The effect of concurrent aspirin upon plasma concentrations of tenoxicam

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1 Br. J. clin. Pharmac. (1988), 26, The effect of concurrent aspirin upon plasma concentrations of tenoxicam R. 0. DAY, P. D. PAULL, S. LAM, B. R. SWANSON, K. M. WILLIAMS & D. N. WADE Departments of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney, N.S.W., 2010 and the School of Physiology and Pharmacology, University of New South Wales, Kensington, N.S.W. 2033, Australia 1 The effect of chronic, high-dose aspirin therapy upon the disposition of a single dose and multiple doses of tenoxicam was examined in normal volunteers. 2 Aspirin caused a 24% drop in the t½/2 (P < 0.005), a 49% rise in the volume of distribution (P < ) and a 98% increase in the clearance (P < ) of tenoxicam after a single dose of the tenoxicam. 3 Steady-state concentrations of tenoxicam decreased significantly from 10.4 ± 1.5 to 4.5 ± 1.6,ug ml-' in the presence of chronic, high-dose aspirin treatment. 4 Tenoxicam percentage free measured in plasma from a normal volunteer was % over the tenoxicam concentration range 1-20,ug ml-' and rose to 1.24 ± 0.07% in the presence of aspirin 150 p.g ml-'. 5 The effect of aspirin upon the disposition of tenoxicam was consistent with a competitive protein binding interaction. Keywords tenoxicam aspirin non-steroidal anti-inflammatory drugs protein binding drug interaction Introduction Tenoxicam (Ro ) is a non-steroidal antiinflammatory drug (NSAID). The drug is a thienothiazine derivative of the oxicam class. Tenoxicam inhibits prostaglandin synthesis, displays anti-inflammatory and anti-rheumatic activity in standard animal models and good efficacy and tolerability in the rheumatic diseases (Kirchheiner et al., 1982; Day et al., 1985; Gonzalez & Todd, 1987). The oral bioavailability of the drug is 99% and tenoxicam is bound extensively to albumin (> 99%). Tenoxicam has an average half-life of 70 h in normal volunteers but there is considerable intersubject variability (Francis et al., 1985; Heintz et al., 1984; Day et al., 1987). The drug is cleared from the body by metabolism with only 0.4% excreted unchanged in the urine. The major urinary metabolite is 5'- hydroxy-tenoxicam, which accounts for about 27% of the dose. Variable amounts of C-7 or C-8, o-glucuronides of tenoxicam are found in bile (Data on file, F. Hoffman La Roche, Basle, Switzerland). Despite little evidence for increased therapeutic benefit of combining aspirin with other NSAID in the treatment of rheumatic diseases, the practice is widespread. Aspirin and NSAID are greater than 90% bound to plasma albumin and a large number of protein binding displacement interactions between these drugs have been reported (Day et al., 1984). Total concentrations of NSAID fall in the presence of steady-state, anti-inflammatory concentrations of salicylates, presumably as a consequence of protein binding displacement. However, unbound concentrations of NSAID in vivo generally have not been measured in previous studies of interactions with aspirin. An exception is the study of Esquivel et al. (1984). These investigators examined the Correspondence: Dr R. 0. Day, Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Darlinghurst, Sydney, N.S.W., Australia

2 456 R. 0. Day et al. effect of concurrent aspirin therapy on the pharmacokinetics of single doses of isoxicam and found a significant decrease in the protein binding of isoxicam when aspirin was also taken. The majority of studies of the interactions of NSAID and aspirin have not examined the effect of aspirin on steady-state disposition of NSAID. The present study examines the effect of chronic, high dose aspirin therapy upon the disposition of total plasma tenoxicam concentrations following both single and multiple doses of tenoxicam. In addition the effect of aspirin on tenoxicam binding to plasma in vitro is examined. Methods These studies were approved by the Ethics and Research Committee of St Vincent's Hospital, Sydney. Eight normal volunteers gave informed consent to participate in the single and multiple dose tenoxicam studies respectively. The subjects were four males and four females with mean age 22 (range 21-24) years and mean weight 66 kg (range 56-80). Single dose tenoxicam studies Single doses of tenoxicam (20 mg tablets; batch number GPS 095 B 01 U 0301) were administered at h with 200 ml of water after an overnight fast which was continued for 4 h post-dosing. Venous blood samples of 10 ml were collected from a forearm vein into VacutainersTM which contained a small amount of sodium edetate (50 mg). Twenty samples were collected at prescribed times over a period of 15 days in order to encompass at least 4 to 5 half-lives of elimination. At the completion of this collection period, subjects were commenced on 650 mg slow release aspirin tablets (SRAT tablets; The Boots Company Australia Pty Ltd, batch number 345/ SS/B) in a dose of 1300 mg every 8 h with food to give a total daily dose of 3.9 g. The dose was reduced to 2.6 g day-' in subject TK after 4 days and after 5 days in MF because of gastrointestinal intolerance and tinnitus. Subject DS had the dose reduced to 3.25 g day1 after 10 days for severe tinnitus. The remaining five subjects tolerated 3.9 g day-'. Aspirin dosing was continued for 7 days so that plateau, anti-inflammatory concentrations of salicylates were achieved prior to the second single dose of tenoxicam. Aspirin dosing was continued for the subsequent 15 days of blood sampling in order to encompass the sampling period for the second dose of tenoxicam. Multiple dose tenoxicam study Five of the volunteers, three male and two female, completed this study. Volunteers SN, TK and AC were unable to complete the protocol because of gastrointestinal intolerance. The average age of the remaining five volunteers was 21.6 (range 21-22) years and average weight 66 (56-80) kg. Slow release aspirin had been administered for a total of 21 days at the completion of the single dose study. On day 22 (day 0 of the multiple dose study), the slow release aspirin was continued as before at a dose of 3.9 g day- l in three subjects, 3.25 g day-' in one subject and 2.6 g day-' in one subject. Regular dosing with tenoxicam 20 mg day-', taken at h, also commenced on day 0 of the multiple dose study. Venous blood was collected into VacutainerTM tubes at h ondays l, 4, 6, 8, 11, 13, 15, 18, l9and20ofthe multiple dose study in order to follow the approach to steady-state concentrations of tenoxicam. Additional blood was taken on day 19 at 2, 4, 6, 8 and 12 h after the dose of tenoxicam in order to determine plasma tenoxicam concentrations during a dosage interval at steady-state. Slow release aspirin administration was ceased after the evening dose on day 19 of the multiple dose study but tenoxicam dosing was continued until day 34. Venous blood samples were taken at h on days 22, 25, 27, 29, 32, 33 and 34 in order to observe the establishment of the new steady-state concentrations of tenoxicam. On day 33 blood was collected at 2, 4, 6, 8 and 12 h after dosage with tenoxicam to determine plasma tenoxicam concentrations during a dosage interval at steady-state in the absence of aspirin. Analysis of total plasma tenoxicam concentrations Plasma tenoxicam concentrations were measured by h.p.l.c. (Day et al., 1987). The absolute recovery of drug was determined to be 98% from spiked plasma samples and interassay coefficients of variation were < 4.2% for concentrations of 2 and 10,ug ml-1 respectively (n = 6). The sensitivity of the assay was 0.1,ug ml- with a signal to noise ratio of 350: 1. Studies of tenoxicam binding to plasma in the presence and absence of aspirin Unbound tenoxicam concentrations were measured on most plasma samples collected in the single-dose and multiple dose arms of the study. Unbound tenoxicam was measured by ultrafiltration using [14C]-labelled tenoxicam.

3 Tenoxicam aspirin interaction 457 These data are not presented because subsequent work (manuscript in preparation) has led to a lack of confidence in the accuracy of these unbound concentration results. Tenoxicam binding to plasma in vitro, however, was examined following resolution of the problems with the unbound tenoxicam assay. Tenoxicam standards (1, 5, 10 and 20 p.g ml-') were established in a normal volunteer's plasma and the effect of salicylate (150,ug ml-') on the free fraction of tenoxicam was determined. Unbound concentrations of tenoxicam were measured by ultrafiltration of plasma after addition of a known amount of radiolabelled tenoxicam. [14C]-tenoxicam (specific activity 84,uCi mg'1; lot number PD IV/147) was obtained from F. Hoffman La Roche A. G., Basle. Purity was checked repeatedly by thin layer chromatography using chloroform/acetone/methanol/ acetic acid in the proportions 80/20/10/2. The [I4C]-tenoxicam was dissolved in sodium chloride solution (0.9%) such that 10,ud contained 76,000 d min-1 and 740 ng of tenoxicam. [14C]-tenoxicam (10,ul) solution was added to plasma (1 ml) and the sample was mixed. A small volume (20,ul) of the mixture was removed and added to PCSTM Scintillation Solution (Amersham) and counted (5 min) in a Packard Liquid Scintillation Counter (Tri-Carb, 4000 series) to determine total counts. The balance of the mixture was centrifuged (20 min at 2000 g) through a CentrifreeTM filter (Amicon), at 25 C. Tenoxicam binding, estimated using this method but performed at 37 C, was not different. An aliquot of the ultrafiltrate (200,ul) was mixed with PCS and counted. The 'fraction free' was calculated by dividing the unbound counts by the total counts and this was expressed as the 'percentage free' by multiplying the fraction free by 100. The free, or unbound concentration of tenoxicam was calculated by multiplying the free fraction by the total tenoxicam concentration derived from the h.p.l.c. measurements. Analysis of total plasma salicylate concentrations Steady-state concentrations of salicylate were monitored, in order to assess compliance, using the method of Trinder (1954). Data analysis and statistics It was assumed that absorption of tenoxicam was complete as previous studies had reported the bioavailability to be >99% (Heintz et al., 1984). The areas under plasma tenoxicam concentrationtime curves (AUC) for each individual following single doses and during a dosage interval at steady-state were calculated by the trapezoidal rule. The area under the first moment curve (AUMC) was calculated for the single doses of tenoxicam, using the trapezoidal rule, from the relationship between elapsed time and the product of time by concentration (Gibaldi & Perrier, 1982). In the single dose study, the AUC to infinity was estimated by adding the quotient C(360 h) to the AUC computed up to kel 360 h. The concentration at 360 h was less than 2% of the peak concentrations so that the area, up to 360 h, is essentially equivalent to AUC(o,). The elimination rate constant kel was estimated from the terminal slopes of the log concentration tenoxicam-time curves for each individual, measured between 24 and 360 h using least squares linear regression analysis. The total clearance, CL, was computed by a model independent procedure from the ratio of drug dose divided by AUC, either following single doses of tenoxicam, or during the dosage interval at steady-state. Average steady-state concentrations of tenoxicam were computed by dividing the AUC during a dosage interval by the dosage interval. The steady-state volume of distribution, Vss, also was estimated by a model independent procedure: Vss = D* where D is the dose of AUC2 tenoxicam (Gibaldi & Perrier, 1982). Peak tenoxicam concentrations and the time taken to reach peak concentrations following the single doses of tenoxicam, were obtained from visual inspection of individual plasma tenoxicam concentration-time relationships. Group data are presented as the mean with one standard deviation. Statistical tests employed in this study were parametric: Student's paired t- test and analysis of variance. Results Single dose pharmacokinetics of tenoxicam Total tenoxicam The effect of concurrent administration of aspirin on the mean disposition of a single dose of tenoxicam is shown in Figure 1. Aspirin was associated with a 24% decrease in the tl, (P < 0.005) and significant increases in Vss (49%; P < ) and CL (98%; P < ) of tenoxicam (Table 1). The mean peak concentration of tenoxicam was 3.0 ± 0.6,ug ml-l in the absence of aspirin

4 458 R. 0. Day et al. 3.0 E C 0 co a) E m Time (h) Figure 1 The effect of concurrent, high-dose aspirin on the disposition of a single, 20 mg dose of tenoxicam. Mean data for eight normal volunteers is presented. + without aspirin, 0 with aspirin. Table 1 The effect of aspirin upon total clearance (ml h- 1), volume of distribution (1) and half-life of elimination (h) of tenoxicam following a single dose of tenoxicam Vsst,,2 CL Subjects (ml h-') (1) (h) Weight Sex (kg) No ASA ASA No ASA ASA No ASA ASA SN M DS* M MM* M MY* M TK F MF* F JW* F AC F Mean Paired t-test P < P < P < * Subjects who also participated in the multiple dose tenoxicam study. and 2.3 ± 0.7,ug ml-' with concurrent aspirin, a the presence and absence of aspirin over a range 23% reduction (P < 0.02). The mean time to of tenoxicam concentrations of 1 to 20,ug mlpeak concentration of tenoxicam alone was 2.9 revealed a percentage free of 0.56 ± 0.05% in ± 2.7 h but this was biased by subject MF, who the absence of aspirin and 1.24 ± 0.07% in the did not achieve a peak concentration until 9 h presence of aspirin (P < 0.001; paired t-test, after administration. With concurrent aspirin, degrees of freedom 14). There was no significant the time to peak concentration was 1.8 ± 0.9 h, change in the percentage free of tenoxicam over which was not significantly different from the range of tenoxicam concentrations studied in tenoxicam alone. When subject MEF was excluded the absence of aspirin. from this analysis, the mean times to peak were 2.0 with tenoxicam alone and 1.8 with concurrent Salicylate concentrations Trough concentrations aspirin, again not significantly different. of salicylate were monitored throughout (n = 11 for each subject) the 15 day collection period Unbound tenoxicam concentrations - in vitro following the single dose of tenoxicam and Studies of tenoxicam binding to plasma in vitro in compliance appeared to be generally satisfactory.

5 There was a significant decline in trough salicylates over this period from 201 ± 84.0 to 123 ± 86.2,tg ml-' (P < 0.005). This can be explained by: the dose reductions for TK, MF and DS; four short episodes of apparent reduced compliance, maximum duration of 3 days, in subjects SN, DS and MY towards the end of the 15 day collection period; the expected decline in steady-state salicylate concentrations, due to auto-induction of its metabolism (Day et al., 1983, 1988; Rumble et al., 1980). Overall, the mean concentration of salicylate during these 15 days was ,ug ml-' (n= 88). Tenoxicam aspirin interaction 459 Multiple dose pharmacokinetics of tenoxicam Total tenoxicam Steady-state, trough tenoxicam concentrations decreased significantly from ,ug ml-' in the absence of chronic aspirin treatment to 4.5 ± 1.6,ug ml- 1 in the presence of aspirin (Figure 2). Similarly, concurrent aspirin caused a significant drop in average, steady-state tenoxicam concentrations during a dosage interval of 44% and an increase in CL of 81% (Table 2, Figure 3) E =L 8 0 * 406 Co._ E / co Time (h) Figure 2 Mean trough concentration of tenoxicam during the 36 days of dosing with tenoxicam 20 mg day-' in the presence (days 0-20) and absence (days 21-36) of high-dose aspirin. The mean trough concentrations have been fitted to an expression suitable for a two compartment, open pharmacokinetic model of the form, Cmjn = C1-C2 * ekt where Cmin is the trough concentration at time t, Cl and C2 are plasma concentrations and k is the elimination rate constant (Gibaldi & Perrier, 1982). Table 2 The effect of high-dose aspirin (ASA) upon the average steady-state concentrations of tenoxicam (TEN;,ug ml-1) and its steady-state clearance (ml h-') and volume of distribution (1) Average SAL Average TEN CL Subject (,ug ml-]) (>±g ml-') (ml h-') No ASA ASA No ASA ASA DS MM MY MF JW Mean Paired t-test P < P < 0.005

6 460 R. 0. Day et al. 20r E 15 C a) C.)- 0 CD 0~ c II Time (h) Figure 3 Effect of concurrent high-dose aspirin on plasma concentrations of tenoxicam during a dosing interval at steady-state. Comparison of single and multiple dose kinetic parameters Comparison of the data in Tables 1 and 2 shows that the total clearance decreased by 20%, when tenoxicam was given in multiple doses, as compared with its clearance following the single dose. This figure increased to 27% in the presence of aspirin. Two way analysis of variance (ANOVA) revealed that the change from single to multiple dose was a significant contribution to the changes in CL observed (F = 35.7; P < 0.001) as was the co-administration of aspirin (F = 17.3; P < 0.001). Discussion Concurrent aspirin caused significant reductions in plasma tenoxicam concentrations, following single doses of tenoxicam, and also during multiple dosing with tenoxicam. This result is in agreement with many studies of the interactions of other NSAID and aspirin (Day et al., 1984). Aspirin did not alter the time taken to reach peak tenoxicam concentrations, following a single dose of tenoxicam, but did significantly reduce peak concentrations achieved. The lack of effect of aspirin upon the time to peak concentrations of tenoxicam suggests that interference with absorption by aspirin is unlikely. As indicated from the present study, the effect of aspirin upon tenoxicam plasma concentrations is attributable to an increase in total body clearance of the NSAID. This finding, together with the observed increase in tenoxicam free fraction in vitro, is consistent with a competitive albumin binding interaction between tenoxicam and aspirin (Rowland & Tozer, 1980). Competition between aspirin and NSAID for albumin binding sites nas been demonstrated in vitro for many NSAID. Two major binding sites for drugs have been identified on albumin and most NSAID bind preferentially to site II, although phenylbutazone and oxyphenbutazone bind to site I (Sudlow et al., 1976). It is now generally accepted that protein binding interactions in vivo involving highly-bound, low clearance drugs, such as NSAID, usually do not lead to alterations in steady-state, unbound concentrations of displaced drugs. although the free fraction will change (Rowland & Tozer, 1980). This is because the clearance of the unbound displaced drug is not altered unless the drug is subject to non-linear elimination processes such as saturable metabolism. Assuming that the steady-state unbound clearance of tenoxicam is not altered by concurrent aspirin, the observed increase in percentage free from 0.56 to 1.24 (120% increase) would be associated with an increase in steady-state, total clearance of 120% (Rowland & Tozer, 1980) since, at steadystate, the total clearance of a drug is equal to the product of its free fraction by unbound clearance (Rowland & Tozer, 1980). In fact, in the present study, total clearance of tenoxicam, at steadystate, increased by 81% with concurrent aspirin. However, the in vitro binding data presented can only be taken as a rough guide to the in vivo unbound tenoxicam concentrations, as the in vitro study was performed in one plasma sample not belonging to any of the volunteers in the

7 Tenoxicam aspirin interaction 461 tenoxicam dosing study. Also, the clearance obtained during tenoxicam steady-state is based on a small number of subjects. The data presented therefore do not rule out the possibility that some of the dispositional changes induced by aspirin, though largely due to a protein binding displacement interaction, may be due to changes in the unbound clearance of tenoxicam. The current study may be criticised because the order of treatments was not randomized. This could not be avoided for logistical and ethical reasons. Given the long half-life of elimination of tenoxicam, the treatment order for the combined single and multiple dose study led to the minimum possible study duration, although the study remained very long and difficult for the volunteers. The results of this study indicate that the concentrations of tenoxicam, achieved during multiple dose therapy, may not be precisely predicted by the single dose kinetic parameters because of the reduction of total clearance at steady-state. However, the steady-state clearance was calculated from a smaller number of subjects than the single-dose study and is therefore less reliable. A recent study in 12 normal volunteers indicated that clearance, elimination half-life and apparent volume of distribution were independent of dose over a single-dose range of 10 to 40 mg (Francis et al., 1987). The mean peak concentration achieved in the latter study, following the 40 mg dose, was 5.34,ug ml-l, which is lower than the average steady-state concentrations achieved in the present study (10.4 pg ml-'). It might be expected that combinations of aspirin and NSAID would lead to enhanced pharmacodynamic effects as the unbound concentrations of aspirin would exert effects in addition to those exerted by the unbound concentrations of the NSAID (e.g., tenoxicam). The assumption here is that unbound plasma concentrations of NSAID and/or aspirin will determine the amount of anti-inflammatory activity achieved by these drugs. This assumption remains unproven but is generally accepted. The observation that there is a linear relationship between dose or plasma concentration of NSAID and anti-inflammatory effect is supportive of this view, given that there is a direct relationship between unbound concentrations of NSAID and total concentrations (Day et al., 1982; Dunagan et al., 1986). However, other investigators have not found significant relationships between plasma concentrations of single NSAID and clinical efficacy (see Orme, 1982). Most studies of combinations of aspirin with NSAID have failed to show increases in clinical effect for the combination, although at least three studies have demonstrated marginal, but clinically unimportant, enhancement of antiinflammatory efficacy (Wilkens & Segre, 1976; Grennan et al., 1979; Furst et al., 1987). Thus, in general, there would appear to be little rationale for the combination of NSAID with oral aspirin therapy in the treatment of rheumatic diseases. The authors would like to thank Ms K. O'Shea and Mr P. Otrebski for technical assistance, Sister A. Borthwick for managing the study and collection of blood samples and F. Hoffman La Roche, Basle for financial support. The authors would also like to thank Drs G. Graham, University of New South Wales and K. Brown and I. Gonda, University of Sydney for helpful advice. References Bird, H. A., Allen, J. G., Dixon, J. S. & Wright, V. (1985). A pharmacokinetic comparison of tenoxicam in plasma and synovial fluid. Br. J. Rheum., 24, Day, R. O., Shen, D. & Azarnoff, D. L. (1983). Inducton of salicyluric acid formation in rheumatoid arthritis treated with salicylates. Clin. Pharmacokin., 8, Day, R. O., Lam, S., Paull, P. D. & Wade, D. N. (1987). Effect of food and various antacids on the absorption of tenoxicam, a new non-steroidal antiinflammatory agent. Br. J. clin. Pharmac., 24, Day, R. O., Furst, D. E., Dromgoole, S. H. & Paulus, H. E. (1988). Decline in steady-state serum salicylic acid concentrations with high-dose salicylic acid theapy. Biopharm. Drug Dispos. (in press). Day, R. O., Furst, D. E., Dromgoole, S. H., Kamm, B., Rowe, R. & Paulus, H. E. (1982). Relationship of serum naproxen concentration to efficacy in rheumatoid arthritis. Clin. Pharmac. Ther., 31, Day, R. 0, Dejager, J., Sambrook, P., Bieri, D., Borthwick, A., McGirr, E., Champion, G. D., Cohen, M. C. & Browne, C. (1985). Tenoxicam (Ro ) in osteroarthrosis: a controlled trial using the McGill pain questionaire (abstract). Aust. N. Z. J. Med., 15, Suppl. 1, 187. Day. R. O., Graham, G. G., Champion, G. D. & Lee, E. (1984). Clinically significant drug interactions with anti-rheumatic drugs. Clin. Rheum. Dis., 10, Dunagan, F. M., McGill, P. E., Kelman, A. W. & Whiting, B. (1986). Quantitation of dose and concentration-effect relationships for fenclofenac in rheumatoid arthritis. Br. J. clin. Pharmac., 21, Esquivel, M., Cussenot, F., Ogilvie, R. I., East, D. S.

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