Pharmacokinetic Comparison of 5 g of Azlocillin Every ...

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ureidopenicillins. Antimicrob. Agents Chemother. 13:930-938. 7. Gibaldi, M., and D. Perrier. 1982.Pharmacokinetics, 2nd ed. Marcel Dekker, Inc., New York. 8.
Vol. 33, No. 5

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1989, p. 710-713

0066-4804/89/050710-04$02.00/0 Copyright C) 1989, American Society for Microbiology

Pharmacokinetic Comparison of 5 g of Azlocillin Every 8 h and 4 g Every 6 h in Healthy Volunteers ROGER D. LANDER,t* ROBERT P. HENDERSON,t AND DENNIS R. PYSZCZYNSKI School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108 Received 20 July 1988/Accepted 16 January 1989

To compare the multiple-dose pharmacokinetics of two dosage regimens of azlocillin, we studied 12 healthy volunteers via a randomized, crossover design with a 2-week washout phase between regimens. Serum and urine samples were collected for 8 h following the fifth dose of a regimen of 4 g every 6 h and the fourth dose of a regimen of 5 g every 8 h. Data for concentrations in serum were fitted to a two-compartment open model by nonlinear regression. Statistically significant differences (P < 0.05) were observed in the following parameters (mean ± standard deviation) for the 4- and 5-g regimens, respectively: area under the serum concentration-time curve during the dosing interval, 592 ± 140 versus 772 ± 151 ,ig- h/ml; terminal elimination rate constant, 0.5364 ± 0.0912 versus 0.4758 ± 0.0486 h-'; renal clearance, 87.6 ± 16.1 versus 76.1 ± 13.5 ml/min; maximum drug concentration in serum, 381 ± 89 versus 473 ± 90 ,ug/ml; and minimum drug concentration in serum, 19 ± 10 versus 8 ± 4 ,ug/ml. No significant differences were seen in the following parameters: Vl, Vp, klo, k12, k2l, total systemic clearance, and nonrenal clearance. These data support the presence of saturable renal elimination of azlocillin, as well as the feasibility of an 8-h dosing interval.

both major and minor determinant mixtures before entering the study. None of the subjects took long-term medications, and no medications were allowed for 48 h prior to and during the study. All subjects were nonsmokers. Under an open crossover design, subjects were randomly assigned to one of two treatment sequence groups. Group 1 subjects (six subjects) received 4 g of azlocillin every 6 h for five doses (regimen A), and group 2 subjects (six subjects) received 5 g of azlocillin every 8 h for four doses (regimen B). The subjects then underwent 12-day washout periods and were given the alternate regimen. Each dose was infused via a peripheral vein over 30 min, and each subject remained supine for the last infusion of each regimen and during the first hour of serum sampling. Venous blood samples were obtained just prior to (time zero) and 0.25, 0.5, 038, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, and 8.0 h after the start of the drug infusion. Blood samples were placed on ice and immediately centrifuged in a refrigerated centrifuge (IEC model Centra7R), and the plasma was removed. Urine samples were collected from 0 to 2, 2 to 4, and 4 to 8 h after the last dose of each regimen. Plasma and urine aliquots were stored at -70°C until assayed. Azlocillin concentrations in plasma and urine were determined by high-performance liquid chromatography by using a modification of the procedure of Weber et al. (14). This method involves precipitation of plasma protein with methanol. The supernatant is injected into the system and read by detection of A222. The system demonstrated linearity from the lower sensitivity limit of 3 ,ug/ml to 500 ,ug/ml. This analytical technique gave adequate reproducibility, with intraday coefficients of variation of c6% and interday coefficients of variation l10% for all standards. Plasma concentration-time data were fitted to a twocompartment open model by nonlinear iterative leastsquares regression analysis. The pharmacokinetic parameters Vc, k21, k1o and CLs (total systemic clearance) were calculated by conventional methods (7). The area under the concentration-time curve (for the period 0 to T) for each subject was determined through integration of the following

Azlocillin, mezlocillin, and piperacillin are acylampicillins with an extended spectrum of activity and greater in vitro potency than the carboxy penicillins. Azlocillin demonstrates antibacterial activity against a broad spectrum of bacteria, including Pseudomonas aeruginosa, and, in contrast to most cephalosporins, exhibits activity against enterococci (4, 6, 13, 17). Azlocillin is excreted mainly by the kidneys but also undergoes elimination through nonrenal mechanisms, as evidenced by the high clearance values found in several studies (8, 12). The drug undergoes biotransformation and significant concentrations can be found in bile (8, 12). Present evidence indicates that azlocillin exhibits dosedependent elimination, probably through the saturation of renal tubular secretion and metabolism (15). Azlocillin has been shown to produce significantly higher concentrations than piperacillin in serum throughout the usual dosing interval (3). The usual dosing recommendations for azlocillin in the United States are based on a 4- to 6-h dosing interval for patients with adequate renal function. The purpose of this study was to assess the potential significance of the dosedependent elimination characteristics and the impact of an extended dosing interval on the multiple-dose pharmacokinetic profile of azlocillin by comparing a conventional dosing regimen of 4 g administered every 6 h with a regimen of 5 g every 8 h. MATERIALS AND METHODS Twelve healthy volunteers (eight men and four women) ranging in age from 21 to 36 years (mean, 26 ± 4.8 years) and in weight from 55.9 to 105 kg (mean, 72.6 ± 13.3 kg) participated in the study after providing informed written consent. All subjects had satisfactory medical histories, physical examinations, and clinical chemistry screening results. Each subject was skin tested for penicillin allergy with Corresponding author. t Present address: School of Pharmacy, Samford University, Birmingham, AL 35229. *

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TABLE 1. Individual pharmacokinetic parameters for azlocillin given during regimens A and B'

Regimen and

subject no.

(h1)

VI

Vp

(h-1)

1123

(h)

(liters)

(liters)

AUC

(Axg h/ml)

CLs

CLR

CLNR

(ml/min)

(ml/min)

(ml/min)

Regimen A 1 2 3 4 5 6 7 8 9 10 11 12

2.0 11.7 9.8 7.1 3.6 5.7 4.3 8.2 7.0 10.4 3.9 9.4

0.4368 0.4746 0.4494 0.5412 0.4368 0.5208 0.5646 0.6264 0.6642 0.7152 0.5268 0.4776

1.59 1.46 1.54 1.28 1.59 1.33 1.23 1.11 1.04 0.97 1.32 1.45

7.7 7.7 5.7 5.6 8.2 8.2 6.6 6.4 5.5 4.9 5.8 9.2

12.2 14.6 11.1 13.7 13.9 13.3 11.5 16.5 14.0 12.2 9.4 16.8

748 577 799 541 659 579 615 386 432 457 808 500

89.1 115.6 83.5 123.3 101.2 115.2 108.4 172.7 154.5 145.9 82.5 133.4

61.9 84.9 66.8 91.3 96.0 80.4 100.3 103.3 108.5 100.7 64.2 72.1

27.2 30.7 16.7 32.0 5.2 34.7 8.1 69.4 46.0 45.2 18.3 61.3

Mean SD

6.9 3.1

0.5364 0.0912

1.29 0.21

6.8 1.4

13.3 2.1

592 140

118.8 28.7

85.9 16.5

32.9 19.9

8.6 2.2 2.4 12.7 5.4 7.3 2.1 4.0 7.7 3.0 5.1 5.4

0.4116 0.4968 0.4206 0.5088 0.4158 0.5172 0.4950 0.4584 0.5790 0.4710 0.4848 0.4530

1.68 1.39 1.65 1.36 1.67 1.34 1.40 1.51 1.20 1.47 1.43 1.53

3.3 13.4 12.2 4.8 7.2 6.5 7.7 7.8 4.7 7.0 5.7 8.3

11.2 15.6 14.7 14.8 14.2 13.8 14.0 18.1 12.0 13.8 10.0 16.5

1,088 646 810 664 849 701 722 602 719 767 1,029 670

76.6 129.0 102.9 125.5 98.2 118.9 115.5 138.4 115.9 108.6 81.0 124.5

58.6 75.9 NA 98.4 77.4 75.9 91.5 87.9 78.1 72.5 67.7 52.9

18.0 53.1 NA 27.1 20.8 42.0 24.0 50.6 37.8 36.1 13.3 71.6

5.5 3.2

0.4758 0.0486

1.46 0.15

7.4 2.9

14.1 2.2

772 151

111.2 18.8

76.2 13.5

35.8 17.6

Regimen B 1 2 3 4 5 6 7 8 9 10 11 12

Mean SD

tl/2.,

a Abbreviations: a, distribution phase; 0, elimination phase; half-life at P phase; V1, volume of distribution in the central compartment; distribution at P phase; AUC, area under the serum concentration-time curve. b NA, Not available.

equation (which describes a two-compartment model adjusted for multiple dosing): Ct = Ae-' + Be-' + Cmine-' where C, is the concentration at any particular time; A = [KO (k2l C)!Vc Ot (O-1)] (1 e-T); B = [KO (k2l VC( - (x)] (1 - e- T); Cmin is the concentration just prior to the beginning of the study infusion; and T is the infusion time. This equation was developed by using the method of Benet and Turi (1) to obtain the inverse Laplace transform which combines the input and disposition functions for an intermit-

-

-

tent, constant-rate infusion. It was used to allow nonlinear regression of one dosing interval during multiple dosing and accounts for the summation of drug present in the body as a result of all doses prior to the study dose (depicted by Cmine-') and drug present as a result of the study dose (A e-a + B e-'). Statistical comparison of pharmacokinetic data between dosage regimens was performed by using the Student t test for paired data. The absence of a period effect was documented by one-way analysis of variance. Differences were considered significant if P < 0.05. RESULTS After completion of the last 30-min infusion for each of the regimens, the mean values (+ standard deviation) of Cmax

V,3, volume of

(the maximum drug concentration in serum) and Cmin for regimen A were 381 ± 89 and 19 ± 10 jxg/ml, respectively. For regimen B the Cmax and Cmin values were 473 ± 90 and 8 ± 4 ,ug/ml, respectively. The differences between regimens in both the Cmax and Cmin values were significant (P < 0.05). The individual pharmacokinetic parameters for the two regimens are shown in Table 1. Analysis of these parameters for the 4-g versus the 5-g regimens revealed a significant decrease in the mean beta elimination rate constant from 0.5364 to 0.4758 h-' (P < 0.05). This change in elimination rate results in an increase in the harmonic mean half-life from 1.29 to 1.46 h. An increase in the area under the concentration-time curve of 31% during the dosing interval was noted from the 4- to the 5-g regimen (P < 0.05). Figures 1 and 2 illustrate the renal clearance (CLR) for each regimen as measured incrementally over the 8-h sampling period. For regimen A, analysis of variance indicated a significant increase in CLR during each collection interval (Fig. 1) (P < 0.05). Regimen B produced no significant change in CLR from the 0- to 2-h to the 2- to 4-h intervals, but an increase was noted during the 4- to 8-h interval (P < 0.05). These data support the presence of a saturable renal elimination process. The total 8-h CLR values decreased in 9 of 11 evaluable subjects when the dosage was increased from 4 to 5 g. Figure 3 shows CLs plotted against renal function (CLCR)

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LANDER ET AL.

ANTIMICROB. AGENTS CHEMOTHER.

220

160-

210

-

200

-

190

-

180

-

150140-

CIR

0-8

130-

170

-

120-

160

-

110

150

-

100-

140

90-

130

-

120

-

110

-

70-

100-

60-

80-

9080

-

70

-

60

-

50

-

4030-

2010,

4030

-

20

-

2-4

0-2

4-8

Urine Collection Time Interval (HR)

10 0-2

2-4

4-8

Urine Collection rime Interval (HR)

FIG. 1. CLR of azlocillin from regimen A (4 g every 6 hours) during the three collection periods (0 to 2, 2 to 4, and 4 to 8 h). -, Individual patients; .... mean ± standard deviation for each collection period.

over the 8-h sampling period for each regimen. The slope of the regression line for regimen B is essentially flat, whereas for regimen A, the slope depicts a steadily increasing CLs with increasing renal function. This would indicate that the CLs was saturated at all levels of renal function during regimen B but was not saturated throughout the dosing interval with regimen A.

DISCUSSION Previous studies dealing with single doses of azlocillin have demonstrated half-lives ranging from 0.79 ± 0.15 to 0.96 ± 0.17 h after 2-g doses (5, 9, 10, 16). When doses of 80 mg/kg were administered, the half-life increased to 1.10 ± 0.18 h (9, 10). Bergan (2) demonstrated a progressive increase in half-life, of 0.89, 0.98, and 1.53 h, as the dose of azlocillin was increased from 1 to 2 and then to 5 g, respectively. These changes in half-life appeared to have occurred without significant changes in the volume of distribution and indicate dose-dependent elimination of azlocillin (9, 10). These observations are consistent with our findings concerning the multiple-dose, steady-state disposition of azlocillin. Azlocillin is eliminated predominantly by renal mechanisms, but also undergoes biotransformation within body tissues and intraintestinal degradation by bowel bacteria, with high concentrations found in bile (8, 12). The decreases in elimination rate with no significant changes in distribution volume as doses are increased suggest a de-

FIG. 2. CLR of azlocillin from regimen B (5 g every 8 h) during the three collection periods (0 to 2, 2 to 4, and 4 to 8 h). , Individual patients; .... mean ± standard deviation for each collection period. crease in total CLs which is composed of both renal and nonrenal routes. A significant decrease in CLR was noted for our subjects during the 5-g regimen. The nonrenal clearance

(CLNR) did not change significantly, although there was substantial intersubject variability. No significant change was seen in CLs, although a downward trend was observed, and the plot of CLs versus CLCR in Fig. 3 shows some interesting differences between the two dosages. Although the 5-g regimen showed a fairly flat regression line in Fig. 3, the 4-g regimen showed a positive slope, depicting steadily increasing CLs with increasing CLCR. We believe that this is due to renal saturation being more consistently present at the 140 120

*000 om ^,a

100 CL-S

O *

80

B

(ML/M/I/l.73 12) 60

40

20 0 0

20

40

60

80

100

120

140

160

180

CL-CR(M/MEM/i73I112)

FIG. 3. Plot of CLs (adjusted to body surface area) against CLCR for both dosage regimens. Symbols: O, regimen A; *, regimen B. The respective regression equations are as follows: CLs = 0.385CLCR + 68.1 (r = 0.565) (regimen A), and CLs = -0.035CLCR + 106.3 (r = 0.070) (regimen B).

VOL. 33, 1989

5-g dose level and the fact that our data are limited to subjects with CLCR of greater than 75 ml/min per 1.73 m2. Such a response with regimen B is supported by Bergan, who showed that generally one finds changes in CLs at CLCR levels below 70 ml/min per 1.73 m2 (2). In summary, we believe that the plot of CLs versus CLCR, along with Fig. 1 and 2, shows that renal saturation was present for a longer period after the 5-g dose than after the 4-g dose and was present to a greater extent with regimen B even in subjects with the greater renal function. We also observed that the saturable, capacity-limited elimination process was renal in origin. Our findings differ from the findings of other studies that have noted not only decreases in CLR with successively higher doses, but even more pronounced reductions in CLNR (1, 9). This may be due to the small difference between the two doses used in our study. Our data show that Cmax values during regimen B were higher than those during regimen A and that Cmin values were a mean of 48.5% (range, 26.5 to 83.9%) lower with regimen B. However, the influence of Cmax and Cmin on the clinical efficacy of penicillins as a class is inconclusive at present. The clinical efficacy of azlocillin administration on this 8-h interval has been documented and is used extensively in European countries (11). Our data demonstrate pharmacokinetic support for this longer dosage interval through provision of similar total daily areas under the curve. In conclusion, our study indicates that azlocillin exhibits dose-dependent elimination during multiple dosing, primarily as a result of a saturable renal process as the dose is increased from 4 to 5 g. The clinical utilization of an extended dosing interval for azlocillin (every 8 h) would result in savings in drug acquisition, preparation, and administration costs because of the provision of an adequate azlocillin regimen with fewer doses per day. ACKNOWLEDGMENT This work was supported by a grant from Miles Pharmaceuticals, Inc. LITERATURE CITED 1. Benet, L. S., and J. S. Turi. 1971. Use of a general partial fraction theorem for obtaining inverse Laplace transforms in pharmacokinetic analysis. J. Pharm. Sci. 60:1593-1594.

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2. Bergan, T. 1983. Review of the pharmacokinetics and dose dependency of aziocillin in normal subjects and patients with renal insufficiency. J. Antimicrob. Chemother. ll(Suppl. B):101-114. 3. Colaizzi, P. A., R. E. Polk, W. J. Poynor, A. C. Raffalovich, E. A. Cefali, and L. A. Beightol. 1986. Comparative pharmacokinetics of azlocillin and piperacillin in normal adults. Antimicrob. Agents Chemother. 29:938-940. 4. Coppens, L., and J. Klastersky. 1977. Comparative study of anti-Pseudomonas activity of azlocillin, mezlocillin, and ticarcillin. Antimicrob. Agents Chemother. 15:396-399. 5. Fiegel, P., and K. Becker. 1978. Pharmacokinetics of azlocillin in persons with normal and impaired renal functions. Antimicrob. Agents Chemother. 14:288-291. 6. Fu, K. P., and H. C. Neu. 1978. Azlocillin and mezlocillin: new ureidopenicillins. Antimicrob. Agents Chemother. 13:930-938. 7. Gibaldi, M., and D. Perrier. 1982. Pharmacokinetics, 2nd ed. Marcel Dekker, Inc., New York. 8. Gundert-Remy, U., and E. Weber. 1982. Elimination of azlocillin in patients with biliary t-tube drainage. Eur. J. Clin. Pharmacol. 22:435-439. 9. Leroy, A., G. Humbert, and J. P. Fillastre. 1981. Pharmacokinetics of azlocillin in healthy subjects. Scand. J. Infect. Dis. Suppl. 29:49-54. 10. Leroy, A., G. Humbert, M. Godin, and J. P. Fillastre. 1980. Pharmacokinetics of azlocillin in subjects with normal and impaired renal function. Antimicrob. Agents Chemother. 17: 344-349. 11. Schacht, P., G. Arcieri, H. Bruck, E. Griffith, R. Hullman, and D. Tettenborn. 1983. International clinical experience with azlocillin. J. Antimicrob. Chemother. ll(Suppl. B):215-222. 12. Singlas, E., and C. Haegel. 1984. Clinical pharmacokinetics of azlocillin. Presse Med. 13:788-796. 13. Stewart, D., and G. P. Bodey. 1977. Azlocillin: in vitro studies of a new semisynthetic penicillin. Antimicrob. Agents Chemother. 11:865-870. 14. Weber, A., K. E. Opheim, K. Wong, and A. L. Smith. 1983. High-pressure liquid chromatographic quantitation of azlocillin. Antimicrob. Agents Chemother. 24:750-753. 15. Whelton, A., R. L. Stout, P. S. Spilman, F. A. Delgado, and A. J. Watson. 1987. The novel therapeutic implications of azlocillin's dose-dependent pharmacokinetics: contributing physiologic mechanisms and a prospective, cross-over designed trial. J. Clin. Pharmacol. 27:491-498. 16. Wirth, K., M. Schomeras, and J. H. Hengstmann. 1976. Zur Pharmakokinetik von Azlocillin; einem neuen halbsythetischen Breitspektrumantibiotikum. Infection 4:25-30. 17. Wise, R., A. P. Gillett, J. M. Andrews, and K. A. Bedford. 1978. Activity of azlocillin and meziocillin against gram-negative organisms: comparison with other penicillins. Antimicrob. Agents Chemother. 13:559-565.