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Hartmut Derendorf

Publications and source records attributed to Hartmut Derendorf.

At least 55 records · Page 3Linked to original sources
PubMed2004

How the lung handles drugs: pharmacokinetics and pharmacodynamics of inhaled corticosteroids.

Bronchial asthma and allergic rhinitis are among the most common diseases of modern society and to an increasing degree a major cause of illness, hospitalization, loss of productivity, and death. Despite improvements in drug therapy over the years, the incidence is still increasing. Inhaled and intranasal corticosteroids are the drugs of choice in the therapy of asthma and allergic rhinitis. Inhalation and intranasal use result in better, target-specific delivery of corticosteroids. Higher concentrations at the site of action and minimized systemic exposure provide improved therapeutic ratios. However, there is still considerable concern over the risk of systemic side effects. It is the goal of inhaled and intranasal corticosteroid therapy to produce long-lasting therapeutic effects at the site of action and minimize systemic side effects with high clearance, low oral bioavailability and high plasma protein binding. This article reviews the pharmacokinetic and pharmacodynamic properties of corticosteroids used in asthma and allergic rhinitis.

Administration, Inhalation↗
PubMed2003

Microdialysis of triamcinolone acetonide in rat muscle.

The objective of this study was to compare plasma and muscle concentrations of triamcinolone acetonide (TA) in the rat by microdialysis. Microdialysis experiments were carried out at steady state in rats after an initial I.V. bolus 50 mg/kg of the phosphate ester of TA (TAP) followed by 23 mg/kg/h infusion. In vivo recovery was calculated by retrodialysis. The concentration determined at steady state in microdialysate, corrected for recovery, was 2.73 +/- 0.42 microg/mL compared to 21.9 +/- 2.3 microg/mL in plasma. The pharmacokinetics of TA in plasma was described by an open two-compartment model with a terminal half-life of 2.7 h. The clearance of TA in rats determined by compartmental analysis was 0.94 L/h/kg. The measured microdialysate levels of TA in muscle, corrected for recovery, were comparable to the predicted free drug levels in the peripheral compartment. Protein binding in rat plasma, measured by ultrafiltration, was 90.1%. The microdialysis in vivo recovery in muscle was similar to the in vitro recovery under stirred conditions. The results show the applicability of microdialysis to measure free tissue concentrations of TA in rats.

Algorithms↗
PubMed2003

Inhaled corticosteroids: past lessons and future issues.

Inhaled corticosteroids play a pivotal role in the treatment of asthma. Inhalation permits effective delivery of the corticosteroid in high concentration to target sites within the lung while minimizing systemic exposure. Consequently, the safety profile of inhaled corticosteroids is markedly better than that of oral corticosteroid therapy. However, although it was first thought that direct delivery might eliminate systemic adverse effects, this has not been confirmed by clinical trials and experience. Inhaled corticosteroids are absorbed from the lungs into the systemic circulation, in which they can acutely decrease growth velocity in children, an effect that fortunately appears to be temporary and might have no effect on final adult height. In sufficient dosages, they also produce bone mineral loss leading to osteoporosis and might increase the risk of cataracts, glaucoma, skin atrophy, and vascular changes that increase the risk of ecchymoses. Effective evaluation of the severity and significance of these complications is challenging because highly sensitive tests do not reliably predict clinically significant events, and short-term observations do not predict long-term consequences. Also, compliance wanes with long-term treatment, and susceptibility to a particular adverse event can vary over time, even in the same individual, because of developmental or hormonal changes. This journal supplement will review what has been learned about the safety of inhaled cortico-steroids during the past decade, discussing some of the questions that remain and considering the characteristics of an "ideal" inhaled corticosteroid: one with high local activity in the lung and minimal or no adverse systemic effects.

Administration, Inhalation↗
PubMed2003

Antimicrobial tissue concentrations.

The clinical outcome of anti-infective treatment is determined by both PK and PD properties of the antibiotic. Only the free tissue concentrations of antibiotics at the target site, which are usually lower than the total plasma concentrations, are responsible for therapeutic effect. The free antibiotic concentrations at the site of action are a more appropriate PK input value for PK-PD analysis. The unbound tissue concentrations can be measured directly by microdialysis. Using plasma concentrations overestimates the target site concentrations and its clinical efficacy. The optimal dosing regimens of antibiotics have an impact on patients' outcome and cost of therapy, and reduce the emergence of resistance.

Animals↗
PubMed2003

Single- and multiple-dose pharmacokinetics of oral creatine.

Supplementation with exogenous creatine (Cr) has shown physiological benefits in humans, but little is known about the pharmacokinetics of Cr in humans. Six healthy males completed an open-label study consisting of a full pharmacokinetic analysis following a single oral dose of Cr monohydrate (71 mg kg-1) and at steady-state after 6 days of Cr administration (71 mg kg-1 qid). After the single oral dose, the clearance (CL/F) was 0.20 +/- 0.066 L h-1 kg-1, tmax was 1.9 +/- 0.88 hours, and Cmax = 102.1 +/- 11.2 mg h L-1. At steady-state, CL/F decreased to 0.12 +/- 0.016 L h-1 kg-1, tmax did not change, and Cmax increased to 162.2 +/- 30.0 mg L-1. Penetration (AUCMUSCLE/AUCPLASMA) of Cr into the interstitial muscle space, as determined by microdialysis, was 0.47 +/- 0.09 and 0.37 +/- 0.27 for the single dose and at steady-state, respectively. Plasma and muscle data were simultaneously fitted with a model incorporating a saturable absorption and first-order elimination process. In conclusion, repeated dosing of Cr caused a reduction in clearance that could result from saturation of the skeletal muscle pool of Cr.

Administration, Oral↗
PubMed2003

Pharmacokinetic/pharmacodynamic modeling of luteinizing hormone (LH) suppression and LH surge delay by cetrorelix after single and multiple doses in healthy premenopausal women.

Cetrorelix (CET) is a potent luteinizing hormone-releasing hormone (LH-RH) antagonist and is used to prevent premature ovulation in IVF (in vitro fertilization) procedures. The objective of the present study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the LH suppression and LH surge delay after single doses (SD) and multiple doses (MD) of CET in healthy premenopausal women without ovarian stimulation. CET was given by subcutaneous route (SD, 0.25, 0.5, or 1 mg) on cycle day 3 and as similar multiple once-a-day doses from cycle day 3 to day 16 in two consecutive menstrual cycles. The concentration-time data of CET and LH were used for PK/PD modeling. A two-compartment model described the PK of CET with median terminal half-life estimates of 9.2 and 54.5 hours after SD and MD, respectively. An indirect-response Emax model was used to describe the LH suppression and the LH surge delay. LH suppression was linked to plasma concentrations of CET, while the delay in the LH surge was linked to the PK of CET through a hypothetical effect compartment. Since the SD regimen on day 3 did not cause significant delay, these values were used as controls in the analysis of surge delay in MD data. The IC50 (for suppression) estimate was 0.73 ng/ml for SD, and EC50 (surge delay) was 1.42 ng/ml for MD. The PK/PD model adequately described the LH suppression and the surge delay.

Adolescent↗
PubMed2003

Population kinetics, efficacy, and safety of dichloroacetate for lactic acidosis due to severe malaria in children.

The authors conducted a randomized, double-blind, placebo-controlled trial of intravenous dichloroacetate (DCA) for the purpose of treating lactic acidosis in 124 West African children with severe Plasmodium falciparum malaria. Lactic acidosis independently predicts mortality in severe malaria, and DCA stimulates the oxidative removal of lactate in vivo. A single infusion of 50 mg/kg DCA was well tolerated. When administered at the same time as a dose of intravenous quinine, DCA significantly increased the initial rate and magnitude of fall in blood lactate levels and did not interfere with the plasma kinetics of quinine. The authors developed a novel population pharmacokinetic-pharmacodynamic indirect-response model for DCA that incorporated characteristics associated with disease reversal. The model describes the complex relationships among antimalarial treatment procedures, plasma DCA concentrations, and the drug's lactate-lowering effect. DCA significantly reduces the concentration of blood lactate, an independent predictor of mortality in malaria. Its prospective evaluation in affecting mortality in this disorder appears warranted.

Acidosis, Lactic↗
PubMed2002

Pharmacokinetic/pharmacodynamic studies in drug product development.

In the quest of ways for rationalizing and accelerating drug product development, integrated pharmacokinetic/pharmacodynamic (PK/PD) concepts provide a highly promising tool. PK/PD modeling concepts can be applied in all stages of preclinical and clinical drug development, and their benefits are multifold. At the preclinical stage, potential applications might comprise the evaluation of in vivo potency and intrinsic activity, the identification of bio-/surrogate markers, as well as dosage form and regimen selection and optimization. At the clinical stage, analytical PK/PD applications include characterization of the dose-concentration-effect/toxicity relationship, evaluation of food, age and gender effects, drug/drug and drug/disease interactions, tolerance development, and inter- and intraindividual variability in response. Predictive PK/PD applications can also involve extrapolation from preclinical data, simulation of drug responses, as well as clinical trial forecasting. Rigorous implementation of the PK/PD concepts in drug product development provides a rationale, scientifically based framework for efficient decision making regarding the selection of potential drug candidates, for maximum information gain from the performed experiments and studies, and for conducting fewer, more focused clinical trials with improved efficiency and cost effectiveness. Thus, PK/PD concepts are believed to play a pivotal role in streamlining the drug development process of the future.

Clinical Trials as Topic↗
PubMed2002

Rational dosing of antibiotics: the use of plasma concentrations versus tissue concentrations.

At the moment, the most common pharmacokinetic/pharmacodynamic (PK/PD) approaches for anti-infective agents, such as time above MIC, C(max)/MIC and AUC(24)/MIC, rely on plasma concentration as the PK input value and minimum inhibitory concentration (MIC) as the PD input value. However, only the free tissue concentrations of antibiotics at the target site are responsible for the therapeutic effect. Using plasma concentrations frequently overestimates the target site concentrations and therefore clinical efficacy. Microdialysis is a new technique that allows direct measurement of unbound tissue concentrations. Furthermore, a better PD approach, bacterial time-kill curves, can offer more detailed information about the antibacterial activity as a function of time and antibiotic concentration than MICs.

Anti-Bacterial Agents↗
PubMed2002

Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs.

Over the last decades, the interest in the relationships between the pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial agents has increased and, therefore, the use of PK/PD indices and expressions has spread widely. The appropriate definition and use of these parameters is a matter of controversy. This paper contains a proposal to use PK/PD expressions for antimicrobial agents and their units in a uniform manner.

Anti-Infective Agents↗
PubMed2002

Pharmacokinetics and bioavailability of herbal medicinal products.

The use of herbs for treating various ailments dates back several centuries. Usually, herbal medicine has relied on tradition that may or may not be supported by empirical data. The belief that natural medicines are much safer than synthetic drugs has gained popularity in recent years and led to tremendous growth of phytopharmaceutical usage. Market driven information on natural products is widespread and has further fostered their use in daily life. In most countries there is no universal regulatory system that insures the safety and activity of phytopharmaceuticals. Evidence-based verification of the efficacy of HMPs (herbal medicinal products, botanicals) is still frequently lacking. However, in recent years, data on evaluation of the therapeutic and toxic activity of herbal medicinal products became available. The advances in analytical technology have led to discovery of many new active constituents and an ever-increasing list of putatively active constituents. Establishing the pharmacological basis for efficacy of HMPs is a constant challenge. Of particular interest is the question of bioavailability to assess to what degree and how fast compounds are absorbed after administration of HMPs. Of further interest is the elucidation of metabolic pathways (yielding potentially new active compounds), and the assessment of elimination routes and their kinetics. These data become an important issue to link data from pharmacological assays and clinical effects. Of interest are currently also interactions of herbal medicinal products with synthetically derived drug products. A better understanding of the pharmacokinetics and bioavailability of phytopharmaceuticals can also help in designing rational dosage regimens. In this review, pharmacokinetic and bioavailability studies that have been conducted for some of the more important or widely used phytopharmaceuticals are critically evaluated. Furthermore, various drug interactions are discussed which show that caution should be exercised when combining phytopharmaceuticals with chemically derived active pharmaceutical ingredients.

Biological Availability↗
PubMed2002

Interstitial tissue concentrations of cefpodoxime.

Microdialysis is a technique that allows the measurement of concentrations of free antibiotic in tissue. The free antibiotic concentration is responsible for the antibacterial effect at the target site. We used microdialysis in animal and human studies to investigate the tissue penetration of cefpodoxime. In the animal study, total plasma and free muscle and lung concentrations of cefpodoxime were measured after male Wistar rats had received either 10 mg/kg or 20 mg/kg i.v. cefpodoxime over 5 h or a continuous i.v. infusion of 260 microg/h cefpodoxime after a loading dose of 6 mg/kg. Free muscle concentrations of cefpodoxime were similar to free lung concentrations and therefore provided a surrogate measure of cefpodoxime concentrations at the pulmonary target site. In an open, randomized, two-way crossover, single-dose study in six healthy male volunteers, total plasma and free muscle concentrations were measured after a single oral dose of cefpodoxime 400 mg or cefixime 400 mg. The total plasma concentrations of each antibiotic were similar and higher than free muscle concentrations. The tissue penetration of cefpodoxime was, however, greater than that of cefixime, as shown by two-fold higher peak free muscle concentrations after dosing with cefpodoxime than with cefixime (2.1 mg/L versus 0.9 mg/L). In addition, the area under the curve for tissue (AUC(t)) of cefpodoxime (400 mg) was more than double that of cefixime (400 mg), based on free antibiotic concentrations (15.4 mg x h/L versus 7.3 mg x h/L). These findings indicate that, taking into account pharmacokinetic/pharmacodynamic considerations, cefpodoxime is likely to be more efficacious than cefixime, due to its greater tissue penetration.

Animals↗
PubMed2002

Bioavailability and metabolism of mometasone furoate: pharmacology versus methodology.

The degree of systemic exposure ofter inhalation of corticosteroids is of great clinical concern. For optimum outcome, the pulmonary deposition should be sufficiently high to produce the desired anti-inflammatory effect in the lungs, whereas the plasma concentrations due to the absorption of the corticosteroid from the lung and the gut should be minimal. Recently, it has been reported that inhaled mometasone furoate has a systemic bioavailability of less than 1%, which is much lower than other corticosteroids currently available. However, critical evaluation of the study methodology and results does not support this finding. A major shortfall of the study was an insufficient analytical sensitivity, resulting in a calculated average plasma concentration profile that was entirely below the limit of quantification. These numbers were generated by replacing all concentrations below the limit of quantification byzero and then calculating an average value. This procedure can lead to erroneous results and misinterpretation. Furthermore, the potential contribution of active metabolites needs to be adequately addressed in comparisons of inhaled corticosteroids. Reliable estimates of systemic drug exposure are critical in evaluating the real safety profiles and therapeutic index for inhaled corticosteroids that are effective in treating chronic asthma.

Administration, Inhalation↗
PubMed2002

Comparative target site pharmacokinetics of immediate- and modified-release formulations of cefaclor in humans.

Optimal dosing of beta-lactam antibiotics aims at maximizing the time at which drug levels in the interstitial space fluid (ISF)--the fluid that surrounds the causative microorganisms at the target site--exceed the minimal inhibitory concentration (MIC). One potentially attractive strategy to achieve this goal is to administer antibiotics as oral sustained-release formulations. The present study was designed to test the hypothesis that sustained-release formulations could lead to a more suitable pharmacokinetic profile in the ISF at the relevant target site. For this purpose, time versus cefaclor concentration profiles attained in the ISF were measured following administration of two formulations, an immediate- (500 mg IR) and a modified-release formulation in two different doses (500 mg MR and 750 mgMR) in a three-way crossover study of healthy male volunteers (n = 12). For the measurement of unbound cefaclor concentrations in the ISF of human skeletal muscle, the in vivo microdialysis technique was employed. For all three formulations, unbound cefaclor concentration in the ISF closely followed individual plasma concentration profiles in a dose-dependent pattern, with ISF to unbound plasma ratios ranging from 0.67 to 0.73. The mean residence time was found to be significantly longer for the MR formulations versus the IR formulation. The data of the present study indicate that time above MIC values at the target site can be substantially prolonged if an antibiotic is administered as a sustained-release product.

Adult↗
PubMed2002

Systemic availability and pharmacokinetics of thymol in humans.

Essential oil compounds such as found in thyme extract are established for the therapy of chronic and acute bronchitis. Various pharmacodynamic activities for thyme extract and the essential thyme oil, respectively, have been demonstrated in vitro, but availability of these compounds in the respective target organs has not been proven. Thus, investigation of absorption, distribution, metabolism, and excretion are necessary to provide the link between in vitro effects and in vivo studies. To determine the systemic availability and the pharmacokinetics of thymol after oral application to humans, a clinical trial was carried out in 12 healthy volunteers. Each subject received a single dose of a Bronchipret TP tablet, which is equivalent to 1.08 mg thymol. No thymol could be detected in plasma or urine. However, the metabolites thymol sulfate and thymol glucuronide were found in urine and identified by LC-MS/MS. Plasma and urine samples were analyzed after enzymatic hydrolysis of the metabolites by headspace solid-phase microextraction prior to GC analysis and flame ionization detection. Thymol sulfate, but not thymol glucuronide, was detectable in plasma. Peak plasma concentrations were 93.1+/-24.5 ng ml(-1) and were reached after 2.0+/-0.8 hours. The mean terminal elimination half-life was 10.2 hours. Thymol sulfate was detectable up to 41 hours after administration. Urinary excretion could be followed over 24 hours. The amount of both thymol sulfate and glucuronide excreted in 24-hour urine was 16.2%+/-4.5% of the dose.

Administration, Oral↗
PubMed2002

How important are gender differences in pharmacokinetics?

Gender-related differences in pharmacokinetics have frequently been considered as potentially important determinants for the clinical effectiveness of drug therapy. The mechanistic processes underlying gender-specific pharmacokinetics can be divided into molecular and physiological factors. Major molecular factors involved in drug disposition include drug transporters and drug-metabolising enzymes. Men seem to have a higher activity relative to women for the cytochrome P450 (CYP) isoenzymes CYP1A2 and potentially CYP2E1, for the drug efflux transporter P-glycoprotein, and for some isoforms of glucuronosyltransferases and sulfotransferases. Women were suggested to have a higher CYP2D6 activity. No major gender-specific differences seem to exist for CYP2C19 and CYP3A. The often-described higher hepatic clearance in women compared with men for substrates of CYP3A and P-glycoprotein, such as erythromycin and verapamil, may be explained by increased intrahepatocellular substrate availability due to lower hepatic P-glycoprotein activity in women relative to men. Physiological factors resulting in gender-related pharmacokinetic differences include the generally lower bodyweight and organ size, higher percentage of body fat, lower glomerular filtration rate and different gastric motility in women compared with men. Although gender disparity in pharmacokinetics has been identified for numerous drugs, differences are generally only subtle. For a few drugs, e.g. verapamil, beta-blockers and selective serotonin reuptake inhibitors, gender-related differences in pharmacokinetics have been shown to result in different pharmacological responses, but their clinical relevance remains unproven. In contrast, gender differences of clinical importance have clearly been identified for pharmacodynamic processes such as QTc prolongation, and intensive future research efforts are needed to assess the full scope and impact of pharmacodynamic gender disparity on applied pharmacotherapy.

Female↗
PubMed2002

Novel formulations of cetrorelix acetate in healthy men: pharmacodynamic effects and noncompartmental pharmacokinetics.

The objective of this study was to investigate the effects on the pharmacodynamics and noncompartmental pharmacokinetics after weekly subcutaneous administration of novel formulations of cetrorelix acetate in healthy men. In a randomized parallel-group study, single subcutaneous doses of cetrorelix acetate (concentration: 2.5 mg peptide base/ml) dissolved in aqueous gluconic acid (CET/glu, dose: 5 or 10 mg peptide base) or in water (CET/wat, dose: 10 mg peptide base) were given to 36 subjects once weekly in the morning for 4 weeks. Cetrorelix plasma, serum testosterone, luteinizing hormone, andfollicle-stimulating hormone concentrations were monitored after each administration for 1 week, with extensive profiling after the first and fourth administration. Cetrorelix plasma concentrations were analyzed by radioimmunoassay and serum hormone concentrations by enzyme immunoassays. At least half-maximum testosterone suppression started with all treatments within less than 1 day. Deepest and longest testosterone suppression was achieved by 10 mg CET/glu. Duration of atleasthalf-maximum suppression was after the first dose median of 82 hours and after the fourth dose median of 122 hours, respectively. Substantial suppression was also evidentfor luteinizing hormone (LH) and, to a lesser extent, forfollicle-stimulating hormone (FSH). On average, Cmax was nearly doubled after single and multiple doses, and AUC(tau) was increased by about 50% after single doses and about 30% after multiple doses of 10 mg CET/glu as compared to 10 mg CET/wat. For tmax and t1/2, no significant differences were found between formulations. It was concluded that testosterone suppression increased with weekly subcutaneous administrations of 10 mg CET/glu. Compared to CET/wat, bioavailability and duration of suppression were increased with CET/glu.

Adult↗