Br. J. clin. Pharmac. (1991), 32, 761-764
Single and multiple dose pharmacokinetics of ticlopidine in young and elderly subjects J. SHAH', P. TEITELBAUM', B. MOLONY', T. GABUZDA2 & I. MASSEY' 'Syntex Research, A3-BMR, Palo Alto, CA 94304 and 2Division of Hematology-Oncology, The Lankenau Hospital and Medical Research Center, Philadelphia, PA 19151, USA
The pharmacokinetics of orally administered ticlopidine hydrochloride, a novel inhibitor of platelet aggregation, were determined both after a single dose and after 21 days of twice daily dosing in 12 young (mean 28.6 years) and 13 elderly (mean 69.5 years) subjects. Concentrations of unchanged ticlopidine in plasma were measured by g.l.c. After a single 250 mg dose of ticlopidine, the mean area under the curve, AUC (0-12 h) was 1.11 ,ug ml-1 h in young subjects and 2.04 ,ug ml-1 h in old subjects (P = 0.002). Mean values of t½/2,z in young and elderly subjects were 7.9 h and 12.6 h, respectively (P = 0.01). Steady state plasma drug concentrations were attained after 14 days of dosing with ticlopidine. After the final dose on day 21, AUC values in elderly subjects were 2-3 times those in young subjects (P < 0.001). The plasma t½/2,z averaged 4.0 days for young subjects and 3.8 days for elderly subjects (P = 0.7). The longer t/2,z and higher AUC values after multiple dosing probably reflect an increase in bioavailability of ticlopidine after repeated dosing, saturation of metabolism or insufficient analytical sensitivity to characterize the terminal elimination phase after single dose.
Keywords ticlopidine platelet aggregation
pharmacokinetics
age
steady state
Introduction
Ticlopidine hydrochloride [(chloro-2 benzyl)-5 tetrahydro 4, 5, 6 thieno (3, 2-c) pyridine] is a novel inhibitor of platelet function that differs in its structure and mechanism of action from aspirin and other NSAIDs (Bruno & Molony, 1983; Knudsen & Gormsen, 1979; Panak et al., 1983). Ticlopidine acts primarily by inhibiting the adenosine diphosphate (ADP) pathway of platelet aggregation (Feliste et al., 1987). Although the exact mechanism of action of ticlopidine has not been fully elucidated, it is thought that the drug may interfere with the membrane functions of the thrombocyte by inhibiting platelet-fibrinogen binding, platelet-platelet interactions, and binding of ADP to membrane receptors. Ticlopidine does not inhibit cyclic-AMP phosphodiesterase or the cyclooxygenase pathway, and it does not block production of thromboxane by platelets or of prostacyclin by endothelial cells (Bruno, 1983). In humans, ticlopidine is absorbed rapidly and extensively, and causes a time- and dose dependent inhibition of ADP-induced platelet aggregation. At the recommended therapeutic dose of 500 mg day-', inhibition of platelet aggregation is maximal after approximately 1
week and returns to baseline approximately 1-2 weeks after therapy is discontinued. The metabolism of ticlopidine is complex; at least four metabolites have been isolated in man and 13 metabolites have been isolated in rats (Panak et al., 1983; Picard-Fraire, 1984). The main quantitative metabolic routes in man are Ndealkylation and oxidation of the thiophene ring (Bruno & Molony, 1983). Hepatic clearance accounts for most of the total body clearance of ticlopidine, as only trace amounts of ticlopidine are eliminated unchanged via the kidney. The duration of inhibition of platelet function corresponds to the normal life-span of the platelet (Panak et al., 1983). Approximately 98% of ticlopidine in plasma is reversibly bound to plasma proteins, mainly to serum albumin and lipoproteins. Ticlopidine also binds to cxlacid glycoprotein (Glasson et al., 1982) but at concentrations associated with therapeutic doses 15% or less of ticlopidine is bound to this protein. Two large multicentre trials have recently established the efficacy of ticlopidine for the prevention of threatened and recurrent stroke. The Ticlopidine-Aspirin Stroke Study (TASS) demonstrated that ticlopidine was more
Correspondence: Dr J. Shah, Syntex Research, A3-BMR, Palo Alto, CA 94304, USA
761
762
J. Shah et al.
effective than aspirin for the prevention of stroke in patients who have suffered from transient cerebrovascular ischaemic events and who are consequently at increased risk of stroke (Hass et al., 1989). The results of the Canadian-American Ticlopidine Study (CATS) indicated that ticlopidine was superior to placebo for the prevention of recurrent strokes in patients who had already experienced a stroke (Gent et al., 1988). Ticlopidine treatment is associated with a variety of mild gastrointestinal side effects and skin rashes. About 1-2% of patients experience drug induced neutropenia usually within the first 3 months of treatment with ticlopidine. The average age of the subjects in TASS and CATS were 63 and 66 years, respectively. A growing awareness of the potential for altered drug disposition in the elderly has prompted examination of the pharmacokinetics of many drugs in elderly subjects. The effect of ageing on drug absorption, distribution, metabolism, and elimination is variable and often unpredictable. The present study was undertaken to compare the pharmacokinetics of ticlopidine in young and elderly subjects and to determine the pharmacokinetics of ticlopidine after multiple dosing.
Analysis of ticlopidine in plasma A methanolic solution (100 pLI, 2 jig mlF- 1) of the dichloro analogue of ticlopidine was added to 1 ml of plasma as an internal standard. After addition of 66 mm phosphate buffer (pH 8; 1 ml), the plasma was extracted with 10 ml hexane. The hexane layer was removed and then extracted with 0.2N HCl (2 ml). Potassium hydroxide solution (2N; 0.3 ml) was added to the acidic extract, and the aqueous phase was extracted with hexane: pentyl acetate (1:1; 50 ,ul). The lower aqueous layer was removed using a Pasteur pipet. A portion (3-5 ,lI) of the pentyl acetate extract was injected into a gas chromatographic column. A 5880A Hewlett Packard gas chromatograph equipped with a nitrogen-phosphorous detector and a level-four integrating terminal was used. The injection port and the detector temperatures were maintained at 2500 C and 3000 C, respectively. The accuracy and reproducibility of this method was assessed by the analysis of samples of plasma fortified with ticlopidine at concentrations of 0-150 ng ml-1. Drug recovery ranged from 98.7-102.2% and the CV of the assay was < 4% at all concentrations. The lower limit of reliable measurement was 10 ng ml-1, which was the lowest point on the calibration curve.
Data adjustments Methods
Study design Following approval of the study protocol and the consent form by the Institutional Review Board of the Lankenau Medical Research Center, 12 young subjects (seven men and five women), and 13 elderly subjects (eight men and five women) were recruited. The mean age and weight of young and elderly subjects were 28.6 and 69.5 years and 87.4 and 76.5 kg, respectively. Females participating in the study were either surgically sterile or postmenopausal. Subjects were judged to be healthy on the basis of medical histories, normal physical examination, routine blood chemistries, normal blood counts, urinalysis, ECG, normal chest X-ray and creatinine clearance. All concomitant medications, including nonprescription drugs, were discontinued; alcohol was prohibited for 24 h prior to and during the study period. After receiving an explanation of the risks and inconveniences that could reasonably be expected, all of the subjects signed an informed consent form. In the first part of the study, a single 250 mg tablet of ticlopidine was administered with a light breakfast and 10 ounces of water. Samples of blood were collected for analysis of concentrations of ticlopidine at intervals of 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 and 48 h after dosing. Following a 1 week washout period, the second part of the study began. The subjects received ticlopidine at a dose of 250 mg twice a day for 3 weeks. Samples of blood (10 ml) were collected at time 0 (pre-dose) and 2 h after the morning dose on days 1, 2, 3, 7 and 14 of the dosing regimen. On day 21 samples of blood were collected at 0, 1, 2, 3, 4, 6, 8, 24, 48, 72 and 96 h after the last dose. Samples of blood were collected in heparinized Vacutainer® (Becton Dickinson) tubes. The plasma was separated, frozen and stored until analysis.
The concentration of ticlopidine in the plasma at 12 h after dosing on day 1 was calculated by linear regression of the data for the elimination phase following the single dose. The concentration of ticlopidine in the plasma 12 h after dosing on day 21 was assumed to be the same as that at time zero on day 21. Data from two subjects in the elderly group were not used in the pharmacokinetic analysis for day 21. One of these subjects did not take any medication after day 8; the other had an unusually long half-life (510 h). Analysis of data Pharmacokinetic parameters were calculated using compartment model-independent methods. The elimination half-life (tl,,Z) of ticlopidine was calculated by least squares regression analysis of the terminal loglinear portion of the plasma drug concentration-time curve. The total area under the plasma drug concentration-time curve (AUC) was determined by the linear trapezoidal rule with extrapolation to infinity by adding the ratio of the last measurable plasma drug concentration divided by the terminal elimination rate constant (C(last)/z). Values of AUC and t½l,,z were calculated for each subject following the single oral dose and on day 21 following repeated oral dosing. Peak plasma drug concentration, Cmax (,ug ml-l), and time to peak plasma concentration, tmax (h), were obtained from the individual curves. The average steady-state plasma drug concentration (Cav) was calculated from:
Cav
=
AUC(T)
(1)
T
where AUC(T) is the AUC within the dosing interval at steady state and T is the dosing interval (12 h).
Short report In addition, the following ratios were calculated for each subject and averaged for each group. R (a measure of linearity) = AUC(T) day 21 (2) AUC day 1 and Rac (a measure of accumulation) = AUC(T) day 21 (3) AUC (0-12) day 1 For statistical analysis, an analysis of variance model appropriate for the 2 x 2 factorial design was used, with P c 0.05 as the level of significance. The model incorporated effects due to sex, age, and an age-by-sex interaction term.
Results
Single dose study The mean concentrations of ticlopidine in plasma following administration to young and elderly subjects are shown in Figure 1. The mean concentration of ticlopidine in plasma at 1 h was 0.28 and 0.52 ,ug ml-' for the young and the elderly subjects, respectively. From 2-8 h, the concentrations of ticlopidine in plasma for elderly subjects were significantly greater than those in young subjects. The average plasma elimination halflife (t½.2 Z) of ticlopidine in elderly subjects (12.7 h) was significantly longer than that for young subjects (7.9 h, P = 0.013) (Table 1). Likewise, values for Cmax and AUC were significantly higher for elderly subjects than for young subjects.
¶s.DAYI
P.+k E..
~0.031_
s-0.001 _
763
Table 1 Pharmacokinetic parameters (mean ± s.d) of ticlopidine in young and elderly subjects
Parameters
Young
Elderly
12 0.41 (0.24) 2.0 (1.0-3.0)
13 0.70 (0.52) 2.0 (1.0-4.0) 12.7 (0.9) 2.8 (1.2)
P-value
Day 1 n
Cmax (,ug ml-') # tmax (h) t,12 z (h)
AUC(jxgml 'h) Day 21
7.9 (3.0) 1.4 (0.8)
12 11 0.89 (0.37) 1.42 (0.75) 1.0 (1.0-3.0) 2.0 (1.0-4.0) 98 (64) 91 (33) 3.6 (1.7) 8.3 (3.2) 0.30 (0.14) 0.69 (0.27) R 3.1 (1.6) 3.2 (0.8) 3.5 (5.5) 4.2 (3.0) Rac *Significantly different (P c 0.05). #Median value and the upper and lower range.
0.035* ns
0.013* 0.002*
n
Cmax (p.g ml-') # tmaX (h) t½/2z (h) AUC(p.gml-lh) Cav (Rg mI-1)
0.015* ns ns
0.001* 0.003*
Multiple dose study Administration of 250 mg ticlopidine twice daily to the young subjects resulted in mean trough plasma concentrations of 0.103, 0.187 and 0.146 pug ml- 1 on days 7, 14, and 21, respectively. At all time points, the trough concentrations for the elderly subjects were higher. Trough levels on weeks 2 and 3 of dosing were respectively 0.441 and 0.397 ,ug ml-' for elderly subjects. Steadystate trough concentrations (Css,min) were reached by 14 days. Figure 1 shows plasma concentrations of ticlopidine in young and elderly subjects following the last dose of ticlopidine on day 21. Values of tmax were 1.4 and 2.1 h for the young and the elderly subjects, respectively (Table 1). Values of Cmax were 0.89 and 1.42 ,ug ml-', respectively. The plasma elimination half-life (t,/2 Z) averaged 98 and 91 h for young and elderly subjects (P = 0.652). Mean Cay was greater for elderly than for younger subjects (P = 0.003). The mean R and Rac values were 3.1 and 3.5, respectively, for young subjects and 3.2 and 4.2 for elderly subjects, respectively. There was no significant effect of gender on the pharmacokinetics of ticlopidine after multiple doses.
.'I I
--|
Discussion
.1
0
OU..
0.1
Time in hours Figure 1 Mean (± s.e. mean) plasma ticlopidine concentrations in young (n = 12) (o) and elderly (n 13) (V) subjects a) day 1, b) day 21. *Significantly different P _ 0.05. =
-
Therapeutic use of ticlopidine will be mainly in older individuals. The present investigation was carried out to investigate the relative pharmacokinetics of ticlopidine in young and elderly normal volunteers. The increased AUC of ticlopidine observed in the elderly subjects could result from an increased extent of absorption from the gut or a decreased metabolic clearance. Any lowering of plasma albumin in old age (Shand, 1982; Vestal, 1978) is likely to mask an even greater difference in intrinsic clearance based upon unbound drug concentration. The degree of accumulation of ticlopidine in plasma on multiple dosing was similar in the young and elderly subjects. Values of R were greater than unity in both groups, t½l,z values were greater after
764
J. Shah et al.
multiple than single dosing and an increase was seen in Rac values. Possible explanations for these findings include an increase in bioavailability after repeated administrations of ticlopidine, saturation of the metabolism of ticlopidine or failure to detect the slow elimination phase after the single dose because of the sensitivity limit of the analytical method.
Recent studies in elderly subjects failed to demonstrate any differences in the effects of ticlopidine in elderly and young subjects (Molony, unpublished data). Thus the differences in the pharmacokinetics of ticlopidine between young and elderly subjects identified in this study should not contribute to any unexpected pharmacological or adverse effects.
References Bruno, J. J. (1983). The mechanisms of action of ticlopidine. Thrombosis Res., Suppl. IV, 59-87. Bruno, J. J. & Molony, B. A. (1983). Cardiovascular drugs. In New Drugs Annual, ed. Scriabine, A., volume 1, pp. 295316. New York: Raven Press. Feliste, R., Delebassee, D. & Simon, M. F. (1987). Broad spectrum anti-platelet activity of ticlopidine and PCR 4099 involves the suppression of the effects of released ADP. Thrombosis Res., 48, 403-415. Gent, M., Blakely, J. A., Easton, J. D., Ellis, D. J., Hachinski, V. C., Harbison, J. W., Panak, E., Roberts, R. S., Sicurella, J. & Turpie, A. G. (1988). The Canadian American ticlopidine study in thromboembolic stroke. Stroke, 19, 12031210. Glasson, S., Zim, R. & Tillement, J. P. (1982). Multiple human serum binding of two thienopyridine derivatives, ticlopidine and PCR 2362 and their distribution between HSA, a-acid glycopritein and lipo-proteins. Biochem. Pharmac., 31, 831-835. Hass, W. K., Easton, J. D., Adams, H. P., Pryse-Phillips, W., Molony, B. A., Anderson, S. & Kamm, B. (1989). A randomized trial comparing ticlopidine hydrochloride with
aspirin for the prevention of stroke in high-risk patients. New Engi. J. Med., 321, 501-507. Knudsen, J. B. & Gormsen, J. (1979). The effect of ticlopidine on platelet function in normal volunteers and in patients with platelet hyperaggregability in vitro. Thrombosis Res., 16, 663-671. Panak, E., Maffrand, J. P., Picard-Fraire, C., Vallee, E. & Blanchard, J. (1983). Ticlopidine: a promise for the prevention and treatment of thrombosis. Hemostasis, 13, Suppl. 1, 1-54. Picard-Fraire, C. (1984). Pharmacokinetics and metabolic characteristics of ticlopidine in relation to its inhibitory properties on platelet function: Agents and Actions Supplements. Ticlopidine: Quo Vadis?, 15, (Suppl.) 68-75. Shand, D. G. (1982). Biological determinants of altered pharmacokinetics in the elderly. Gerontology, 28, Suppl. 8-17. Vestal, R. E. (1978). Drug use in the elderly: a review of problems and special considerations. Drugs, 16, 358-382.
(Received 4 September 1990, accepted 7 August 1991)
Single and multiple dose pharmacokinetics of ticlopidine in young and elderly subjects J. SHAH', P. TEITELBAUM', B. MOLONY', T. GABUZDA2 & I. MASSEY' 'Syntex Research, A3-BMR, Palo Alto, CA 94304 and 2Division of Hematology-Oncology, The Lankenau Hospital and Medical Research Center, Philadelphia, PA 19151, USA
The pharmacokinetics of orally administered ticlopidine hydrochloride, a novel inhibitor of platelet aggregation, were determined both after a single dose and after 21 days of twice daily dosing in 12 young (mean 28.6 years) and 13 elderly (mean 69.5 years) subjects. Concentrations of unchanged ticlopidine in plasma were measured by g.l.c. After a single 250 mg dose of ticlopidine, the mean area under the curve, AUC (0-12 h) was 1.11 ,ug ml-1 h in young subjects and 2.04 ,ug ml-1 h in old subjects (P = 0.002). Mean values of t½/2,z in young and elderly subjects were 7.9 h and 12.6 h, respectively (P = 0.01). Steady state plasma drug concentrations were attained after 14 days of dosing with ticlopidine. After the final dose on day 21, AUC values in elderly subjects were 2-3 times those in young subjects (P < 0.001). The plasma t½/2,z averaged 4.0 days for young subjects and 3.8 days for elderly subjects (P = 0.7). The longer t/2,z and higher AUC values after multiple dosing probably reflect an increase in bioavailability of ticlopidine after repeated dosing, saturation of metabolism or insufficient analytical sensitivity to characterize the terminal elimination phase after single dose.
Keywords ticlopidine platelet aggregation
pharmacokinetics
age
steady state
Introduction
Ticlopidine hydrochloride [(chloro-2 benzyl)-5 tetrahydro 4, 5, 6 thieno (3, 2-c) pyridine] is a novel inhibitor of platelet function that differs in its structure and mechanism of action from aspirin and other NSAIDs (Bruno & Molony, 1983; Knudsen & Gormsen, 1979; Panak et al., 1983). Ticlopidine acts primarily by inhibiting the adenosine diphosphate (ADP) pathway of platelet aggregation (Feliste et al., 1987). Although the exact mechanism of action of ticlopidine has not been fully elucidated, it is thought that the drug may interfere with the membrane functions of the thrombocyte by inhibiting platelet-fibrinogen binding, platelet-platelet interactions, and binding of ADP to membrane receptors. Ticlopidine does not inhibit cyclic-AMP phosphodiesterase or the cyclooxygenase pathway, and it does not block production of thromboxane by platelets or of prostacyclin by endothelial cells (Bruno, 1983). In humans, ticlopidine is absorbed rapidly and extensively, and causes a time- and dose dependent inhibition of ADP-induced platelet aggregation. At the recommended therapeutic dose of 500 mg day-', inhibition of platelet aggregation is maximal after approximately 1
week and returns to baseline approximately 1-2 weeks after therapy is discontinued. The metabolism of ticlopidine is complex; at least four metabolites have been isolated in man and 13 metabolites have been isolated in rats (Panak et al., 1983; Picard-Fraire, 1984). The main quantitative metabolic routes in man are Ndealkylation and oxidation of the thiophene ring (Bruno & Molony, 1983). Hepatic clearance accounts for most of the total body clearance of ticlopidine, as only trace amounts of ticlopidine are eliminated unchanged via the kidney. The duration of inhibition of platelet function corresponds to the normal life-span of the platelet (Panak et al., 1983). Approximately 98% of ticlopidine in plasma is reversibly bound to plasma proteins, mainly to serum albumin and lipoproteins. Ticlopidine also binds to cxlacid glycoprotein (Glasson et al., 1982) but at concentrations associated with therapeutic doses 15% or less of ticlopidine is bound to this protein. Two large multicentre trials have recently established the efficacy of ticlopidine for the prevention of threatened and recurrent stroke. The Ticlopidine-Aspirin Stroke Study (TASS) demonstrated that ticlopidine was more
Correspondence: Dr J. Shah, Syntex Research, A3-BMR, Palo Alto, CA 94304, USA
761
762
J. Shah et al.
effective than aspirin for the prevention of stroke in patients who have suffered from transient cerebrovascular ischaemic events and who are consequently at increased risk of stroke (Hass et al., 1989). The results of the Canadian-American Ticlopidine Study (CATS) indicated that ticlopidine was superior to placebo for the prevention of recurrent strokes in patients who had already experienced a stroke (Gent et al., 1988). Ticlopidine treatment is associated with a variety of mild gastrointestinal side effects and skin rashes. About 1-2% of patients experience drug induced neutropenia usually within the first 3 months of treatment with ticlopidine. The average age of the subjects in TASS and CATS were 63 and 66 years, respectively. A growing awareness of the potential for altered drug disposition in the elderly has prompted examination of the pharmacokinetics of many drugs in elderly subjects. The effect of ageing on drug absorption, distribution, metabolism, and elimination is variable and often unpredictable. The present study was undertaken to compare the pharmacokinetics of ticlopidine in young and elderly subjects and to determine the pharmacokinetics of ticlopidine after multiple dosing.
Analysis of ticlopidine in plasma A methanolic solution (100 pLI, 2 jig mlF- 1) of the dichloro analogue of ticlopidine was added to 1 ml of plasma as an internal standard. After addition of 66 mm phosphate buffer (pH 8; 1 ml), the plasma was extracted with 10 ml hexane. The hexane layer was removed and then extracted with 0.2N HCl (2 ml). Potassium hydroxide solution (2N; 0.3 ml) was added to the acidic extract, and the aqueous phase was extracted with hexane: pentyl acetate (1:1; 50 ,ul). The lower aqueous layer was removed using a Pasteur pipet. A portion (3-5 ,lI) of the pentyl acetate extract was injected into a gas chromatographic column. A 5880A Hewlett Packard gas chromatograph equipped with a nitrogen-phosphorous detector and a level-four integrating terminal was used. The injection port and the detector temperatures were maintained at 2500 C and 3000 C, respectively. The accuracy and reproducibility of this method was assessed by the analysis of samples of plasma fortified with ticlopidine at concentrations of 0-150 ng ml-1. Drug recovery ranged from 98.7-102.2% and the CV of the assay was < 4% at all concentrations. The lower limit of reliable measurement was 10 ng ml-1, which was the lowest point on the calibration curve.
Data adjustments Methods
Study design Following approval of the study protocol and the consent form by the Institutional Review Board of the Lankenau Medical Research Center, 12 young subjects (seven men and five women), and 13 elderly subjects (eight men and five women) were recruited. The mean age and weight of young and elderly subjects were 28.6 and 69.5 years and 87.4 and 76.5 kg, respectively. Females participating in the study were either surgically sterile or postmenopausal. Subjects were judged to be healthy on the basis of medical histories, normal physical examination, routine blood chemistries, normal blood counts, urinalysis, ECG, normal chest X-ray and creatinine clearance. All concomitant medications, including nonprescription drugs, were discontinued; alcohol was prohibited for 24 h prior to and during the study period. After receiving an explanation of the risks and inconveniences that could reasonably be expected, all of the subjects signed an informed consent form. In the first part of the study, a single 250 mg tablet of ticlopidine was administered with a light breakfast and 10 ounces of water. Samples of blood were collected for analysis of concentrations of ticlopidine at intervals of 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 and 48 h after dosing. Following a 1 week washout period, the second part of the study began. The subjects received ticlopidine at a dose of 250 mg twice a day for 3 weeks. Samples of blood (10 ml) were collected at time 0 (pre-dose) and 2 h after the morning dose on days 1, 2, 3, 7 and 14 of the dosing regimen. On day 21 samples of blood were collected at 0, 1, 2, 3, 4, 6, 8, 24, 48, 72 and 96 h after the last dose. Samples of blood were collected in heparinized Vacutainer® (Becton Dickinson) tubes. The plasma was separated, frozen and stored until analysis.
The concentration of ticlopidine in the plasma at 12 h after dosing on day 1 was calculated by linear regression of the data for the elimination phase following the single dose. The concentration of ticlopidine in the plasma 12 h after dosing on day 21 was assumed to be the same as that at time zero on day 21. Data from two subjects in the elderly group were not used in the pharmacokinetic analysis for day 21. One of these subjects did not take any medication after day 8; the other had an unusually long half-life (510 h). Analysis of data Pharmacokinetic parameters were calculated using compartment model-independent methods. The elimination half-life (tl,,Z) of ticlopidine was calculated by least squares regression analysis of the terminal loglinear portion of the plasma drug concentration-time curve. The total area under the plasma drug concentration-time curve (AUC) was determined by the linear trapezoidal rule with extrapolation to infinity by adding the ratio of the last measurable plasma drug concentration divided by the terminal elimination rate constant (C(last)/z). Values of AUC and t½l,,z were calculated for each subject following the single oral dose and on day 21 following repeated oral dosing. Peak plasma drug concentration, Cmax (,ug ml-l), and time to peak plasma concentration, tmax (h), were obtained from the individual curves. The average steady-state plasma drug concentration (Cav) was calculated from:
Cav
=
AUC(T)
(1)
T
where AUC(T) is the AUC within the dosing interval at steady state and T is the dosing interval (12 h).
Short report In addition, the following ratios were calculated for each subject and averaged for each group. R (a measure of linearity) = AUC(T) day 21 (2) AUC day 1 and Rac (a measure of accumulation) = AUC(T) day 21 (3) AUC (0-12) day 1 For statistical analysis, an analysis of variance model appropriate for the 2 x 2 factorial design was used, with P c 0.05 as the level of significance. The model incorporated effects due to sex, age, and an age-by-sex interaction term.
Results
Single dose study The mean concentrations of ticlopidine in plasma following administration to young and elderly subjects are shown in Figure 1. The mean concentration of ticlopidine in plasma at 1 h was 0.28 and 0.52 ,ug ml-' for the young and the elderly subjects, respectively. From 2-8 h, the concentrations of ticlopidine in plasma for elderly subjects were significantly greater than those in young subjects. The average plasma elimination halflife (t½.2 Z) of ticlopidine in elderly subjects (12.7 h) was significantly longer than that for young subjects (7.9 h, P = 0.013) (Table 1). Likewise, values for Cmax and AUC were significantly higher for elderly subjects than for young subjects.
¶s.DAYI
P.+k E..
~0.031_
s-0.001 _
763
Table 1 Pharmacokinetic parameters (mean ± s.d) of ticlopidine in young and elderly subjects
Parameters
Young
Elderly
12 0.41 (0.24) 2.0 (1.0-3.0)
13 0.70 (0.52) 2.0 (1.0-4.0) 12.7 (0.9) 2.8 (1.2)
P-value
Day 1 n
Cmax (,ug ml-') # tmax (h) t,12 z (h)
AUC(jxgml 'h) Day 21
7.9 (3.0) 1.4 (0.8)
12 11 0.89 (0.37) 1.42 (0.75) 1.0 (1.0-3.0) 2.0 (1.0-4.0) 98 (64) 91 (33) 3.6 (1.7) 8.3 (3.2) 0.30 (0.14) 0.69 (0.27) R 3.1 (1.6) 3.2 (0.8) 3.5 (5.5) 4.2 (3.0) Rac *Significantly different (P c 0.05). #Median value and the upper and lower range.
0.035* ns
0.013* 0.002*
n
Cmax (p.g ml-') # tmaX (h) t½/2z (h) AUC(p.gml-lh) Cav (Rg mI-1)
0.015* ns ns
0.001* 0.003*
Multiple dose study Administration of 250 mg ticlopidine twice daily to the young subjects resulted in mean trough plasma concentrations of 0.103, 0.187 and 0.146 pug ml- 1 on days 7, 14, and 21, respectively. At all time points, the trough concentrations for the elderly subjects were higher. Trough levels on weeks 2 and 3 of dosing were respectively 0.441 and 0.397 ,ug ml-' for elderly subjects. Steadystate trough concentrations (Css,min) were reached by 14 days. Figure 1 shows plasma concentrations of ticlopidine in young and elderly subjects following the last dose of ticlopidine on day 21. Values of tmax were 1.4 and 2.1 h for the young and the elderly subjects, respectively (Table 1). Values of Cmax were 0.89 and 1.42 ,ug ml-', respectively. The plasma elimination half-life (t,/2 Z) averaged 98 and 91 h for young and elderly subjects (P = 0.652). Mean Cay was greater for elderly than for younger subjects (P = 0.003). The mean R and Rac values were 3.1 and 3.5, respectively, for young subjects and 3.2 and 4.2 for elderly subjects, respectively. There was no significant effect of gender on the pharmacokinetics of ticlopidine after multiple doses.
.'I I
--|
Discussion
.1
0
OU..
0.1
Time in hours Figure 1 Mean (± s.e. mean) plasma ticlopidine concentrations in young (n = 12) (o) and elderly (n 13) (V) subjects a) day 1, b) day 21. *Significantly different P _ 0.05. =
-
Therapeutic use of ticlopidine will be mainly in older individuals. The present investigation was carried out to investigate the relative pharmacokinetics of ticlopidine in young and elderly normal volunteers. The increased AUC of ticlopidine observed in the elderly subjects could result from an increased extent of absorption from the gut or a decreased metabolic clearance. Any lowering of plasma albumin in old age (Shand, 1982; Vestal, 1978) is likely to mask an even greater difference in intrinsic clearance based upon unbound drug concentration. The degree of accumulation of ticlopidine in plasma on multiple dosing was similar in the young and elderly subjects. Values of R were greater than unity in both groups, t½l,z values were greater after
764
J. Shah et al.
multiple than single dosing and an increase was seen in Rac values. Possible explanations for these findings include an increase in bioavailability after repeated administrations of ticlopidine, saturation of the metabolism of ticlopidine or failure to detect the slow elimination phase after the single dose because of the sensitivity limit of the analytical method.
Recent studies in elderly subjects failed to demonstrate any differences in the effects of ticlopidine in elderly and young subjects (Molony, unpublished data). Thus the differences in the pharmacokinetics of ticlopidine between young and elderly subjects identified in this study should not contribute to any unexpected pharmacological or adverse effects.
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(Received 4 September 1990, accepted 7 August 1991)
