Pharmacokinetic-pharmacodynamic modeling of testosterone and luteinizing hormone suppression by cetrorelix in healthy volunteers.

Cetrorelix (CET), a potent luteinizing hormone-releasing hormone (LH-RH) antagonist, was recently approved for the prevention of premature ovulation in patients undergoing a controlled ovarian stimulation (COS), followed by oocyte pickup and assisted reproductive techniques (ART), and is currently under clinical trials for benign prostate hyperplasia, endometriosis, and tumors sensitive to sex hormones. CET suppresses luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) in men. The purpose of this study was to evaluate the pharmacokinetics and absolute bioavailability of 3 mg intravenously and subcutaneously administered CET in healthy male and female volunteers and to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to link the plasma concentrations of CET to the T and LH suppression in males. Following intravenous (IV) (n = 5) and subcutaneous (SC) (n = 6) administration of CET acetate, CET and hormone plasma levels were measured by radioimmunoassay (RIA) and enzyme immunoassay (EIA) methods, respectively. Pharmacokinetics of CET was explained by a three-compartment model for the IV route and by a two-compartment model with first-order absorption for the SC route. Average absolute bioavailability after SC administration was 85%. There were no differences in the pharmacokinetics between male and female subjects (ANOVA, p > 0.05). Single IV and SC doses of CET caused immediate and distinct suppression of LH, FSH, and T levels by 80%, 45% and 95% of their baseline levels, respectively. The duration of hormone suppression was longer for the SC route. An indirect-response PK-PD Emax model was developed to link the measured CET plasma concentrations with the respective T or LH levels. In addition, the circadian rhythm of T levels was accounted by including a cosine function in a second separate PD model. The PD model with cosine function was applied to T baseline levels as well as to the suppressed concentrations after CET dosing. The two models adequately described the PK-PD relationship between plasma levels of CET and T suppression following IV and SC dosing. The EC50 values (mean +/- SD) for the suppression of T were similar (p > 0.05) between the two routes of administration and the two models.

Systemic delivery of the GnRH antagonist cetrorelix by intratracheal instillation in anesthetized rats.

Pulmonary absorption of the decapeptide cetrorelix acetate was studied in rats by a non-surgical intratracheal instillation method. The pharmacological effect (decrease of testosterone plasma concentration) following intratracheal (i.t.) instillation was determined in four groups of seven rats each at three different concentrations (0.5, 1.0 and 2.5 mg/kg body weight). The applied doses reduced testosterone plasma concentration to subnormal level (

Human pharmacokinetic profile of 1,25-dihydroxyvitamin D3-glycoside of herbal origin.

A natural form of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active metabolite of vitamin D, was identified in glycosylated form in Solanum glaucophyllum (SG). Solbone P, an extract of SG with high and homogenous content of glycosylated 1,25(OH)2D3, was chemically characterized and produced under GMP conditions. Three different doses of glycosylated 1,25(OH)2D3 were given as single oral dose to 16 healthy volunteers in a first-in-man trial. The oral pharmacokinetic properties of 1,25(OH)2D3 of SG origin were established and the subjects were monitored until day 28 for safety reasons. This included regular monitoring of vital signs, electrocardiogram (ECG) data, calcium, phosphate and creatinine values. Subjects were exposed to up to the equivalent of a 40-fold level of the recommended human daily dose for synthetic 1,25(OH)2D3 (0.5µg/subject/day) without experiencing any untoward effects. When compared with the historically established pharmacokinetics profile of synthetic 1,25(OH)2D3, glycosylated 1,25(OH)2D3 of herbal origin exhibited delayed absorption characteristics. The phenomenon is species independent, as similar pharmacokinetic patterns were observed in rats and chickens. This modified release pattern may be attributed to the glycosylation of herbal 1,25(OH)2D3 because de-glycosylation by ubiquitous intestinal enzymes prior to intestinal uptake of the unmodified 1,25(OH)2D3 is the rate-limiting step. The major relevance of this finding is that the human pharmacokinetic profile of glycosylated 1,25(OH)2D3 of herbal origin is reminiscent of a delayed release formulation of free 1,25(OH)2D3, resulting in a wider therapeutic window, a potentially longer therapeutic effectiveness, and thus, a better pharmacologic tolerance. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

Tolerability and pharmacokinetics of single and multiple doses of azelastine hydrochloride in elderly volunteers.

The tolerability and pharmacokinetics of azelastine hydrochloride (CAS 73907-93-0, A-05610) after single and multiple dosing (4.4 mg as tablet, tau = 12 h) were investigated in 14 volunteers (6 female, 8 male) older than 65 years (70 +/- 5 years, mean +/- SD). The medication was administered as tablets in the morning of days 1 and 11, and b.i.d. on days 4 to 10 in a randomized, open-labelled, uncontrolled study. Tolerance proved to be very good. Reported number of adverse events was independent from height of plasma levels measured, which showed pronounced inter- and intraindividual variation. When comparing pharmacokinetic parameters from plasma levels (determined with a radioimmunoassay (RIA)) of the elderly with those of young volunteers (26 +/- 5 years), there is a difference in half lives (t1/2 elderly vs young: single dose: 38.5 +/- 15.3 h vs 25.0 +/- 5.2 h; multiple dose: 35.5 +/- 16.3 h vs 55.4 +/- 24.9 h), and also after a single dose AUC and after multiple dosing AUCss tau, tssmax, Cssmax, Cssmin (pre dose levels), and the ratios of accumulation Rmax and Rmin (calculated from Cssmax/Cmax and Cssmin/Cmin) are approximately twice as high in elderly as those in young volunteers. The RIA co-detects besides azelastine the pharmacodynamically active metabolite N-demethyl-azelastine and thus, the parameters describe the pharmacokinetic behaviour as a resultant from both compounds, i.e. the "active principle". N-Demethylated metabolites are known to have longer half-lives usually than their parent compounds and thus, accumulate in a higher degree during multiple dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Tolerability, pharmacokinetics and dose linearity of azelastine hydrochloride in healthy subjects.

In a double-blind, randomized, 4-period crossover study, single oral doses of azelastine hydrochloride tablets (A-05610, Allergodil, Radethazin, Azeptin, CAS 79307-93-0) were ingested by 12 healthy volunteers (6 males, 6 females, mean age 25.2 +/- 3.5 years). Dose linearity was demonstrated for 2.2, 4.4, 8.8 and 17.6 mg of azelastine hydrochloride. The values of AUC0-infinity and Cmax increased linear to the dose (means of AUC0-infinity: 47.3, 93.7, 208.0 and 405.90 ng-eq h/ml; means of Cmax: 1.5, 3.3, 6.0 and 12.5 ng-eq/ml), whereas tmax and the terminal half-life of elimination (t1/2 beta) were obviously not influenced by the dose. Mean values over all doses and subjects amounted to 4.6 h (tmax) and 25.5 h (t1/2 beta). Plasma levels showed relatively high inter- and somewhat less intraindividual variations. This is most likely due to a varying degree of enterohepatic circulation resulting from alimentary factors. As for the co-detection of azelastine and the pharmacodynamically active metabolite N-desmethyl-azelastine by the radio-immuno-assay (RIA) used, the parameters describe the pharmacokinetic behaviour as a resultant from both compounds and thus the active principle of the drug. Independently of the dosages administered the overall tolerance proved to be very good. According to this trial the therapeutic range is wide enough to recommend 4.4 mg b.i.d. or single doses of 8.8 mg of azelastine hydrochloride per day for therapy in adult patients.

Systemic delivery of cetrorelix to rats by a new aerosol delivery system.

PURPOSE: To study the pulmonary absorption and tolerability of various formulations of the decapeptide cetrorelix acetate in rats by a new aerosol delivery system (ASTA-ADS) for intratracheal application. METHODS: Using the ASTA-ADS, cetrorelix liquid formulations (aqueous solutions for ultrasonic nebulization) were firstly selected and subsequently delivered as nebulized aerosol to orotracheally cannulated rats. The pharmacologic effect (decrease of testosterone serum level) of four cetrorelix formulations was determined in rats by enzyme linked immunosorbant assay, and pharmacokinetic data were determined after measurement of cetrorelix serum level by radioimmunoassay. Histological examination of the lung was performed at the end of the experiments, and in a supplementary experiment the respiratory parameters (resistance and compliance) of rats were monitored by a validated pulmonary monitoring system during the aerosol application of the same formulations. RESULTS: After an exposure time of 5 min, the applied formulations reduced the testosterone concentration in serum to subnormal levels (< or =1 ng/ml) over a period of 24 h. Comparing the plasma concentration after intratracheal aerosolization with data of intravenous administration, the mean calculated bioavailabilities for the four formulations using the corrected dose (delivered--exhaled amount) were between 48.4 +/- 27.0% and 77.4 +/- 44.0%. The histologic examination of the lungs revealed different tolerability of the various tested formulations ranging from locally intolerable to well tolerated. The measurement of the lung function parameters did not reveal any compound or formulation related changes. CONCLUSIONS: Our studies show that cetrorelix can be effectively administered as aerosol and that intratracheal aerosolization via the ASTA-ADS provides results that are well comparable to other application routes, as demonstrated by statistical comparison of the newly obtained data with previous results from intratracheal instillation of cetrorelix solutions in rats.

Plasma and follicular fluid concentrations of LHRH antagonist cetrorelix (Cetrotide) in controlled ovarian stimulation for IVF.

Cetrorelix was administered in differing daily dosages for controlled ovarian stimulation. The dosage levels were 3 mg (9 cycles), 1 mg (19 cycles), 0.5 mg (43 cycles), 0.25 mg (46 cycles) and 0.1 mg (7 cycles). In the 3 mg, 1 mg and 0.5 mg group the respective median plasma concentrations of cetrorelix on the day of oocyte pick-up (OPU) were 2.10 ng/ml, 1.42 ng/ml and 0.88 ng/ml and 1.03 ng/ml, 0.46 ng/ml and 0.49 ng/ml on the day of embryo transfer (ET). In the 0.25 mg and 0.1 mg groups plasma cetrorelix levels were below the limit of quantification. The cetrorelix concentrations in follicular fluid (FF) in the 0.25 mg group were detectable in only 14 out of 44 samples, while in the 0.1 mg group no detectable concentrations could be obtained. We also examined 80 cycles after single doses of 5 mg (7 cycles), 3 mg (42 cycles), and 2 mg (31 cycles) cetrorelix. On the day of OPU the respective median plasma concentrations of cetrorelix were 0.57 ng/ml, 0.62 ng/ml, and 0.56 ng/ml, and 0.61 ng/ml and 0.28 ng/ml on the day of ET in the 5 mg and 3 mg groups. In the 2 mg group, the plasma concentrations fell to below limits of quantification in 8/9 samples on the day of ET. In 26 out of 27 FF samples cetrorelix was detectable in the 3 mg single dose group (median level: 0.69 ng/ml).