Pharmacokinetics of the trimethoprim-sulphamethoxazole combination in the elderly

Transcription

1 Br. J. clin. Pharmac. (1985), 20, Pharmacokinetics of the trimethoprim-sulphamethoxazole combination in the elderly 0. VAROQUAUX1, D. LAJOIE2, C. GOBERT3, P. CORDONNIER1, C. DUCREUZET2, M. PAYS1 & C. ADVENIER1 'Centre Hospitalier de Versailles, Laboratoires de Pharmacologie et de Biochimie, 177, rue de Versailles, F Le Chesnay, 2Centre Hospitalier de Versailles, Service de Geriatrie, 1, rue Richaud, F Versailles and 3Hospice Intercommunal, 74, avenue de Stalingrad, F Fontenay/Bois, France 1 The pharmacokinetics of a co-trimoxazole preparation (Bactrim Forteg) containing trimethoprim (TMP) 160 mg and sulphamethoxazole (SMZ) 800 mg were determined in six young adults (29.3 ± 4.4 s.d. years) and six elderly people ( s.d. years). 2 Following oral administration of a single dose, the pharmacokinetic parameters of SMZ and its N4-acetylated metabolite (N4SMZ) were similar in both groups. However Cmax of TMP was greater ( s.d. vs s.d. mg 1-1; P < 0.01) and its area under the curve was larger ( s.d. vs s.d. mg 1-' h; P < 0.001) in elderly people than in younger subjects. Total clearance (CLIF) of TMP normalized to body weight was not significantly different in the two groups. 3 There was no significant difference in serum protein binding of TMP and SMZ between the two groups. 4 Urinary excretion of TMP, SMZ and N4SMZ was reduced by about 50% in the elderly compared to the young subjects. Renal clearance of TMP was significantly lower in the elderly group ( s.d. vs s.d. ml h-1 kg-'; P < 0.001). Renal clearance of SMZ was not significantly different in the two groups. 5 A study of plasma concentrations of TMP, SMZ and N4SMZ during continuous dosing in seven elderly patients treated for urinary or respiratory infections showed that steady state was reached after 3 days of treatment and that plasma drug concentrations were about two to three times higher than those observed after a single dose. Keywords trimethoprim sulphamethoxazole pharmacokinetics elderly Introduction Changes in the kinetics of drugs in elderly people systematic reduction of dosage may render treathave often been reported (Crooks et al., ment ineffective, and this could be particularly 1976; Mitchard, 1979; O'Malley et al., 1981; dangerous in the case of antibacterial agents. Greenblatt et al., 1982). A slower metabolic Among antibacterial drugs, the trimethoprimbreakdown of drugs with subsequent increase in sulphamethoxazole combination known as cotheir plasma concentrations may result in en- trimoxazole is used against a variety of infechanced toxicity when 'standard' doses are tions, notably in elderly patients, but to our administered to elderly patients. Conversely, knowledge no pharmacokinetic study of its Correspondence: Dr 0. Le Chesnay, France Varoquaux, Centre Hospitalier de Versailles, 177, rue de Versailles, F

2 Varoquaux et al. constituents has yet been conducted in such patients. The purpose of the present study was to compare the pharmacokinetics of trimethoprim (TMP), sulphamethoxazole (SMZ) and its N4- acetylated metabolite (N4 SMZ) in elderly and young patients. Methods Single dose pharmacokinetics Six young volunteers (four men and two women, mean + s.d. age years) and six elderly volunteers (one man and five women, mean ± s.d. age years) entered the study after being informed fully of its purpose and giving written consent. Before the experimental procedure began, both young and elderly subjects underwent a thorough clinical examination. All were found to have haemoglobin, plasma BUN, creatinine, electrolytes, bilirubin, total proteins, SGOT and SGPT levels within the normal range for their age and sex. Subjects with a history of cardiac, renal, hepatic or gastrointestinal disease and those receiving major medical treatments were excluded beforehand. None of the subjects investigated had taken drugs for 24 h at the time of investigation. After a 12 h fast, all subjects received one single tablet of a co-trimoxazole preparation (Bactrim Forte ) containing trimethoprim 160 mg and sulphamethoxazole 800 mg. They continued to fast for 2 h after which they were allowed a light breakfast. Venous blood samples were drawn 0.25, 0.50, 1, 1.50, 2, 3, 4, 6, 8, 12 and 24 h after dosing. Blood was collected into heparinized tubes; plasma was separated by centrifugation and stored at -60 C. Urines were collected over 48 h in five fractions: viz. 0-4, 4-8, 8-12, and h; they were also stored at -60 C. Serum protein binding Six hours after a first dose of the trimethoprimsulphamethoxazole combination, venous blood samples were taken from six elderly people (mean + s.d. age years) with respiratory or urinary infection justifying the use of this antibacterial agent and from six young healthy volunteers (mean + s.d. age years) who gave their informed consent. The sera were separated, kept frozen at -60 C and defrosted immediately before dialysis. Protein binding was measured by the equilibrium dialysis technique, using a Dianorm apparatus (Diachema A. G.) with multiple cells, each cell consisting of two 2.5 ml chambers separated by a semi-permeable Cellophane membrane (Diachema 1015). In all studies one of the chambers was filled with 1 or 2 ml of serum, the other with 1 or 2 ml of a M phosphate buffer at ph 7.4, prepared according to Woo & Greenblatt (1979). The composition of the buffer per litre was: Na2HPO4, 2H20: 14.6 g; KH2PO4: 2.59 g and NaCl: 1.99 g. The cells were placed in a water bath at 37 C and agitated by slow rotation for 4 h. A preliminary study carried out had shown that equilibrium was reached within 4 h and that trimethoprim and sulphamethoxazole did not adhere significantly to the membrane. At the end of the equilibration period, the sera and the buffer solution were removed from the cells and assayed for trimethoprim, sulphamethoxazole and N4SMZ. Protein binding was calculated from the equation: C- Cb X 100 where C is the concentration in serum and Cb the concentration in the buffer phosphate. No corrections were made for volume shifts. Plasma drug concentrations in elderly patients during continuous dosage This part of the study was carried out in seven elderly patients (two men and five women, mean age s.d. years). Five patients (numbers 2, 3, 4, 5 and 7) presented with urinary tract infection and two patients (numbers 1 and 6), with respiratory infection. They received one tablet of the same co-trimoxazole preparation twice a day until they were cured. Venous blo3d samples were drawn 3 h after the morning dose on days 1, 3 and 5 of treatment. In addition to a urinary tract infection, patient 2 had arterial hypertension and arteritis of the lower limbs and was taking buflomedil and clonidine; patient 3, also with arteritis, was being treated with gliclazide and pentoxifylline, and patient 5, with chronic heart failure, was receiving digoxin and amiodarone. TMP, SMZ and N4SMZ assays TMP, SMZ and N4SMZ concentrations were measured in plasma and urine by high performance liquid chromatography (Spreux- Varoquaux et al., 1983). Calculations For each subject and each compound the rate constant of the terminal phase of elimination, Xz

3 was calculated by least squares regression of logplasma drug concentration vs time data. The corresponding half-life was calculated from: Trimethoprim sulphamethoxazole in the elderly 577 t= (1) Lag time for absorption was defined as the intersection of the extrapolated elimination and residual curves. Areas under the curve (AUC) were measured by the trapezoidal method and extrapolated to infinity according to: AUC = AUC(t) + Kt (2) where C(t) is plasma concentration in the last sample. CL/F was obtained from: CL _ F D AUC (3) where D is the dose oftmp or SMZ administered and F is the bioavailability. Renal clearances of TMP and SMZ were calculated from the amount excreted in the 24 h urine divided by AUC at 24 h. md 50- E 0Lo* 25- x m 0 c. _ I 400 ). E 300 E Time (h) Figure 2 Cumulative urinary excretion of trimethoprim (TMP), sulphamethoxazole (SMZ) and N4- acetylsuphamethoxazole (N4SMZ) in six young adults (0) and six elderly subjects (0) after oral administration of a single dose of TMP 160 mg and SMZ 800 mg. Points represent mean ± s.e. mean values. Statistical analysis of the results ~ ~ ~ ~ ~~I II E c 0 Statistical analysis of the results was performed using student's t-test. Values in the text are mean ± s.d. o Time (h) Figure 1 Mean s.e. mean plasma concentration vs time of trimethoprim (TMP), sulphamethoxazole (SMZ) and N4-acetylsulphamethoxazole (N4SMZ) in six young adults (o) and six elderly subjects (o) after oral administration of a single dose of TMP 160mg and SMZ 800 mg. Results Single dose study Mean plasma concentrations and 48 h cumulative urinary excretion of TMP, SMZ and N4SMZ are shown in Figures 1 and 2. Pharmacokinetic values, calculated from the plasma data on each subject, are given in Tables 1, 2 and 3. The halflife of N4SMZ must be considered as apparent and cannot be calculated with accuracy, since this compound was formed significantly and excreted throughout the study period. Pharmacokinetic values of SMZ and N4SMZ were not significantly different in young and elderly subjects. However, there were

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5 Trimethoprim sulphamethoxazole in the elderly Table 2 Pharmacokinetic values of sulphamethoxazole after oral administration of 800 mg to six young and six elderly subjects - Age, weight and sex of subjects are described in Table 1. fe (48) is the fraction of the dose excreted in 48 h urine. Lag time C t",= t1, AUC CL/F CL Subjects (h) (mg ') (h) (h) (mg t' h) (ml h-' kg') fe (48) (ml h- kg') Young subjects Mean s.d Elderly subjects Mean s.d P NS NS NS NS NS < 0.05 NS 579 Table 3 Pharmacokinetic values of N4-acetylsulphamethoxazole after oral administration of 800 mg sulphamethoxazole to six young and six elderly subjects; age, weight and sex of the subjects are described in Table 1. fe (48) is the fraction of the dose excreted in 48 h urine. C, t x t* z Subjects (mg U') (h) (h) fe (48) Young subjects Mean s.d Elderly subjects Mean s.d P NS - NS < 0.05 significant age-related differences in the kinetics of TMP (Table 1): Cma (P < 0.01) and AUC (P < 0.001) values were higher in the elderly subjects. Serum protein binding of TMP ( % in the elderly, and % in young subjects) and of SMZ (60.1 ± 8.8% in the elderly, and % in young subjects) were not significantly different in the two groups. The amounts of TMP, SMZ and N4SMZ recovered in the 48 h urines were significantly smaller in the elderly group. Renal clearance of TMP was significantly lower (P < 0.001) in the elderly than in the young subjects (Table 1), but metabolic clearance, estimated from (CL/F)- CLR was not significantly different in the two groups ( ml h-1 kg71 in the elderly vs ml h-1 kg~1 in young subjects). Renal clearance of SMZ was not significantly different in the two groups. Repeated dose study Individual plasma concentrations of TMP, SMZ and N4SMZ 3 h after dosing on days 1, 3 and 5 of co-trimoxazole treatment in seven elderly patients with urinary tract or respiratory infections are shown in Figure 3. Plasma concentrations of all three substances were approximately the same on day 3 and on day 5 in five patients; in two patients (number 2 and 5), TMP and SMZ (but not N4SMZ) concentrations were distinctly higher on day 5 than on day 3. However, no significant difference in plasma drug concentrations between day 3 and day 5 was noted in this group of patients as a whole.

6 Varoquaux et al. L~ ~ ~~~~fx ID\0$ * IE 0; t.50~~~~~~5 {1!AP 1 1 Dy Psl 3 6, Figure 3 Individual plasma concentrations of trimethoprim (TMP), sulphamethoxazole (SMZ) and N4-acetylsulphamethoxazole (N4SMZ) in seven elderly subjects with urinary or respiratory infection. Blood samples were taken 3 h after the first (morning) of two daily doses oftmp 160 mg and SMZ 800 mg. Discussion Our results concerning the pharmacokinetics and serum protein binding of the drugs in young subjects were in agreement with data from the literature (Bach etal., 1973; Bergan etal., 1979; Kaplan et al., 1973; Patel & Welling, 1980; Schwartz & Rieder, 1970; Welling et al., 1973). The amounts of TMP, SMZ and N4SMZ excreted in the 48 h urines were slightly lower than those reported by Patel & Welling (1980) and by Nolte & Buttner (1983), but were similar to those reported by Bergan etal. (1979) and by Kaplan et al. (1973). In elderly people, the pharmacokinetic values and the serum protein binding of SMZ and N4SMZ, calculated from plasma or serum data were not very different from those found in younger adults. The renal clearance of TMP was significantly reduced and the AUC and Cm,a, were significantly increased in elderly people as compared with younger subjects. However, these significant changes observed with the first dose of TMP appeared to have little influence on other pharmacokinetic values, such as t,,z or CLIF kg-' body weight, which were not significantly modified. They also had negligible effects on steady state plasma drug concentrations after repeated doses, since these were two or three times higher on days 3 and 5 than after administration of a single dose, as is the case with young subjects (Kaplan et al., 1973; Nolte & Buttner, 1983; Patel & Welling, 1980). The significant changes observed in AUC and Cmax of TMP in elderly people seem to be attributable to reduced renal clearance, since the apparent metabolic clearance and protein binding of this compound were not significantly modified. In conclusion, the plasma concentrations of trimethoprim and sulphamethoxazole were found to be only slightly modified in a group of elderly people as compared with young adults, and this suggests that there may be no need to reduce co-trimoxazole dosage for pharmacokinetic reasons when treating infections in elderly patients, provided that renal function is not markedly impaired. The authors wish to thank Dr G. Roux, Paris, for his English translation. References Bach, M. C., Gold, 0. & Finland, M. (1973). Absorption and urinary excretion of trimethoprim, sulfamethoxazole and trimethoprim-sulfamethoxazole: results with single dose in normal young adults and preliminary observations during therapy with trimethoprim-sulfamethoxazole. J. infect. Dis., 128 (suppl), S584-S599. Bergan, T., Brodwall, E. K., Vik-Mho, H. & Anstad, U. (1979). Pharmacokinetics of sulfadiazine, sulfamethoxazole and trimethoprim in patients with varying renal function. Infection, 7 (suppl), 382S-386S. Crooks, J., O'Malley, K. & Stevenson, I. H. (1976). Pharmacokinetics in the elderly. Clin. Pharmacokin., 1, Greenblatt, J. O., Sellers, E. M. & Shader, R. I. (1982). Drug disposition in old age. New Engl. J. Med., 306, Kaplan, S. A., Weinfeld, R. E., Abruzzo, C. W., McFadden, K., Jack, M. L. & Weissman, L. (1973).

7 Pharmacokinetic profile of trimethoprimsulfamethoxazole in man. J. infect. Dis., 128 (suppl), S547-S555. Mitchard, M. (1979). Drug distribution in the elderly. In Drugs and the Elderly, eds Crooks, J. & Stevenson, I. H., pp London: MacMillan. Nolte, H. & Buttner, H. (1983). Pharmacokinetics of trimethoprim and its combination with sulfamethoxazole in Man after single and chronic oral administration. Chemotherapy, 18, O'Malley, K., Crooks, K., Duke, E. & Stevenson, I. H. (1981). Effect of age and sex on human drug metabolism. Br. med. J., 3, Patel, R. B. & Welling, P. G. (1980). Clinical pharmacokinetics of co-trimoxazole (trimethoprim + sulfamethoxazole). Clin. Pharmacokin., 5, Reeves, D. S. & Wilkinson, P. J. (1979). The pharmacokinetics of trimethoprim and trimethoprim/ sulfonamide combinations, including penetration in body tissues. Infection, 7, 330S-341S. Trimethoprim sulphamethoxazole in the elderly 581 Schwartz, D. E. & Rieder, J. (1970). Pharmacokinetics of sulfamethoxazole + trimethoprim in man and their distribution in the rat. Chemotherapy, 15, Spreux-Varoquaux, O., Chapalain, J. P., Cordonnier, P., Advenier, C., Pays, M. & Lamine, L. (1983). Determination of trimethoprim, sulfamethoxazole, and its N4 acetyl metabolite in biological fluids by high-performance liquid chromatography. J. Chromatogr., 274, Welling, P. G., Craig, W. A., Amidon, G. L. & Kunin, C. M. (1973). Pharmacokinetics of trimethoprim and sulfamethoxazole in normal subjects and in patients with renal failure. J. infect. Dis., 128 (suppl), Woo, E. & Greenblatt, D. J. (1979). Pharmacokinetic and clinical implications of quinidine protein binding. J. pharm. Sci., 68, (Received 3 October 1984, accepted 8 August 1985)