Cirrhosis does not affect the pharmacokinetics and pharmacodynamics of clopidogrel.

Clopidogrel, a new platelet ADP receptor antagonist used for the prevention of vascular ischemic events, is converted to an active metabolite via the cytochrome P450 system. Patients with cirrhosis may not metabolize drugs normally and may, in addition, have a number of defects in the coagulation system. To assess the effect of cirrhosis on the pharmacokinetics and pharmacodynamics of clopidogrel, the authors performed an open-label, parallel-group study of 12 patients with Child-Pugh Class A or B cirrhosis and 12 matched controls. All 24 subjects received clopidogrel 75 mg PO QD for 10 days. Pharmacokinetics of clopidogrel and the major metabolite SR 26334 were analyzed on Days 1 and 10; pharmacodynamics were assessed by the inhibition of ADP-induced platelet aggregation and by bleeding time prolongation factor. Pharmacokinetic analysis of clopidogrel was limited due to low plasma concentrations arising from rapid hydrolysis to SR 26334. The Cmax at SS for clopidogrel was higher in cirrhotics than in normals. However, exposures to the metabolite SR 26334, as measured by AUC(tau), were comparable. At Day 10, there was not a statistically significant difference in mean inhibition of platelet aggregation (49.2% +/- 38.6% in cirrhotics vs. 66.7% +/- 7.5% in normals) or in bleeding time prolongation factor (1.64 +/- 0.49 in cirrhotics vs. 1.54 +/- 0.87 in normals) between groups. No significant adverse events, including bleeding events, were reported. In conclusion, there were no significant differences in the pharmacokinetics and pharmacodynamics of clopidogrel in this group of subjects with cirrhosis and matched normals. Therefore, no dosage adjustment of clopidogrel is required in patients with Child-Pugh Class A or B cirrhosis.

Pharmacokinetics of clopidogrel.

Clopidogrel is extensively metabolized, as evidenced by the absence of detectable amounts of unchanged clopidogrel in plasma samples in most clinical trials. The major circulating compound is the inactive carboxylic acid derivative SR26334, and information on the absorption and elimination of clopidogrel after oral administration is derived from the pharmacokinetics of this metabolite. Single-dose pharmacokinetics of SR26334 were investigated in a randomized, dose-proportionality study comparing single 50, 75, 100, and 150 mg oral doses of clopidogrel administered to 12 subjects. Multiple-dose pharmacokinetics of SR26334 were primarily derived from a study carried out in 18 subjects treated with clopidogrel 75 mg once daily for 14 days. Further data on multiple-dose pharmacokinetics were provided by the results of a long-term study carried out in a group of 35 subjects who received clopidogrel 75 mg once daily for 12 weeks. All subjects were healthy male volunteers and, in all cases, clopidogrel was taken in the morning after an overnight fast. The mean Cmax values (+/-SD) for SR26334 following single doses of 50, 75, 100, and 150 mg were 1.6+/-0.30 mg/L, 2.9+/-0.68 mg/L, 3.1+/-0.94 mg/L, and 4.9+/-1.22 mg/L, respectively. The ANOVA performed on dose-normalized Cmax showed no statistically significant dose effect, demonstrating a dose-proportional increase of Cmax in this range of clopidogrel doses. The urinary excretion of SR26334 was low-2.2 to 2.4% of the dose administered-and Cl(r-2-24) remained virtually constant at all four doses. Median T(max)(0.8-1.0 hour) and mean plasma t1/2 (7.2-7.6 hours) values were not significantly different between doses. Following repeated dosing with clopidogrel 75 mg, mean (+/-SD) C(trough) values (values before dosing) for SR26334 at steady state ranged from 0.8+/-0.04 mg/L to 0.11+/-0.07 mg/L. These values are similar to those observed during the 12-week administration of clopidogrel indicating that steady-state values are reproducible and that the esterasic biotransformation of clopidogrel into its carboxylic acid metabolite remains constant over a number of months of treatment.

Pharmacokinetic profile of 14C-labeled clopidogrel.

In order to obtain a global assessment of circulating clopidogrel-related products and of the excretion of the drug, the pharmacokinetic behavior and the excretion balance of 14C radioactivity following the administration of a single dose of 75 mg of 14C-labeled clopidogrel were compared in 6 clopidogrel-free healthy male subjects (Period I) and after 7 days of once daily therapy with the unlabeled drug in these subjects (at steady state) (Period II). The two study periods were separated by a 4-week washout period. For each administration of 14C-clopidogrel, blood samples were collected before and at regular intervals over 28 days after administration of the radiolabeled drug. Expired air samples were collected before and over 24 hours after the administrations of 14C-clopidogrel. All urine voided and all stools were collected before and for up to 120 hours after the administration of 14C-clopidogrel, in consecutive periods of 12 to 24 hours. The mean radiocarbon plasma concentration profiles after administration of 14C-clopidogrel given as a single dose (Period I) and during steady state (Period II) were superimposable. There were no statistically significant differences between the two treatments for any parameters. A Cmax of 3.9 mg-Eqv/L was reached after a median time of 1 hour (Tmax). The plasma elimination half-life, t1/2, ranged from 336 hours to 672 hours in Period I and from 275 to 433 hours in Period II. The radiocarbon excretion over 10 to 12 hours post-dose (time to last measurable radioactivity) in expired air represented 0.31 to 0.35% of the administered dose. Mean cumulative urinary excretion over 120 hours represented 41% of the dose after a single-dose administration and 46 % after administration at steady state. The cumulative fecal recovery over 120 hours ranged from 35 to 57% of the dose in Period I and from 39 to 59% of the dose in Period II. Mean total excretion of radioactivity was 92% of the dose during Period I and 93% during Period II. These data indicate that, following multiple-dose administration of clopidogrel, the biodisposition of the drug remains unaltered compared to a single dose.

Clopidogrel and drug metabolism: absence of effect on hepatic enzymes in healthy volunteers.

The influence of clopidogrel 75 mg, given once daily for 10 days on hepatic P-450 mixed function oxidases, was examined by assessing its effect on the disposition of antipyrine, on urinary 6-betahydroxycortisol (6beta-OHC) and on the plasma activity of gamma-glutamyl transpeptidase. This double-blind, randomized, placebo-controlled study was conducted in two parallel groups of 10 healthy young volunteers. Subjects were required to fast for 12 hours before and for 4 hours after dosing. Antipyrine 10 mg/kg was administered in the morning, two days before treatment (day -2) and 24 hours after the last dose of clopidogrel or placebo. Plasma levels of antipyrine, and urinary excretion of antipyrine, 3-hydroxymethyl-antipyrine and nor-antipyrine were measured over 36 hours post-drug for pharmacokinetic determinations. Bleeding time and platelet aggregation induced by 5 microM of ADP were measured before treatment (baseline) and at regular intervals after dosing during treatment. Clopidogrel treatment had a marked effect on platelet aggregation and bleeding time. No significant change in the disposition of antipyrine was observed after the ingestion of clopidogrel over 10 days: mean AUC ratio (+/-SEM) for plasma antipyrine was 1.021+/-0.023 for the clopidogrel group versus 1.001+/-0.019 for the placebo group; mean day 10/day -2 t 1/2 ratios were 1.019+/-0.018 and 1.027+/-0.023, respectively. Urinary excretions of antipyrine and metabolites were unchanged by clopidogrel compared to placebo. The changes in plasma cortisol concentrations, 6beta-OHC excretion and serum gamma-glutamyl transpeptidase activities observed at the end of treatment were fully comparable between the two treatment groups. Thus, the different tests showed no evidence of hepatic enzyme induction by clopidogrel in a pharmacologically effective dose regimen.

Clopidogrel antiplatelet activity is independent of age and presence of atherosclerosis.

The pharmacodynamic and pharmacokinetic effects of clopidogrel 75 mg taken once daily in the morning before breakfast for 10 days were compared among three groups: 12 healthy young subjects, 10 healthy elderly subjects (>65 years) and 10 otherwise healthy elderly subjects with atherosclerosis, manifested by intermittent claudication. Platelet aggregation induced by 5 microM of ADP was measured in plasma samples taken at screening, 2 hours after dosing on day 1 to day 9; 2, 5, and 24 hours after dosing on day 10; and on alternate days until day 24. The inhibition of platelet aggregation was expressed as the percent reduction in maximum platelet aggregation with respect to baseline. The bleeding time was measured at screening, 5 hours after dosing on day 10, and on day 18. Plasma concentrations of SR26334, the main circulating metabolite of clopidogrel, were determined before dosing on day 1 to day 10 and at regular intervals over 72 hours after dosing on day 10. Inhibition of platelet aggregation appeared 2 hours after the first dose, became significant after the second dose, and progressed to a steady-state value of 55 to 57% by day 7 in the three groups, with no statistically significant difference between groups. A moderate, statistically significant prolongation of bleeding time of similar extent (prolongation factor of 1.5 to 1.6) was found on day 10 in the three groups. The pharmacodynamic parameters generally returned to baseline within 8 days after treatment. Based on AUC(0-24th) values, drug exposures were very similar for the two groups of elderly subjects but approximately twice that for the young group. The pharmacodynamic effects of clopidogrel were comparable in all three groups.

Clopidogrel bioavailability: absence of influence of food or antacids.

Two open, randomized, crossover bioavailability studies were carried out to assess the influence of concurrent antacid medication and food on the bioavailability of clopidogrel. A fed/fasting study was conducted in 12 elderly male subjects. Each subject took a single 75 mg dose of clopidogrel on two occasions-in the morning after an overnight fast, either during a standardized breakfast, or with breakfast delayed by 4 hours after dosing. A washout period of 7 days was observed between the two dosings. Twelve healthy male subjects participated in the antacid study. They fasted overnight and for 4 hours after dosing and took a single 75 mg dose of clopidogrel at 8:00 a.m. on two occasions separated by a washout period of 14 days. For one dose, Maalox 2 x 400 mg tablets were taken 1 hour before the clopidogrel dose. Pharmacokinetic parameters of SR26334, the main circulating metabolite of clopidogrel, were derived from plasma concentrations of the latter compound determined before and at regular intervals over 36 hours after dosing. For the fed/fasting study, mean Cmax values (+/-SD) were 2.7+/-0.62 mg/L and 2.1+/-0.96 mg/L for the fasting state and the fed state, respectively and the 90% CI of Cmax ratio was [0.57 - 0.97]. Mean AUC(0-obs) values (AUC to the last observed value) were 7.1+/-1.6 mg.h/L and 7.4+/-1.64 mg.h/L, respectively, and the 90% Cl of AUC ratios were [0.90 - 1.02] and [0.89 - 0.97], respectively. For the antacid study, mean Cmax values were 2.6+/-0.84 mg/L and 2.5+/-0.87 mg/L for the no-antacid regimen and the antacid regimen, respectively, and the 90% CI of Cmax ratio was [0.74 - 1.16]. Mean AUC(0-obs) values were 6.3+/-1.34 mg.h/L and 5.8+/-1.33 mg.h/L, respectively, and the 90% CI of AUC ratios was [0.89+/-0.97]. Thus, exposure to SR26334, and therefore net absorption of clopidogrel, was not significantly modified by food or by prior antacid ingestion.

Clopidogrel, a novel antiplatelet agent, and digoxin: absence of pharmacodynamic and pharmacokinetic interaction.

The safety, and the pharmacodynamic and pharmacokinetic compatibility of clopidogrel, 75 mg daily, with the cardiac glycoside digoxin, were assessed in 12 healthy male subjects who took digoxin 0.25 mg once daily for 20 days and, in addition, clopidogrel 75 mg once daily from day 11 to day 20, so as to achieve steady-state conditions with both drugs. The drugs were taken after an overnight fast, and a standardized breakfast was served 30 minutes later. Blood samples for digoxin determination were drawn pre-dose on days 1, 8, 9, 10, 18, 19, and 20 of the schedule, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post-dose on days 10 and 20. Urine samples were collected pre-dose and from 0-4, 4-8, 8-12, and 12-24 hours post-dose on days 10 and 20. Platelet aggregation studies were carried out using ADP at 5 micromol/L final concentration as an agonist. Establishment of steady-state plasma concentrations of digoxin on days 8-11 and 18-21 was confirmed by application of Dunnett's test on the trough plasma concentrations. The plasma pharmacokinetics and urinary excretions of digoxin for day 10 and day 20 were very similar: the day 20/day 10 ratios (90% Cl) were 1.1 (0.99; 1.24) for Cmax, 1.0 (0.92; 1.08) for Cmin, 1.02 (0.96; 1.07) for AUC(0-24), and 0.99 (0.94; 104) for urinary excretion. Mean inhibition of ADP-induced platelet aggregation at the end of the clopidogrel treatment period was 34%. The clinical, cardiac, and biological evidence from the study indicated that clopidogrel administration does not enhance digoxin's cardiac effects. Overall, the data indicated that there is no reason to anticipate an interaction when clopidogrel is added to digoxin for long-term management of patients with cardiac disease.

Clopidogrel does not affect the pharmacokinetics of theophylline.

The potential influence of clopidogrel on the pharmacokinetics of theophylline was evaluated in 15 healthy male subjects during the pharmacokinetic steady state of theophylline, after single and multiple doses. Theophylline was administered orally as one 300-mg capsule in the morning before breakfast and one in the evening before dinner for 13 days (day 1 through day 13), and one capsule on the morning of day 14. Clopidogrel was administered orally as one 75-mg tablet in the morning before breakfast from day 5 through day 14. Plasma concentration of theophylline was determined at the following times: before the morning dose on days, 1, 6-9, and 12; before administration, then at 0.5, 1,2, 3, 4, 5, 6, 7, 8, 10, and 12 hours after administration on days 4, 5, and 14. Tests of hemostasis (ADP-induced platelet aggregation and bleeding time) were carried out 2 hours after clopidogrel dosing on days 5, 7, 9, 11, and 14. The curves of the mean plasma concentration of theophylline over 12 hours post-morning dose on day 4 (drug alone), day 5 (after a single dose of clopidogrel), and day 14 (after 10 days of clopidogrel coadministration) were superimposable, indicating the absence of an effect of clopidogrel on the steady-state pharmacokinetics of theophylline. There were no statistically significant differences between the days of administration for the log-transformed values of theophylline C(bt) (concentration before treatment) Cmax, AUC(0-12h), and Cmin; and the 90% confidence intervals of the day 5/day 4, day 14/day 4, and day 14/day 5 ratios of the geometric means of C(bt) all fell within the (0.80; 1.25) interval. These results show that the administration of clopidogrel during steady state theophylline administration had no effect on the plasma concentration of the latter drug. The average steady-state (days 11-14) percentage of inhibition of ADP-induced platelet aggregation by clopidogrel with respect to day 1 was 46%. The geometric mean of the bleeding time prolongation factor was about 2 at steady state. The latter results indicate that the pharmacodynamics of clopidogrel were not affected by concomitant theophylline.

Aging and venous thromboembolism influence the pharmacodynamics of the anti-factor Xa and anti-thrombin activities of a low molecular weight heparin (nadroparin).

Venous thromboembolism may be efficiently treated by one single daily administration of a high dose of low molecular weight heparin (LMWH). The present study investigates if the physiological deterioration of renal function associated with normal aging or the presence of an acute venous thromboembolism influences the pharmacodynamic pattern of the anti-factor Xa and anti-thrombin activities. Three groups of 12 subjects were investigated. The first 2 groups were composed of healthy volunteers differing by age (25 +/- 4 and 65 +/- 3 yrs) and creatinine clearance (114 +/- 15 and 62 +/- 6 ml x min(-1)). The third group was composed of patients hospitalized for deep vein thrombosis, having a mean age of 65 +/- 11 yrs and creatinine clearance of 76 +/- 8 ml x min(-1). Nadroparin was administered subcutaneously once daily at the dose of 180 anti-factor Xa IU.kg(-1) for 6 to 10 days. Serial sampling on day 1 and on the last day of administration (day n) allowed the pharmacodynamic parameters of the anti-factor Xa and anti-thrombin activities to be compared at the beginning and at the end of the treatment. The main findings were the following: (1) After repeated administration, a significant accumulation of the anti-factor Xa activity was observed in the healthy elderly and in the patients but not in the healthy young subjects (accumulation factor: 1.3). There was no evidence of accumulation of anti-thrombin activity; (2) There were significant correlations between the clearance of creatinine and the clearance of the anti-factor Xa activity but not with that of the anti-thrombin activity; (3) In the patients, the clearance of the anti-factor Xa and of the anti-thrombin activities were 1.4 and 2 times higher respectively than those calculated in the healthy elderly; (4) The mean ratio of the of anti-factor Xa and anti-thrombin clearances was close to 2 in the healthy subjects but equal to 5.4 in the patients. These results suggest that the mechanisms involved in the clearance of polysaccharide chains which support the anti-thrombin activity are different from those of the anti-factor Xa activity and that the enhanced binding properties of plasma proteins to unfractionated heparin reported in patients presenting an acute venous thromboembolism also exists for LMWH, predominantly for the anti-thrombin activity.

Pharmacodynamics and tolerance of two nadroparin formulations (10,250 and 20,500 anti Xa IU x ml(-1)) delivered for 10 days at therapeutic dose.

Venous thromboembolism may be efficiently treated by once-a-day (o.d.) administration of a high dose of low molecular weight heparin (LMWH) instead of administration of the same total dose in two injections a day (b.i.d.). To reduce the volume of the subcutaneous (s.c.) injection, a more concentrated form of the drug is advisable. This study was designed to compare the bioavailability of 2 formulations of nadroparin containing 10,250 and 20,500 anti-Xa IU x ml(-1) respectively. This was an open, randomized, cross-over study where 12 healthy volunteers (age 18-35) were enrolled. They received either 90 anti-Xa IU x kg(-1) b.i.d. of the 10,250 IU preparation (treatment A), or 180 anti-Xa IU x kg(-1) o.d. of the 20,500 IU preparation (treatment B) for 10 days. On day 1, the subjects were sampled between 0 and 12 h (treatment A) or between 0 and 24 h (treatment B). On day 10, they were sampled between 0 and 12 h and between 12 and 24 h (treatment A) or between 0 and 24 h (treatment B). Anti-Xa and anti-IIa activities were determined by specific chromogenic assays. The main result of the study was that the bioavailability of the anti-Xa activity of the 2 nadroparin formulations was equivalent, as shown by the comparison of the AUC(0-12 h) plus AUC(12-24 h) (treatment A) and the AUC(0-24 h) (treatment B), calculated on day 10. This study also allowed a number of interesting observations to be made. 1) Between day 1 and day 10, there was an accumulation of the anti-Xa activity for treatment A but not for treatment B (accumulation factors: 1.6 and 1.1 respectively); 2) On day 10, the AUC(0-12 h) were slightly but significantly lower than the AUC(12-24 h) suggesting a circadian effect for anti-Xa and anti-IIa activities; 3) the clearance of the anti-Xa activity was comparable at the 2-dose regimens, while that of the anti-IIa activity was lower in treatment B than in treatment A, indicating a significant dose effect for the pharmacodynamics of the longer heparin chains; 4) On average, the clearance of the anti-IIa activity was twice as high as that of the anti-Xa activity; 5) For treatment B, significant APTT prolongations were noticed at Tmax (prolongation factor: 1.7 +/- 0.25), in relation with the anti-IIa activity (0.3 +/- 0.1 IU x ml(-1)).

Assay method for the carboxylic acid metabolite of clopidogrel in human plasma by gas chromatography-mass spectrometry.

This paper describes a GC-MS method for the analysis of the carboxylic acid metabolite (SR26334, II) of methyl (+)-(S)-alpha-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5( 4H)-acetate hydrogensulfate (clopidogrel, SR 25990, I) in plasma and serum. The analytical procedure involves a robotic liquid-liquid extraction with diethyl ether followed by a solid-liquid extraction on C18 cartridges. The derivatization process was performed using n-ethyl diisopropylethylamine and alpha-bromo-2,3,4,5,6-pentafluoro toluene. A structural analogue (III) of II, was used as internal standard. The 1/X2; weighted calibration curve obtained in the range 5-250 ng/ml was well described by a quadratic equation. The extraction efficiency was better than 48% over the range studied; for the internal standard it averaged 51% at 50 ng/ml. Precision ranged from 3.6 to 15.8%, and accuracy was between 92 and 114%. Dilution has no influence on the performance of the method which could then be used to quantitate plasma samples containing up to 25000 ng/ml. The limit of quantification was 5 ng/ml. The method validation results indicate that the performance characteristics of the method fulfilled the requirements for assay methods for use in pharmacokinetic studies.

Clopidogrel activities in patients with renal function impairment.

OBJECTIVES: To assess the tolerability, pharmacodynamic effects and pharmacokinetic parameters after repeated doses of clopidogrel (Plavix((R))) in patients with moderate or severe renal failure. PATIENTS: Eight patients with severe renal failure (endogenous creatinine clearance 5 to 15 ml/min) and eight patients with moderate renal impairment (endogenous creatinine clearance 30 to 60 ml/min) were included. STUDY DESIGN: An open, uncontrolled, parallel-group study over 8 days' administration of 75mg once-daily clopidogrel. METHODS: Measurement of changes in ADP-induced platelet aggregation and skin bleeding time and of plasma concentrations and urinary excretion of clopidogrel and its main metabolite, SR 26334. Assessment of clinical tolerance and serial haematological and biochemical investigations. RESULTS: At the end of the dosage period, platelet aggregation was equally inhibited, by about 25%, and bleeding time equally extended, by a factor of about 2, in the two groups. There were no tolerability concerns. Maximum plasma concentration (C(max)) and time to reach C(max ) (t(max)) for clopidogrel were not significantly different between the two groups. SR 26334 excreted into the urine and renal clearance rate were significantly lower in the severely impaired group, while plasma elimination half-lives were not significantly different. C(max) and t(max) did not differ significantly between the two groups, but trough levels and area under the plasma concentration-time curve from zero to 24 hours (AUC(0-24h)) after the last dose were significantly higher in the moderately impaired group. CONCLUSIONS: Clopidogrel 75mg once daily was well tolerated in patients with either moderate or severe renal failure, and provided good inhibition of ADP-induced platelet aggregation without excessive extension of bleeding time. Dose adjustment in such patients does not appear to be required.

Multiple dose pharmacokinetics of tiludronate in healthy volunteers.

OBJECTIVES: A double-blind, placebo-controlled study was conducted to assess the pharmacokinetics and pharmacodynamics of the bisphosphonate tiludronic acid, administered once daily as sodium tiludronate 200, 400, 600 and 800 mg for 12 days. Four groups of ten subjects participated in the study, with a drug to placebo ratio of 4:1. METHODS: Pre-dose blood samples were taken on alternate days, starting on Day 1 and additional samples were collected over 144 h following the final dose on Day 12. Urine was collected over 24 h after the final dose. Indices of calcium homeostasis and biochemical markers of bone turnover were assessed during the study as pharmacodynamic parameters. Tolerability was evaluated with special emphasis on renal function and gastrointestinal irritation. Adverse experiences were assessed at regular time intervals. RESULTS AND CONCLUSIONS: Steady state was attained from Day 4 (200 mg) or from Day 6 (400, 600 and 800 mg). Following the final dose on Day 12, minimal plasma concentrations (Cmin) ranged between 0.19 and 1.5 mg.1(-1), and maximal plasma concentrations (Cmax) between 1.1 and 7.8 mg.1(-1) for the lowest and highest doses, respectively. A supra-proportional increase in Cmax, AUC24 and Ae24 with dose was observed. There was a linear relationship between the plasma tiludronic acid and its urinary excretion rate, so, the disproportional rise in Cmax and AUC24 with increasing dose could not be attributed to saturation of renal excretion. Certain indices of calcium homeostasis changed significantly during the study, but generally, became only prominent at the highest dose level of 800 mg. Total serum calcium and the urinary calcium/creatinine clearance ratio fell, indicating depression of osteoclastic bone resorption, which was not revealed by serum osteocalcin levels probably because of the brevity of the treatment (12 days). In response to the decline in serum calcium, serum 1,25-dihydroxyvitamin D3 and intact PTH (1-84) levels increased. None of the safety parameters raised any concerns about the safety of sodium tiludronate administered in this way.

Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/Org31540) with high affinity to antithrombin III in man.

This paper reports the results of the first administration of the synthetic natural pentasaccharide with high affinity to antithrombin III (NP) in man. This study was mainly focused upon the pharmacokinetic properties and general tolerance of the compound. Subcutaneous injections of doses < 1.43 mg (1000 anti Xa IU) did not generate measurable anti-Xa activities. After subcutaneous injection of increasing doses from 1.43 to 22.9 mg (1000 to 16,000 anti-Xa IU) to young healthy volunteers, it was found that the maximal concentration (Cmax) and the area under curve (AUC) were linearly correlated to the dose, that the total plasma clearances (CI) were constant and almost 3 times lower than those of the current low molecular weight heparins. Cmax were reached between 1 h and 3 h after the injection and the half-lives (t 1/2) were remarkably constant (13.1 h to 13.9 h). During the first 24 h following the injection, around 50% of the total administered dose was recovered in the urine in an active form, indicating that kidney plays a major roles in the elimination of NP. Consistent with these results, when NP was administered to healthy elderly volunteers having a lower creatinine clearance, the half-life of the compound was longer and the clearance lower. At doses exceeding 22.9, Cmax, and AUC were slightly lower than expected, the percentage of the dose recovered in the urine and the total apparent plasma clearance increased, suggesting that the excess of NP unbound to antithrombin III was excreted faster. NP was also administered at various dosages once or twice a day for 7 days to 20 elderly volunteers. Due to the long half-life of the compound the "steady state" was obtained 2 to 3 days after the first injection at which the mean Cmax was increased 1.5 to 2 times. The general tolerance of the compound was excellent. No relevant prolongations of the prothrombin time, of the activated partial thromboplastin time or of the bleeding time were observed. A re-bleeding phenomenon of the bleeding time incision, probably related to friability of the haemostatic plug, occurred in 3 subjects treated with the highest dose regimens: single injection of 26.6 mg (20,000 anti-Xa IU) (young volunteers) and repeated injections of 11.4 mg (8,000 anti-Xa IU) once a day for 7 days (elderly volunteers). At these times, plasma NP concentrations were between 2.9 and 3.6 micrograms.ml-1 (2 and 2.5 anti-Xa IU.ml-1).

Human pharmacokinetics of tiludronate.

Tiludronate is a bisphosphonate evaluated extensively as an osteoregulator in the treatment of metabolic bone disorders. It is highly polar and has a low and variable oral absorption similar to its related compounds. An absolute bioavailability of approximately 6% has been reported with large inter- and intra-subject variability. The extent of absorption is increased at doses above 400 mg and may be reduced by a factor of 5 when tiludronate is administered with, or within 2 h after, food or dairy products. Approximately 90% of tiludronate is bound to serum albumin, and the binding is linear in the concentration range 1-10 mg/L. Preliminary in vitro studies using human hepatocytes failed to show any evidence of biotransformation of tiludronate. The elimination half-life in patients with normal renal function is approximately 40-60 h, but is significantly increased in subjects with severe renal impairment. The renal clearance (0.7 L/h) is independent of dose and suggests that glomerular filtration is the mechanism responsible for elimination. Approximately 50% of the absorbed dose is bound to bone and the rate of release of the drug from this site is limited by bone turnover. In vitro experiments indicate that tiludronate is not an enzyme inducer or inhibitor. Drug interaction studies with the nonsteroidal agents acetylsalicylic acid, indomethacin, and diclofenac indicate that only with indomethacin was there any change in the pharmacokinetic parameters, and that these changes were minimal and unlikely to be of clinical significance. Tiludronate does not influence the pharmacokinetics of digoxin at steady state. Tiludronate appears to exhibit similar pharmacokinetic behavior to other bisphosphonates with the exception that its absolute bioavailability is significantly higher than that previously reported for clodronate and pamidronate. The impact of its pharmacokinetic properties on clinical outcome has yet to be determined.

A double Weibull input function describes the complex absorption of sustained-release oral sodium valproate.

The pharmacokinetics of valproic acid after oral administration of sustained-release formulations were studied in 12 healthy volunteers. The objective of the present study was to find an appropriate mathematical model to describe the complex drug intake process. The concentration of valproic acid in plasma was measured by HPLC. For each subject, during the input process a double peak phenomenon was observed, the plasma concentrations were fitted according to a single or a double Weibull input function, and then a first-order elimination rate was used to describe the observed data. The Weibull model was considered as an approximation of the overall process. The mean peak plasma concentration, 34.6 +/- 8.9 mg/L, was reached after 8.6 +/- 2.7 h. A single Weibull function adequately described the observed data for three subjects; the mean Weibull parameters were td (the time necessary to transfer 63% of the administered drug into the systemic circulation) of 7.87 +/- 3.53 h and gamma (shape) of 1.16 +/- 0.66. A double Weibull input function was used for nine subjects; the mean Weibull parameters were td1 = 2.35 +/- 1.18 h and td2 = 9.36 +/- 4.47 h and gamma 1 = 1.77 +/- 2.27 and gamma 2 = 3.68 +/- 3.26. The mean half-life value of the elimination phase was 14.4 +/- 4.6 h.

Cefpiramide kinetics and plasma protein binding in cholestasis.

Cefpiramide is a new parenteral cephalosporin mainly excreted in the bile. Eight patients with cholestasis and 11 healthy subjects received a single 1 g i.v. dose. Cefpiramide concentrations in plasma and urine were measured by h.p.l.c. and plasma binding was determined by ultrafiltration. Total clearance of cefpiramide (mean +/- s.d.) was 15.5 +/- 7.1 ml min-1 in patients and 25.6 +/- 4.6 ml min-1 in healthy subjects. As a result, the terminal elimination half-life was longer in patients (12.0 +/- 2.9 h vs 5.3 +/- 0.9 h). Owing to impaired biliary elimination of cefpiramide in cholestasis, the urinary recovery of unchanged drug in patients was about five times greater than in healthy subjects (85.1 +/- 10.3% vs 16.2 +/- 3.9%). Plasma binding was significantly lower in cholestasis (fu = 0.23 +/- 0.13 vs 0.02 +/- 0.004 in healthy subjects). Accordingly, the dosage regimen of cefpiramide should be modified in patients with cholestasis.

Influence of food and body weight on the pharmacokinetics of penticainide.

The pharmacokinetics of penticainide, a class Ic antiarrhythmic drug, was studied in 16 healthy adults (eight males and eight females) after a single 300-mg oral dose in fasting conditions and with a standard meal. Penticainide concentrations in plasma and urine were measured by hplc. The pharmacokinetic parameters of penticainide including Cmax, tmax, AUC and t1/2 were not significantly altered in the presence of food. AUC values (mean +/- sd) were 50.68 +/- 10.8 mg.h.l-1 and 49.52 +/- 9.87 mg.h.l-1 in the absence and presence of food, respectively. However, a significant difference was observed between males and females in both fasting and fed conditions with a higher value of the apparent oral clearance in the second group. The values of apparent oral clearance, expressed in weight-normalized units were 1.33 +/- 0.35 ml.mn-1.kg-1 (male) and 1.93 +/- 0.34 ml.mn-1.kg-1 (female) in fast conditions (P < 0.01) and 1.38 +/- 0.28 ml.mn-1.kg-1 (male) and 1.93 +/- 0.49 ml.mn-1.kg-1 (female) in fed conditions (P < 0.02), respectively. The pharmacokinetics of penticainide is not modified by the presence of food, but an influence of body weight may be considered.

Influence of food intake on the pharmacokinetics of a sustained release formulation of sodium valproate.

The effect of food intake on the pharmacokinetics of DEPAKINE CHRONO 500 mg (Sanofi, France), a sustained release formulation containing 333 mg sodium valproate and 145 mg valproic acid, was studied in 12 young healthy female volunteers. Relative to fasting conditions (F), when the tablet was given at the midpoint of the breakfast (NF), the maximum concentration (F: 34.6 +/- 8.9 micrograms ml-1 and NF: 40.9 +/- 7.3 micrograms ml-1; p = 0.014) and the mean cumulative amount absorbed up to time 6 h (F: 76.3 +/- 11.8% and NF: 90 +/- 10.4%; p = 0.0099) were significantly increased. Nevertheless, the extent of absorption (F: 46.7 +/- 9.9 mg l-1; NF: 48.7 +/- 7 mg l-1) was not significantly affected. There was no change in the area under the curve (1129 micrograms.h ml-1), in the mean residence time (28 h), or in the elimination half-life (16 h). On the basis of this study, the question as to whether DEPAKINE CHRONO should be administered to subjects in the fasting or non-fasting state would not appear to be a major consideration when deciding on the regimen.

Pharmacokinetics and protein binding of cefpiramide in patients with alcoholic cirrhosis.

The pharmacokinetics of cefpiramide, a new cephalosporin, were investigated after a single 1 gm intravenous injection in 11 patients with alcoholic cirrhosis and compared with those of 11 healthy subjects. In patients with cirrhosis the plasma elimination half-life was three times longer than that in normal subjects. The total plasma clearance was decreased significantly (p less than 0.001): 12.3 +/- 6.5 ml/min in patients and 25.6 +/- 4.6 ml/min in healthy volunteers, respectively. The urinary excretion of unchanged drug (percent of intravenous dose) for patients (69.8% +/- 29.9%) was statistically higher (p less than 0.01) than that for subjects (16.2% +/- 3.9%). The renal elimination became increasingly important with hepatic impairment. Protein binding of cefpiramide was reduced significantly in the group with cirrhosis. The average unbound fraction was 10.4% +/- 9.5% in patients with cirrhosis and 1.9% +/- 0.3% in normal subjects (p less than 0.01). Because the rate of elimination from plasma in patients is slower, the dosage regimen of cefpiramide would probably be modified in cirrhosis.