lehmann David F.
Published: July 2003

Despite a common interest in the effect of drugs in humans, clinical pharmacologists and pharmacoepidemiologists often operate in isolation since the knowledge base underlying the respective parent disciplines of pharmacology and epidemiology is quite distinct. This lack of communication may lead to a potential for lost opportunities that would otherwise be mutually beneficial. Accordingly, this article juxtaposes the two disciplines to emphasize common areas of interest despite differences in methodology. In addition, weaknesses and strengths are contrasted in an effort to document the mirror image nature of both clinical pharmacology and pharmacoepidemiology in this regard. Specific examples underlying the complementary nature of the two disciplines are also offered that may help to stimulate collaboration. The possibility of greater formal cooperation between societies representing the two disciplines is also suggested to cross‐educate both clinical pharmacologists and pharmacoepidemiologists as a means to foster collaboration.
Lessons Learned from the Past: A Guide for the Future of Clinical Pharmacology in the 21st Century
Authors: Lathers Claire M.
Published: July 2003

This article is a documentary of the history of the American College of Clinical Pharmacology (ACCP) and the Journal of Clinical Pharmacology. The history of the college and of the journal is presented as summarized by a few of the many leaders who played key roles in the growth of the profession of Clinical Pharmacology. Together, the college, the journal, and all clinical pharmacologists working in academia, industry, CROs, or government in many different subspecialty areas of the discipline contribute to the advancement of clinical pharmacology, the development of new drugs, and to an improved quality of life for mankind. Achieving leadership in health care in an era of change requires actions to be dynamic and flexible. Leaders must be capable of self‐development and self‐education. Leaders must examine challenges from top to bottom and build on the leadership foundations of vision, courage, and knowledge. Strong leaders are needed for the future of clinical pharmacology to address the rapidly changing environment for health care givers and the challenges faced by those working in drug development or training new leaders. One lesson from the past, from the professional life of Harry Gold, is that it is very important to convey the excitement of the field of clinical pharmacology and to pass on this excitement and knowledge base to those currently leading the educational process necessary to keep clinical pharmacologists in the forefront of the medical arena of today and tomorrow. The college became an instrument for change in the field of clinical pharmacology. Forward thinking efforts of the college did not allow stagnation. All founding leaders of the college were possessed of a dream of “what could be and what should be.” Two points should be emphasized: the importance of teaching teachers how to teach and the importance of forming national networks, such as the college, to concentrate on the role of teaching students. Today's students are the leaders of tomorrow. The training of any given student in the field of clinical pharmacology continues over many years and requires the effort of many qualified mentors. The ACCP continues to prepare for the changing demands of a new millennium. The college responded to three challenges: (1) utilization of new technologies consistent with contemporary trends; (2) identification of new member services; and (3) dissemination of a position paper defining the philosophical foundations of the college. The basic tenant of the college remains the same today as it has been over the years: provide a multidisciplinary educational environment to have a broad appeal to the membership interested in clinical pharmacology.
Evolution of Drugs That Preserve Renal Function
Authors: Basta Emad , Bakris George L.
Published: July 2003

Over the past 50 years, many advances have been made in slowing the progression of renal disease from various causes. These advances have been primarily linked to defining new lower levels for blood pressure goals as well as understanding the importance of proteinuria reduction. To achieve these goals, it is also appreciated that agents that lower blood pressure must also lower proteinuria. This is not true for all antihypertensive drug classes—notably, direct‐acting vasodilators, alpha‐blockers, and dihydropyridine calcium antagonists. Interestingly, antihypertensive agents that also reduce proteinuria have been associated with cardiovascular risk reduction. Moreover, an understanding of combinations of antihypertensive medications that provide additive reductions in proteinuria may be even more efficacious for slowing renal disease progression. It is hoped that these advances and the projected advances in pharmacogenetics will reduce the current increasing incidence of people going on dialysis.
The Birth of Ocular Pharmacology in the 20th Century
Authors: Williams Patricia B. , Crouch Earl R. , Sheppard John D. , Lattanzio Frank A. , Parker Todd A. , Mitrev Peter V.
Published: July 2003

Nineteenth century ophthalmology, characterized by significant gains in diagnostic techniques, provided the basis for great advancements in treatment during the 20th century. Drug therapy at the turn of the century was empiric, palliative, and often toxic. The development of ocular pharmacology during the 20th century provided the basis for a rational therapeutic approach to ocular disease. Foremost among the therapeutic developments were antibiotics, due to their potential to cure conditions that frequently resulted in blindness. Second, other therapeutic classes provided palliative therapy for chronic diseases, and thus decreased morbidity. For example, drugs specifically targeting many different aspects of glaucoma have had remarkable success controlling intraocular pressure and forestalling development of blindness. In addition, other new approaches provided palliative therapy for nonblinding conditions and effective adjuncts to surgical procedures. Antiallergy and anti‐inflammatory drugs greatly increased patient comfort and facilitated treatment of allergic and inflammatory reactions. Local anesthetics and analgesia reduced patient discomfort during surgery. Other adjunct drugs improved surgical outcomes by reducing inflammation and infectious complications. The 21st century will undoubtedly provide novel approaches to address many of today's therapeutic dilemmas. Photodynamic therapy, growth factors, antisense technology, and genetic‐based therapies all show great promise. Many of the conditions that are only treated palliatively today will be curable in the next century using many of these pharmacological advances.
Inhibition of Human Cytochrome P450 Isoforms by Nonnucleoside Reverse Transcriptase Inhibitors
Authors: von Moltke Lisa L. , Greenblatt David J. , Granda Brian W. , Giancarlo Gina M. , Duan Su Xiang , Daily Johanna P. , Harmatz Jerold S. , Shader Richard I.
Published: July 2003

The capacity of three clinically available nonnucleoside reverse transcriptase inhibitors (NNRTIs) to inhibit the activity of human cytochromes P450 (CYPs) was studied in vitro using human liver microsomes. Delavirdine, nevirapine, and efavirenz produced negligible inhibition of phenacetin O‐deethylation (CYP1A2) or dextromethorphan O‐demethylation (CYP2D6). Nevirapine did not inhibit hydroxylation of tolbutamide (CYP2C9) or S‐mephenytoin (CYP2C19), but these CYP isoforms were importantly inhibited by delavirdine and efavirenz. This indicates the likelihood of significantly impaired clearance of CYP2C substrate drugs (such as phenytoin, tolbutamide, and warfarin) upon initial exposure to these two NNRTIs. Delavirdine and efavirenz (but not nevirapine) also were strong inhibitors of CYP3A, consistent with clinical hazards of initial cotreatment with either of these drugs and substrates of CYP3A. The in vitro microsomal model provides relevant predictive data on probable drug interactions with NNRTIs when the mechanism is inhibition of CYP‐mediated drug biotransformation. However, the model does not incorporate interactions attributable to enzyme induction.
Effect of Rofecoxib on the Pharmacokinetics of Digoxin in Healthy Volunteers
Authors: Schwartz Jules I. , De Smet Marina , Larson Pat J. , Verbesselt R. , Ebel David L. , Lins Robert , Lens Simonne , Porras Arturo G. , Gertz Barry J.
Published: July 2003

The authors examined the effect of the cyclooxygenase‐2 (COX‐2) inhibitor, rofecoxib, at steady state on the pharmacokinetics of digoxin following a single dose in healthy subjects. Each healthy subject (N = 10) received rofecoxib (75 mg once daily) or placebo for 11 daysina double‐blind, randomized, balanced, two‐period crossover study. A single 0.5 mg oral dose of digoxin elixir was administered on the 7th day of each 11‐day period. Each treatment period was separated by 14 to 21 days. Samples for plasma and urine immunoreactive digoxin concentrations were collected through 120hours following the digoxin dose. No statistically significant differences between treatment groups were observed for any of the calculated digoxin pharmacokinetic parameters. For digoxin AUC(0‐∞), AUC(0–24), and Cmax, the geometric mean ratios (90% confidence interval) for (rofecoxib + digoxin/placebo + digoxin) were 1.04 (0.94, 1.14), 1.02 (0.94, 1.09), and 1.00 (0.91, 1.10), respectively. The digoxin median tmax was 0.5 hours for both treatments. The harmonic mean elimination half‐life was 45.7 and 43.4 hours for rofecoxib + digoxin and placebo + digoxin treatments, respectively. Digoxin is eliminated renally. The mean (SD) cumulative urinary excretion of immunoreactive digoxin after concurrent treatment with rofecoxib or placebo was 228.2 (± 30.8) and 235.1 (± 39.1) μg/120 hours, respectively. Transient and minor adverse events occurred with similar frequency on placebo and rofecoxib treatments, and no treatment‐related pattern was apparent. Rofecoxib did not influence the plasma pharmacokinetics or renal elimination of a single oral dose of digoxin.
The Tolerability of Newer Immunosuppressive Medications in a Patient with Acute Intermittent Porphyria
Authors: Barone Gary W. , Gurley Bill J. , Anderson Karl E. , Ketel Beverley L. , Abul‐Ezz Sameh R.
Published: July 2003

Acute intermittent porphyria results from a deficiency of the porphobilinogen deaminase enzyme of heme biosynthesis and is commonly exacerbated by a wide variety of medications. When referred a patient with acute intermittent porphyria for a renal transplant, only steroids and azathioprine were discovered as safe in patients with acute intermittent porphyria. The administration of many newer immunosuppressive medications, including calcineurin inhibitors, has not been documented in acute intermittent porphyria. Actually, cyclosporine is presently considered contraindicated in acute intermittent porphyria. To determine if calcineurin inhibitors would be tolerated in acute intermittent porphyria, cyclosporine and tacrolimus were administered pretransplant and were documented not to exacerbate acute intermittent porphyria. A successful renal transplant was then performed using tacrolimus. This is the first reported patient with documented acute intermittent porphyria to tolerate safely several of the newer immunosuppressive medications, including tacrolimus, mycophenolate, and rabbit antithymocytic globulin following renal transplantation. This patient's pretransplant evaluation also suggested that cyclosporine may be safe for some patients with acute intermittent porphyria.
The Process of Knowledge Discovery from Large Pharmacokinetic Data Sets
Authors: Ette Ene I. , Williams Paul , Sun He , Fadiran Emmanuel , Ajayi Funmilayo O. , Onyiah Leonard C.
Published: July 2003

The advent of statistical software with powerful graphical and modeling capabilities has revolutionized the manner in which pharmacokinetic and pharmacodynamic analyses are performed. Knowledge discovery from a large (population) pharmacokinetic data set incorporates all steps taken from data assembly to the development of a population pharmacokinetic model and the communication of the results thereof. The process can be formalized into a number of steps: (1) creation of a data set for pharmacokinetic knowledge discovery, (2) data quality analysis, (3) data structure analysis (exploratory examination of raw data), (4) determination of the basic pharmacokinetic model that best describes the data and generating post hoc empiric individual Bayesian parameter estimates, (5) the search for patterns and relationships between parameters and parameters and covariates by visualization, (6) the use of modern statistical modeling techniques for data structure revelation and covariate selection, (7) consolidation of the discovered knowledge into irreducible form (i.e., developing a population pharmacokinetic model), (8) the determination of model robustness (determination of the reliability of model parameter estimates), and (9) the communication and integration of the discovered pharmacokinetic knowledge. This process is discussed, and a motivating example is presented. The use of modern graphical, modeling, and statistical techniques for knowledge discovery from large pharmacokinetic data sets has given the data analyst the freedom to choose statistical methodology appropriate to the problem at hand with the maximization of information extraction, rather than on the basis of mathematical/statistical tractability.
Single‐Dose Pharmacokinetics of Sotalol in a Pediatric Population with Supraventricular and/or Ventricular Tachyarrhythmia
Authors: Saul J. Philip , Schaffer Michael S. , Karpawich Peter P. , Erickson Christopher C. , Epstein Michael R. , Melikian Armen P. , Shi Jun , Karara Adel H. , Cai Bin , Hinderling Peter H.
Published: July 2003

The pharmacokinetics (PK) of the antiarrhythmic sotalol, which elicits Class III and beta‐blocking activity, has not been adequately defined in a pediatric population with tachyarrhythmias. The goal of this single‐dose study with administration of sotalol HCl at a dose level of 30 mg/m2 body surface area (BSA) was to define the PK of the drug in the following four age groups: neonates (0–30 days), infants (1 month to 2 years), younger children (> 2 to < 7 years), and older children (7–12 years) with tachyarrhythmias of either supraventricular or ventricular origin. The drug was administered in an extemporaneously compounded syrup formulation prepared from the tablets containing sotalol HCl. For safety, vital signs and adverse events were recorded and the QTc interval and heart rate telemetrically monitored. Scheduled blood samples were taken over a 36‐hour time interval following dose administration. The drug concentrations in plasma were measured by a sensitive and specific LC/MS/MS assay. Standard compartment model‐independent methods were applied to compute the salient PK parameters of sotalol. Twenty‐four clinical sites enrolled 34 patients. Thirty‐three had analyzable data. Sotalol was rapidly absorbed, with mean peak concentrations occurring 2 to 3 hours after administration. The elimination of sotalol was characterized by an average half‐life of between 7.4 and 9.2 hours in the four age groups. There existed statistically significant linear relationships between apparent total clearance (CL/f) or apparent volume of distribution (VΛz/f) after oral administration and the covariates BSA, creatinine clearance (CLcr), body weight (BW), or age. The best predictors for CL/f were CLcr and BSA, whereas BW best predicted the VΛz/f. The total area under the drug concentration‐time curve in the smallest children with a BSA < 0.33 m2 was significantly greater than that in the larger children. This finding indicated that the BSA‐based dose adjustment used in this study led to a larger exposure in the smallest children, whereas the exposure to the drug was similar in the larger children. The dose of 30 mg/m2 was tolerated well. No serious drug‐related adverse events were reported. It can be concluded that the PK of sotalol in the pediatric patients depended only on body size, except for the neonates and smallest infants in whom the disposition of sotalol was determined by both body size and maturation of eliminatory processes.
Pharmacokinetic‐Pharmacodynamic Modeling of Atracurium in Intensive Care Patients
Authors: Farenc Christine , Lefrant Jean‐Yves , Audran Michel , Bressolle Françoise
Published: July 2003

The authors have studied 10 critically ill patients with acute respiratory distress syndrome who required a neuromuscular blocking drug to assist mechanical ventilation. Patients received a bolus dose of 1 mg/kg of atracurium followed by a constant infusion rate of 1 mg/kg/h of this drug for 72 hours. Neuromuscular block was monitored using an accelerograph. Blood samples were obtained over a 96‐hour period. A preliminary independent analysis was done to estimate the individual pharmacokinetic parameters; data were consistent with a one‐compartment model. The pharmacodynamic data analysis was then performed using the changes in train‐of‐four (TOF) count as an index of the therapeutic effect of atracurium. Pharmacokinetic‐dynamic variables were calculated using the Sheiner model and the Hill equation. The elimination half‐life of atracurium averaged 22 minutes. Mean volume of distribution and plasma clearance were 217 ml/kg and 550 ml/min, respectively. There was a significant hysteresis loop when the TOF count was plotted against predicted plasma atracurium concentrations. The mean sigmoidicity factor, γ, was 4.04. The concentration producing 50% of the Emax was 1.36 μg/mL, and the mean ke0 was 0.059 min−1. Recovery time ranged from 30 to 80 minutes, and none of the patients of this study had residual paralysis.
Pharmacokinetic‐Pharmacodynamic Modeling of the Electroencephalogram Effects of Scopolamine in Healthy Volunteers
Authors: Ebert Ulrike , Grossmann Matthias , Oertel Reinhard , Gramatté Thomas , Kirch Wilhelm
Published: July 2003

Scopolamine is a muscarinic receptor antagonist commonly used as a pharmacological model substance based on the “cholinergic hypothesis” of memory loss in senile dementia of the Alzheimer type. The objective of the study was to relate pharmacodynamic electroencephalogram (EEG) changes and scopolamine serum concentration using pharmacokinetic‐pharmacodynamic (PK‐PD) modeling techniques. This was a randomized, three‐way crossover, open‐label study involving 10 healthy nonsmoking young male volunteers who received either scopolamine 0.5 mg as an intravenous (IV) infusion over 15 minutes or an intramuscular (IM) injection oraplacebo. The pharmacodynamic EEG measure consists of the total power in delta, theta, alpha, and beta bands over frontal, central, and occipital brain areas. The values of the pharmacokinetic parameters of scopolamine after IV infusion were clearance (CL) 205 ± 36.6 L/h, volume of distribution (Vd) 363 ±66.7 L, distribution half‐life (t1/2α) 2.9±0.67 min, and terminal half‐life (t1/2β) 105.4 ±9.94 min (mean ± SEM). Mean peak serum concentrations (Cmax) were 4.66 and 0.96 ng/ml after IV and IM administration, respectively (p < 0.05). The area under the serum concentration versus time curve (AUC) after IM administration (81.27±11.21 ng/ml/min) was significantly lower compared to the value after IV infusion (157.28 ±30.86 ng/ml/min) (mean ±SEM, p < 0.05). Absolute bioavailability of scopolamine after IM injection was 57% ±0.08% (mean ±SEM). After both IV and IM administration, scopolamine induced a decrease in EEG alpha power (7.50‐11.25 Hz) over frontal, central, and occipital brain areas compared to placebo (p < 0.05). The individual concentration‐EEG effect relationships determined after IV infusion of scopolamine were successfully characterized by a sigmoidal Emax model. The averaged values of the pharmacodynamic parameters were E0 = 0.58 μV2, Emax = 0.29 μV2, EC50 = 0.60 ng/ml, and γ = 1.17. No time delay between serum concentrations and changes in alpha power was observed, indicating a rapid equilibration between serum and effect site. The results provide the first demonstration of a direct correlation between serum concentrations of scopolamine and changes in total power in alpha frequency band in healthy volunteers using PK‐PD modeling techniques. As regards the effect on the EEG, 0.5 mg of scopolamine administered IV appears to be a suitable dose.
Pharmacokinetic‐Pharmacodynamic Modeling of the Antilipolytic Effects of an Adenosine Receptor Agonist in Healthy Volunteers
Authors: Zannikos Peter N. , Rohatagi Shashank , Jensen Bradford K.
Published: July 2003

ARA is an adenosine receptor agonist with high affinity for A1 and A2 receptors, which are involved in regulation of free fatty acid (FFA) production. Two parallel groups of 13 healthy males were enrolled in a Phase I study to evaluate the pharmacokinetics of this compound and to characterize its effect on plasma FFA concentrations following administration of a single 6‐hour intravenous infusion of ARA or placebo. ARA plasma concentrations were measured by a validated high‐performance liquid chromatographic method (fluorescence detection). ARA is a highly cleared compound (Cl: 0.79 L/h/kg) with a modest volume of distribution (Vss: 0.91 L/kg) and short half‐life (t1/2: ∼1 hour). The mean percent change in plasma FFA concentrations relative to placebo was best described by an Emax‐based tolerance model, in which a hypothetical metabolite/antagonist was used to describe the apparent development of tolerance to the suppressive effects of ARA on FFA levels. The EC50 values (%RSE of estimate) for ARA and the hypothetical antagonist were 17.0 (5.4) and 15.6 (12.8) ng/mL, respectively. The use of adenosine A1 agonists as antilipolytic drugs may be restricted due to the potential development of tolerance, and thus a period of abstinence from the agonist may be required before the response of FFA returns to pretolerant conditions. In the case of ARA, the value of 0.33 h−1 for Kant0 indicates that a period of approximately 11 hours should suffice. In agreement with preclinical data previously reported in literature, the present study provides evidence that desensitization of adenosine receptor‐mediated inhibition of lipolysis may occur in humans. In conclusion, the ability of ARA to reduce circulating levels of FFA can be related to plasma ARA concentrations using a modified Emax‐based tolerance model.
Pharmacokinetics of Tilidine in Terminal Renal Failure
Authors: Seiler K.‐U. , Jähnchen E. , Trenk D. , Brennscheidt U. , Heintz B.
Published: July 2003

The aim of the present study was to investigate the pharmacokinetics of tilidine and its metabolites during the dialysis procedure and in the dialysis‐free interval. Tilidine is a prodrug that is metabolized presystemically into the active metabolite nortilidine. Nortilidine is degraded thereafter to bisnortilidine and several polar metabolites. Nine patients with a creatinine clearance < 5 ml/min were treated in a crossover design with single oral doses of 1.5 mg/kg on the day of dialysis (dialysis performed from 3 to 6 hours after drug administration) and on a day in the dialysis‐free interval. Blood samples were taken frequently and analyzed for tilidine, nortilidine, and bisnortilidine. Drug and metabolite concentrations were also measured in aliquots of dialysate collected during dialysis. Only negligible amounts of tilidine, nortilidine, and bisnortilidine (about 0.9% of the dose) were recovered from the dialysate. The pharmacokinetics of nortilidine and its inactive metabolite bisnortilidine was not affected by dialysis. The presystemic apparent clearance of the prodrug tilidine was decreased significantly during the dialysis‐free interval. A significant decrease of the rate of elimination and an increase of the AUC of bisnortilidine were observed if these parameters were compared with data obtained from healthy volunteers. The plasma concentrations of nortilidine were comparable in patients and normal volunteers. Thus, a reduction of the dose of tilidine in patients with severely impaired kidney function seems not to be required. Tilidine and its metabolites cannot be removed from the body by dialysis.
Sevelamer Hydrochloride (Renagel®), a Nonabsorbed Phosphate‐Binding Polymer, Does Not Interfere with Digoxin or Warfarin Pharmacokinetics
Authors: Burke Steven , Amin Naseem , Incerti Carlo , Plone Melissa , Watson Norma
Published: July 2003

Sevelamer hydrochloride (Renagel®) is a nonabsorbed phosphate‐binding polymer marketed for the treatment of hyperphosphatemia in adult patients receiving hemodialysis. Sevelamer also exhibits bile acid‐binding properties resulting in LDL cholesterol lowering. Potential drug interactions between digoxin and warfarin and sevelamer were studied. These two drugs were chosen because they are known to bind to the bile acid‐binding polymers, cholestyramine and colestipol. Studies were single dose, crossover, with or without six 2.4 g doses of sevelamer. Plasma concentrations were determined using validated analytical methods. The pharmacokinetic profiles of digoxin and warfarin were not altered by the simultaneous and continued administration of sevelamer. Values for the ratio of ∞ln[AUC(0‐∞)], ln[AUC(0‐t)], and ln[Cmax] with and without sevelamer were close to 100%, and the 90% confidence intervals for these ratios were within the 80% to 125% range. It was concluded that sevelamer does not interfere with the absorption or excretion of digoxin or warfarin.
Lack of Interaction between Levofloxacin and Oxycodone: Pharmacokinetics and Drug Disposition
Authors: Grant Edward M. , Zhong Ming Kang , Fitzgerald James F. , Nicolau David P. , Nightingale Charles , Quintiliani Richard
Published: July 2003

Previous studies have demonstrated a significant reduction in the oral bioavailability of trovafloxacin and ciprofloxacin when administered concomitantly with an intravenous opiate such as morphine. This decrease in absorption results in a 36% and 50% lower AUC for trovafloxacin and ciprofloxacin, respectively, which could cause clinical failures. The authors investigated the possibility of a similar interaction between oxycodone and levofloxacin. Eight healthy volunteers were randomized in an open‐label, two‐way crossover study to receive oxycodone, 5 mg po Q4H, and levofloxacin, 500 mg po 1 hour after starting the oxycodone or levofloxacin 500 mg po alone. Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours for Cmax, tmax, and AUC determinations. There was not a significant difference (p < 0.05) in AUC (48.59 ± 8.52 vs. 49.9 ± 9.93), Cmax (7.73 ± 2.6 vs. 6.6 ± 2.0), and tmax (1.1 ± 0.6 vs. 1.6 ± 1.1) for levofloxacin versus levofloxacin/oxycodone regimens. It was concluded that oral oxycodone and levofloxacin can be administered concomitantly without a significant decrease in AUC, Cmax, or tmax.
Lack of an Effect of Azithromycin on the Disposition of Zidovudine and Dideoxyinosine in HIV‐Infected Patients
Authors: Amsden Guy , Flaherty John , Luke David
Published: July 2003

Two studies were conducted in HIV‐infected subjects to assess the potential for azithromycin to interact with zidovudine and dideoxyinosine. Both studies used 12 subjects. The zidovudine study dosed subjects with 1200 mg/day of azithromycin (n =7) (later changed to 600 mg/day [n = 5]) for Days 8 to 21 of a 21‐day course of 100 mg, five times/day of zidovudine. Subjects treated with 200 mg of dideoxyinosine twice daily for 21 days received 1200 mg of azithromycin or an equivalent amount of placebo/day for Days 8 to 21. Antiretroviral plasma and urine sampling were conducted on Days 1, 7, and 21 for zidovudine and on Days 7 and 21 for dideoxyinosine. Peripheral mononuclear cells were also collected for quantitation of phosphorylated zidovudine. Azithromycin had no significant impact on the Cmax and AUC of zidovudine, although it significantly decreased the zidovudine tmax by 44% and increased the intracellular exposure to phosphorylated zidovudine by 110%. Azithromycin had no significant effect on dideoxyinosine pharmacokinetics. Based on the results of these studies, it is concluded that azithromycin may be safely coadministered with both zidovudine and dideoxyinosine.
Visual Hallucination and Tremor Induced by Sertraline and Oxycodone in a Bone Marrow Transplant Patient
Authors: Rosebraugh Curtis J. , Flockhart David A. , Yasuda Sally U. , Woosley Raymond L.
Published: July 2003

The authors report a case of probable serotonin syndrome caused by the coadministration of sertraline and oxycodone. A 34 year‐old male patient experienced visual hallucinations and severe tremor after dramatically increasing his dosage of oxycodone while on stable amounts of sertraline and cyclosporin. Discontinuation of cyclosporin did not result in resolution of his symptoms. Consideration of a possible sertraline‐oxycodone interaction led to withholding sertraline, which resulted in symptom resolution. Serotonin syndrome has been noted with sertraline in combination with other drugs, but this is the first report in combination with a narcotic analgesic. Possible pharmacological mechanisms are discussed. In complicated patients that are taking multiple medications, physicians should be aware of this possible interaction to avoid delay in the diagnosis of serotonin syndrome.