Günther Hochhaus

Pharmacokinetics and pharmacodynamics of inhaled corticosteroids

There are significant differences in the pharmacokinetic properties of inhaled corticosteroids currently used in medical practice. All are rapidly cleared from the body but they show varying levels of oral bioavailability and more importantly variation in the rate of absorption after inhalation. Oral bioavailability is lowest for fluticasone propionate, indicating a low potential for unwanted systemic corticosteroid effects. Mathematical modeling has shown pulmonary residence times to be longest for fluticasone propionate and triamcinolone acetonide but shortest for budesonide and flunisolide. These properties appear to relate to pulmonary solubility, which appears to be the rate-limiting step in the absorption process.

Receptor‐Based Pharmacokinetic‐Pharmacodynamic Analysis of Corticosteroids

The pharmacodynamics of three corticosteroids were investigated after intravenous administration of the phosphate esters of methylprednisolone, dexamethasone, and triamcinolone acetonide to healthy subjects at 20, 50, and 80 mg as well as placebo. Twenty‐two different pharmacodynamic parameters were followed as a function of time for 48 hours. Statistically significant effects of the glucocorticoids were an increase in blood glucose levels, a decrease in the number of lymphocytes, eosinophils, basophils, and monocytes, and an increase in the number of granulocytes and stab cells. For the most significant pharmacodynamic effects (lymphocytes, granulocytes, and glucose) a previously derived integrated pharmacokinetic/pharmacodynamic model using plasma concentrations, protein‐binding data, and in vitro receptor‐binding affinities was used to predict the pharmacodynamic effect‐time profiles. Good agreement of predicted and measured effects was observed, confirming the validity of the model. The clinical significance of the model was demonstrated by comparison of model‐predicted maintenance doses with empirically determined clinical equivalency doses.

Population Pharmacokinetics and Pharmacodynamics of Ciclesonide

Ciclesonide is a novel glucocorticoid that is converted into ciclesonide—active principle (CIC‐AP) in the lung. The study objectives were to identify a structural model for population pharmacokinetic (PK) analysis of CIC‐AP using nonlinear mixed‐effects modeling, assess the influence of select covariates on PK and/or pharmacodynamic (PD) parameters, and investigate the effects of CIC‐AP on endogenous cortisol. Pooled concentration data from nine phase I studies (dose: 400–3600 μg) involving healthy and asthmatic patients were included in the PK analysis. There were 151 subjects (3300 observations) for the CIC‐AP population PK analysis. Various models examined inter‐ and intrasubject variability for the PK parameters. Population estimates of the PK parameters of clearance and volume of distribution were 396 L/h (64.8% coefficient of variation [CV]) and 1190 L (41.2% CV), respectively. Pharmacodynamic population estimates included maximum cortisol release rate, 3140 ng/h (5.4% CV). The EC50 of CIC‐AP was 0.88 ng/mL. Ciclesonide is a safe corticosteroid that causes negligible cortisol suppression. The disposition and effect of CIC‐AP can be described using mixed‐effect modeling. The estimated EC50 is similar to mean Cmax from an 800–μg dose, further suggesting CIC‐AP has little effect on cortisol suppression.

Pharmacokinetics of triamcinolone acetonide after intravenous, oral, and inhaled administration

The pharmacokinetics of triamcinolone acetonide were studied after intravenous (2 mg), oral (5 mg), and inhaled (2 mg) administration. Triamcinolone acetonide concentrations were measured in plasma by high‐performance liquid chromatography/radioimmunoassay. After intravenous administration, triamcinolone acetonide was eliminated with a total body clearance of 37 L/h and a half‐life of 2.0 hours. The volume of distribution was 103 L, and oral bioavailability averaged 23%. Absorption was rapid, achieving maximum triamcinolone acetonide levels of 10.5 ng/mL after 1 hour. After inhalation, bioavailability averaged 22% with maximum levels of 2.0 ng/mL observed after 2.1 hours. The resulting systemic levels for all three treatments caused a significant decrease in the number of lymphocytes in blood.

Pharmacokinetic/Pharmacodynamic Aspects of Aerosol Therapy using Glucocorticoids as a Model

Glucocorticoids are predominantly prescribed in asthma therapy as aerosols to achieve high pulmonary effects with reduced systemic spill‐over and pronounced pulmonary selectivity. A variety of pharmacokinetic parameters are potentially important for determining pulmonary selectivity. The intent of this article, is to provide a practice‐relevant theoretical approach to put the importance of these parameters on pulmonary targeting using pharmacokinetic/pharmacodynamic modeling as a tool in perspective. The applied pulmonary pharmacokinetic/pharmacodynamic model revealed that, in addition to recognized parameters such as systemic clearance, oral bioavailability, and efficiency of pulmonary deposition, other factors, such as the pulmonary release (dissolution) rate and dose, are relevant. However, the volume of distribution (for effect parameters not undergoing a diurnal rhythm) and the receptor affinity of a given glucocorticoid are not important for achieving lung targeting. J Clin Pharmacol 1997;37:881–892.

Budesonide in previously untreated autoimmune hepatitis

Abstract: Background: Autoimmune hepatitis (AIH) is a chronic liver disease that is effectively treated with immunosuppressive therapy. Predniso(lo)ne, often in combination with azathioprine, is the basic therapeutic option to induce remission. However, this regimen can cause numerous side effects. The aim of the present study was to evaluate budesonide as a treatment option in the induction of remission in patients with previously untreated AIH.

Pharmacokinetics of the Dietary Supplement Creatine

Creatine is a nonessential dietary component that, when supplemented in the diet, has shown physiological benefits in athletes, in animal-based models of disease and in patients with various muscle, neurological and neuromuscular disease. The clinical relevance of creatine supplementation is based primarily on its role in ATP generation, and cells may be able to better handle rapidly changing energy demands with supplementation.Although the pharmacological outcome measures of creatine have been investigated, the behaviour of creatine in the blood and muscle is still not fully understood. Creatine is most probably actively absorbed from the gastrointestinal tract in a similar way to amino acids and peptides. The distribution of creatine throughout the body is largely determined by the presence of creatine transporters. These transporters not only serve to distribute creatine but serve as a clearance mechanism because of creatine ‘trapping’ by skeletal muscle. Besides the pseudo-irreversible uptake by skeletal muscle, creatine clearance also depends on renal elimination and degradation to creatinine.Evidence suggests that creatine pharmacokinetics are nonlinear with respect to dose size and frequency. Skeletal muscle, the largest depot of creatine, has a finite capacity to store creatine. As such, when these stores are saturated, both volume of distribution and clearance can decrease, thus leading to complex pharmacokinetic situations. Additionally, other dietary components such as caffeine and carbohydrate can potentially affect pharmacokinetics by their influence on the creatine transporter. Disease and age may also affect the pharmacokinetics, but more information is needed.Overall, there are very limited pharmacokinetic data available for creatine, and further studies are needed to define absorption characteristics, clearance kinetics and the effect of multiple doses. Additionally, the relationship between plasma creatine and muscle creatine needs to be elucidated to optimise administration regimens.

Soft drugs--10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate.

An improved synthesis of loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene 17 beta-carboxylate) was achieved. The design of the new type of glucocorticoid was based on the soft drug concept. The relative binding affinities of loteprednol and its putative metabolites (PJ90 and PJ91) to rat lung type II glucocorticoid receptor were determined in a competitive binding experiment with [3H]triamicinolone acetonide. The medium contained cortienic acid (10(-5) M) in order to block transcortin binding sites. Loteprednol etabonate exhibited a binding affinity which was 4.3 times that of dexamethasone, both compounds having a Hill factor close to 1 whereas PJ90 and PJ91 did not show any affinity to the receptor. Loteprednol etabonate was compared to betamethasone 17 alpha-valerate in a vasoconstriction test which was performed on the forearm skin of human volunteers. The results showed that loteprednol etabonate has good skin-permeation properties and strong glucocorticoid activity.

Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration

AbstractObjective: To evaluate the pharmacokinetic and systemic pharmacodynamic properties of inhaled fluticasone propionate (FP). Methods: Single doses of 0.25, 0.5, 1.0 and 3.0 mg FP were administered to groups of six healthy subjects. Serum concentration profiles of FP were monitored over 24 h by means of high-performance liquid chromatography/mass spectrometry (HPLC/MS–MS). Systemic pharmacodynamic effects were evaluated by measuring endogenous serum cortisol and circulating white blood cells, and analyzed with previously developed integrated pharmacokinetic/pharmacodynamic (PK/PD) models. Results: FP showed a dose-independent terminal half-life with a mean (SD) of 6.0 (0.7) h. Maximum serum concentrations occurred 1.0 (0.5) h after administration, ranging from 90 pg · ml−1 for the 0.25 mg dose to 400 pg · ml−1 for the 3.0 mg dose. This, together with an estimated mean absorption time of nearly 5 h and a known oral bioavailability of less than 1%, indicates prolonged residence at and slow absorption from the lungs. In the investigated dose range, the cumulative systemic effect was dose-dependent for both markers of pharmacodynamic activity. For doses of 0.25, 0.50, 1.0 and 3.0 mg FP, the PK/PD-based cumulative systemic-effect parameters were 159, 186, 257 and 372% · h for lymphocyte suppression, 107, 186, 202 and 348% · h for granulocyte induction and 23.6%, 33.8%, 51.0% and 73.6% for cortisol reduction, respectively. The time courses of lymphocytes, granulocytes and endogenous cortisol could be sufficiently characterized with the applied PK/PD models. The measured in vivo EC50 values, 30 pg · ml−1 and 7.3 pg · ml−1 for white blood cells and cortisol, respectively, were in good agreement with predictions based on the in vitro relative receptor affinity of FP. Conclusion: After inhalation, FP follows linear pharmacokinetics and exhibits dose-dependent systemic pharmacodynamic effects that can be described by PK/PD modeling.

Drugs used in the treatment of opioid tolerance and physical dependence: a review.

Opioid drugs used in the treatment of severe pain are known to produce tolerance that requires a dose increase to maintain a sufficient analgesic effect. As this is connected with side effects such as respiratory depression, it is highly desirable to avoid or at least attenuate the development of tolerance. Closely related, but in some respect dissociable, is the phenomenon of physical dependence, which becomes apparent particularly in heroin withdrawal. Our knowledge about the mechanisms underlying tolerance has increased dramatically in recent years, but a final picture of the importance of each particular mechanism under in vivo conditions has not yet emerged. Recent studies suggest that the so-called receptor down-regulation is not the main mechanism in vivo. A desensitization on the basis of receptor decoupling, receptor internalization and increased alternative coupling to stimulatory G-proteins have been demonstrated. However, a functional antagonism of the opioid effects seems to be clinically most important, mediated by the activation of NMDA receptors, up-regulation of adenylyl cyclase and nitric oxide synthase. Drugs blocking these mechanisms are the most promising option in the treatment of tolerance. Namely, alpha2-adrenoreceptor agonists such as clonidine and NMDA antagonists such as ketamine or dextromethorphan have been used to minimize tolerance development during opioid treatment. Moreover, clinical strategies such as opioid rotation and multimodal analgesia, i.e. the simultaneous application of several analgetics of different type, have proven to be successful approaches.