Search PubMed⌕ Search

Biomedical subjects

Hartmut Derendorf

Publications and source records attributed to Hartmut Derendorf.

At least 37 records · Page 2Linked to original sources
PubMed2005

Comparative pharmacology, bioavailability, pharmacokinetics, and pharmacodynamics of inhaled glucocorticosteroids.

A comparison of the pharmacodynamics and pharmacokinetics of inhaled corticosteroids is necessary for their assessment. A good knowledge of these two aspects allows the optimization of efficacy and safety.The currently available inhaled corticosteroids already show some of the desired PK/PD parameters. The local adverse effects are decreased as soon as the inhaled corticosteroid is administered as an inactive prodrug or shows a bet-ter lung deposition. HFA-MDI beclomethasone dipropionate (BDP) and ciclesonide are two agents that illustrate this. Low oral bioavailability, rapid systemic clearance, and high plasma protein binding can minimize systemic adverse effects. Mometasone furoate, ciclesonide, and fluticasone propionate possess those characteristics. The pulmonary efficacy is maximized by high lung deposition and long pulmonary residence times. This effect can be achieved by slow dissolution in the lungs, as is the case for fluticasone propionate or lipid conjugation and has been shown for budesonide and ciclesonide. Furthermore, the lung deposition depends on the inhalation device, the particle size, and the inhalation technique. Therefore,improvement in the design of MDIs, DPIs, and nebulizers, and the development of more effective drug particles will lead to an optimized pulmonary targeting. Much progress has been made in the treatment of asthma. The available inhaled corticosteroids show a high safety profile and a good pulmonary selectivity. Development of newer compounds showed that improvement is possible as the result of a complete understanding of the PK/PD concepts. However,the introduction of further improved formulations with a better efficacy/safety profile will be difficult and protracted because the existing drugs are already highly efficient.

Administration, Inhalation↗
PubMed2005

Pharmacokinetics of piperacillin-tazobactam: intermittent dosing versus continuous infusion.

In the present study 24 hospitalized patients requiring empirical antibiotic treatment were randomly assigned to receive the beta-lactam antibiotic/beta-lactamase inhibitor combination piperacillin-tazobactam either as an intermittent or as a continuous infusion. According to pharmacokinetic modelling, the daily dose was reduced by 33% in patients receiving continuous infusion compared with intermittent infusion. Dose reduction because of impaired renal function was required in the intermittent dosing group for 5 of 12 patients compared with 1 of 12 patients in the continuous infusion group. However, the mean daily dose in the continuous group was 15% less than the intermittent infusion group. Mean serum concentrations of piperacillin were to 39.0 microg/ml after the end of bolus distribution, exceeding by far the minimal inhibitory concentration of the most clinically relevant pathogens. The corresponding mean value for tazobactam was 6.3 microg/ml. Pharmacokinetic/pharmacodynamic modelling suggests that both treatment schemes should produce virtually identical anti-infective responses to sensitive, intermediate and resistant strains. In the present study the continuous infusion of piperacillin/tazobactam provided adequate antibacterial activity over the 24-h dosing period and offers the potential for a substantial reduction in the total daily dose.

Adult↗
PubMed2005

Pharmacokinetic-pharmacodynamic modelling of antibacterial activity of cefpodoxime and cefixime in in vitro kinetic models.

The bacterial time-kill curves of cefpodoxime and cefixime against four bacterial strains (Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae/penicillin sensitive and S. pneumoniae/penicillin intermediate) were compared in in vitro infection models in which various human pharmacokinetic profiles of unbound antibiotic were simulated. This approach offers more detailed information than the minimum inhibitory concentration (MIC) does about the time course of antibacterial efficacy of an antibiotic. A pharmacokinetic-pharmacodynamic (PK-PD) model based on unbound antibiotic concentrations at the site of infection, and a sigmoid Emax-relationship with EC50 as the antibiotic concentration necessary to produce 50% of the maximum effect, effectively described the antimicrobial efficacy of both cefpodoxime and cefixime. The EC50 values of cefpodoxime and cefixime were consistent with their respective MIC values. Both antibiotics had similar high potency against H. influenzae (EC50: 0.04 mg/L) and M. catarrhalis (EC50: 0.12 mg/L), while the potency of cefpodoxime against S. pneumoniae strains was about 10-fold higher than that of cefixime (EC50s/sensitive strain: 0.02 mg/L versus 0.27 mg/L; EC50s/intermediate strain: 0.09 mg/L versus 0.69 mg/L). Applications of this model and unbound tissue PK profiles obtained from a previous clinical study performed in our group, showed that cefpodoxime has higher bacteriological potency than cefixime against S. pneumoniae. Simulations based on this model allow the comparison of antibacterial efficacy of different antibiotics and dosing regimens.

Anti-Bacterial Agents↗
PubMed2005

Tissue penetration of cefpodoxime and cefixime in healthy subjects.

Microdialysis is a technique that allows the measurement of free antibiotic concentrations in different tissues, which are responsible for the antibacterial activity at the infection site. In an open, randomized, 2-way crossover study in healthy volunteers, the muscle penetration of orally administered cefpodoxime (400 mg) and cefixime (400 mg) was compared using microdialysis. The results show that the total plasma concentration-time profiles of each antibiotic were similar; the area under the curve for cefpodoxime was 22.4 +/- 8.7 versus 25.6 +/- 8.5 mg/L*h for cefixime. However, tissue penetration was twice as high for cefpodoxime (area under the curve 15.4 +/- 5.1 mg/L*h) as for cefixime (area under the curve 7.3 mg/L*h). This degree of tissue distribution is consistent with their protein binding of 21% for cefpodoxime and 65% for cefixime. After equilibration, the unbound tissue concentrations of both antibiotics were similar to their unbound plasma concentrations. Pharmacokinetic modeling was applied to describe the pharmacokinetic profiles in plasma and muscle. The study demonstrates that cefpodoxime shows greater tissue penetration than cefixime.

Anti-Bacterial Agents↗
PubMed2005

Population pharmacokinetics of eniporide and its metabolite in healthy subjects and patients with acute myocardial infarction.

Eniporide (EMD 96 875) is a novel and selective inhibitor of the Na+-H+ exchange (NHE-1) inhibitor. The study objectives were to identify a structural model for population pharmacokinetic analysis of eniporide and its metabolite (EMD 112 843) using nonlinear mixed-effects modeling after short-term infusion (dose: 2.5-400 mg) in healthy subjects and patients undergoing myocardial reperfusion therapy. Pooled concentrations of eniporide and its metabolite from healthy subjects (n = 153; 4815 observations) and patients (n = 304; 1465 observations) were included in the pharmacokinetic analysis. Population estimates of clearance and volume of distribution of eniporide were 29.2 L/h (24.1% coefficient of variation [CV], healthy), 20.8 L/h (28.0% CV, patients) and 20.4 L (13.1% CV, healthy), 16.9 L (24.9% CV, patients), respectively. Statistical significance was achieved for the effect of age on clearance and creatinine clearance on volume of distribution of eniporide. The impact of the covariates on eniporide pharmacokinetics is minimal to warrant any dosage adjustments in patient population.

Adult↗
PubMed2005

Penetration of ertapenem into different pulmonary compartments of patients undergoing lung surgery.

Ertapenem is approved for the treatment of community-acquired pneumonia (CAP), but its in vivo penetration into lung tissue (LT), epithelial lining fluid (ELF), and alveolar cells (AC) is unknown. Fifteen patients undergoing thoracotomy were treated with 1 g intravenously for perioperative prophylaxis. Bronchoalveolar lavage was performed 1, 3, and 5 hours after ertapenem infusion. Normal LT was sampled at the time of lung extraction. Blood was collected before and at different time points up to 24 hours after infusion. Mean concentrations of ertapenem in plasma, ELF, and AC were at 1.0 hour, 63.1, 4.06, 0.004 mg/L; at 3.0 hours, 39.7, 2.59, 0.003 mg/L; and at 5.0 hours, 27.2, 2.83, 0.007 mg/L. Mean (range) concentration in LT was 7.60 (2.5-19.4) mg/kg tissue 1.5 to 4.5 hours after infusion. In plasma, ertapenem exhibited a Cmax of 94.7 +/- 23.3 mg/L and an AUC(0-last) of 501.1 +/- 266.3 mg x h/L. These results, combined with the reported (MIC)90 of most CAP bacteria, support the previously observed clinical efficacy of ertapenem in the treatment of CAP.

Adult↗
PubMed2005

Effect of simulated microgravity on the disposition and tissue penetration of ciprofloxacin in healthy volunteers.

This study evaluated the effects of simulated microgravity (smuG) on the pharmacokinetics of ciprofloxacin. Six healthy volunteers participated in a crossover study to compare the pharmacokinetics of ciprofloxacin after a single 250-mg oral dose in normal gravity (1G) and smuG. Plasma and urine samples were collected, and in vivo microdialysis was employed to obtain the free interstitial concentrations in the thigh muscle. Tissue penetration (f) was determined as the ratio of the free tissue area under the concentration versus time curve (AUC(tiss,free))/AUC(plasma,free). Plasma and free interstitial ciprofloxacin concentrations were simultaneously fit to a 1-compartment body model after correction for protein binding and tissue penetration. Total and free plasma concentrations were very similar in smuG and 1G. Tissue penetration in smuG (f =0.61 +/- 0.36) was slightly lower than in 1G (f =0.92 +/- 0.63); however, the difference was not significant. The authors conclude that the disposition of ciprofloxacin was not affected by simulated microgravity.

Adult↗
PubMed2005

Dipyridamole bioavailability in subjects with reduced gastric acidity.

Dipyridamole (DP) is an antiplatelet agent that shows decreased oral bioavailability with increased gastric pH that occurs with commonly prescribed antacids. An extended-release (ER) formulation of DP that employs tartaric acid to improve bioavailability of DP in the presence of elevated gastric pH was developed as a combination antiplatelet product with immediate-release aspirin. This crossover-designed study examined the relative bioavailability of DP from the composite product compared to conventional DP tablets during reduced gastric acidity. Gastric pH was increased (pH > 4.0) in 20 healthy subjects with lansoprazole (30 mg/d for 5 days). Dipyridamole systemic exposure over 12 hours was compared after oral administration of a single composite ER capsule (200 mg DP + 25 mg aspirin) versus two 100-mg conventional DP tablets given 6 hours apart combined with 81 mg aspirin. DP relative bioavailability was reduced 53% with conventional tablets compared to the composite buffered ER capsule in reduced gastric acid conditions. Peak DP plasma concentrations were 57% lower with immediate-release tablets compared to the composite formulation with high stomach pH. Substituting generic DP plus low-dose aspirin may be less effective than the buffered DP composite product in patients with concomitant antacid therapies.

Achlorhydria↗
PubMed2005

Pharmacokinetic/pharmacodynamic evaluation of anti-infective agents.

Pharmacokinetic/pharmacodynamic modeling has become an extremely important tool in evaluating and optimizing anti-infective therapy. By systematically linking the pharmacokinetic and pharmacodynamic properties of the anti-infective agent, it is possible to make educated decisions about the correct drug to be used, correct dosing regimen and to estimate the probability of success with the selected dose regimen. This article gives an overview of the current pharmacokinetic/pharmacodynamic approaches for anti-infective agents and discusses their use in optimizing drug therapy.

Anti-Bacterial Agents↗
PubMed2004

In vitro microdialysis sampling of docetaxel.

Microdialysis is a technique that allows sampling compounds from the extracellular fluid in different tissues, such as muscle, lung, and brain. However, the feasibility of using this technique with lipopohilic and high molecular weight compounds has been questioned, since these compounds are less likely to diffuse through the dialysis membrane. Therefore, it was the objective of this study to investigate the feasibility of doing microdialysis of docetaxel by determining its recovery by the microdialysis probe. Three different methods were investigated: extraction efficiency, retrodialysis, and no-net-flux. For the first two methods, three different concentrations were tested: 2.5, 5, and 9 mg/l. The recovery obtained for each concentration was 49.3 +/- 6.7 (n = 4), 44.6 +/- 5.4 (n = 3), and 34.7 +/- 2.1 (n = 4) by extraction efficiency, and 53.4 +/- 7.9 (n = 3), 61.4 +/- 7.6 (n = 3), and 64.2 +/- 1.9 (n = 3) by retrodialysis, respectively. The average recovery obtained by no-net-flux was 68.7 +/- 9.6 (n = 5). Although it has been reported that microdialysis cannot be applied to lipophilic compounds, the results here show the opposite. The high recoveries obtained for docetaxel in all methods applied show that the compound can diffuse through the probe membrane. Overall, docetaxel seems to be very suitable for microdialysis despite its lipophilicity and high molecular weight.

Docetaxel↗
PubMed2004

PK-PD modelling of the effect of cefaclor on four different bacterial strains.

The effect of cefaclor against relevant bacterial strains was studied by employing a combined in vivo pharmacokinetic (PK)-in vitro pharmacodynamic (PD) approach. For this purpose selected isolates of Escherichia coli, Moraxella catarrhalis, Haemophilus influenzae and Streptococcus pneumoniae were exposed in vitro to the interstitial cefaclor profile obtained in vivo in the interstitial space fluid of human tissue after administration of commonly used doses of cefaclor and the change in the number of colony forming units per millilitre (CFU/ml) versus time was monitored. Fitting of the data using a modified E(max)-model resulted in a set of mean pharmacodynamic parameters (k0, k(max), EC50) for each bacterial strain. The parameters derived from these experiments were used in a computer-simulation of the antibacterial effects for different dosing regimens and formulations of cefaclor, notably an immediate (IR) and a modified (MR) release formulation. Dosage regimens were compared using the ratio between the number of bacteria remaining after 24 h of a given treatment (N24h). The results indicate that the number of bacteria of all investigated strains killed per day is equivalent when the same daily dose is administered twice a day with the MR dosage form than when given three times a day with the IR dosage form, in spite of the fact that the MR dosage form has approximately 20% lower bioavailability. Best results were obtained with the three-times a day regimen of the MR formulation. In conclusion, the present in vivo-PK/in vitro-PD simulations of the antimicrobial effects of cefaclor indicate that a twice-daily treatment with a MR formulation may offer a convenient and safe alternative to the conventional tid treatment.

Anti-Bacterial Agents↗
PubMed2004

Pharmacokinetic herb-drug interactions: are preventive screenings necessary and appropriate?

Pharmacokinetic interactions often occur as a result of activity changes of drug-metabolizing and transporting proteins, especially cytochrome P450 (CYP) isoenzymes and P-glycoprotein (P-gp). The activity of these enzymes and drug transporters can be enhanced or inhibited by synthetic drugs as well as by natural products. Since the number of herb-drug interactions has increased in recent years, systematic in vitro screenings and more clinical studies to identify such interactions were proposed for herbal medicinal products. However, previous results regarding this issue are not only contradictory but also of less predictability. One reason for the discrepancies could be the lack of validation of the recommended in vitro tests. Furthermore, it has to be considered that pharmacokinetic drug interactions are not only mediated by herbal medicines but also by several foods, beverages and life-style products. Since herbal medicines are considered to have a broad therapeutic range, a preventive risk assessment for pharmacokinetic drug interactions should first be realized for synthetic drugs with a narrow therapeutic index. Efforts to identify all possible interactions will lead to limitless investigations and to inconsistent decisions.

Cytochrome P-450 Enzyme System↗
PubMed2004

Risk-benefit value of inhaled glucocorticoids: a pharmacokinetic/pharmacodynamic perspective.

Inhaled glucocorticoids induce therapeutic and adverse systemic effects via the same types of receptors. Analysis of the pharmacokinetic/pharmacodynamic parameters of inhaled glucocorticoids generates a risk-benefit value (RBV). Targeted efficacy with minimal adverse effects helps to quantify an appropriate RBV. High lung deposition/targeting, high receptor binding, longer pulmonary retention, and high lipid conjugation are among the pharmacokinetic parameters to be considered for improved efficacy of the compound. Low or negligible oral bioavailability, small particle size and inactive drug at the oropharynx, high plasma protein binding, rapid metabolism, high clearance, and lower systemic concentrations are associated with low risks for adverse effects. Inhaled glucocorticoid potency is enhanced by solution inhalers, which result in higher pulmonary deposition and minimize local adverse effects. These properties, among others, determine the efficacy and safety of inhaled glucocorticoids. Currently available inhaled glucocorticoids do not provide the complete pharmacokinetic/pharmacodynamic parameters to optimize RBV, leaving room for improvement in the development of future agents.

Administration, Inhalation↗
PubMed2004

Intranasal loteprednol etabonate in healthy male subjects: pharmacokinetics and effects on endogenous cortisol.

Loteprednol etabonate (LE) is a glucocorticoid soft drug that is currently in development for intranasal use. The main objectives of this study were to examine the pharmacokinetics and potential effects on systemic cortisol of two intranasal suspension formulations of LE and to compare these findings with placebo and fluticasone propionate (FP, Flonase) control treatments. In this randomized, double-blind (except for FP), parallel-group study (n = 8/group), all subjects received for 14 days once daily in the morning two puffs of the following nasal spray formulations into each nostril: LE 0.1% (400 microg/day), LE 0.2% (800 microg/day), FP 0.05% (200 microg/day), and placebo. Drug trough levels were determined on days 1, 5, 12, 13, and 14, and a full pharmacokinetic profile was established on day 14, and 24-hour serum cortisol profiles were assessed prior to treatment (i.e., at baseline) and after the last dose. All subjects completed the protocol without treatment-emergent adverse findings. All formulations were rapidly absorbed (t(max) less than 1 h). The rather short mean terminal half-lives of 2.2 +/- 1.5 hours and 1.8 +/- 1.0 hours for LE 400 microg and LE 800 microg, respectively, and 4.2 +/- 1.8 hours for the 200-microg FP treatment explained the lack of any accumulation. Mean peak concentrations (C(max)) were 139 +/- 57 pg/mL with LE 400 microg and 164 +/- 54 pg/mL with LE 800 microg and thus fairly independent from dose. The 200-microg FP treatment resulted in a C(max) of only 15.5 +/- 5.9 pg/mL. Mean measured AUC(0-t) values (193 +/- 87 pg/h/mL(-1), 300 +/- 183 pg/h/mL(-1), and 40 +/- 34 pg/h/mL(-1) for LE 400 microg, LE 800 microg, and FP 200 microg, respectively) showed high variability and suggested nonlinear pharmacokinetics for the LE formulations, indicative of a less complete systemic uptake of LE from the 0.2% concentration. None of the treatments (LE 400 microg, LE 800 microg, and FP 200 microg) showed evidence for serum cortisol suppression when compared with placebo, respectively. The uptake and systemic exposure appears less complete from the 0.2% LE concentration, which principally favors this formulation for further clinical development.

Administration, Intranasal↗
PubMed2004

Physiological, pharmacokinetic, and pharmacodynamic changes in space.

Medications have been taken since the first Mercury flight in 1967 and, since then, have been used for several indications such as space motion sickness, sleeplessness, headache, nausea, vomiting, back pain, and congestion. As the duration of space missions get longer, it is even more likely that astronauts will encounter some of the acute illnesses that are frequently seen on Earth. Microgravity environment induces several physiological changes in the human body. These changes include cardiovascular degeneration, bone decalcification, decreased plasma volume, blood flow, lymphocyte and eosinophil levels, altered hormonal and electrolyte levels, muscle atrophy, decreased blood cell mass, increased immunoglobulin A and M levels, and a decrease in the amount of microsomal P-450 and the activity of some of its dependent enzymes. These changes may be expected to have severe implications on the pharmacokinetic and pharmacodynamic properties of drug substances.

Aerospace Medicine↗
PubMed2004

Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms.

Interethnic variability in pharmacokinetics can cause unexpected outcomes such as therapeutic failure, adverse effects, and toxicity in subjects of different ethnic origin undergoing medical treatment. It is important to realize that both genetic and environmental factors can lead to these differences among ethnic groups. The International Conference on Harmonization (ICH) published a guidance to facilitate the registration of drugs among ICH regions (European Union, Japan, the United States) by recommending a framework for evaluating the impact of ethnic factors on a drug's effect, as well as its efficacy and safety at a particular dosage and dosage regimen. This review focuses on the pharmacokinetic differences between East Asians and Caucasians. Differences in metabolism between East Asians and Caucasians are common, especially in the activity of several phase I enzymes such as CYP2D6 and the CYP2C subfamily. Before drug therapy, identification of either the genotype and/or the phenotype for these enzymes may be of therapeutic value, particularly for drugs with a narrow therapeutic index. Furthermore, these differences are relevant for international drug approval when regulatory agencies must decide if they accept results from clinical trials performed in other parts of the world.

Asian People↗