bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ribavirin dosing in chronic hepatitis C: Application of population pharmacokinetic‐pharmacodynamic models
Authors: Jen Juif , Laughlin Mark , Chung Carol , Heft Samuel , Affrime Melton B. , Gupta Samir K. , Glue Paul , Hajian Gerald 
Published: November 2002

BackgroundCombination therapy of ribavirin with interferon alfa‐2b and pegylated interferon alfa‐2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight.ObjectiveOur objective was to evaluate ribavirin dosing strategies by comparison of their relative efficacy and toxicity profiles.MethodsThree models were developed on the basis of data collected from a large phase III trial. A population pharmacokinetic model was used to describe the ribavirin dose‐concentration relationship and the influence of covariates. Logistic regression models were developed for both sustained virologic response and hematologic toxicity. Ribavirin concentration was an important explanatory variable for both response and toxicity. Simulations of these models were developed for different ribavirin doses to obtain efficacy and toxicity profiles across the various dosing strategies. These strategies included a fixed 800‐mg/d dose, empiric weight‐adjusted doses (ie, 1000 mg/d for patients who weighed ≤75 kg and 1200 mg/d for patients who weighed >75 kg [1000/1200 mg/d on the basis of body weights ≤75/>75 kg] and 800 mg/d for patients who weighed <65 kg, 1000 mg/d for patients who weighed from 65 to 85 kg, and 1200 mg/d for patients who weighed >85 kg [800/1000/1200 mg/d on the basis of body weights <65/65‐85/>85 kg]), a dose of 13 mg/kg per day, and other per‐body weight doses between 9 and 16 mg/kg per day.ResultsSimulation results showed that both efficacy and toxicity increased as the milligrams‐per‐kilogram dose of ribavirin increased. The body weight‐based 800/1000/1200‐mg/d dose had overall response and toxicity rates that were 6.3% and 2.5% higher than those of the fixed 800‐mg/d dose. In particular, patients with genotype‐1 disease had a 7.4% increase in response rate. There were no differences in response and toxicity rates between the 800/1000/1200‐mg/d and 13‐mg/kg per day dose groups.ConclusionsThis simulation suggests that ribavirin dosage (in combination with pegylated interferon alfa‐2b) for patients with chronic hepatitis C should be based on body weight.Clinical Pharmacology & Therapeutics (2002) 72, 349–361; doi: 10.1067/mcp.2002.127112
Immunosuppressive therapy regimen and platelet activation in renal transplant patients
Authors: Graff Jochen , Klinkhardt Ute , Harder Sebastian , Wegert Wolfgang , Lenz Tomas , Scheuermann Ernst‐Heinrich , Gossmann Jan 
Published: November 2002

BackgroundIncreased platelet activation caused by an immunosuppressive therapy regimen may contribute to the high incidence of death from cardiovascular disease in renal transplant patients. Cyclosporine (INN, ciclosporin) and azathioprine are reported to activate platelets, but data are rare and controversial for tacrolimus and mycophenolate mofetil.MethodsThis cross‐sectional study assessed markers of platelet degranulation (P‐selectin; CD62), the activated glycoprotein IIb/IIIa receptor (PAC1, indicating the fibrinogen binding site), platelet aggregation, and secretion of platelet‐derived growth factor (PDGFAB) in renal transplant patients treated with 4 different therapy regimens. Immunosuppression was based on low‐dose steroids (5 mg/d prednisone) in combination with a single agent: (1) cyclosporine (n = 16), (2) azathioprine (n = 18), (3) tacrolimus (n = 17), or (4) mycophenolate mofetil (n = 13). Effects were compared with those in an age‐matched control group of patients with hypertension (n = 11).ResultsIn all renal transplant patient groups, unactivated platelets exhibited an increased expression of CD62. When stimulated with 2‐μmol/L thrombin receptor‐activating peptide, CD62 expression in platelets from patients treated with azathioprine (63% ± 17%; P < .05), cyclosporine (51% ± 23%; P < .05), and tacrolimus (50% ± 22%; P < .05) was elevated compared with control subjects (33% ± 19%). PAC1 expression was significantly increased in the patient groups that received azathioprine and cyclosporine. PDGFAB secretion was elevated in patients treated with azathioprine only (51 ± 24 ng/109 platelets [versus 35 ± 17 ng/109 platelets for control subjects]; P < .05). Platelet aggregation in response to collagen (0.5 μg/mL) was decreased in patients treated with tacrolimus (49% ± 29%; P < .05) and mycophenolate mofetil (55% ± 32%; P < .05) compared with control subjects (73% ± 25%).ConclusionThis is the first study to compare the effects on platelet function of different immunosuppressive regimens that are based on monotherapy. All renal transplant patients showed preactivated platelets compared with those of patients with hypertension. However, the “newer” immunosuppressive agents tacrolimus and mycophenolate mofetil seemed to have fewer unfavorable effects on platelet CD62 expression and PAC1 expression and aggregation. Whether this finding is accompanied by fewer cardiovascular events remains to be elucidated.Clinical Pharmacology & Therapeutics (2002) 72, 411–418; doi: 10.1067/mcp.2002.127115
Plasma concentrations of inhaled budesonide and its effects on plasma cortisol are increased by the cytochrome P4503A4 inhibitor itraconazole
Authors: Raaska Kari , Niemi Mikko , Neuvonen Mikko , Neuvonen Pertti J. , Kivistö Kari T. 
Published: November 2002

ObjectiveOur objective was to examine the effects of itraconazole on the pharmacokinetics and cortisol‐suppressant activity of budesonide administered by inhalation.MethodsIn a randomized, double‐blind, 2‐phase crossover study, 10 healthy subjects took 200 mg itraconazole or placebo orally once a day for 5 days. On day 5, 1 hour after the last dose of itraconazole or placebo, 1000 μg budesonide was administered by inhalation. Plasma budesonide and cortisol concentrations were measured up to 23 hours.ResultsItraconazole increased the mean total area under the plasma concentration‐time curve of inhaled budesonide 4.2‐fold (range, 1.7‐fold to 9.8‐fold; P < .01) and the peak plasma concentration 1.6‐fold (P < .01) compared with placebo. The mean terminal half‐life of budesonide was prolonged from 1.6 to 6.2 hours (ie, 3.7‐fold; range, 1.5‐fold to 9.3‐fold; P < .001) by itraconazole. The suppression of cortisol production after inhalation of budesonide was significantly increased by itraconazole as compared with placebo, as shown by a 43% reduction in the area under the plasma cortisol concentration‐time curve from 0.5 to 10 hours (P < .001) and a 12% decrease in the cortisol concentration measured 23 hours after administration of budesonide, at 8 am (P < .05).ConclusionsItraconazole markedly increased systemic exposure to inhaled budesonide, probably by inhibiting the cytochrome P4503A4‐mediated metabolism of budesonide during both the first‐pass and the elimination phases. This interaction resulted in enhanced systemic effects of budesonide, as shown by suppression of cortisol production. Long‐term coadministration of budesonide and a potent CYP3A4 inhibitor may be associated with an increased risk of adverse effects of budesonide.Clinical Pharmacology & Therapeutics (2002) 72, 362–369; doi: 10.1067/mcp.2002.127397
The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment
Authors: Brockmöller Jürgen , Kirchheiner Julia , Schmider Jürgen , Walter Silke , Sachse Christoph , Müller‐Oerlinghausen Bruno , Roots Ivar 
Published: November 2002

ObjectivesThe genetically polymorphic enzyme cytochrome P450 (CYP) 2D6 contributes to the biotransformation of the antipsychotic drug haloperidol. The impact of the polymorphism on haloperidol pharmacokinetics, adverse events, and efficacy was prospectively evaluated under naturalistic conditions in 172 unselected psychiatric inpatients with acute psychotic symptoms.MethodsSerum trough levels of haloperidol and reduced haloperidol of patients receiving clinically adjusted doses were analyzed on days 3, 14, and 28 after hospital admission. Adverse events such as extrapyramidal symptoms were assessed by standardized rating scales. Efficacy was documented by recording the change in positive and negative schizophrenic symptoms. These parameters were correlated with the CYP2D6 genotype determined by polymerase chain reaction analysis for alleles *1 to *15 and *17.ResultsThe serum concentrations showed wide interindividual variation. Reduced haloperidol trough levels and haloperidol total clearance correlated significantly with the number of active CYP2D6 genes. In addition, body weight and smoking had significant effects on haloperidol kinetics, whereas age, gender, and comedication showed only slight effects. The ratings for pseudoparkinsonism were significantly higher in poor metabolizers of substrates of CYP2D6. On the other hand, there was a trend toward lower therapeutic efficacy with increasing number of active CYP2D6 genes.ConclusionsTreatment with haloperidol should be avoided in extremely slow and extremely rapid metabolizers of CYP2D6 substrates. Both genotyping and blood concentration measurement explained only a fraction of the adverse events; about 20 patients would have to be genotyped to achieve a significant benefit in 1 patient. It is interesting that genotyping was at least as good a predictor of adverse events as the measured drug concentrations.Clinical Pharmacology & Therapeutics (2002) 72, 438–452; doi: 10.1067/mcp.2002.127494
Development of an optimal furosemide infusion strategy in infants with modeling and simulation
Authors: Schoemaker Rik C. , van der Vorst Maria M. J. , van Heel Isabelle Ruijs‐Dudok , Cohen Adam F. , Burggraaf Jacobus ,   on behalf of the Pediatric Pharmacology Network
Published: November 2002

BackgroundThe optimal dosing strategy for continuous intravenous furosemide infusion is unknown in pediatric patients. Eighteen patients less than 1 year old were studied after cardiac surgery during routine clinical care. The current strategy starts with a continuous infusion of 0.1 mg/kg · h, which may be adapted.MethodsA pharmacokinetic‐pharmacodynamic model was developed that linked furosemide dose to furosemide serum concentrations, renal function (creatinine clearance), and urine output. Various regimens were simulated that adapt according to urine production. The modified dosing schedule was prospectively tested in a subsequent population of 18 pediatric patients after cardiac surgery.ResultsData from the follow‐up study suggest that urine production is more controlled for the proposed regimen.ConclusionsBoth the modeling and simulation results and the follow‐up study indicated that a bolus dose of 1 mg/kg followed 6 hours later with a 1‐ or 2‐mg/kg loading dose and a 0.2‐mg/kg · h intravenous infusion provides a rational starting point for furosemide therapy after cardiac surgery in pediatric patients less than 1 year old. Adjustment of this regimen every 12 hours in steps of 0.1 mg/kg · h on the basis of clinical assessment should lead to adequate control over urinary output.Clinical Pharmacology & Therapeutics (2002) 72, 383–390; doi: 10.1067/mcp.2002.127608
Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole
Authors: Furuta Takahisa , Shirai Naohito , Watanabe Fumitoshi , Honda Satoru , Takeuchi Ken , Iida Takayuki , Sato Yoshihiko , Kajimura Masayoshi , Futami Hajime , Takayanagi Shigekazu , Yamada Masami , Ohashi Kyoichi , Ishizaki Takashi , Hanai Hiroyuki 
Published: November 2002

Background and ObjectivesThe acid‐inhibitory effect of lansoprazole depends on differences in cytochrome P450 (CYP) 2C19 genotypes. We assessed whether therapeutic effects of lansoprazole on gastroesophageal reflux disease (GERD) depended on the CYP2C19 genotype status in relation to the grade of GERD.MethodsA total of 65 patients with GERD (grades A‐D) completed treatment with lansoprazole, by taking 30 mg orally once a day for 8 weeks. The CYP2C19 genotype status of patients was determined by polymerase chain reaction‐restriction fragment length polymorphism analysis. Before and after treatment, esophageal endoscopy was performed. GERD was considered to be cured on the basis of endoscopic findings at the end of treatment. Plasma lansoprazole levels could be determined at 3 hours after the last 30‐mg dose of lansoprazole in the 27 genotyped patients.ResultsCure rates for GERD depended significantly on the CYP2C19 genotype status, as well as the grade of GERD before treatment. Cure rates in the homozygous extensive, heterozygous extensive, and poor metabolizer groups were 45.8%, 67.9%, and 84.6%, respectively. Cure rates in the groups with GERD grade A, grade B, and grade C or D were 85.0%, 60.0%, and 45.0%, respectively. The cure rate in patients with the homozygous extensive metabolizer genotype of CYP2C19 with a GERD grade of C or D was very low (16.7%). Plasma lansoprazole levels in patients with the homozygous extensive metabolizer genotype were the lowest of the 3 groups.ConclusionsCYP2C19 genotype status, as well as the grade of GERD before treatment, is one of the determinants for the success or failure of treatment of GERD with lansoprazole. The low cure rate in patients with the homozygous extensive metabolizer genotype appeared to be a result of these patients having the lowest plasma lansoprazole levels among the 3 genotype groups.Clinical Pharmacology & Therapeutics (2002) 72, 453–460; doi: 10.1067/mcp.2002.127637
Concentration‐effect relationships of two rilmenidine single‐dose infusion rates in hypertensive patients
Authors: de Visser Saco J. , van der Post Jeroen‐Paul , Nanhekhan Loyd , Schoemaker Rik C. , Cohen Adam F. , van Gerven Joop M. A. 
Published: November 2002

ObjectivesThis study was designed to assess the concentration‐effect relationships for the antihypertensive effects of rilmenidine in patients to aid in the design of an optimized concentration profile of a sustained‐release formulation.MethodsA placebo‐controlled, randomized, double‐blind, 2‐way partial crossover study was performed in subjects with hypertension. Patients were randomized to receive 2 of 3 possible 12‐hour infusion regimens, each consisting of a loading phase (2 hours) and a maintenance phase (10 hours): low‐profile infusion (total dose of rilmenidine, 1.45 mg), high‐profile infusion (total dose, 3.3 mg), or placebo. Drug plasma concentrations, adverse events, blood pressure, heart rate, and visual analog scales were measured frequently, up to 24 hours after dosing. Salivary flow was determined for up to 15 hours.ResultsThe high concentration profile was well tolerated and continued to produce a significant blood pressure reduction of 10.4 mm Hg (systolic)/5.8 mm Hg (diastolic) after 24 hours. The low concentration profile showed no significant effects on blood pressure compared with placebo after 24 hours. Decreases in salivary flow were −36% for the high‐profile infusion and −20% for the low‐profile infusion compared with placebo. Pharmacokinetic‐pharmacodynamic analyses showed infusion rate‐independent, linear concentration‐dependent reductions in diastolic blood pressure and salivary flow up to the maximum observed rilmenidine concentration for both types of infusion.ConclusionsThe high concentration profile was well tolerated and still produced a significant blood pressure reduction after 24 hours. Pharmacokinetic‐pharmacodynamic relationships were linear and unaffected by the rate of infusion. These results should aid in the design of an optimal slow‐release profile.Clinical Pharmacology & Therapeutics (2002) 72, 419–428; doi: 10.1067/mcp.2002.127638
Pharmacodynamics of active site‐inhibited factor VIIa in endotoxin‐induced coagulation in humans
Authors: Jilma Bernd , Marsik Claudia , Mayr Florian , Graninger Monika T. , Taylor Fletcher B. , Ribel Mette C. , Erhardtsen Elisabeth , Handler Sylvia , Eichler Hans Georg 
Published: November 2002

BackgroundInhibition of the tissue factor‐factor VIIa pathway attenuated the activation of coagulation and prevented death in a gram‐negative bacteremia primate model of sepsis. This lethal animal model suggested that tissue factor also influences inflammatory cascades.MethodsThis trial examined the pharmacodynamic effects of active site‐inhibited factor VIIa (FFR‐recombinant factor VIIa [rFVIIa]; ASIS) on endotoxin‐induced procoagulant, fibrinolytic, and inflammatory responses in healthy humans. A double‐blind, randomized, placebo‐controlled, parallel‐group study was conducted in 12 healthy male volunteers. Subjects received a bolus infusion of 2‐ng/kg endotoxin, followed by a bolus infusion of ASIS (400 μg/kg) or placebo 10 minutes later.ResultsEndotoxin injection induced inflammation, activation of coagulation, and activation and subsequent inhibition of fibrinolysis. ASIS infusion completely blocked thrombin and fibrin generation, as measured by plasma levels of prothrombin fragment (no increase in the ASIS group, as compared with a 13‐fold increase in the placebo group at 4 hours; P < .01), soluble fibrin, and fibrin split product D‐dimer. ASIS did not alter endotoxin‐induced changes in the fibrinolytic system, cytokine levels, or markers of endothelial (E‐selectin, thrombomodulin) or platelet (P‐selectin) activation.ConclusionsIn summary, ASIS effectively and selectively attenuates tissue factor‐induced thrombin generation. Because ASIS was well tolerated, this study provides seminal data to further characterize its anticoagulant and putative anti‐inflammatory effects in critically ill patients.Clinical Pharmacology & Therapeutics (2002) 72, 403–410; doi: 10.1067/mcp.2002.127740
Simvastatin‐induced lactic acidosis: A rare adverse reaction?
Authors: Goli Anil K. , Goli Sujatha A. , Byrd Ryland P. , Roy Thomas M. 
Published: November 2002

Simvastatin, a hydroxymethylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor, is a commonly used cholesterol‐lowering agent. The long‐term safety profile of simvastatin, established over 10 years of clinical use, is excellent. HMG‐CoA reductase inhibitors block 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, the rate‐limiting enzyme in cholesterol synthesis. However, other important nonsterol compounds, such as coenzyme Q10 (CoQ10), are also derived from the same synthetic pathway. CoQ10 is an essential carrier in the mitochondrial respiratory chain that participates in oxidative phosphorylation. Simvastatin and other HMG‐CoA reductase inhibitors have been documented to lower serum concentrations of CoQ10. It has been suggested that the adverse effect of myopathy caused by HMG‐CoA reductase inhibitors is due to CoQ10 deficiency in the tissue mitochondria. Documentation of this cause‐and‐effect phenomenon, however, has been lacking. We offer evidence that lactic acidosis may develop as a complication of simvastatin therapy. Our patient also manifested the well‐known HMG‐CoA reductase inhibitor drug toxicities of rhabdomyolysis and hepatitis. The occurrence of these known adverse events with lactic acidosis in our patient suggests that interference of the mitochondrial respiratory chain may play a role in the toxicity of this class of drugs.Clinical Pharmacology & Therapeutics (2002) 72, 461–464; doi: 10.1067/mcp.2002.127943
Pharmacokinetic and pharmacodynamic interactions between diltiazem and methylprednisolone in healthy volunteers
Authors: Booker Brent M. , Magee Mindy He , Blum Robert A. , Lates Christian D. , Jusko William J. 
Published: November 2002

ObjectivesThe pharmacokinetics and pharmacodynamics after administration of methylprednisolone alone, diltiazem alone, and both drugs jointly were assessed in healthy volunteers.MethodsAn unblinded, controlled, fixed‐sequence, 2‐period study was carried out in 5 healthy white men who received a single dose of intravenous methylprednisolone, 0.3 mg/kg, on day 2, followed by diltiazem alone, 180 mg, on days 5, 6, and 7, with joint dosing of both drugs on day 8. Methylprednisolone and diltiazem disposition was assessed from plasma concentrations. Pharmacodynamic factors were assessed by plasma cortisol and T‐helper and T‐suppressor lymphocytes by means of extended indirect response models.ResultsThe clearance of methylprednisolone was significantly reduced in the presence of diltiazem (25.2 L/h versus 16.8 L/h), resulting in a longer half‐life (2.28 hours versus 3.12 hours) and increased area under the plasma concentration‐time curve (AUC) (871 ng · h/mL versus 1299 ng · h/mL). The AUC of diltiazem was unchanged in the presence of methylprednisolone. No significant intrinsic pharmacodynamic differences were observed for methylprednisolone versus methylprednisolone‐diltiazem. The 50% inhibitory concentration values were 0.446 ng/mL versus 0.780 ng/mL for cortisol, 9.20 ng/mL versus 10.7 ng/mL for T‐helper cells, and 18.5 ng/mL versus 20.9 ng/mL for T‐suppressor cells (P > .05). Greater net suppression, as indicated by the area between the effect curve and suppression ratios, was observed for the methylprednisolone‐diltiazem combination versus methylprednisolone alone, which was attributed to reduced elimination of methylprednisolone.ConclusionsControlled‐delivery diltiazem, 180 mg, significantly increased methylprednisolone AUC and half‐life and reduced clearance, lending to greater systemic exposure to the steroid. However, significant differences between 50% inhibitory concentration values for methylprednisolone when given alone and for methylprednisolone in combination with diltiazem were not seen, which implies no change in cortisol or cell‐trafficking sensitivity in the presence of diltiazem.Clinical Pharmacology & Therapeutics (2002) 72, 370–382; doi: 10.1067/mcp.2002.127944
Pharmacokinetic‐pharmacodynamic analysis of drotrecogin alfa (activated) in patients with severe sepsis
Authors: Macias William L. , Dhainaut Jean‐Francois , Yan Sau Chi Betty , Helterbrand Jeffrey D. , Seger Mary , Johnson Gerald , Small David S. 
Published: November 2002

ObjectiveWe aimed to characterize the pharmacokinetics and pharmacodynamics of drotrecogin alfa (activated) (recombinant human activated protein C) in patients with severe sepsis.MethodsPatients (N = 1690) in a randomized, double‐blind, placebo‐controlled phase 3 trial received a 96‐hour infusion of placebo (n = 840) or drotrecogin alfa (activated) (n = 850), 24 μg · kg−1 · h−1. Plasma samples from 680 patients were collected for pharmacokinetic assessment. Pharmacodynamic effects on activated partial thromboplastin time, D‐dimer, protein C, and interleukin 6 were analyzed by drotrecogin alfa (activated) steady‐state plasma concentration (Css) quartile.ResultsTransient endogenous activated protein C concentrations above 10 ng/mL were observed in 11 placebo‐treated patients (3.3%). In drotrecogin alfa (activated)‐treated patients, the median Css was 44.9 ng/mL and the median plasma clearance (CLp) was 40.1 L/h. Css was reached within 2 hours after the infusion was started. Plasma concentrations were below the assay quantitation limit of 10 ng/mL within 2 hours after the infusion was stopped in 92% of patients. CLp increased with increasing body weight, so infusion rates should be based on predose body weight. Mean CLp associated with age, sex, or baseline hepatic or renal function differed by less than 30% from the mean CLp in all patients and resided within the interquartile range of CLp in all patients. Dose adjustment is not required on the basis of these factors alone or in combination. No correlation was detected between Css quartile and bleeding risk or the magnitudes of effect on biomarkers of coagulopathy (D‐dimers and protein C) and inflammation (interleukin 6).ConclusionsPlasma concentrations of drotrecogin alfa (activated) attain steady state rapidly after the infusion is started and decline rapidly after the infusion is stopped. The infusion rate should be based on predose body weight and not on any other demographic or baseline clinical covariate.Clinical Pharmacology & Therapeutics (2002) 72, 391–402; doi: 10.1067/mcp.2002.128148