Katharina Erb

Dose-proportionality of oral thioctic acid : coincidence of assessments via pooled plasma and individual data

Thioctic acid (TA), a racemate of R-(+)- and S-(-)-enantiomers of alpha-lipoic acid, acts as a powerful lipophilic, free-radical scavenger and is used in the treatment of diabetic neuropathy. This trial investigated the dose-linearity of enantiomer pharmacokinetics following the oral administration of single doses of 50 to 600 mg TA (formulation provided by ASTA (Medica)) in healthy volunteers. TA enantiomer concentrations in individual and pooled plasma samples were determined using enantioselective, high-performance liquid chromatography. TA was rapidly absorbed (tmax, 0.5 to 1 h). Maximum plasma concentrations (Cmax) of the R-(+)-enantiomer were about 40-50% higher than those of the S-(-)-enantiomer (50 mg: 135.45 ng/ml R-(+)-TA, 67.83 ng/ml S-(-)-TA; 600 mg: 1812.32 ng/ml R-(+)-TA, 978.20 ng/ml S-(-)-TA; geometric means). The decline observed in the plasma concentration was steep (t1/2, 0.5 h). The dose-linearity and proportionality of pharmacokinetic parameters could be demonstrated on an intra-individual basis and for the group geometric means. An analysis of pooled plasma samples proved to be a suitable means for deriving reliable first-sight results prior to individual assessments.

Effects of age and sex on the disposition of retigabine

The novel antiepileptic drug retigabine is the first selective M‐current potassium channel opener for KCNQ2/3 and KCNQ3/5 channels. Retigabine undergoes phase II metabolism (N‐glucuronidation, acetylation) exclusively and renal excretion.

Influence of antihypertensive therapy with cilazapril and hydrochlorothiazide on the stiffness of the aorta

SummaryThe purpose of this study was to examine the effects of the angiotensin-converting enzyme (ACE) inhibitor cilazapril on the elastic properties of the aorta. A standard diuretic antihypertensive drug, hydrochlorothiazide, served for comparisons. Increased aortic stiffness leads to a reduction of the buffering windkessel function and is a major component in the pathophysiology of systolic hypertension, inducing an increase in left ventricular afterload and arterial pulsatile stress as well as a decrease in the subendocardial blood supply. Stiffness of arteries increases with age and blood pressure, and depends on the functional elastic structures of the aortic wall. ACE inhibitors have been shown to directly influence elastic properties of peripheral arteries. Seventeen patients with mild to moderate essential hypertension (age 45–67 years) were treated for 3 months double-blind randomized with either cilazapril (C) 5 mg daily (n=9) or hydrochlorothiazide (HCTZ) 25 mg daily (n=8). Aortic elastic properties were noninvasively assessed by measurement of pulse wave velocity along the aorta at rest and during isometric handgrip stress. Accelerated pulse wave velocity indicates elevated arterial stiffness and vice versa. A pressure standardized index of aortic cross-sectional distensibility (2 m) was calculated from arterial mean pressure and pulse wave velocity. Compared with pretreatment values, both therapies significantly reduced blood pressure and pulse wave velocity at rest (C: 9.4±0.9 vs. 7.7±0.7 m/sec; HCTZ: 8.9±0.3 vs. 7.8±0.4 m/sec; means ± SEM p<0.05). During isometric stress only C showed a significant decrease in pulse wave velocity (C: 11.3±0.8 vs. 9.1±0.8 m/sec; HCTZ: 9.9±0.5 vs. 9.0±0.5 m/sec; means ± SEM p<0.05). The index 2m at rest and during handgrip increased significantly (p<0.05) after C but not after HCTZ. With cilazapril we obtained steeper slopes for the treatment-induced reductions in blood pressure and pulse wave velocity for both rest and handgrip stress values. Correlation of the data at rest and during stress revealed a direct relationship between blood pressure and pulse wave velocity. HCTZ linearly extended the relation observed before treatment toward lower values of blood presure and corresponding pulse wave velocity without changing the relation per se. Cilazapril, in contrast, moved the relation between these variables and decelerated the pulse wave velocities to a greater extent than would have been expected from the corresponding blood pressure reduction (delta approximately 1 m/sec). These results in patients with mild to moderate essential hypertension support the idea that ACE inhibitors, in addition to reducing blood pressure, may exert an additional hemodynamic effect in improving the elastic properties of the aorta.

A rapid and simple CYP2D6 genotyping assay—case study with the analgetic tramadol

There is substantial evidence for a causal relationship between genetic variability of the CYP2D6 gene and changes in the pharmacokinetics of drugs. Therefore, knowledge of single-nucleotide polymorphisms (SNPs) prior to drug administration is highly desired for assisting in the development of individualized pharmacotherapy. We therefore developed a robust assay that detects common CYP2D6 alleles within 60 minutes of blood withdrawal and links carriers of the variant CYP2D6*3 and *4 alleles to the pharmacokinetics of tramadol. This new genotyping assay employs fluorescence resonance energy transfer (FRET) analysis, which permits parallel identification of the CYP2D6*3 and CYP2D6*4 alleles within 60 minutes of blood withdrawal. We determined the genotypes of 100 healthy unrelated individuals and studied the pharmacokinetics of tramadol in 24 CYP2D6 genotyped healthy subjects. The total allelic frequencies of homozygote carriers were 0.015 and 0.25 for the CYP2D6*3 and *4 alleles, respectively, and the plasma area under the curve (AUC) was 84% above those of extensive metabolizers (homozygous EM group): 3,941.2 ng/mL.h (95% confidence interval [CI], 2,928.9 ng/mL.h to 4,953.5 ng/mL.h) versus 2,142.6 ng/mL.h (95% CI, 1,829.6 ng/mL.h to 2,455.7 ng/mL.h). Likewise, the AUC for the O-desmethyl-tramadol metabolite (M1) was significantly reduced in poor metabolizers (PMs): 300.2 ng/mL.h (95% CI, 260.3 ng/mL.h to 340.0 ng/mL.h) versus 842,6 ng/mL.h (95% CI, 715.1 ng/mL.h to 970.0 ng/mL.h). We observed a statistically significant correlation between plasma tramadol AUC and production of the O-desmethyl metabolite in CYP2D6 genotyped healthy volunteers. Our assay can be used reliably in clinical pharmacology studies and may be used for dose adjustment.

Pharmacodynamic effects and plasma pharmacokinetics of single doses of cetrorelix acetate in healthy premenopausal women

OBJECTIVE To investigate the pharmacodynamic effects and plasma pharmacokinetics of single subcutaneous doses of cetrorelix acetate in healthy premenopausal women. SETTING Phase I clinical research unit. PATIENT(S) Healthy, premenopausal women aged 19 to 35 years. INTERVENTION(S) Single subcutaneous morning doses of cetrorelix acetate (1, 3, or 5 mg peptide base) were investigated in a randomized, single-blind, placebo-controlled, parallel-group design. After a control cycle, 36 women received cetrorelix acetate (12 per dose) and 12 received placebo on the eighth individual cycle day. Transvaginal ultrasound was performed, and blood samples for LH, FSH, E2 were collected during both cycles and for pharmacokinetics up to 168 hours after dosing. The serum hormone levels were determined by electrochemicoluminescence immunoassay and plasma cetrorelix concentrations by radioimmuno assay. RESULTS Cetrorelix acetate administration led to a rapid, marked, and reversible suppression of serum LH, E2, and to a lesser extent FSH concentrations. The median intra-individual shifts between treatment and control cycle were -1.0, 4.0, 8.0, and 9.5 days for serum LH maximum and -1.0, 4.5, 7.0, and 10.0 days for ovulation following placebo or 1, 3, and 5 mg cetrorelix acetate, peptide base, respectively. The area under the concentration-time curve (AUC) and peak cetrorelix concentrations in plasma (Cmax) increased proportionally with dose. CONCLUSIONS Cetrorelix acetate showed pronounced and reversible LH and E2 suppression and a dose-dependent postponement of LH surge and ovulation after single subcutaneous administrations to healthy premenopausal women. Dose proportionality over the range of 1 mg to 5 mg cetrorelix acetate, peptide base was demonstrated.

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.

Pituitary and gonadal endocrine effects and pharmacokinetics of the novel luteinizing hormone‐releasing hormone antagonist teverelix in healthy men—a first‐dose‐in‐humans study

Teverelix is a novel synthetic peptidic luteinizing hormone‐releasing hormone (LHRH) antagonist.

Clinical pharmacological equivalence of a novel FCH-free GTN spray with low ethanol content vs a FCH-containing GTN spray

The overall therapeutic equivalence of a fluorochlorohydrocarbon (FCH)-free glyceryl trinitrate (GTN) pump spray with a low ethanol content (TL) was investigated relative to an FCH-containing GTN spray (Nitrolingual; R), in terms of: (1) pharmacokinetic bioavailability, (2) pharmacodynamic responses as assessed by digital plethysmography (DPG), and (3) clinical perception upon application.Pharmacokinetically, the time courses of the plasma concentrations of GTN and its dinitrate metabolites, 1,2- and 1,3-GDN, subsequent to the sublingual administration of 0.8 mg GTN showed somewhat lower bioavailability of GTN and its metabolites than to the reference. Pharmacodynamically, the changes in the DPG signals after the application of 0.8 mg GTN with TL were biostatistically euivalent with R (estimated ratio TL/R for the maximum decrease of the ratio between the systolic a wave and c incisure: 0.98; 90% CI: 0.84–1.14; and for the average decrease of the c: a ratio: 0.97; 90% CI: 0.80–1.16). The time of occurrence of the maximum effect of TL was not significantly different from that of R (estimated difference TL-R: -2.25 min; 95% CI:-9.5 min to 2 min).In contrast, after the administration of an FCH-free GTN spray with a higher ethanol content (TH, active control), the effect had a slightly earlier onset (TH-R:-6 min, 95% CI: -9.5 to -2 min) and there was a higher average response (TH/R: 1.12: 90% CI: 0.95 to 1.34). However, TH was consistently judged to cause an extremely unpleasant burning sensation in the mouth and thus was perceived as distinctly different from R. In contrast, TL was well tolerated and could not be distinguished from R.Therefore only TL met the criteria of overall therapeutic equivalence to R.

Usefulness, Usability, and Quality Criteria for Noninvasive Methods in Cardiovascular Clinical Pharmacology

Validation of study methods is a prerequisite for their usability. Empirical quality criteria based on test‐theoretical principles are useful for this purpose. These criteria are discussed for several noninvasive methods used in cardiovascular clinical pharmacology: electrocardiography, systolic time intervals, blood pressure, and estimates of stroke volume. Several of these methods are highly reliable and sensitive to drug effects. However, they are inherently low in validity because they are based on oversimplified algorithms and yield estimates rather than measurements of function and changes therein. These estimates are method‐specific and are likely to be subject to method* subject* effect interaction. Highlighting these constraints and the limitations of these methods need not preclude their useful contribution to the early evaluation of drug action in humans.

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 phaimacodj/namics 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, and follicle‐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 acmevea oy iu mg CET/glu. Duration of at least half‐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 evident for luteinizing hormone (LH) and, to a lesser extent, for follicle‐stimulating hormone (FSH). On average, Cmax was nearly doubled after single and multiple doses, and AUCt 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.