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Hartmut Derendorf

Publications and source records attributed to Hartmut Derendorf.

At least 19 recordsLinked to original sources
PubMed2006

Pharmacokinetic/pharmacodynamic modeling of in vitro activity of azithromycin against four different bacterial strains.

The bacterial time-kill curves of azithromycin against four bacterial strains (Streptococcus pneumoniae/penicillin-intermediate, S. pneumoniae/penicillin-sensitive, Haemophilus influenzae and Moraxella catarrhalis) were determined by in vitro infection models. Eighteen different pharmacokinetic/pharmacodynamic models were fitted to the time-kill data using non-linear regression and compared for best fit. A simple, widely used E(max) model was not sufficient to describe the pharmacodynamic effects for the four bacterial strains. Appropriate models that gave good curve fits included additional terms for saturation of the number of bacteria (N(max)), delay in the initial bacterial growth phase and/or the onset of anti-infective activity (1-exp(-zt)) as well as a Hill factor (h) that captures the steepness of the concentration-response profile. Azithromycin was highly effective against S. pneumoniae strains and M. catarrhalis while the efficacy against H. influenzae was poor. Applications of these pharmacokinetic/pharmacodynamic models will eventually provide a tool for rational antibiotic dosing regimen decisions.

Anti-Bacterial Agents↗
PubMed2006

Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration.

OBJECTIVES: Most information about pharmacokinetics of antimicrobial agents is obtained from studies in healthy volunteers. However, antibiotics are therapeutically used in infected patients with very different pharmacokinetic properties compared with healthy individuals. PATIENTS AND METHODS: In a single-centre, prospective, open-label study, 17 adult critically ill patients with early-onset ventilator-associated pneumonia (VAP) were treated with 1 g of ertapenem infusion once a day. Blood and urine samples were collected before and at different time-points up to 24 h after medication on day 1. Concentrations of ertapenem in plasma were determined with a validated HPLC method. Free-drug concentrations were estimated using a two-class binding site equation. RESULTS: The overall clinical success rate of the assessable cases was 66.7% (12/16). Pharmacokinetic parameters of ertapenem in our critically ill patients were clearly different when compared to those reported in the literature for healthy volunteers. The enhanced V(z) (17 vs. 8 L) and CL(TOT) (43 vs. 20 mL/min) with resulting lower C(max) (90 vs. 253 mg/L) and AUC(0-infinity) (418 vs. 817 mg x h/L) values were mainly related to hypoalbuminaemia (range 9.2-25.6 g/L) in our patient population. A population pharmacokinetic analysis using the NONMEM program indicated creatinine clearance as a significant covariate for explaining the between-subject variability of ertapenem in the patient population. Estimated free plasma concentrations of ertapenem exceeded a MIC(90) of 2 mg/L only for 6 h (25%) after infusion. CONCLUSIONS: For an adequate dose adjustment of highly protein-bound drugs like ertapenem, knowledge of actual albumin concentrations is necessary. A shortening of the dosage interval or continuous infusion of ertapenem should be considered to ensure optimal free concentrations in critically ill patients with severe hypoalbuminaemia and normal renal function.

Adult↗
PubMed2006

Absorption, metabolism, and antioxidant effects of pomegranate (Punica granatum l.) polyphenols after ingestion of a standardized extract in healthy human volunteers.

The intake of polyphenols has been demonstrated to have health-promoting and disease-preventive effects. The pomegranate (Punica granatum L.), which is rich in several polyphenols, has been used for centuries in ancient cultures for its medicinal purposes. The potential health benefits of pomegranate polyphenols have been demonstrated in numerous in vitro studies and in vivo experiments. This study investigated the absorption and antioxidant effects of a standardized extract from pomegranate in healthy human volunteers after the acute consumption of 800 mg of extract. Results indicate that ellagic acid (EA) from the extract is bioavailable, with an observed C(max) of 33 ng/mL at t(max) of 1 h. The plasma metabolites urolithin A, urolithin B, hydroxyl-urolithin A, urolithin A-glucuronide, and dimethyl ellagic acid-glucuronide were identified by HPLC-MS. The antioxidant capacity measured with the oxygen radical absorbance capacity (ORAC) assay was increased with a maximum effect of 32% after 0.5 h, whereas the generation of reactive oxygen species (ROS) was not affected. The inflammation marker interleukin-6 (IL-6) was not significantly affected after 4 h after the consumption of the extract. Overall, this study demonstrated the absorbability of EA from a pomegranate extract high in ellagitannin content and its ex vivo antioxidant effects.

Adult↗
PubMed2006

Once-daily tobramycin in cystic fibrosis: better for clinical outcome than thrice-daily tobramycin but more resistance development?

OBJECTIVES: Once-daily administration of aminoglycosides in cystic fibrosis (CF) patients is considered equally efficacious and potentially less nephrotoxic than dosing three times a day. However, the choice of the most suitable PK/PD index (C(max)/MIC versus AUC(24)/MIC) to ensure optimum clinical outcome in this patient population is not clear. PATIENTS AND METHODS: In a single-centre, open, randomized, controlled, non-blinded study 33 adult CF patients (20 females, 19-37 years) were treated with intravenous tobramycin (10 mg/kg/day) for 14 days given either as single dose once a day (Q24; 17 patients) or divided into three equal doses every 8 h (Q8; 16 patients). Tobramycin serum concentrations and MICs for Pseudomonas aeruginosa were determined on days 1 and 14. The clinical outcome parameter, correlated to PK/PD indices, was the percentage predicted forced expiratory volume in 1 s (FEV(1)% pred.). RESULTS: FEV(1)% pred. improved significantly for both treatments. There was a log-linear relationship between C(max)/MIC and FEV(1)% pred. and AUC/MIC and FEV(1)% pred. for both treatments. For equal values of AUC24/MIC, however, Q24 treatment provided better improvement in lung function than Q8 dosing, whereas C(max)/MIC did not show any dosing interval dependence. A statistically significant increase was observed for MIC (day 1) versus MIC (day 14) for Q24 treatment, however, no such difference was observed for Q8 treatment. CONCLUSIONS: The most important PK/PD parameter for clinical outcome in CF patients was C(max)/MIC. Outcome prediction of AUC(24)/MIC was dependent on the regimen. The increase of P. aeruginosa resistance after once-daily administration is linked to a long dosing interval. More and larger studies are needed to optimize the dosing regimen for maximum clinical outcome with minimum resistance development.

Adult↗
PubMed2006

Penetration of ertapenem into skeletal muscle and subcutaneous adipose tissue in healthy volunteers measured by in vivo microdialysis.

OBJECTIVES: Ertapenem is FDA approved for the treatment of skin and skin-structure infections (SSSI), but its in vivo penetration into the interstitial space of soft tissues is unknown. The present microdialysis study was conducted to measure free, protein-unbound ertapenem concentrations in muscle and subcutaneous tissue. VOLUNTEERS AND METHODS: In a single-centre, prospective, open-label study six healthy volunteers (three females, 22-37 years) were treated with 1 g ertapenem given as a single intravenous dose. Microdialysis and plasma samples were collected before and at different time points up to 12 h after medication. Drug concentrations were determined by a validated LC-MS-MS method. RESULTS: No serious or microdialysis-associated adverse events were observed. Ertapenem concentrations in plasma reached a maximum (C(max)) of 103.3 +/- 26.3 mg/L, a terminal elimination half-life (t(1/2)) of 3.8 +/- 0.6 h and an AUC(0-infinity) of 359.7 +/- 66.5 mg.h/L. Mean peak concentrations of free, protein-unbound ertapenem in interstitial space fluid of skeletal muscle and subcutaneous adipose tissue were much lower (C(max) = 6.7 +/- 4.1 and 4.0 +/- 1.6 mg/L, respectively). This degree of tissue distribution is consistent with high concentration-dependent plasma protein binding of ertapenem (84-96%). AUC(0-infinity) values for both muscle and adipose tissue were lower as well (39.7 +/- 24.8 and 18.6 +/- 4.6 mg.h/L). However, unbound interstitial fluid concentrations exceeded MIC(90) values for the important SSSI pathogens for 7 (subcutis) and 10 h (muscle) after dosing. CONCLUSIONS: These results support the previously observed clinical efficacy of ertapenem in the treatment of SSSI.

Adult↗
PubMed2006

Pharmacokinetic/pharmacodynamic modeling of total lymphocytes and selected subtypes after oral budesonide.

In the present pharmacokinetic/pharmacodynamic (PK/PD) evaluation, cortisol, total lymphocytes, and lymphocyte subpopulations were monitored following single oral doses of two oral formulations of 3 mg budesonide (BUD) (Dosage Forms A and B) in order to assess the differential effects that BUD may have on cortisol suppression and the modulation of blood lymphocyte subtypes. On a single occasion, five subjects received one 3 mg capsule of Dosage Form A, four received three capsules of Dosage Form A (single dose of 9 mg), and five received three capsules of Dosage Form B (single dose of 9 mg). Placebo capsules were administered to six subjects in the study. Cortisol concentrations, total lymphocyte counts, and lymphocyte subpopulation counts for the CD3, CD4, CD8, CD19, and CD56/16 were fitted to an in direct PK/PD response model that described the effects of BUD on serum cortisol concentrations as well as the combined effects of BUD and cortisol on total lymphocytes and the CD3, CD4, CD8, CD19, and CD56/16 subtypes. Data were also analyzed using noncompartmental methods. The PK/PD model fitted the data with the exception of data for CD56/16. The IC(50) value for unbound BUD acting on total lymphocytes was 0.276 ng/ml while the IC(50) values for unbound BUD acting on lymphocyte subtypes ranged from 0.150 ng/ml for CD4 to 0.364 ng/ml for CD8. The IC(50) values for the effects of BUD on serum cortisol were lower (0.079 ng/ml). The results of PK/PD modeling and noncompartmental analysis indicate that BUD has a smaller effect on the CD8 subtype and larger effects on the CD4 and CD19 subtypes, relative to the effect on total lymphocytes, and that cortisol suppression, although not a direct immunological biomarker, may be a more sensitive marker for the systemic effect of corticosteroids.

Administration, Oral↗
PubMed2006

Microdialysis as a tool in local pharmacodynamics.

In many cases the clinical outcome of therapy needs to be determined by the drug concentration in the tissue compartment in which the pharmacological effect occurs rather than in the plasma. Microdialysis is an in vivo technique that allows direct measurement of unbound tissue concentrations and permits monitoring of the biochemical and physiological effects of drugs throughout the body. Microdialysis was first used in pharmacodynamic research to study neurotransmission, and this remains its most common application in the field. In this review, we give an overview of the principles, techniques, and applications of microdialysis in pharmacodynamic studies of local physiological events, including measurement of endogenous substances such as acetylcholine, catecholamines, serotonin, amino acids, peptides, glucose, lactate, glycerol, and hormones. Microdialysis coupled with systemic drug administration also permits the more intensive examination of the pharmacotherapeutic effect of drugs on extracellular levels of endogenous substances in peripheral compartments and blood. Selected examples of the physiological effects and mechanisms of action of drugs are also discussed, as are the advantages and limitations of this method. It is concluded that microdialysis is a reliable technique for the measurement of local events, which makes it an attractive tool for local pharmacodynamic research.

Acetylcholine↗
PubMed2006

Hyperforin in St. John's wort drug interactions.

Recently, interactions of herbal medicines with synthetic drugs came into focus of particular interest. In the past 3 years, more than 50 papers were published regarding interactions between St. John's wort (Hypericum perforatum L.; SJW) and prescription drugs. Co-medication with SJW resulted in decreased plasma concentrations of a number of drugs including amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, dextrometorphane, simvastatin, and oral contraceptives. Sufficient evidence from interaction studies and case reports indicate that SJW is a potent inducer of cytochrome P450 enzymes (particularly CYP3A4) and/or P-glycoprotein. Recent studies could show that the degree of enzyme induction by SJW correlates strongly with the amount of hyperforin found in the product. Products that do not contain substantial amounts of hyperforin (<1%) have not been shown to produce clinically relevant enzyme induction. On the other hand, some evidence suggests that hyperforin may also contribute to the antidepressant activity of SJW. However, clinical studies using SJW preparations with a low hyperforin amount (<1%) clearly demonstrated the superiority of this plant extract over placebo and its equivalence to imipramine and fluoxetine in the treatment of mild to moderate forms of depression. In the present paper clinical significant SJW interactions are critically evaluated against the background of hyperforin.

Bridged Bicyclo Compounds↗
PubMed2006

Variation of flavonoids and furanocoumarins in grapefruit juices: a potential source of variability in grapefruit juice-drug interaction studies.

Grapefruit juice (GFJ) has been found to interact with several medications, increasing their oral bioavailability and the risk of toxicity. Inhibition of CYP3A4 in the small intestine by flavonoids (such as naringin and naringenin) and furanocoumarins (including bergamottin and 6',7'-dihydroxybergamottin) present in GFJ seems to be the predominant mechanism, although P-glycoprotein and influx transporters in the small intestine are also involved. The quantity of interactive compounds ingested may affect the magnitude and mechanism of the food-drug interaction. Therefore, these four compounds were quantified by HPLC analysis in commercially available and fresh-squeezed GFJ and in grapefruit tissues. Considerable variability in naringin (174-1492 micromol/L), bergamottin (1.0-36.6 micromol/L), and 6',7'-dihydroxybergamottin (0.22-52.5 micromol/L) was observed, whereas naringenin could not be detected. White grapefruit showed higher concentrations of naringin and furanocoumarins located in the albedo and flavedo compared with red varieties. Findings from this study suggest considering concentrations of components with a potential for drug interactions in GFJ-drug interaction studies. The concentration of potentially contributing compounds may crucially influence the magnitude of observed interaction and impair direct comparison of studies in which different juices have been used.

Beverages↗
PubMed2006

The systemic safety of inhaled corticosteroid therapy: a focus on ciclesonide.

OBJECTIVE: To review the potential systemic activity of ciclesonide and its active metabolite, desisobutyryl-ciclesonide, by evaluation of the effects on hypothalamic-pituitary-adrenal (HPA) axis function. DATA SOURCES: EMBASE and MEDLINE searches using the keyword ciclesonide, without date restrictions, were conducted to identify published articles that related to clinical trials that included ciclesonide. STUDY SELECTION: The primary articles that reported systemic safety data for ciclesonide were reviewed. RESULTS: Ciclesonide (320-1,280 microg/d) demonstrated no detectable, clinically relevant effect on HPA axis function as evaluated by basal cortisol excretion measurements and dynamic stimulation tests. Furthermore, ciclesonide had no effect on the normal diurnal rhythm of endogenous cortisol secretion while simultaneously improving pulmonary function and reducing bronchial hyperresponsiveness. These results suggest that ciclesonide has a low systemic activity that may be attributable to unique pharmacologic properties, including a high degree of serum protein binding, a low oral bioavailability, and rapid systemic elimination, that reduce the level of systemically available pharmacologically active drug. CONCLUSIONS: Even at the higher doses used to treat more severe cases of asthma, ciclesonide was observed to have no effect on HPA axis function. These data, in conjunction with the observed clinical efficacy, suggest that ciclesonide may have an improved therapeutic margin compared with some other currently available inhaled corticosteroid treatments and, therefore, the potential to improve therapeutic outcomes.

Administration, Inhalation↗
PubMed2006

Moxifloxacin distribution in the interstitial space of infected decubitus ulcer tissue of patients with spinal cord injury measured by in vivo microdialysis.

We investigated the distribution of moxifloxacin in the interstitial space of normal and infected subcutaneous tissue in patients with spinal cord injury and decubitus ulcers using in vivo microdialysis. Drug concentrations achieved in serum, saliva, normal and infected tissues showed approximately parallel time profiles. The interstitial tissue fluids reached bactericidal levels for common bacteria found in infected skin lesions. Our findings suggest that moxifloxacin exhibits good and similar penetration into the interstitial space fluid in normal subcutaneous tissue and infected decubitus ulcers in patients with spinal cord injury.

Adult↗
PubMed2006

Characterizing the effects of caspofungin on Candida albicans, Candida parapsilosis, and Candida glabrata isolates by simultaneous time-kill and postantifungal-effect experiments.

We measured time-kills and postantifungal effects (PAFEs) of caspofungin against Candida albicans, C. parapsilosis, and C. glabrata isolates. One-hour exposure to caspofungin during PAFE experiments accounted for the majority of killing during time-kill experiments. Regrowth of all isolates was inhibited for at least 24 h following drug washout.

Antifungal Agents↗
PubMed2006

Pharmacokinetic/pharmacodynamic profile of voriconazole.

Voriconazole is the first available second-generation triazole with potent activity against a broad spectrum of clinically significant fungal pathogens, including Aspergillus,Candida, Cryptococcus neoformans, and some less common moulds. Voriconazole is rapidly absorbed within 2 hours after oral administration and the oral bioavailability is over 90%, thus allowing switching between oral and intravenous formulations when clinically appropriate. Voriconazole shows nonlinear pharmacokinetics due to its capacity-limited elimination, and its pharmacokinetics are therefore dependent upon the administered dose. With increasing dose, voriconazole shows a superproportional increase in area under the plasma concentration-time curve (AUC). In doses used in children (age < 12 years) voriconazole pharmacokinetics appear to be linear. Steady-state plasma concentrations are reached approximately 5 days after both intravenous and oral administration; however, steady state is reached within 24 hours with voriconazole administered as an intravenous loading dose. The volume of distribution of voriconazole is 2-4.6 L/kg, suggesting extensive distribution into extracellular and intracellular compartments. Voriconazole was measured in tissue samples of brain, liver, kidney, heart, lung as well as cerebrospinal fluid. The plasma protein binding is about 60% and independent of dose or plasma concentrations. Clearance is hepatic via N-oxidation by the hepatic cytochrome P450 (CYP) isoenzymes, CYP2C19, CYP2C9 and CYP3A4. The elimination half-life of voriconazole is approximately 6 hours, and approximately 80% of the total dose is recovered in the urine, almost completely as metabolites. As with other azole drugs, the potential for drug interactions is considerable. Voriconazole shows time-dependent fungistatic activity against Candida species and time-dependent slow fungicidal activity against Aspergillus species. A short post-antifungal effect of voriconazole is evident only for Aspergillus species. The predictive pharmacokinetic/pharmacodynamic parameter for voriconazole treatment efficacy in Candida infections is the free drug AUC from 0 to 24 hour : minimum inhibitory concentration ratio.

Animals↗
PubMed2005

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

Interest in the relationships between the pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial agents has increased over recent years. Since the appearance 2 years ago of our first article describing terminology in PK/PD, the field has continued to expand rapidly, urgently requiring an update. This paper describes in a uniform manner the use of PK/PD expressions for antimicrobial agents, and their units.

Anti-Infective Agents↗
PubMed2005

Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of anti-infective drugs.

Inadequate tissue penetration of antibiotics can lead to therapeutic failure and bacterial resistance. Pharmacokinetic evaluation of antibiotics should therefore be based on tissue rather than serum concentrations. Over several years, tissue concentration data obtained by methods such as tissue biopsies have flawed the correct interpretation of antibiotic tissue distribution. Microdialysis--a semi-invasive catheter-based sampling technique--has been employed for the in vivo measurement of antibiotic tissue pharmacokinetics. Owing to selective access to the target site for most anti-infective drugs, microdialysis satisfies regulatory requirements for pharmacokinetic distribution studies and might become a reference technique for tissue distribution studies in the near future. Furthermore, microdialysis might contribute to the definition of meaningful surrogate markers for antibiotic efficiency during drug development.

Anti-Infective Agents↗