DRUG DISPOSITION
Clin. Phannacokinet. 26 (5): 347-355, 1994 0312-5963/94/0005-0347/$04.50/0 © Adis International Limited. All rights reserved.
Clinical Pharmacokinetics of Ticlopidine lean-Pierre Desager Laboratoire de Pharmacotherapie, Universite Catholique de Louvain, Brussels, Belgium
Contents 347 348 349 349 350 350 35/ 352 353 353 354 354
Summary
Summary 1. Mechanism of Action and Therapeutic Use 2. Assay Methodology 3. Pharmacokinetic Profile of Radiolabelled Ticlopidine 4. Pharmacokinetic Profile in Healthy Volunteers 4.1 Single-Dose Studies 4.2 Multiple-Dose Studies 5. Pharmacokinetics in Special Populations 6. Drug Concentration Monitoring 7. Pharmacokinetic-Pharmacodynarnic Relationship 8. Drug Interactions 9. Conclusions
Platelets contribute significantly to arterial-occlusive thrombosis, one of the major causes of death and disease throughout the world. Consequently, inhibiting platelet function is a potentially important therapeutic goal. Among agents that inhibit platelet function, ticlopidine shows a wide spectrum of antiplatelet activity. There have been a limited number of studies investigating the pharmacokinetic profile of the drug. However, it has been demonstrated that absorption of ticlopidine after oral administration is rapid, is improved when the drug is administered with food, but reduced by the coadministration of antacid. Ticlopidine is extensively metabolised, with little unchanged drug present in the plasma. After administration of a single dose, unchanged ticlopidine can be detected for up to 96 hours postdose. Repeated administration of ticlopidine 250mg twice daily results in 3- to 4-fold accumulation of the drug after 2 weeks. The terminal elimination half-life is between 20 and 50 hours . Dosage selection is not determined by the pharmacokinetic profile of the drug, but rather by determination of the effect of the drug on bleeding time. The clearance of theophylline and phenazone (antipyrine) are reduced by ticlopidine, resulting in increased plasma drug concentrations. In contrast, the plasma concentration of cyclosporin is reduced. Aspirin (acetylsalicylic acid) increases the bleeding time in patients receiving ticlopidine concurrently, while corticosteroids reduce bleeding time. Ticlopidine use is discouraged in patients with severe organ failure. Furthermore, ticlopidine should be discontinued 2 weeks before surgery and dental intervention. Most importantly, the blood cell count should be monitored regularly during the 3 first months of treatment with ticlopidine because I % of patients receiving ticlopidine may experience agranulocytosis.
Clin. Pharmacokinet. 26 (5) 1994
348
1. Mechanism of Action and Therapeutic Use While investigating the possibility that thienopyridines may have anti-inflammatory activity Maffrand and Eloy (1974) prepared ticlopidine. Ticlopidine (fig. 1) is an antiplatelet agent that is structurally different from the other compounds in this therapeutic class (McTavish et al. 1990). Furthermore, its mechanism of action is unique. The broad spectrum of antiaggregating activity of ticlopidine has been investigated extensively because platelet aggregation is established as an important factor in the aetiology of thrombosis. In the early development of the drug it was found that ticlopidine was not active per se, but is a prodrug metabolised in the liver to the active antiaggregating drug. Therefore, the mechanism of action has been studied ex vivo in blood samples from animals and patients receiving ticlopidine. Three mechanisms of action have been identified to date. Most importantly, ticlopidine has a potent dosedependent inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation. Maximum inhibition is observed at a dosage oral of 500 mglday. Ex vivo inhibition of platelet aggregation induced by other platelet agonists (e.g. thrombin, collagen and arachidonic acid) does not appear to be a direct effect of ticlopidine, but results from the
.w~ S
CI
TIclopldlne
.00»5 S
CI
Clopidogrel
Fig. 1. Structural fonnulae of tic10pidine and c1opidogrel. Main site of oxidation is indicated by asterisk (*).
inhibitory effect of ticlopidine on platelet aggregation caused by ADP, which is released by low levels of these agonists (McTavish et al. 1990). In this context, ticlopidine inhibits platelet derived growth factor (PDGF) released from platelets (Dembinska-Kiee et al. 1992) and prevents the inhibitory action of ADP on alprostadil (prostaglandin-Et)stimulated adenylate cyclase (Gachet et al. 1990a). Studies investigating clopidogre1, a new compound of this family (fig. 1), have shown that receptors on the platelets have a high affinity for this drug, and these receptors play a major role in its activity (Mills et al. 1992). Similar high-affinity receptors probably exist for ticlopidine, because the rate of recovery from inhibition is linked to platelet survival, suggesting that ticlopidine has a permanent effect on platelets. Ticlopidine interferes with von Willebrand factor (vWF), which possesses 2 main functions: (i) it plays a key role in platelet interactions with the damaged vessel wall (via platelet membrane glycoproteins); and (ii) it acts as a carrier for factor VIII, stabilising the activity of factor VIII (Meyer et al. 1991). Platelet vWF is released from platelet a.-granules by various agonists, including those mentioned above, and rebinds to the glycoprotein IIhIIIIa receptor complex (Gralnick et al. 1991). Ticlopidine reduces the binding of vWF and fibrinogen on platelet receptors (glycoprotein IIblIIIa complex) by 60% and 95%, respectively (Di Minno et al. 1985). Ticlopidine competes for the same receptors as vWF, and so disturbs the initial steps ofhaemostasis and the process of thrombosis. The clinical consequence is that bleeding time in patients receiving ticlopidine is prolonged. Although the literature published on ticlopidine since 1974 is extensive, few articles contain original material. Furthermore, it is often difficult to differentiate new and substantiated information. However, ticlopidine has been shown to be effective or superior to aspirin (acetylsalicylic acid) or dipyridamole in the treatment of platelet-dependent disorders (Ito et al. 1992). For example, ticlopidine is effective in the treatment of cerebrovascular disease (risk reduction between 12 and
349
Pharmacokinetics of Ticlopidine
30%), ischaemic heart disease (risk reduction by 50%), diabetes mellitus (reduced progression of microaneurisms and retinopathy) and peripheral vascular disease (walking distance improved by 35 to 50%). Interestingly, a recently published critical appraisal of the literature reported less favourable results for the drug in all of these indications (Haynes et al. 1992). Indeed, other investigators have found the risk to benefit ratio to be positive for stroke, but not so well established for other indications (Albers 1992). Furthermore, in peripheral vascular disease, some studies show an improvement with ticlopidine (McTavish et al. 1990; Verstraete 1991), while another has not (Haynes et a1. 1992). It has recently been reported that cutaneous microcirculation can be improved in patients with peripheral vascular disease (Qian et al. 1993). Among the adverse effects associated with ticlopidine therapy, gastrointestinal disorders occurred in 50% of treated patients (Ito et a1. 1992). Some of these adverse effects were reduced or eliminated when ticlopidine was taken with food; however, approximately 10% of patients withdrew from treatment. During the first 3 months of treatment 1% of patients receiving ticlopidine experienced severe agranulocytosis (Ito et al. 1992) and, therefore, a twice monthly blood cell count is required when a patient is initiated on therapy. Importantly, the agranulocytosis is reversible on discontinuation of therapy. Adverse hepatic effects are less well documented (Dukes 1991), but regular monitoring of the activity of hepatic enzymes is recommended. Recently, the occurrence of severe thrombocytopenia purpura, including one fatal episode (Page et a1. 1991), has been reported in the literature. Furthermore, a single episode of severe aplastic anaemia has been reported (Mataix et a1. 1992).
2. Assay Methodology The 3 main analytical instruments used to measure unchanged ticlopidine in plasma or urine are: (i) high performance liquid chromatography (HPLC) with ultraviolet (UV) detection (Fujimaki et al. 1986; Itoh et a1. 1987); (ii) gas-liquid chro-
matography (GLC) with nitrogen detection (Desager et al. 1990; Shah et al. 1991); and (iii) gas chromatography-mass spectrometry (GC-MS) [Knudsen et al.1992; Shah et a1. 1990]. Recently, the 3 techniques have been compared (Arnoux et al. 1991) and it is clear that HPLC is inadequate for the assessment of the pharmacokinetic profile ofticlopidine. GC-MS is presented as the most sensitive analytical method (limit of detection, 0.005 mglL), but this is not supported by the results of the investigators who used GC-MS (Knudsen et a1. 1992; Shah et al. 1990). Therefore, we consider that GLC with nitrogen detection is the most reproducible, sensitive (we find the limit of detection to be 0.002 mglL) and specific method of analysis.
3. Pharmacokinetic Profile of Radiolabelled Ticlopidine Peak blood drug concentrations (C max ) occurred about 2 hours after oral administration of [14C]ticlopidine 750mg to 6 healthy male volunteers (Bruno & Molony 1983; Panak et al. 1983). About 59% of the radioactivity was recovered from the urine and 25% was recovered from the faeces. 50% of the administered dose was eliminated within 1 day postdose and 70% was eliminated within 3 days. Total recovery of the drug ranged from 74 to 96%. Ticlopidine is 98% reversibly bound to plasma proteins (Ito et a1. 1992). If a single dose of [l4C]ticlopidine 250mg is given to healthy volunteers after administration of unlabelled ticlopidine 250mg for 14 days, unchanged ticlopidine comprises 15% of the total radioactivity in plasma [calculated from the area under the concentration-time curve (AUC) between 0 and 8 hours]. The AUC for ticlopidine is 3-fold higher than that observed after a single 250mg dose of 4C]ticlopidine (Smith et a1. 1988), suggesting that ticlopidine accumulates 3-fold after repeated administration. In rats, tissue distribution shows that 1 hour postdose the highest concentrations of radioactivity were found in the abdominal sphere (liver, stomach, duodenum), while lower tissue concen-
e
350
Clin. Pharmacokinet. 26 (5) 1994
!HOH.c~
W+O ~
THTP
CI
Oxidation
o=cL\ 6HV ~
+ Glycine
g
HO- -CH2 - NH 0'00 CI
/1 ~
OChloro-hippuric acid
e
Fig. 2. Metabolic pathways oftic1opidine in humans, established after administration of 4C]C4- and [14Clphenyl-Iabelled tic1opidine. All metabolites were recovered from urine and were inactive. The decrease in plasma concentrations of unchanged [14C]tic1opidine was expressed as a percentage of total 14C radioactivity (from maximal plasma concentrations until 48 hours postdose); less than 1% of unchanged 4C]tic1opidine was found in the urine (adapted from Picard-Fraire 1983; data on file, Sanofi). Abbreviation: THTP = 4,5,6,7-tetraiIydrothieno [3,2-cl pyridine.
e
trations were reported in lungs, kidneys and adipose tissue. Trace amounts of radioactivity were detected in the tissues 10 days after administration of a single dose of ticlopidine. Ticlopidine is metabolised to 13 metabolites in rats (Picard-Fraire 1984; Tuong et al. 1981). The main metabolites are formed by N-oxidation, Ndealkylation and glycine conjugation (2-chlorohippuric acid). Among these 13 metabolites, the 2-keto derivative appears to inhibit platelet aggregation in rats more potently than the parent drug. In humans, metabolism involves mainly Ndealkylation and oxidation, with opening of the thiophene ring (fig. 2). In addition, numerous other highly polar urinary and biliary metabolites, probably resulting from further metabolism and conjugation, remain unidentified (Panak et al. 1983). The 2-keto metabolite has been identified in animals (see section 2.1), but has not been identified
in humans. However, this metabolite is apparently unstable in biological fluids (Panak et al. 1983). Less than 1% of unchanged ticlopidine is recovered from urine. The total amount of 14C in the plasma, administered as 4C]ticlopidine declines with an apparent elimination half-life (tY2!l) of 14 days (range 8 to 25 days). However, the composition ofradiolabelled material in plasma is unknown (Bruno & Molony 1983; Panak et al. 1983).
e
4. Pharmacokinetic Profile in Healthy Volunteers 4.1 Single-Dose Studies Only 5 studies investigating the pharmacokinetics of ticlopidine have been published (Desager et al. 1990; Knudsen et al. 1992; Picard-Fraire 1983; Shah et al. 1990; Shah et al. 1991). Of these, some are incomplete or appear to contain mistakes. Fur-
351
Pharmacokinetics of Ticlopidine
thermore, some of the pharmacokinetic studies conducted by Sanofi and/or Syntex laboratories remain unpublished. This results in a high degree of frustration for scientists working in this field, and the paucity of information has been emphasised by other reviewers (McTavish et al. 1990). Nevertheless, practical pharmacokinetic information has been summarised in table I. It is difficult to develop a pharmacokinetic model for ticlopidine because it depends on the sensitivity of the analytical method for detection of unchanged ticlopidine in plasma (see section 2). Although data fit to a 2- or 3-compartment model, the correlation between the data and model predictions is sometimes very poor (r < 0.75; Desager et al. 1990). Therefore, investigators have used a less sophisticated approach to determine the pharmacokinetic profile of ticlopidine. Cmax and time to achieve Cmax values (tmax) are observed values. AUC is obtained by the trapezoidal rule extrapolated to infinity [plus the final serum concentration (Clast) divided by the rate constant (ke)]. The tY2~ is calculated by log-linear regression of the last points of the plasma concentration-time curve. The reported Cmax values are dose related, although the values reported by some investigators
were low (Knudsen et al. 1992; Shah et al. 1991). Furthermore, large interindividual variations were observed. The bioavailability of ticlopidine was improved when the drug was administered with food in healthy volunteers (Shah et al. 1990). The mean tmax was approximately 2 hours in all studies (table I). With the exception of our data (Desager et al. 1990), the AUC values were underestimated (Knudsen et al. 1992; Shah et al. 1990, 1991) or not reported (Picard-Fraire 1983). The tY2~ was approximately 20 hours (Desager et al. 1990; PicardFraire 1983). It should be noted that the values reported by Shah and colleagues (1990, 1991) are meaningless because they are values that contain both distribution and elimination data. To collect enough data to provide a reliable estimate of tV:,~, an observation period of at least 96 hours is required. 4.2 Multiple-Dose Studies In all 3 published studies, ticlopidine 250mg was administered twice daily for 3 weeks (Knudsen et al. 1992; Picard-Fraire 1983; Shah et al. 1991). The maximal pharmacological effect was observed after 5 to 10 days of therapy. All studies reported values for Cmax that were similar after the final administration of ticlopidine.
Table I. Mean values (± SD) for pharmacokinetic parameters of ticlopidine after administration of single oral doses to healthy volunteers Dose (mg)
1000
No. of study participants (gender) Not reported
500
12 (M)
Gmax (mg/L)
tmax (h)
2.13
1-3
AUG (mg/L· h)
tl/2~
(h)
Observation period
Reference
(h) Picard-Fraire (1983)
24.0±7.5
1.49 ± 0.44
2.3 ± 0.5
4.82 ± 1.27
19.4 ± 5.5
120
Desager et al. (1990)
500
12 (M)
1.40 ± 0.51
2.1±0.7
4.66 ± 0.94
16.3 ± 2.5
120
250
12 (M)
0.57 ± 0.34
1.9 ± 0.6
1.81 ± 1.05
6.9 ± 1.2
24
Shah et al. (1990)
250a
12 (M)
0.69 ± 0.19
1.7±0.3
2.16 ± 0.81
7.6 ± 1.7
24
Shah et al. (1990)
250 b
12 (M)
0.37 ± 0.24
2.0±0.6
1.48 ± 0.85
6.9 ± 0.9
24
Shah et al. (1990)
250
12 (M,F)
0.41 ± 0.24
2
1.40 ± 0.80
7.9 ± 3.0
48
Shah et al. (1991)
250
10 (M,F)
0.35 ± 0.22
2.1±0.7
1.30 ± 0.90
12
Knudsen et al. (1992)
a
After a standardised (755 kcal) meal.
b
Taken after antacid.
Abbreviations: AUG
Desager et al. (1990)
= area under the plasma concentration-time curve; Gmax = maximal plasma concentration; F =female; M = male;
tmax = time taken to achieve Gmaxvalues; t1J,~ = elimination half-life.
Clin. Pharmacokinet. 26 (5) 1994
352
Table II. Mean values (± SO) for pharmacokinetic parameters of ticlopidine after administration of 250mg twice daily to healthy volunteers for 3 weeks No. of study participants (gender)
Cmax (mg/L)
tmax (h)
Not reported
0.90±0.18
1 to 3
12 (M,F)
0.89 ± 0.37
1.0
10 (M,F)
1.08±0.S6
1.S±0.S
a
AUC (mg/Lo h)
hl1P (h)
Observation period (h)
Picard-Fraire (1983)
33.2±3.8 3.6 ± 1.7a 16.7± 19.6b
Reference
98±64
96
Shah et al. (1991)
33.2 ± 11.4b
96
Knudsen et al. (1992)
Probably AUC between 0 and 12 hours at steady-state.
b Calculated from the results of 9 individuals.
Abbreviations: see table I.
Mean steady-state plasma ticlopidine concentrations were 146 )lg/L (Shah et al. 1991) and 180 )lg/L (Knudsen et al. 1992) after 14 days, and 187 )lg/L (Shah et al. 1991) and 230 )lg/L (Knudsen et al. 1992) after 21 days. The tmax tended to be shorter after repeated administration than after single-dose administration (see tables I and II). Several investigators calculated AUC values. However, in some papers the calculated AUC value did not correspond to the AUC extrapolated from zero to infinity after the last dose. Indeed, Shah and colleagues reported an AUC of 3.6 ± 1.7 mgIL • h (Shah et al. 1991), but it appears that this value represented the AUC between 0 and 12 hours. On the basis of the graphical data published, we have calculated a mean AUC of approximately 15.5 mg/L • h, which corresponds to the accumulation factor of 3.5 reported by these investigators (Shah et al. 1991). Knudsen and colleagues (1992) reported the individual plasma concentrations at 0, 12 and 30 hours, and followed the plasma concentrations of ticlopidine for most individuals for 96 hours. In addition, Cmax values were provided. Surprisingly, 4 of 10 individuals had plasma ticlopidine concentrations at 30 hours [C(30)] that were higher than those reported at 12 hours postdose [C(12)]. Plasma ticlopidine concentrations for one of the individuals was only measured for 48 hours; therefore, the mean value of AUC was calculated based on results obtained in the other 9 individuals. When we calculated the AUC, by the trapezoidal rule, for each volunteer from the 4 plasma concen-
trations provided by the investigators, we found a meanAUCof: 10.04 + mean C(30)lke = 16.7 mg/L. h
where ke was assumed to be 0.0198 hours-i. This value corresponded to the mean AUC calculated from the individual AUC values reported by Knusden et al. (1992). In healthy volunteers, the tJ/21i was approximately 33 hours in 2 studies (Knudsen et al. 1992; Picard-Fraire 1983), but was 98 hours in the third (Shah et al. 1991). Therefore, the quality of the analytical procedures used in these studies must be questioned.
5. Pharmacokinetics in Special Populations In elderly patients (mean age 69.5 years; range 65 to 76 years) the bioavailability of ticlopidine was significantly increased compared with that observed in young adult volunteers (Shah et al. 1991). The Cmax and AUC values were twice those found by the same investigators in young volunteers after single and repeated administration (see tables I and II). The accumulation factor is raised from 3.5 (± 5.5) in young volunteers to 4.2 (± 3.0) in elderly individuals. The investigators concluded that 'these differences should not contribute to any pharmacological or adverse effect'. Therefore, no reduction in dosage is considered necessary in elderly patients.
353
Pharmacokinetics of Ticlopidine
Similarly, gender has no influence on the pharmacokinetics of ticlopidine (Knudsen et al. 1992; Shah et al. 1991). The toxicity and teratogenicity of ticlopidine has been evaluated in pregnant rats. The highest dose (400 mg/kg) impaired sternebral calcification and reduced the fetal growth rate (Bruno & Molony 1983; Panak et al. 1983). Furthermore, appreciable amounts ofticlopidine were measured in the fetus, placenta and amniotic fluid of pregnant rats (Saltiel & Ward 1987). Due to the lack of data in humans, it has been recommended that ticlopidine should be used in pregnant women with caution (Ito et al. 1992). Pharmacokinetic studies undertaken in patients with liver or renal dysfunction are not available (McTavish et al. 1990). Given the extensive hepatic metabolism and high urinary excretion (60%) of metabolites in humans, ticlopidine is contraindicated in patients with severe hepatic impairment and/or renal failure. However, ticlopidine has been used in patients undergoing haemodialysis to prevent clotting of the arteriovenous shunt. Malabsorption and malnutrition could theoretically increase the incidence of gastrointestinal adverse effects, but the effect on the pharmacokinetic profile of ticlopidine is unpredictable. Patients with hypercholesterolaemia should not receive treatment with tic1opidine. Indeed, it has been shown that total serum cholesterol levels were increased by 9% in a large population of patients receiving ticlopidine (McTavish et al. 1990). The mechanism underlying this effect is unknown.
6. Drug Concentration Monitoring Therapeutic monitoring of plasma ticlopidine concentrations is not necessary because the therapeutic range is wide. However, monitoring may be used help to assess compliance, particularly when there is a long interval between follow-up visits. In a study that aimed to demonstrate the efficacy of ticlopidine versus placebo in the treatment of intermittent claudication over a 21-month period (Balsano et al. 1989), we measured unchanged plasma ticlopidine concentrations to assess com-
pliance. The mean plasma concentration of ticlopidine (± SD) was 269 ± 211 Ilg/L (range 16 to 1047 Ilg/L). In the ticlopidine-treated group (n = 54), compliance was 100% for 43 patients. In the remaining 11 patients, ticlopidine was detected in only 16 of the 34 plasma samples available. In the placebo group (n = 53), ticlopidine could not be detected in the plasma samples from 50 patients, while 3 positive plasma samples (possibly ticlopidine or an interfering drug) were found among a total of 9 samples that were collected from the remaining 3 patients. This method of assessing compliance may be more accurate, although certainly more expensive, than relying on tablet counts to determine compliance.
7. Pharmacokinetic-Pharmacodynamic Relationship After administration of a single dose, no correlation could be found between Cmax of the drug in plasma (obtained after 2 hours) and the start of a significant inhibition of platelet aggregation (occurring after 4 hours) [Panak et al. 1983]. The high hepatic transformation of ticlopidine explains the delay between administration of drug and maximal inhibitory effects that occur 24 hours postdose (Picard-Fraire 1983). However, inhibitory activity is dose-related after repeated administration. Maximal activity is observed after several days of administration, but no correlation between activity and the plasma concentration of unchanged ticlopidine or any active metabolites could be established. The inhibitory activity persisted for 10 to 15 days after withdrawal of the drug, and long after plasma ticlopidine became undetectable. Consequently, ticlopidine should be discontinued 2 weeks before any surgical or dental intervention if possible. About 75% of ticlopidine binds irreversibly to the circulating platelets. Therefore, it is not unexpected that the duration of inhibition of platelet function will correspond to the normal lifespan of the platelet.
354
8. Drug Interactions Ticlopidine pharmacokinetics are affected by the intake of antacid ('Maalox' 30ml) immediately before administration of the drug (Shah et al. 1990). Mean plasma ticlopidine concentrations were reduced from the first to the fourth hour postdose compared with those measured in the same fasted individuals who did not receive antacid. AUC was decreased by 20%, but this does not appear to be clinically relevant. Conversely, the absorption of ticlopidine was improved by 20% when administered to the same fed individuals one week later (Shah et al. 1990). This interaction also did not appear to have any clinical significance. Theophylline pharmacokinetics were modified by ticlopidine (Colli et al. 1987). After 10 days of ticlopidine 250mg twice daily, total body clearance of theophylline was significantly reduced (decreased by 37%) and V/2~ was increased (42%). Unfortunately, plasma ticlopidine concentrations were not reported in this study. Possible adverse effects may result from this interaction in patients receiving concurrent theophylline therapy, particularly if they are controlled with theophylline concentrations at the upper limit of the therapeutic range. Similarly, ticlopidine was found to inhibit liver cytochrome P450 activity in patients receiving phenazone (antipyrine) [Knudsen et al. 1992]. The tY2~ and AUC of phenazone were increased in each individual after 3 weeks on a regimen of ticlopidine 250mg twice daily. Ticlopidine is also thought to reduce the efficacy of cyclosporin in corticosteroid-dependent nephrotic syndrome (BirmeIe et al. 1991). During a challenge test, cyclosporin blood concentrations were reduced by one-half after 10 days when ticlopidine 500 mg/day was added to the drug regimen. Several other studies have investigated the possible interaction between ticlopidine and other drugs, but these studies have focused on the pharmacodynamic consequences of an interaction. For example, aspirin (50 or 500 mg/day) prolonged bleeding time whereas methylprednisolone (20mg
Clin. Pharmacokinet. 26 (5) 1994
intravenously) decreased bleeding time in patients receiving ticlopidine (Saltiel & Ward 1987).
9. Conclusions In conclusion, the pharmacological activity of ticlopidine is not clearly related to its pharmacokinetic profile. Indeed, from what is known about the pharmacokinetics of ticlopidine, measurement of the bleeding time is the most useful clinical parameter on which to evaluate the patient's response to therapy.
Acknowledgements We wish to thank the Professor C. Harvengt for his comments and helpful discussions. Parts of the bibliography were kindly provided by Dr J. Dricot (Sanofi-Winthrop, Brussels, Belgium).
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Pharmacokinetics of Ticlopidine
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Correspondence and reprints: Dr lean-Pierre Desager, Laboratoire de Pharmacotherapie, Universite Catholique de Louvain, 53 Avenue E. Mounier, B-1200, Brussels, Belgium.