Effect of hospitalisation on liver enzymes in healthy subjects.

OBJECTIVES: The aims of the present evaluation were to determine whether the elevations in liver enzymes observed in phase-I trials are more common in subjects being hospitalised than in ambulatory subjects and to assess the relevance of these elevations. We therefore investigated the effect of hospitalisation on liver enzyme levels in subjects of all phase-I trials of sufficient length performed at the two Human Pharmacology Centres of Boehringer Ingelheim, located in Biberach and Ingelheim, Germany, over a 10-year period. METHODS: The evaluation was based on 29 phase-I trials conducted between 1987 and 1996. These trials consisted of at least 4 days of observation of 220 subjects on placebo treatment in 273 trial participations. The mean changes (transformed into reference ranges) in the liver enzymes alkaline phosphatase, gamma glutamyl transpeptidase, aspartate aminotransferase, alanine aminotransferase and the AST/ALT ratio of hospitalised subjects were compared with those of ambulatory subjects. RESULTS: A small but statistically significant increase in the mean of the parameters GGT, AST and ALT during phase-I trials was observed in hospitalised subjects compared with ambulatory subjects. The increases were: 8% of the reference range width for GGT, 8% for AST and 17% for the ALT, although the differences were small in absolute terms. A relevant increase (defined as an increase to above the reference range or by at least 50% of the reference range) was more common in hospitalised subjects. CONCLUSION: Hospitalisation, although it is believed to protect subjects from confounding environmental factors, can itself be associated with increases in liver enzyme levels. The definition of a relevant increase can be used to identify subjects who need further evaluation. The cause of the increase in liver enzyme levels remains unclear.

Absorption of lefradafiban from different sites of the gastrointestinal tract.

AIMS: Fibrinogen receptor antagonists show a close relationship between plasma concentrations and inhibitory effect. Optimal efficacy at an acceptable bleeding risk requires low inter- and intrasubject variability on low peak trough fluctuation in receptor occupancy and therefore also of plasma concentrations. Therefore, the enteral absorption of lefradafiban, an orally available fibrinogen receptor antagonist prodrug, was investigated after local administrations to different sites of the gastrointestinal tract in order to investigate the feasibility of an oral extended release formulation. METHODS: Twelve healthy male subjects received in a randomised, open-labelled, four-period crossover trial four consecutive administrations of lefradafiban: 1. orally; 2. administration into the jejunum, 3. administration into the lower jejunum/ileum (300 cm distally to the teeth), and 4. administration into the lumen of the sigmoid region (30 cm proximally to the anus). Local intestinal administrations were performed through a gastrointestinal tube. RESULTS: Compared with oral administration, ratios [mean (two-sided 90% confidence intervals)] of maximum drug plasma concentrations and AUC(0,24 h) of fradafiban were 1.05 (0.80, 1.39) and 1.06 (0.85,1.31) after jejunal, 0.98 (0.75,1.30) and 0.98 (0.79,1.21) after ileal, 0.52 (0.39,0.69) and 0.68 (0.55,0.85) after colonic administration. Urinary excretion of fradafiban was about 16% of the dose after oral, jejunal and ileal applications whereas after rectal administration about 11% were excreted. CONCLUSIONS: Lefradafiban is absorbed throughout the entire gastrointestinal tract. Therefore, an extended release formulation seems to be feasible with regard to bioavailability.

Profound and sustained inhibition of platelet aggregation by Fradafiban, a nonpeptide platelet glycoprotein IIb/IIIa antagonist, and its orally active prodrug, Lefradafiban, in men.

BACKGROUND: Clinical trials have demonstrated that platelet glycoprotein (GP) IIb/IIIa antagonists effectively prevent acute thrombotic events. Orally active GP IIb/IIIa antagonists are essential to evaluate the clinical benefit of long-term treatment. We therefore investigated platelet inhibition by the GP IIb/IIIa antagonist Fradafiban (BIBU 52; Fradafiban is the recommended INN of BIBU 52) and its orally administered prodrug, Lefradafiban (BIBU 104; Lefradafiban is the recommended INN of BIBU 104) in healthy subjects. METHODS AND RESULTS: The activity and plasma levels of Fradafiban and Lefradafiban were evaluated in double-blind, placebo-controlled studies in 130 healthy male subjects. One to 15 mg Fradafiban continuously infused over 30 minutes reversibly inhibited platelet aggregation in platelet-rich plasma ex vivo in response to 20 micromol/L ADP (5 mg, 100% inhibition at 27 minutes after administration) and to both 1.0 (5 mg, 100%) and 10 microg/mL (15 mg, 97+/-3%) collagen. Single oral doses of Lefradafiban inhibited ADP-induced aggregation by 59+/-14% (50 mg [mean+/-SD]; n=8), 90+/-12% (100 mg), and 99+/-2% (150 mg) 8 hours after administration. Correlations between activity and Fradafiban plasma levels were identical after Fradafiban and Lefradafiban treatment. After day 1, oral TID Lefradafiban treatment for 7 days inhibited aggregation by > or = 31+/-9.6% (25 mg TID; n=8), 53+/-12% (50 mg; n=7), and 88+/-6.6% (75 mg; n=8) just before the next dose. A similar correlation between the activity and Fradafiban plasma levels was observed at days 1, 2, and 7. CONCLUSIONS: Oral administration of Lefradafiban maintains the potent platelet GP IIb/IIIa antagonism of Fradafiban during treatment of healthy subjects for 1 week without signs of loss of the antiplatelet activity.

Clinical pharmacokinetics of meloxicam.

Meloxicam (CAS 71125-38-7, UH-AC 62 XX) is a new non-steroidal anti-inflammatory drug (NSAID) which was developed for the treatment of osteoarthritis and rheumatoid arthritis. The basic clinical pharmacokinetics of meloxicam (7.5-30 mg) have been investigated in 78 healthy male volunteers after single and multiple dosing via oral, intravenous and rectal routes. Plasma concentrations of meloxicam were determined by validated high performance liquid chromatography (HPLC) methods. The pharmaco-kinetic profile of meloxicam is characterized by almost complete absorption over a prolonged phase-avoiding high initial drug concentrations- and is bound to plasma proteins by more than 99.5%. Meloxicam is metabolized to four biologically inactive metabolites and excreted in urine and faeces with an elimination half-life (t1/2) of around 20 h. This is reflected in a total plasma clearance of 7 to 8 ml/min. Steady state is achieved within 3 to 5 days. In addition, the pharmacokinetic parameters are linear over the entire dose range, there are no changes with multiple dosing and bioequivalence was shown for a number of different formulations. The results indicate that meloxicam is suitable for once-daily administration and that a switch from one formulation to another is easily possible if necessary or convenient for the patient.

Inhibition of platelet aggregation as a surrogate marker.

Using acetylsalicylic acid-dipyridamole, a combined thromboxane receptor antagonist-thromboxane synthase inhibitor, and a fibrinogen receptor antagonist as examples, this article discusses the predictive value of several methods that may be employed in the evaluation of antiaggregatory effects and their suitability as surrogate markers for the planning of patient studies. Platelet aggregation in various ex vivo tests and the effects of drugs on these tests were investigated using platelet aggregation in platelet-rich plasma and in whole blood, and in thrombus formation on a thrombogenic surface. Drug-induced inhibition of platelet aggregation is based on the modulation of metabolic processes or interactions at the membrane-receptor level. These effects must be assessed by methods adapted specifically to each mode of action, for example, mediator synthesis inhibition (cyclooxygenase), thromboxane receptor antagonism-thromboxane synthase inhibition, or fibrinogen receptor blockade. Thus a combination of both general and specific methods adapted to the respective mode of action of the test substance can serve as surrogate markers of drug efficacy for the efficient planning of clinical trials.

Pharmacokinetics and tolerability of meloxicam after i.m. administration.

1. The pharmacokinetics and tolerability of a new nonsteroidal anti-inflammatory drug (NSAID), meloxicam, administered i.m., were investigated in two studies conducted in healthy male volunteers. Study 1 was an open, placebo-controlled design in which 32 volunteers were randomized to a single ascending i.m. dose of meloxicam (5, 10, 20, and 30 mg) or placebo. Study 2 had an open, randomized two way crossover design in which 12 volunteers received single i.m. and i.v. doses of meloxicam (15 mg). 2. Meloxicam showed an excellent tolerability in both studies. No effect was seen on serum creatinphosphokinase (CK, the isoenzyme of the skeletal muscle enzyme, CK-MM, was determined). 3. Following i.m. administration meloxicam was rapidly and completely absorbed (mean absolute bioavailability 102%). Dose-proportionality was demonstrated with respect to Cmax (maximum plasma concentration) and AUC (extrapolated area under the plasma concentration-time curve from zero time to infinity) over a range of 5-30 mg. 4. Intravenous administration of meloxicam (15 mg) resulted in higher initial plasma concentrations (C3min, i.e. concentration in plasma 3 min after start of injection = 2.99 +/- 0.75 microgram.ml-1) than after i.m. injection (Cmax: 1.62 +/- 0.20 mg ml-1). All other pharmacokinetic parameters were similar for both routes of administration (apparent elimination half-life = 15-22 h; plasma clearance = 7-9 ml min-1). 5. In conclusion, the excellent tolerability of i.m. meloxicam together with its rapid and complete absorption may provide an alternative to oral administration of this drug.

Pharmacokinetics of meloxicam in patients with end-stage renal failure on haemodialysis: a comparison with healthy volunteers.

OBJECTIVE: The pharmacokinetics of meloxicam have been studied following administration of a single 15-mg capsule to 12 patients with end-stage renal failure. Pharmacokinetic parameters were determined after haemodialysis. The pharmacokinetic profile obtained in these patients is compared to data obtained from age- and gender-matched healthy volunteers. RESULTS: Total plasma meloxicam concentrations were lower in patients with end-stage renal failure (AUC0-infinity 12.6 micrograms.h.ml-1) in comparison with healthy volunteers (AUC0-infinity 39.3 micrograms.h.ml-1). This was reflected by an increase in total clearance (+211%). However, there was an enhanced free meloxicam fraction (unbound drug) in the end-stage renal failure patients (0.9% vs. 0.3% in healthy volunteers). This was observed in association with raised free Cmax (5.0 vs. 2.6 ng/ml) but similar free AUC0-infinity (0.13 vs. 0.11 microgram.h.ml-1) in both groups. Therefore, the raised free fraction is compensated for by the increased total clearance such that no accumulation of meloxicam occurs. Meloxicam plasma concentrations were similar before and after haemodialysis. CONCLUSION: Meloxicam has displayed a pharmacokinetic profile in end-stage renal failure which is similar to that observed for other highly protein bound nonsteroidal anti-inflammatory drugs (NSAIDs). However, in view of the higher free Cmax value, and despite no evidence of accumulation, it may be prudent to treat this group of patients with a 7.5-mg dose of meloxicam. This is the lower dose normally recommended for adults. Meloxicam is not dialysable.

Interaction of meloxicam with cimetidine, Maalox, or aspirin.

Meloxicam is a new enol carboxamide nonsteroidal antiinflammatory drug (NSAID). Preclinical studies have indicated that it possesses a high antiinflammatory potency and a low ulcerogenic potency. This open, randomized, crossover study was conducted to examine the effects of aspirin, the antacid Maalox (Rhone-Poulenc Rorer, Cologne, Germany), and cimetidine on the pharmacokinetics and bioavailability of a single oral dose of meloxicam 30 mg in healthy male volunteers. Plasma concentrations of meloxicam were determined and subjected to noncompartmental pharmacokinetic analysis. Meloxicam was well tolerated, and concomitant treatment with cimetidine or Maalox had little or no effect on the plasma concentration-time curves, maximum plasma concentration (Cmax), or the area under the plasma concentration-time curve (AUC0-infinity) of meloxicam. Concurrent treatment with aspirin increased plasma concentrations of meloxicam, increasing Cmax by approximately 25% and AUC0-infinity by 10%. These differences were not considered to be clinically relevant, and no adjustments of meloxicam dose should be required with coadministration of aspirin, Maalox, or cimetidine.

The effect of meloxicam on the pharmacokinetics of beta-acetyl-digoxin.

The influence of multiple-dose administration of meloxicam on the pharmacokinetics of oral beta-acetyl-digoxin was studied in 12 healthy male volunteers in a randomized double-blind two-way crossover study. The primary endpoint, Cminss, was within the accepted range for bioequivalence, as were Cmaxss and AUCss. The 90% confidence interval and the point estimator of 98.7 for Cminss were within the equivalence range of 0.8-1.25. MRT and tmax were also unchanged, while the elimination rate constant was decreased slightly by 12%, which is of no therapeutic relevance. It is concluded that co-treatment with meloxicam has no effect on the pharmacokinetics of oral digoxin.

The effect of cholestyramine on the pharmacokinetics of meloxicam, a new non-steroidal anti-inflammatory drug (NSAID), in man.

The influence of multiple oral doses of cholestyramine on the single dose pharmacokinetics of meloxicam has been studied in 12 healthy male volunteers. Each subject received on two occasions a single IV injection of meloxicam 30 mg. The cholestyramine group received the material suspended in water 3 times a day. Compared to controls, cholestyramine accelerated the elimination of meloxicam. The mean terminal phase elimination half-life was reduced from 19.5 h to 12.7 h due to an increase in clearance of the drug (0.426 vs 0.636 l.h-1). Also, as a consequence of increased clearance in the presence of cholestyramine, the mean residence time of the drug in the body was significantly decreased (39%) P < 0.01. However, the volume of distribution for meloxicam was largely unaffected by cholestyramine which suggests that meloxicam undergoes gut recirculation. These changes are of the same magnitude as those previously reported for the structurally related piroxicam and are much smaller than those observed for tenoxicam.

A pharmacodynamic and pharmacokinetic comparison of pindolol 20 mg retard and a conventional tablet.

In 10 healthy volunteers the time course of cardiac beta-adrenoceptor blocking activity, plasma levels and cumulative urinary excretion of pindolol were compared during a 4-day course of pindolol 5 mg (Visken) t. d. s., and one tablet of pindolol 20 mg retard (Visken retard) once a day. After oral administration of the 20 mg retard tablet, plasma concentrations of pindolol higher than half the maximum value (1/2 Cp (tmax)) were maintained about 2.5 times as long as after administration of the conventional 5 mg tablet. This is evidence for an important and marked retardation of drug release. During treatment with pindolol 20 mg retard once daily, cardiac beta-adrenoceptor blockade, measured by the reduction in exercise-induced tachycardia and in the exercise-induced rise in systolic blood pressure, at almost all times throughout the 24 h period was at least as great as during treatment with pindolol 5 mg t. d. s. This suggests that patients successfully treated with pindolol 5 mg t. d. s. can be maintained with the same beta-adrenoceptor blockade by a single tablet of pindolol 20 mg retard once daily.