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Effects of Age on the Clinical Pharmacokinetics of Ibuprofen
Effects of Age on the Clinical Pharmacokinetics of Ibuprofen
KENNETH S. ALBERT, Ph.D. WILLIAM R. GILLESPIE, M.S. JOHN G. WAGNER, Ph.D. ALICE PAU, Pharm.D. G.F. LOCKWOOD, Ph.D. Kalamazoo, Michigan
The pharmacokinetics of ibuprofen (Motrin) were studied in 17 normal elderly men and women aged 65 to 78 ·years. Total and free unbound plasma concentrations of Ibuprofen were determined 12 hours after single oral doses of 400, 800, and 1,200 mg. These results were then compared with those of a similar study involving 15 normal young men 22 to 35 years old. The two age groups showed no statistically significant differences in any pharmacoklnetlc parameter studied. Therefore, according to this study, advanced age has only minimal Influence on the pharmacokinetics of ibuprofen, and dosage apparently does not need to be adjusted fol' age. Ibuprofen (Motrin, Upjohn) is a widely prescribed nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of osetoarthritis and rheumatoid arthritis. Because the incidence of these conditions increases with age, the elderly represent a significant proportion of patients Ul~ing ibuprofen. Radiologic evidence of osteoarthritis was found in 87 percent of men and 74 percent of women aged 65 to 74 years [1], and an estimated 50 percent of patients with rheumatoid arthritis are more than 50 years old [2]. Yet the pharmacokinetic activity of the NSAIDs in this age group has not been well described [3] despite the implication of age-related kinetic changes as the cause of increased adverse reactions, Including fatal cholestatic jaundice, in geriatric patients taking benoxaprofen [4-6]. Therefore, the present study was undertaken to evaluate the pharmacokinetics of a single oral dose of ibuprofen in 17 normal, relatively healthy, elderly men and women and to compare these findings with those in a similar trial in young adult volunteers.
METHODS Subjects. Seventeen normal, relatively healthy, elderly volunteers particiFrom the Upjohn Center for Clinical Pharmacology, the Upjohn Company, Kalamazoo, and the College of Pharmacy, the University of Michigan, Ann Arbor, Michigan. Requests for reprints should be addressed to Dr. K.S. Albert, Upjohn Center for Clinical Pharmacology, Upjohn Company, Kalamazoo, Michigan, 49001. The work presented was based on the admioistration of Motrin tablets, aregistered trademark of the Upjohn Manufacturing Company.
pated in the study, after written informed consent, physical examination, and blood and urine analyses were obtained. The subjects ranged in age from 65 to 78 years (mean 70) and in body weight from 54 to 89 kg (mean 69). No participant was receiving any drug on a long-term basis when recruited into the study. No new drug therapy, short- or long-term, was initiated for at least seven days before or during the study. Study Design. The study was approved for use in human subjects by an institutional review board. Single oral doses of 400, 800, and 1,200 mg of ibuprofen were administered in tablet form to each subject according to a three-way Latin-square crossover experimental design. The volunteers were required to fast for nine hours before and four hours after drug administration. Treatment phases were separated by seven days.
July 13, 1984
The American Journal of Medicine
47
IBUPROFEN SYMPOSIUM-GILLESPIE ET AL
TABLE I
Mean Plasma Concentrations of Total and Free Ibuprofen in 17 Elderly Volunteers after a Single Oral Dose Free Concentration (ng/ml)
Total Concentration (lLg/ml) Time (hours) 0.167 0.333 0.5 1.0 1.5 2.0 3.0 4.0 6.0 8.0 10 12
400 mg
800 mg
1,200 mg
400 mg
800 mg
1,200 mg
0.15 (0.15)* 8.46 (1.94) 19.9 (3.30) 32.5 (2.91) 30.4 (1.92) 29.2 (1.29) 20.3 (1.27) 15.6 (1.29) 6.08 (0.55) 3.18 (0.25) 1.85 (0.20) 0.65 (0.20)
0.69 (0.49) 13.7 (3.03) 32.2 (4.30) 57.1 (3.89) 60.2 (3.85) 51.9 (3.28) 37.8 (2.25) 29.5 (2.15) 11.5 (1.25) 5.85 (0.77) 3.61 (0.52) 1.86 (0.33)
0.80 (0.62) 17.0 (4.28) 35.7 (5.91) 63.6 (5.97) 71.1 (6.21) 63.1 (4.48) 46.2 (3.09) 34.6 (2.58) 13.0 (1.22) 7.18 (0.62) 4.45 (0.45) 2.28 (0.34)
0.94 (0.94) 56.9 (13.9) 147 (26.4) 250 (31.4) 231 (21.0) 211 (14.1) 139 (12.0) 106 (11.1 ) 38.7 (4.39) 19.3 (1.69) 11.3 (1.26) 3.58 (1.11 )
3.52 (2.46) 108 (29.9) 357 (128) 534 (58.6) 628 (106.)
5.30 (4.04) 124 (35.8) 292 (74.7) 615 (98.8) 687 (95.5) 627 (79.8) 387 (39.7) 264 (25.7) 85.4 (9.23) 44.9 (4.23) 26.6 (2.82) 13.7 (2.04)
483 (67.2) 289 (21.9) 224 (27.5) 73.2 (8.65) 36.7 (5.25) 22.2 (3.60) 11.4 (2.13)
• Values in parentheses are standard errors of the means.
Blood was collected from a forearm vein into evacuated blood collection tubes containing sodium heparin at the following times relative to drug administration: 0, 0.167, 0.333, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, and 12 hours. The plasma specimens were assayed for total ibuprofen by gasliquid chromatography with flame ionization detection [7]. Specimens taken at 1.0, 1.5, 4.0, 6.0, and 8.0 hours were also assayed by equilibrium dialysis [8) to estimate free ibuprofen plasma concentrations at each sampling time. Kinetic Analysis. The apparent elimination rate constant (TZ) for each subject was determined from a least-squares linear regression fit of the terminal log-linear region of the semilogarithmic plasma concentration-time curves. Area under the concentration-time curve (AUCoo) and the first moment curve (AUMC",) were estimated by trapezoidal rule with extrapolation to infinity. Apparent clearance (CUF) atter oral dosing was calculated from: CUF = dose/AUCoo • Apparent volume of distribution (Vd area/F) was calculated according to Vd arealF = (dose/TZAUC",) = (CUF/TZ). Mean reSidence time (MRT) was estimated by the equation: MRT = AUMCooIAUC",. Statistical Analysis. The influence of dose on the pharmacokinetics of ibuprofen in elderly volunteers was statistically evaluated using a mixed effects analysis of variance model with group, period, and dose as fixed effects and subject within group as a random effect. The influence of advanced age on ibuprofen kinetics was
48
July 13, 1984
The American Journal of Medicine
assessed by comparing the results of the study in elderly volunteers with those of a similar trial conducted in 15 young adult males [9) aged 22 to 35 years (mean 25) and weighing 70 to 84 kg (mean 78). Statistical comparisons of the two age groups were performed using a mixed effects analysis of variance model, with dose and age group as fixed effects, subject within age group as a random effect, and the first order interaction of age group and dose. RESULTS Pharmacoklnetic Dose-Response. Mean plasma concentrations of total and free unbound ibuprofen at each dose and sampling time are listed in Table I. Mean kinetic parameters, obtained from total and free concentrations at each dose, are shown in Table II. Apparent clearance (CUF) and apparent distribution volume (Vd area/F) based on total concentrations increased significantly (p <0.05) with increasing dose. A statistically significant dose dependency of CUF for free drug was also demonstrated, but it was of a lesser magnitude. Free drug CUF increased 18 percent over the dosage range studied versus 40 percent for total ibuprofen. The value of free drug Vd area/F was independent of dose. CUF and Vd arealF were significantly correlated with total body weight for all three doses and for free and total drug. Therefore, these
IBUPROFEN SYMPOSIUM-GILLESPIE ET AL
TABLE II
Mean Pharmacoklnetic Parameters Obtained from Total and Free Ibuprofen Plasma Concentrations in 17 Elderly Volunteers after a Single Oral Dose Dose (mg)
400
800
1,200
p'
46.8 147 0.326 3.58
52.4 167 0.314 3.57
65.4 204 0.328 3.61
:s 0.0001 t 0.0005 t 0.68 0.90
7.07 23.8 0.314 3.45
6.98 23.0 0.302 3.23
8.31 26.8 0.334 3.24
0.025t 0.35 0.28 0.092
Parameter Total CUF (ml/hour/kg) V~ arealF (ml/kg) 7Z (hours- 1) MAT (hours) Free CUF (liters/hour/kg) Vd arealF (liters/kg) 7Z (hours- 1) MAT (hours)
• Level of significance for comparison of means for each dose. tStatistically Significant difference among the means (p:s 0.05). CUF = apparent clearance; Vd arealF = apparent volume of distribution;
TABLE III
7Z
= apparent elimination rate constant;
MAT
= mean residence time.
Mean Pharmacoklnetlc Parameters Obtained from Total and Free Ibuprofen Plasma Concentrations In 17 Elderly and 15 Young Adult Volunteers after a Single Oral Dose Dose (mil)
400 Parameter Total CUF (mllhour/kg) Vd .realF (mllkg) 7Z
(hours- 1)
MAT (hours) Free CUF (liters/hour/kg) Vd arealF (liters/kg) 7Z
(hours- 1)
MAT (hours)
1,200
800
Elderly
Young
Elderly
Young
Elderly
Young
p'
46.8 (2.4Ojf 147 (9.20) 0.326 (0.013) 3.58 (0.130)
41.9 (2.07) 157 (10.7) 0.273 (0.012) 3.84 (0.212)
52.4 (3.73) 167 (8.03) 0.314 (0.016) 3.57 (0.111)
49.8 (2.50) 183 (28.2) 0.303 (0.018) 3.73 (0.122)
65.4 (3.70) 204 (12.4) 0.328 (0.016) 3.61 (0.111)
54.1 (2.52) 174 (11.7) 0.319 (0.012) 3.66 (0.137)
0.087
(0.486) 23.8 (2.52) 0.314 (0.014) 3.45 (0.144)
(0.416) 29.8 (2.16) 0.271 (0.012) 3.72 (0.215)
(0.626) 23.0 (2.05) 0.302 (0.011) 3.23 (0.100)
(0.449) 28.7 (1.63) 0.308 (0.015) 3.49 (0.125)
(0.676) 26.8 (3.10) 0.334 (0.021) 3.24 (0.104)
(0.425) 28.4 (1.34) 0.134 (0.015) 3.32 0.148)
0.94 0.13 0.35
0.091 0.17 0.24
• Level of significance for comparison of the overall means for each age group. tValues in parentheses are standard errors of the means. For abbreviations, see Table II.
parameters are expressed as value per kilogram of total body weight. The dose administered had no detectable influence on the apparent elimination rate constant (7Z), whether estimated from total or from free concentrations. The overall mean rate constants were 0.323 hours- 1 for total drug and 0.317 hours- 1 for free drug, which corresponded to harmonic mean apparent elimination half-lives of 2.15 and
2.19 hours, respectively. Estimates of mean residence time (MRT) based on total and free ibuprofen levels were also unaffected by dose. Influence of Age. Table III compares the mean kinetic parameters in the 17 elderly volunteers with those in 15 young adult men who participated in another trial, the results of which were previously reported in detail [9]. Of all parameters evaluated, the first order interaction of age
July 13. 1984
The American Journal of Medicine
49
IBUPROFEN SYMPOSIUM-GILLESPIE ET AL
400
o
TOTAL DRUG
6l!6
."
..=, ::::J
0 6. 6
6.
~ 300 .<=
f.
o
6.
o ... -to
_---0---
06 / "..... ~ 0 .... / 06766
000 o
200
Cb
<
o
o
o
0
.....
;! co
AGE GROUP
o Elderly
I-
12
16
20
24
DOSE (mg/kg)
5000
COMMENTS
o
FREE DRUG
4000 'i .....
o
.<=
.s3000 8
~ 2000 w w
fE 1000 8
12
DOSE (mg/kg)
derly. The aged subjects differed from the young adults with respect to mean estimates of total ibuprofen Vd area/F, TZ, and MRT by only +0.7, +8.1, and -4.1 percent, respectively. The elderly group had an 11 percent lower mean CUF and a 15 percent lower mean Vd area/F on the basis of free ibuprofen plasma concentrations than did the young subjects. However, neither difference was statistically significant. The two age groups elicited quite similar estimates of free drug TZ and MRT, with means within 7 percent of each other.
16
20
24
The dose-dependent changes in CUF and Vd area/F, estimated from total ibuprofen plasma concentrations, in the elderly volunteers are largely explained by nonlinear plasma protein binding. This finding is supported by the lack of dose-related changes in free drug Vd area/F and by the increase in free drug CUF with the dose. This occurred to a lesser degree than that seen with CUF based on total concentrations. The residual dose dependence of free ibuprofen CUF may be due to a small decrease in the fraction of dose absorbed from the tablets as the dose is increased. The AUC", versus dose plots shown in Figure 1 emphasize the nonlinear relation between total drug levels with dose and the more linear relation for free concentrations. These results are consistent with those recently reported in young adult subjects [9).
Figure 1. Plots of total and free ibuprofen in the area under the time-concentration curve (AUG",) versus dose (mg/kg) in 17 elderly and 15 young adult subjects. The curves drawn through the plots are least-squares parabolas (total drug) or lines (free drug) forced through the origin.
CONCLUSIONS
group and dose was not statistically significant (p >0.05). Therefore, it was appropriate to compare the two age groups across all doses, rather than to perform separate analyses for each dosage level. No statistically significant age-related differences were detected in any parameter estimated from total ibuprofen plasma concentrations. The only trend of note was for total drug CUF, which was 13 percent greater in the el-
Patients in the two age groups did not show any statistically significant differences in any parameter of ibuprofen pharmacokinetics studied. The age-related trends that were observed, that is, a 10 to 15 percent difference between age group means in some kinetic parameters, were small compared with ibuprofen's large therapeutic index. As a result, such differences are unlikely to be manifested in any clinically detectable form. Because advanced age has only minimal influence on the pharmacokinetics of ibuprofen, there is no apparent need to adjust dosage in elderly patients.
REFERENCES 1.
2. 3. 4.
50
Lawrence JS, DeGraff R, Laine VA: Degenerative joint diseases in random samples of occupational groups. In: Kellgren JH, Jeffrey MR, Ball J, eds. The epidemiology of chronic rheumatism. Oxford: Blackwell Scientific, 1963; 98. Kolodny AL, Klipper AR: Bone and joint diseases in the elderly. Hosp Pract 1976; 11: 91-101. Verbeeck RK, Blackburn JL, Loewen GR: Clinical pharmacokinetics of non-steroidal anti-inflammatory drugs. Clin Parmacokinet 1983; 8: 297-331. Hamdy RC, Murnane B, Perera N, Woodcock K, Koch 1M: The pharmacokinetics of benoxaprofen in elderly subjects. Eur J Rheumatollnflam 1982; 5: 69-75.
July 13, 1984
The American Journal of Medicine
5. 6. 7. 8. 9.
Halsey JP, Cardoe N: Benoxaprofen: side-effect profile in 300 patients. Br Med J 1982; 284; 1365-1368. Taggart HM, Alderdice JM: Fatal cholestatic jaundice in elderly patients taking benoxaprofen. Br Med J 1982; 284: 1372. Kaiser DG, VanGiessen GJ: GLC determination of ibuprofen in plasma. J Pharm Sci 1974; 63: 219-221. Lockwood GF, Albert KS, Wagner JG: Pharmacokinetics of ibuprofen in man. III. Plasma protein binding. J Pharmacokin Biopharm, in press. Lockwood GF, Albert KS, Gillespie WR, et al: Pharmacokinetics of ibuprofen in man. I. Free and total area/dose relationships. . Clin Pharmacol Ther 1983; 34: 97-103.
KENNETH S. ALBERT, Ph.D. WILLIAM R. GILLESPIE, M.S. JOHN G. WAGNER, Ph.D. ALICE PAU, Pharm.D. G.F. LOCKWOOD, Ph.D. Kalamazoo, Michigan
The pharmacokinetics of ibuprofen (Motrin) were studied in 17 normal elderly men and women aged 65 to 78 ·years. Total and free unbound plasma concentrations of Ibuprofen were determined 12 hours after single oral doses of 400, 800, and 1,200 mg. These results were then compared with those of a similar study involving 15 normal young men 22 to 35 years old. The two age groups showed no statistically significant differences in any pharmacoklnetlc parameter studied. Therefore, according to this study, advanced age has only minimal Influence on the pharmacokinetics of ibuprofen, and dosage apparently does not need to be adjusted fol' age. Ibuprofen (Motrin, Upjohn) is a widely prescribed nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of osetoarthritis and rheumatoid arthritis. Because the incidence of these conditions increases with age, the elderly represent a significant proportion of patients Ul~ing ibuprofen. Radiologic evidence of osteoarthritis was found in 87 percent of men and 74 percent of women aged 65 to 74 years [1], and an estimated 50 percent of patients with rheumatoid arthritis are more than 50 years old [2]. Yet the pharmacokinetic activity of the NSAIDs in this age group has not been well described [3] despite the implication of age-related kinetic changes as the cause of increased adverse reactions, Including fatal cholestatic jaundice, in geriatric patients taking benoxaprofen [4-6]. Therefore, the present study was undertaken to evaluate the pharmacokinetics of a single oral dose of ibuprofen in 17 normal, relatively healthy, elderly men and women and to compare these findings with those in a similar trial in young adult volunteers.
METHODS Subjects. Seventeen normal, relatively healthy, elderly volunteers particiFrom the Upjohn Center for Clinical Pharmacology, the Upjohn Company, Kalamazoo, and the College of Pharmacy, the University of Michigan, Ann Arbor, Michigan. Requests for reprints should be addressed to Dr. K.S. Albert, Upjohn Center for Clinical Pharmacology, Upjohn Company, Kalamazoo, Michigan, 49001. The work presented was based on the admioistration of Motrin tablets, aregistered trademark of the Upjohn Manufacturing Company.
pated in the study, after written informed consent, physical examination, and blood and urine analyses were obtained. The subjects ranged in age from 65 to 78 years (mean 70) and in body weight from 54 to 89 kg (mean 69). No participant was receiving any drug on a long-term basis when recruited into the study. No new drug therapy, short- or long-term, was initiated for at least seven days before or during the study. Study Design. The study was approved for use in human subjects by an institutional review board. Single oral doses of 400, 800, and 1,200 mg of ibuprofen were administered in tablet form to each subject according to a three-way Latin-square crossover experimental design. The volunteers were required to fast for nine hours before and four hours after drug administration. Treatment phases were separated by seven days.
July 13, 1984
The American Journal of Medicine
47
IBUPROFEN SYMPOSIUM-GILLESPIE ET AL
TABLE I
Mean Plasma Concentrations of Total and Free Ibuprofen in 17 Elderly Volunteers after a Single Oral Dose Free Concentration (ng/ml)
Total Concentration (lLg/ml) Time (hours) 0.167 0.333 0.5 1.0 1.5 2.0 3.0 4.0 6.0 8.0 10 12
400 mg
800 mg
1,200 mg
400 mg
800 mg
1,200 mg
0.15 (0.15)* 8.46 (1.94) 19.9 (3.30) 32.5 (2.91) 30.4 (1.92) 29.2 (1.29) 20.3 (1.27) 15.6 (1.29) 6.08 (0.55) 3.18 (0.25) 1.85 (0.20) 0.65 (0.20)
0.69 (0.49) 13.7 (3.03) 32.2 (4.30) 57.1 (3.89) 60.2 (3.85) 51.9 (3.28) 37.8 (2.25) 29.5 (2.15) 11.5 (1.25) 5.85 (0.77) 3.61 (0.52) 1.86 (0.33)
0.80 (0.62) 17.0 (4.28) 35.7 (5.91) 63.6 (5.97) 71.1 (6.21) 63.1 (4.48) 46.2 (3.09) 34.6 (2.58) 13.0 (1.22) 7.18 (0.62) 4.45 (0.45) 2.28 (0.34)
0.94 (0.94) 56.9 (13.9) 147 (26.4) 250 (31.4) 231 (21.0) 211 (14.1) 139 (12.0) 106 (11.1 ) 38.7 (4.39) 19.3 (1.69) 11.3 (1.26) 3.58 (1.11 )
3.52 (2.46) 108 (29.9) 357 (128) 534 (58.6) 628 (106.)
5.30 (4.04) 124 (35.8) 292 (74.7) 615 (98.8) 687 (95.5) 627 (79.8) 387 (39.7) 264 (25.7) 85.4 (9.23) 44.9 (4.23) 26.6 (2.82) 13.7 (2.04)
483 (67.2) 289 (21.9) 224 (27.5) 73.2 (8.65) 36.7 (5.25) 22.2 (3.60) 11.4 (2.13)
• Values in parentheses are standard errors of the means.
Blood was collected from a forearm vein into evacuated blood collection tubes containing sodium heparin at the following times relative to drug administration: 0, 0.167, 0.333, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, and 12 hours. The plasma specimens were assayed for total ibuprofen by gasliquid chromatography with flame ionization detection [7]. Specimens taken at 1.0, 1.5, 4.0, 6.0, and 8.0 hours were also assayed by equilibrium dialysis [8) to estimate free ibuprofen plasma concentrations at each sampling time. Kinetic Analysis. The apparent elimination rate constant (TZ) for each subject was determined from a least-squares linear regression fit of the terminal log-linear region of the semilogarithmic plasma concentration-time curves. Area under the concentration-time curve (AUCoo) and the first moment curve (AUMC",) were estimated by trapezoidal rule with extrapolation to infinity. Apparent clearance (CUF) atter oral dosing was calculated from: CUF = dose/AUCoo • Apparent volume of distribution (Vd area/F) was calculated according to Vd arealF = (dose/TZAUC",) = (CUF/TZ). Mean reSidence time (MRT) was estimated by the equation: MRT = AUMCooIAUC",. Statistical Analysis. The influence of dose on the pharmacokinetics of ibuprofen in elderly volunteers was statistically evaluated using a mixed effects analysis of variance model with group, period, and dose as fixed effects and subject within group as a random effect. The influence of advanced age on ibuprofen kinetics was
48
July 13, 1984
The American Journal of Medicine
assessed by comparing the results of the study in elderly volunteers with those of a similar trial conducted in 15 young adult males [9) aged 22 to 35 years (mean 25) and weighing 70 to 84 kg (mean 78). Statistical comparisons of the two age groups were performed using a mixed effects analysis of variance model, with dose and age group as fixed effects, subject within age group as a random effect, and the first order interaction of age group and dose. RESULTS Pharmacoklnetic Dose-Response. Mean plasma concentrations of total and free unbound ibuprofen at each dose and sampling time are listed in Table I. Mean kinetic parameters, obtained from total and free concentrations at each dose, are shown in Table II. Apparent clearance (CUF) and apparent distribution volume (Vd area/F) based on total concentrations increased significantly (p <0.05) with increasing dose. A statistically significant dose dependency of CUF for free drug was also demonstrated, but it was of a lesser magnitude. Free drug CUF increased 18 percent over the dosage range studied versus 40 percent for total ibuprofen. The value of free drug Vd area/F was independent of dose. CUF and Vd arealF were significantly correlated with total body weight for all three doses and for free and total drug. Therefore, these
IBUPROFEN SYMPOSIUM-GILLESPIE ET AL
TABLE II
Mean Pharmacoklnetic Parameters Obtained from Total and Free Ibuprofen Plasma Concentrations in 17 Elderly Volunteers after a Single Oral Dose Dose (mg)
400
800
1,200
p'
46.8 147 0.326 3.58
52.4 167 0.314 3.57
65.4 204 0.328 3.61
:s 0.0001 t 0.0005 t 0.68 0.90
7.07 23.8 0.314 3.45
6.98 23.0 0.302 3.23
8.31 26.8 0.334 3.24
0.025t 0.35 0.28 0.092
Parameter Total CUF (ml/hour/kg) V~ arealF (ml/kg) 7Z (hours- 1) MAT (hours) Free CUF (liters/hour/kg) Vd arealF (liters/kg) 7Z (hours- 1) MAT (hours)
• Level of significance for comparison of means for each dose. tStatistically Significant difference among the means (p:s 0.05). CUF = apparent clearance; Vd arealF = apparent volume of distribution;
TABLE III
7Z
= apparent elimination rate constant;
MAT
= mean residence time.
Mean Pharmacoklnetlc Parameters Obtained from Total and Free Ibuprofen Plasma Concentrations In 17 Elderly and 15 Young Adult Volunteers after a Single Oral Dose Dose (mil)
400 Parameter Total CUF (mllhour/kg) Vd .realF (mllkg) 7Z
(hours- 1)
MAT (hours) Free CUF (liters/hour/kg) Vd arealF (liters/kg) 7Z
(hours- 1)
MAT (hours)
1,200
800
Elderly
Young
Elderly
Young
Elderly
Young
p'
46.8 (2.4Ojf 147 (9.20) 0.326 (0.013) 3.58 (0.130)
41.9 (2.07) 157 (10.7) 0.273 (0.012) 3.84 (0.212)
52.4 (3.73) 167 (8.03) 0.314 (0.016) 3.57 (0.111)
49.8 (2.50) 183 (28.2) 0.303 (0.018) 3.73 (0.122)
65.4 (3.70) 204 (12.4) 0.328 (0.016) 3.61 (0.111)
54.1 (2.52) 174 (11.7) 0.319 (0.012) 3.66 (0.137)
0.087
(0.486) 23.8 (2.52) 0.314 (0.014) 3.45 (0.144)
(0.416) 29.8 (2.16) 0.271 (0.012) 3.72 (0.215)
(0.626) 23.0 (2.05) 0.302 (0.011) 3.23 (0.100)
(0.449) 28.7 (1.63) 0.308 (0.015) 3.49 (0.125)
(0.676) 26.8 (3.10) 0.334 (0.021) 3.24 (0.104)
(0.425) 28.4 (1.34) 0.134 (0.015) 3.32 0.148)
0.94 0.13 0.35
0.091 0.17 0.24
• Level of significance for comparison of the overall means for each age group. tValues in parentheses are standard errors of the means. For abbreviations, see Table II.
parameters are expressed as value per kilogram of total body weight. The dose administered had no detectable influence on the apparent elimination rate constant (7Z), whether estimated from total or from free concentrations. The overall mean rate constants were 0.323 hours- 1 for total drug and 0.317 hours- 1 for free drug, which corresponded to harmonic mean apparent elimination half-lives of 2.15 and
2.19 hours, respectively. Estimates of mean residence time (MRT) based on total and free ibuprofen levels were also unaffected by dose. Influence of Age. Table III compares the mean kinetic parameters in the 17 elderly volunteers with those in 15 young adult men who participated in another trial, the results of which were previously reported in detail [9]. Of all parameters evaluated, the first order interaction of age
July 13. 1984
The American Journal of Medicine
49
IBUPROFEN SYMPOSIUM-GILLESPIE ET AL
400
o
TOTAL DRUG
6l!6
."
..=, ::::J
0 6. 6
6.
~ 300 .<=
f.
o
6.
o ... -to
_---0---
06 / "..... ~ 0 .... / 06766
000 o
200
Cb
<
o
o
o
0
.....
;! co
AGE GROUP
o Elderly
I-
12
16
20
24
DOSE (mg/kg)
5000
COMMENTS
o
FREE DRUG
4000 'i .....
o
.<=
.s3000 8
~ 2000 w w
fE 1000 8
12
DOSE (mg/kg)
derly. The aged subjects differed from the young adults with respect to mean estimates of total ibuprofen Vd area/F, TZ, and MRT by only +0.7, +8.1, and -4.1 percent, respectively. The elderly group had an 11 percent lower mean CUF and a 15 percent lower mean Vd area/F on the basis of free ibuprofen plasma concentrations than did the young subjects. However, neither difference was statistically significant. The two age groups elicited quite similar estimates of free drug TZ and MRT, with means within 7 percent of each other.
16
20
24
The dose-dependent changes in CUF and Vd area/F, estimated from total ibuprofen plasma concentrations, in the elderly volunteers are largely explained by nonlinear plasma protein binding. This finding is supported by the lack of dose-related changes in free drug Vd area/F and by the increase in free drug CUF with the dose. This occurred to a lesser degree than that seen with CUF based on total concentrations. The residual dose dependence of free ibuprofen CUF may be due to a small decrease in the fraction of dose absorbed from the tablets as the dose is increased. The AUC", versus dose plots shown in Figure 1 emphasize the nonlinear relation between total drug levels with dose and the more linear relation for free concentrations. These results are consistent with those recently reported in young adult subjects [9).
Figure 1. Plots of total and free ibuprofen in the area under the time-concentration curve (AUG",) versus dose (mg/kg) in 17 elderly and 15 young adult subjects. The curves drawn through the plots are least-squares parabolas (total drug) or lines (free drug) forced through the origin.
CONCLUSIONS
group and dose was not statistically significant (p >0.05). Therefore, it was appropriate to compare the two age groups across all doses, rather than to perform separate analyses for each dosage level. No statistically significant age-related differences were detected in any parameter estimated from total ibuprofen plasma concentrations. The only trend of note was for total drug CUF, which was 13 percent greater in the el-
Patients in the two age groups did not show any statistically significant differences in any parameter of ibuprofen pharmacokinetics studied. The age-related trends that were observed, that is, a 10 to 15 percent difference between age group means in some kinetic parameters, were small compared with ibuprofen's large therapeutic index. As a result, such differences are unlikely to be manifested in any clinically detectable form. Because advanced age has only minimal influence on the pharmacokinetics of ibuprofen, there is no apparent need to adjust dosage in elderly patients.
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Lawrence JS, DeGraff R, Laine VA: Degenerative joint diseases in random samples of occupational groups. In: Kellgren JH, Jeffrey MR, Ball J, eds. The epidemiology of chronic rheumatism. Oxford: Blackwell Scientific, 1963; 98. Kolodny AL, Klipper AR: Bone and joint diseases in the elderly. Hosp Pract 1976; 11: 91-101. Verbeeck RK, Blackburn JL, Loewen GR: Clinical pharmacokinetics of non-steroidal anti-inflammatory drugs. Clin Parmacokinet 1983; 8: 297-331. Hamdy RC, Murnane B, Perera N, Woodcock K, Koch 1M: The pharmacokinetics of benoxaprofen in elderly subjects. Eur J Rheumatollnflam 1982; 5: 69-75.
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