BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 13, 213-220 (1992)
PHARMACOKINETICS OF TEICOPLANIN UPON MULTIPLE DOSE INTRAVENOUS ADMINISTRATION TO NORMAL HEALTHY MALE VOLUNTEERS GARY A. THOMPSON*, JACQUELYN A . SMITHERS, MICHAELT. KENNY, JACQUELINE K. DULWORTH, HENRIK K. KULMALA, LIANNG Y U H t , ERIC W . LEWIS, KELLY K. ANTONY
Marion Merrell Dow Inc., Cincinnati, OH 45215 and Indianapolis, IN 46268, U.S.A.
ABSTRACT Teicoplanin pharmacokinetics were investigated upon multiple dose intravenous administration of 6 and 12 mg kg-l in 10 normal, healthy, male volunteers, using a two-period, randomized, crossover design; six subjects completed both periods. On day 1, 6 or 12 mg kg-' was administered every 12 h as a 30-min constant rate intravenous infusion (two doses). Starting on day 2, the same dose (6 or 12 mg kg-I) was administered every 24 h for an additional 13 days. Blood and urine samples were collected over 21 days. Serum and urine were analyzed using a microbiological assay. Following a minimum of 3 weeks after completion of the first period, subjects were crossed over to the other dose. Following multiple dose intravenous administration of 6 and 12mg kg-', median pharmacokinetic parameters included: steady-state volume of distribution of 1-4and 1.2 1 kg-I; total clearance of 12.2 and 14.0 ml h-l kg-'; renal clearance of 11.1 and 10.3ml h-' kg-'; and terminal disposition half-life of 159 and 155 h, respectively. No statistically significant dose-related difference was observed. In addition, a cross-study comparison further supports dose proportionality of teicoplanin upon multiple dose intravenous administration of 3 to 12 mg kg-'. KEY WORDS
Teicoplanin Pharmacokinetics Multiple dose Normal volunteers
INTRODUCTION Teicoplanin is a new glycopeptide antibiotic, chemically related to vancomycin and ristocetin. It is active against aerobic and anaerobic gram-positive bacteria.14 Its effect on susceptible bacteria is bactericidal and, like vancomycin, it interferes with cell wall ~ y n t h e s i s . ~ In previous studies, the pharmacokinetics of teicoplanin upon multiple dose intravenous administration of 3 and 6 mg kg-' have been studied in normal healthy volunteer^.^.' Over this range of doses, teicoplanin pharmacokinetics are linear and are characterized by the following median parameters: total
* Addressee for correspondence. Present address: Prockr & Gamble Company, Regulatory and Clinical Development, 11370 Reed Hartman Highway, Cincinnati,OH 45241-2422, U.S.A. t Present address: Warner Lambert Co., Ann Arbor, MI 48105, U.S.A. 0142-2782/92/030213-08$05.00 0 1992 by John Wiley & Sons, Ltd.
Received 21 May 1991 Accepted 16 September 1991
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clearance of 13.6 ml h-I kg-I; renal clearance of 10.9 ml h-' kg-I; steady-state volume of distribution of 1.2 1 kg-l, and a terminal elimination half-life of 147 h. These results indicate that total clearance is predominantly determined by renal clearance, and that dosage regimen adjustments may be necessary in patients with impaired renal function. Upon multiple dosing, steady-state will be obtained in 2 to 3 weeks if no loading dose(s) is administered. As a result of an increase in the dose being used in clinical investigations, this study was undertaken to evaluate the pharmacokinetics of teicoplanin in normal healthy volunteers upon multiple dose intravenous administration of 6 and 12 mg kg-I. METHODS Study design
This was a two-period, randomized, crossover study conducted in normal healthy male volunteers. On day 1, 6 or 12 mg kg-' of teicoplanin (Lot IC-4168) was administered every 12 h for two doses. Starting on day 2, 6 or 12 mg kg-l was administered every 24 h for an additional 13 days. All doses were administered as 30-min constant rate intravenous infusions. Following a minimum of 3 weeks after completion of the first period, subjects were crossed over to the other dose. Blood samples were obtained at the following times: Dose 1: 0, 30, 35, 40, 45, 60, 90, 120 min and 4, 6, 8, and 10 h after the start of the infusion. Dose 2: 0, 30 min after the start of the infusion. Doses 3 through 14: 0 and 30 min after the start of the infusion. Dose 15: 0, 30, 35, 40, 45, 60, 90, 120 min and 4, 6, 8, 10, 12 and 24 h after the start of the infusion and every 12 hours thereafter for an additional 7 days (14 samples). Urine was pooled every 12 h following doses 1 and 2 and every 24 h thereafter for an additional 20 days. Analytical methods
Serum (harvested from blood) and urine samples were analyzed for teicoplanin using a microbiological assay.* Within and between days coefficient of variations were less than 10 per cent. The lower limits of quantitation for serum and urine were 0.2 mg 1-' and 2.0 mg 1-I, respectively. Pharmacokinetic analysis
Serum concentration-time data obtained throughout multiple dosing were analyzed using NONLIN849and the following equation.
TEICOPLANIN KINETICS
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where k is the number of doses administered; n is the number of exponentials necessary to characterize the serum concentration-time profile; Dj is the size of the jth dose (mg kg-I); D 1is the size of the initial dose (mg kg-I); Ci is the ith coefficient which corresponds to 6 or 12 mg kg-'; Ai is the ith exponent; TIj is the duration of the jth infusion; bj is a second independent variable, equal to tj during the jth infusion and equal to TIj after the jth infusion; ti is time after the start of thejth infusion; C,,, is the pre-dose serumconcentration; tpre is the time the pre-dose sample is obtained relative to the first dose; and A4 is the terminal exponent. Initial parameter estimates were obtained from a previous study conducted in normal healthy volunteers.6 Various weightings of the observed serum concentrations (l,l/CO5, l/C, and 1/C) were used in the data analysis. Decisions on the appropriate weighting and the number of exponentials required to characterize the serum concentration-time data were based on visual inspection of the randomness of scatter of the observed data about the fitted line and the sum of weighted squared residuals.I0 Renal clearance was obtained as the ratio of the total amount of teicoplanin recovered in urine over 21 days to the area under the serum concentration-time profile (determined over the same time interval). Since the serum concentration-time profile was not completely characterized each day, area under the curve was determined using predicted instead of observed concentrations and the trapezoidal rule (using a step size of 0.1 h). Volumes of distribution, total clearance, mean residence time, and terminal elimination half-life were obtained from the coefficientsand exponents using standard equations."-13 Statistical analysis An analysis of variance (ANOVA) for a crossover designI4 was conducted to test for differences due to sequence of administration, periods (study day) of the crossover and treatment effects (6 mg kg-l versus 12 mg kg-I). The sequence effect was assessed using the subject variability to form the appropriate F-test. Treatment and period effects were tested using the random error variance term.I5 Results with p < 0.05 were considered statistically significant. Results from this study were summarized using the median and range since results from previous studies6,' indicated that certain parameters were not always normally distributed. RESULTS This study was conducted in 10 normal healthy male volunteers ranging from 21 to 38 years; six subjects completed both periods. Plots of the observed and predicted serum concentration-time profiles for a representative subject follow-
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G . A. THOMPSON ET A L .
ing 6 and 12 mg kg-' are illustrated in Figures 1 and 2, respectively. Excellent agreement between observed and predicted serum concentration-time profiles indicate the adequacy of these analyses. Individual pharmacokinetic parameters of teicoplanin following multiple dose intravenous administration of 6 and 12 mg kg-I are shown in Tables 1 and 2, respectively. Statistical analysis of these results indicates that although total clearance tended to increase with increasing dose, no significant difference was observed (p = 0.052; see Table 2). As a result of total clearance tending to increase with increasing dose, mean residence time tended to decrease with increasing dose; this also failed to reach statistical significance (p = 0.057). No other parameter approached statistical significance, nor was a sequence of period effect for any parameter observed.
-
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Figure 1. Observed (solid circles) and predicted (solid line) serum concentration-time profiles upon multiple dose intravenous administrationof 6 mg kg-l of teicoplanin (Subject 1)
Comparison of the area under the serum concentration-time curve over 24 h following the last dose to the integration of the single dose part of equation (1) from time zero to infinity, indicates that approximately 93 per cent of steadystate is obtained after 14 days of dosing. Predicted median (range) steady-state trough serum concentrations following 6 and 12 mg kg-' every 24 h as a 30-min constant rate intravenous infusion are 14-0 (10.0-16.4) and 22.9 (17629.1) mg 1-', respectively.16 DISCUSSION Teicoplanin is a glycopeptide antibiotic which is active against aerobic and anaerobic gram-positive bacteria. '--I In earlier studies, the pharmacokinetics
217
TEICOPLANIN KINETICS
-
1000
5
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I 100 lP
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0.1
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TIME (DAY)
Figure 2. Observed (solid circles) and predicted (solid line) serum concentration-time profiles upon multiple dose intravenous administration of 12 mg kg-' of teicoplanin (Subject 1)
Table 1. Teicoplanin pharmacokinetic parameters in normal healthy male volunteers based on analysis of all serum concentration-time data obtained upon multiple dose intravenous administration of 6 mg kg-'* Subject 1 3 4 5
6 7 8 9 10 Median
V, (1 kg-') 0.1253 0.1055 0.1081 0.1069 0.09462 0.08372 0.08781 0.1154 0.09404 0.10
vss
(1 kg-') 1.503 1.386 1.058
1.194 0.9530 1.476 1.027 1.615 1.381 1.38
V (1 kg-')
CL
3.446 2.643 2.789 2.745 2.662 4.084 2.383 3.603 3.822 2.79
11.93 11.97 12.17 13.39 15.30 10.91 13.00 12.53 11.39 12.2
(ml h-'
CL,
MRT (h)
T%,z (h)
10.32 11.07 10.43 11.39 13.65 10.07 10.26 11.16 11.33
126.0 115.7 86.89 89.17 62.28 135.3 79.07 128.9 121.2
200.3 152.9 158.8 142.1 120.6 259.4 127.1 199.3 232.6
11.1
115.7
159
kg-')
* V, is the volume of the central compartment; V, is the volume of distribution at steady-state; V is the terminal phase volume of distribution; CL is total clearance; CL, is renal clearance; MRT is the mean residence time; and TIA,r is the terminal elimination half-life.
of teicoplanin were determined based on plasma concentration-times profiles ~ Jmore * recent studies, the duration of sample obtained over 3 to 4 d a y ~ . ~In collection has been increased up to 3 weeks, resulting in a better characterization of the serum concentration-time p r ~ f i l e . ~ .As ~ . ' a~ result of the increased duration of sample collection, teicoplanin total clearance was found to be slightly less and the volumes of distribution and terminal disposition half-life were found to be greater than previously reported. Results from these more recent studies indicate that the pharmacokinetics of teicoplanin upon multiple
218
G . A . THOMPSON ET A L .
Table 2. Teicoplanin pharmacokinetic parameters in normal healthy male volunteers based on analysis of all serum concentration-time data obtained upon multiple dose intravenous administration 12 mg kg-'* Subject 1 2 3 4 6 7 9 Median p-valuet
V, (1 kg-') 0.1061 0.07866 0.1200 0.1067 0.08937 0.07257 0.09391 0.094 0.269
(1 kg-')
V (1 kg-')
1.277 1.340 1.209 1.029 1.175 0.9461 1.061 1.18 0.239
3.131 3.459 3.379 3.078 3.659 2.616 2.504 3.13 0.829
VSS
CL CL, (mlh-' kg-')
13.05 14.01 15.12 14.09 17.20 10.81
13.35 14.0 0.052
10.31 10.34 12.09 11.96 14.47 8.954 10.09 10.3 0.535
MRT (h)
T,,z (h)
97.75 95.59 79.94 73.00 68.34 87.51 79.54 79.9 0.057
166.2 171.1 154.9 151.4 147.4 167.7 130.0 155 0.280
* V,: volume of the central compartment; V,: volume of distribution at steady-state; K terminal phase volume of distribution; CL: total clearance; CL,: renal clearance; MRT: mean resisdence time; T,h,z:terminal elimination half-life. tComparison of results following 6 mg kg-' (Table I ) and 12 mg kg-'(Table 2).
Table 3. Teicoplanin pharmacokinetics in normal healthy volunteers upon multiple dose intravenous administration of 3,6, and 12 mg kg-'* Dose (mg/kg) Parameter?
3$
6§
611
1211
N
8
6
9
7
1.4 (1.c~2.4)
1.o (0.8-2.3)
1.4 (0.9-1.6)
1.2 (0.9- 1 3)
CL (ml h-' kg-')
14.8 (10.7-18.2)
12.4 (1 1.2-14.6)
12.2 (10.9-1 5-3)
14.0 (10.8-17.2)
CLr (ml h-' kg-')
10.4 (6.9-1 1.8)
11.1 (10.2-12.6)
11.1 (10.1-1 3.6)
10.3 (94-14.5)
156 (66-408)
138 (68-327)
159 (121-259)
155 (130-1 71)
VSS
(1 kg-9
T%,z
(h)
*Median (range). t n : Number of subjects: Vss: volume of distribution at steady-state; CL: total clearance; CL,: renal clearance; T,h,z:terminal elimination half-life. $See Data on File: Marion Merrell Dow Inc.6 $See Outman eta/'. IIPresent study.
dose intravenous administration are linear over the range of 3 to 6 mg kg-'.6,7 In the present study, the pharmacokinetics of teicoplanin upon multiple dose intravenous administration of 6 and 12 mg kg-' were investigated. Results obtained upon intravenous administration of 6 mg kg-I are in excellent agreement with those previously obtained in normal healthy volunteers7
TEICOPLANIN KINETICS
219
(See Table 3). Results in the present study indicate that total clearance is predominantly determined by renal clearance, steady-state volume of distribution is approximately 1.2 1 kg-', and the terminal elimination half-life is approximately 150 h. Although total clearance tended to increase and mean residence time tended to decrease with increasing dose, no statistically significant dose related differences were observed following multiple dose intravenous administration of 6 and 12 mg kg-I. In addition, visual inspection of data obtained in several studies using a similar design also indicates that the pharmacokinetics of teicoplanin upon multiple dose intravenous administration are dose independent from 3 to 12 mg kg-I (see Table 3). ACKNOWLEDGEMENTS The authors are grateful to the following individuals for their constructive review of this manuscript, assistance in the analysis of samples and/or in conducting this study: Frank J. Balistreri, Harold Boxenbaum, Nicolette L. Cavallaro, Michael C. Graham, Gillian Ivers-Read, Gerald D. Mayer, Richard A. Okerholm, Israel Rios, Stephen J. Ruberg, and Paul J. Schechter. REFERENCES 1. H. C. Neu and P. Labthavikul, In vitro activity of teichomycin compared with those of other
antibiotics. Antimicrob. Agents Chemother., 24,425428 (1983). 2. M. H. Cynamon and P. A. Granato, Comparison of the in vitro activities of teichomycin A, and vancomycin against staphylococci and enterococci. Antimicrob. Agents Chemother., 21,504-505 (1982). 3. L. Jadeja, V. Fainstein, B. LeBlanc and G. P. Bodey, Comparative in vitro activities of teichomycin and other antibiotics against JK diphtheroids. Antimicrob. Agents Chemother., 24, 145-146 (1983). 4. R. Pallanza, M. Berti, B. Goldstein, E. Mapelli, E. Randisi, R. Scotti and V. Arioli, Teichomycin: in vitro and in vivo evaluation in comparison with other antibiotics. J. Antimicrob. Chemother., 11,419425 (1983). 5 . S. S o m a and L. Gastaldo, Mechanism of action of teichomycin A,, a new antibiotic, in Current Chemotherapy Immunotherapy, P. Periti and G. Grassi (Eds), American Society for Microbiology, Washington, D.C., 1982, pp. 343-345. 6. Data on File : Marion Merrell Dow Inc., Teicoplanin pharmacokinetics in normal healthy volunteers upon multiple dose administration of 3 mgkg. Project Report DR-89-12, 1989. 7. W. R. Outman, C. H. Nightingale, K. R. Sweeney and R. Quintiliani, Teicoplanin pharmacokinetics in healthy volunteers after administration of intravenous loading and maintenance doses. Antimicrob. Agents Chemother., 34,211421 17 (1990). 8. R. C. Erickson, A. R. Hildebrand, P. F. Hoffman and C. B. Gibson, A sensitive bioassay for teicoplanin in the presence or absence of other antibiotics. Diagn. Microbiol. Infect. Dis., 12,235-241 (1989). 9. Statistical Consultants, Inc., PCNONLIN and NONLIN84: Software for the statistical analysis of nonlinear models. Amer. Stat., 40,52 (1986). 10. H. G. Boxenbaum, S. Riegelman and R. M. Elashoff, Statistical estimations in pharmacokinetics. J. Pharmacokin. Biopharm., 2, 123-148 (1974). 11. M. Gibaldi and D. Perrier, Pharmacokinetics, 2nd edn, Marcel Dekker, New York, 1982. 12. J. G. Wagner, Linear pharmacokinetic equations allowing direct calculation of many needed
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pharmacokinetic parameters from the coefficient and exponents of polyexponential equations which have been fitted to the data. J. Pharmacokin. Biopharm., 4,443467 (1976). 13. W. J. Jusko, Guidelines for collection and analysis of pharmacokinetic data, in Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, 2nd edn, W. E. Evans, J. J. Schentag and W. J. Jusko (Eds), Applied Therapeutics, Inc., Spokane, WA, 1986, pp. 9-54, 14. D. J. Finney, Statistical Method in Biological Assay, 3rd edn, Charles Griffin and Company, Ltd, London, 1978. IS. SAS Institute Inc., SAS User’s Guide: Statistics, 5th edn, SAS Institute Inc., Cary, NC, 1985. 16. G. A. Thompson and R. C. Shumaker, MLTIDOSE: A multiple-dose simulation program for linear systems characterized by exponential functions. Drug Metabol. Rev.,21, 463469 ( 1989-90). 17. L. Verbist, T. B. Tjandramaga, B. Hendrickx, A. Van Hecken, P. Van Melle, R. Verbesselt, J. Verhaegen and P. J. DeSchepper, In vitro activity and human pharmacokinetics of teicoplanin. Antimicrobiol. Agents Chemother., 26,881-886 (1984). 18. G. L. Traina and M. Bonati, Pharmacokinetics of teicoplanin in man after intravenous administration. J. Pharmacokin. Biopharm., 12, 119-128 (1984). 19. K. K. Antony, E. W. Lewis, M. T. Kenny, J. K. Dulworth, M. B. Brackman, R. Kuzma, L. Yuh, M. G. Eller and G. A. Thompson, Phamacokinetics and bioavailability of a new formulation of teicoplanin following intravenous and intramuscular administration to humans. J . Pharm. Sci., 80,605-607 (1 99 I).
PHARMACOKINETICS OF TEICOPLANIN UPON MULTIPLE DOSE INTRAVENOUS ADMINISTRATION TO NORMAL HEALTHY MALE VOLUNTEERS GARY A. THOMPSON*, JACQUELYN A . SMITHERS, MICHAELT. KENNY, JACQUELINE K. DULWORTH, HENRIK K. KULMALA, LIANNG Y U H t , ERIC W . LEWIS, KELLY K. ANTONY
Marion Merrell Dow Inc., Cincinnati, OH 45215 and Indianapolis, IN 46268, U.S.A.
ABSTRACT Teicoplanin pharmacokinetics were investigated upon multiple dose intravenous administration of 6 and 12 mg kg-l in 10 normal, healthy, male volunteers, using a two-period, randomized, crossover design; six subjects completed both periods. On day 1, 6 or 12 mg kg-' was administered every 12 h as a 30-min constant rate intravenous infusion (two doses). Starting on day 2, the same dose (6 or 12 mg kg-I) was administered every 24 h for an additional 13 days. Blood and urine samples were collected over 21 days. Serum and urine were analyzed using a microbiological assay. Following a minimum of 3 weeks after completion of the first period, subjects were crossed over to the other dose. Following multiple dose intravenous administration of 6 and 12mg kg-', median pharmacokinetic parameters included: steady-state volume of distribution of 1-4and 1.2 1 kg-I; total clearance of 12.2 and 14.0 ml h-l kg-'; renal clearance of 11.1 and 10.3ml h-' kg-'; and terminal disposition half-life of 159 and 155 h, respectively. No statistically significant dose-related difference was observed. In addition, a cross-study comparison further supports dose proportionality of teicoplanin upon multiple dose intravenous administration of 3 to 12 mg kg-'. KEY WORDS
Teicoplanin Pharmacokinetics Multiple dose Normal volunteers
INTRODUCTION Teicoplanin is a new glycopeptide antibiotic, chemically related to vancomycin and ristocetin. It is active against aerobic and anaerobic gram-positive bacteria.14 Its effect on susceptible bacteria is bactericidal and, like vancomycin, it interferes with cell wall ~ y n t h e s i s . ~ In previous studies, the pharmacokinetics of teicoplanin upon multiple dose intravenous administration of 3 and 6 mg kg-' have been studied in normal healthy volunteer^.^.' Over this range of doses, teicoplanin pharmacokinetics are linear and are characterized by the following median parameters: total
* Addressee for correspondence. Present address: Prockr & Gamble Company, Regulatory and Clinical Development, 11370 Reed Hartman Highway, Cincinnati,OH 45241-2422, U.S.A. t Present address: Warner Lambert Co., Ann Arbor, MI 48105, U.S.A. 0142-2782/92/030213-08$05.00 0 1992 by John Wiley & Sons, Ltd.
Received 21 May 1991 Accepted 16 September 1991
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clearance of 13.6 ml h-I kg-I; renal clearance of 10.9 ml h-' kg-I; steady-state volume of distribution of 1.2 1 kg-l, and a terminal elimination half-life of 147 h. These results indicate that total clearance is predominantly determined by renal clearance, and that dosage regimen adjustments may be necessary in patients with impaired renal function. Upon multiple dosing, steady-state will be obtained in 2 to 3 weeks if no loading dose(s) is administered. As a result of an increase in the dose being used in clinical investigations, this study was undertaken to evaluate the pharmacokinetics of teicoplanin in normal healthy volunteers upon multiple dose intravenous administration of 6 and 12 mg kg-I. METHODS Study design
This was a two-period, randomized, crossover study conducted in normal healthy male volunteers. On day 1, 6 or 12 mg kg-' of teicoplanin (Lot IC-4168) was administered every 12 h for two doses. Starting on day 2, 6 or 12 mg kg-l was administered every 24 h for an additional 13 days. All doses were administered as 30-min constant rate intravenous infusions. Following a minimum of 3 weeks after completion of the first period, subjects were crossed over to the other dose. Blood samples were obtained at the following times: Dose 1: 0, 30, 35, 40, 45, 60, 90, 120 min and 4, 6, 8, and 10 h after the start of the infusion. Dose 2: 0, 30 min after the start of the infusion. Doses 3 through 14: 0 and 30 min after the start of the infusion. Dose 15: 0, 30, 35, 40, 45, 60, 90, 120 min and 4, 6, 8, 10, 12 and 24 h after the start of the infusion and every 12 hours thereafter for an additional 7 days (14 samples). Urine was pooled every 12 h following doses 1 and 2 and every 24 h thereafter for an additional 20 days. Analytical methods
Serum (harvested from blood) and urine samples were analyzed for teicoplanin using a microbiological assay.* Within and between days coefficient of variations were less than 10 per cent. The lower limits of quantitation for serum and urine were 0.2 mg 1-' and 2.0 mg 1-I, respectively. Pharmacokinetic analysis
Serum concentration-time data obtained throughout multiple dosing were analyzed using NONLIN849and the following equation.
TEICOPLANIN KINETICS
215
where k is the number of doses administered; n is the number of exponentials necessary to characterize the serum concentration-time profile; Dj is the size of the jth dose (mg kg-I); D 1is the size of the initial dose (mg kg-I); Ci is the ith coefficient which corresponds to 6 or 12 mg kg-'; Ai is the ith exponent; TIj is the duration of the jth infusion; bj is a second independent variable, equal to tj during the jth infusion and equal to TIj after the jth infusion; ti is time after the start of thejth infusion; C,,, is the pre-dose serumconcentration; tpre is the time the pre-dose sample is obtained relative to the first dose; and A4 is the terminal exponent. Initial parameter estimates were obtained from a previous study conducted in normal healthy volunteers.6 Various weightings of the observed serum concentrations (l,l/CO5, l/C, and 1/C) were used in the data analysis. Decisions on the appropriate weighting and the number of exponentials required to characterize the serum concentration-time data were based on visual inspection of the randomness of scatter of the observed data about the fitted line and the sum of weighted squared residuals.I0 Renal clearance was obtained as the ratio of the total amount of teicoplanin recovered in urine over 21 days to the area under the serum concentration-time profile (determined over the same time interval). Since the serum concentration-time profile was not completely characterized each day, area under the curve was determined using predicted instead of observed concentrations and the trapezoidal rule (using a step size of 0.1 h). Volumes of distribution, total clearance, mean residence time, and terminal elimination half-life were obtained from the coefficientsand exponents using standard equations."-13 Statistical analysis An analysis of variance (ANOVA) for a crossover designI4 was conducted to test for differences due to sequence of administration, periods (study day) of the crossover and treatment effects (6 mg kg-l versus 12 mg kg-I). The sequence effect was assessed using the subject variability to form the appropriate F-test. Treatment and period effects were tested using the random error variance term.I5 Results with p < 0.05 were considered statistically significant. Results from this study were summarized using the median and range since results from previous studies6,' indicated that certain parameters were not always normally distributed. RESULTS This study was conducted in 10 normal healthy male volunteers ranging from 21 to 38 years; six subjects completed both periods. Plots of the observed and predicted serum concentration-time profiles for a representative subject follow-
216
G . A. THOMPSON ET A L .
ing 6 and 12 mg kg-' are illustrated in Figures 1 and 2, respectively. Excellent agreement between observed and predicted serum concentration-time profiles indicate the adequacy of these analyses. Individual pharmacokinetic parameters of teicoplanin following multiple dose intravenous administration of 6 and 12 mg kg-I are shown in Tables 1 and 2, respectively. Statistical analysis of these results indicates that although total clearance tended to increase with increasing dose, no significant difference was observed (p = 0.052; see Table 2). As a result of total clearance tending to increase with increasing dose, mean residence time tended to decrease with increasing dose; this also failed to reach statistical significance (p = 0.057). No other parameter approached statistical significance, nor was a sequence of period effect for any parameter observed.
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:
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0 I4
Ioc
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0 0
5ccw
1
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0.1
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Figure 1. Observed (solid circles) and predicted (solid line) serum concentration-time profiles upon multiple dose intravenous administrationof 6 mg kg-l of teicoplanin (Subject 1)
Comparison of the area under the serum concentration-time curve over 24 h following the last dose to the integration of the single dose part of equation (1) from time zero to infinity, indicates that approximately 93 per cent of steadystate is obtained after 14 days of dosing. Predicted median (range) steady-state trough serum concentrations following 6 and 12 mg kg-' every 24 h as a 30-min constant rate intravenous infusion are 14-0 (10.0-16.4) and 22.9 (17629.1) mg 1-', respectively.16 DISCUSSION Teicoplanin is a glycopeptide antibiotic which is active against aerobic and anaerobic gram-positive bacteria. '--I In earlier studies, the pharmacokinetics
217
TEICOPLANIN KINETICS
-
1000
5
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I 100 lP
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0
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0.1
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Figure 2. Observed (solid circles) and predicted (solid line) serum concentration-time profiles upon multiple dose intravenous administration of 12 mg kg-' of teicoplanin (Subject 1)
Table 1. Teicoplanin pharmacokinetic parameters in normal healthy male volunteers based on analysis of all serum concentration-time data obtained upon multiple dose intravenous administration of 6 mg kg-'* Subject 1 3 4 5
6 7 8 9 10 Median
V, (1 kg-') 0.1253 0.1055 0.1081 0.1069 0.09462 0.08372 0.08781 0.1154 0.09404 0.10
vss
(1 kg-') 1.503 1.386 1.058
1.194 0.9530 1.476 1.027 1.615 1.381 1.38
V (1 kg-')
CL
3.446 2.643 2.789 2.745 2.662 4.084 2.383 3.603 3.822 2.79
11.93 11.97 12.17 13.39 15.30 10.91 13.00 12.53 11.39 12.2
(ml h-'
CL,
MRT (h)
T%,z (h)
10.32 11.07 10.43 11.39 13.65 10.07 10.26 11.16 11.33
126.0 115.7 86.89 89.17 62.28 135.3 79.07 128.9 121.2
200.3 152.9 158.8 142.1 120.6 259.4 127.1 199.3 232.6
11.1
115.7
159
kg-')
* V, is the volume of the central compartment; V, is the volume of distribution at steady-state; V is the terminal phase volume of distribution; CL is total clearance; CL, is renal clearance; MRT is the mean residence time; and TIA,r is the terminal elimination half-life.
of teicoplanin were determined based on plasma concentration-times profiles ~ Jmore * recent studies, the duration of sample obtained over 3 to 4 d a y ~ . ~In collection has been increased up to 3 weeks, resulting in a better characterization of the serum concentration-time p r ~ f i l e . ~ .As ~ . ' a~ result of the increased duration of sample collection, teicoplanin total clearance was found to be slightly less and the volumes of distribution and terminal disposition half-life were found to be greater than previously reported. Results from these more recent studies indicate that the pharmacokinetics of teicoplanin upon multiple
218
G . A . THOMPSON ET A L .
Table 2. Teicoplanin pharmacokinetic parameters in normal healthy male volunteers based on analysis of all serum concentration-time data obtained upon multiple dose intravenous administration 12 mg kg-'* Subject 1 2 3 4 6 7 9 Median p-valuet
V, (1 kg-') 0.1061 0.07866 0.1200 0.1067 0.08937 0.07257 0.09391 0.094 0.269
(1 kg-')
V (1 kg-')
1.277 1.340 1.209 1.029 1.175 0.9461 1.061 1.18 0.239
3.131 3.459 3.379 3.078 3.659 2.616 2.504 3.13 0.829
VSS
CL CL, (mlh-' kg-')
13.05 14.01 15.12 14.09 17.20 10.81
13.35 14.0 0.052
10.31 10.34 12.09 11.96 14.47 8.954 10.09 10.3 0.535
MRT (h)
T,,z (h)
97.75 95.59 79.94 73.00 68.34 87.51 79.54 79.9 0.057
166.2 171.1 154.9 151.4 147.4 167.7 130.0 155 0.280
* V,: volume of the central compartment; V,: volume of distribution at steady-state; K terminal phase volume of distribution; CL: total clearance; CL,: renal clearance; MRT: mean resisdence time; T,h,z:terminal elimination half-life. tComparison of results following 6 mg kg-' (Table I ) and 12 mg kg-'(Table 2).
Table 3. Teicoplanin pharmacokinetics in normal healthy volunteers upon multiple dose intravenous administration of 3,6, and 12 mg kg-'* Dose (mg/kg) Parameter?
3$
6§
611
1211
N
8
6
9
7
1.4 (1.c~2.4)
1.o (0.8-2.3)
1.4 (0.9-1.6)
1.2 (0.9- 1 3)
CL (ml h-' kg-')
14.8 (10.7-18.2)
12.4 (1 1.2-14.6)
12.2 (10.9-1 5-3)
14.0 (10.8-17.2)
CLr (ml h-' kg-')
10.4 (6.9-1 1.8)
11.1 (10.2-12.6)
11.1 (10.1-1 3.6)
10.3 (94-14.5)
156 (66-408)
138 (68-327)
159 (121-259)
155 (130-1 71)
VSS
(1 kg-9
T%,z
(h)
*Median (range). t n : Number of subjects: Vss: volume of distribution at steady-state; CL: total clearance; CL,: renal clearance; T,h,z:terminal elimination half-life. $See Data on File: Marion Merrell Dow Inc.6 $See Outman eta/'. IIPresent study.
dose intravenous administration are linear over the range of 3 to 6 mg kg-'.6,7 In the present study, the pharmacokinetics of teicoplanin upon multiple dose intravenous administration of 6 and 12 mg kg-' were investigated. Results obtained upon intravenous administration of 6 mg kg-I are in excellent agreement with those previously obtained in normal healthy volunteers7
TEICOPLANIN KINETICS
219
(See Table 3). Results in the present study indicate that total clearance is predominantly determined by renal clearance, steady-state volume of distribution is approximately 1.2 1 kg-', and the terminal elimination half-life is approximately 150 h. Although total clearance tended to increase and mean residence time tended to decrease with increasing dose, no statistically significant dose related differences were observed following multiple dose intravenous administration of 6 and 12 mg kg-I. In addition, visual inspection of data obtained in several studies using a similar design also indicates that the pharmacokinetics of teicoplanin upon multiple dose intravenous administration are dose independent from 3 to 12 mg kg-I (see Table 3). ACKNOWLEDGEMENTS The authors are grateful to the following individuals for their constructive review of this manuscript, assistance in the analysis of samples and/or in conducting this study: Frank J. Balistreri, Harold Boxenbaum, Nicolette L. Cavallaro, Michael C. Graham, Gillian Ivers-Read, Gerald D. Mayer, Richard A. Okerholm, Israel Rios, Stephen J. Ruberg, and Paul J. Schechter. REFERENCES 1. H. C. Neu and P. Labthavikul, In vitro activity of teichomycin compared with those of other
antibiotics. Antimicrob. Agents Chemother., 24,425428 (1983). 2. M. H. Cynamon and P. A. Granato, Comparison of the in vitro activities of teichomycin A, and vancomycin against staphylococci and enterococci. Antimicrob. Agents Chemother., 21,504-505 (1982). 3. L. Jadeja, V. Fainstein, B. LeBlanc and G. P. Bodey, Comparative in vitro activities of teichomycin and other antibiotics against JK diphtheroids. Antimicrob. Agents Chemother., 24, 145-146 (1983). 4. R. Pallanza, M. Berti, B. Goldstein, E. Mapelli, E. Randisi, R. Scotti and V. Arioli, Teichomycin: in vitro and in vivo evaluation in comparison with other antibiotics. J. Antimicrob. Chemother., 11,419425 (1983). 5 . S. S o m a and L. Gastaldo, Mechanism of action of teichomycin A,, a new antibiotic, in Current Chemotherapy Immunotherapy, P. Periti and G. Grassi (Eds), American Society for Microbiology, Washington, D.C., 1982, pp. 343-345. 6. Data on File : Marion Merrell Dow Inc., Teicoplanin pharmacokinetics in normal healthy volunteers upon multiple dose administration of 3 mgkg. Project Report DR-89-12, 1989. 7. W. R. Outman, C. H. Nightingale, K. R. Sweeney and R. Quintiliani, Teicoplanin pharmacokinetics in healthy volunteers after administration of intravenous loading and maintenance doses. Antimicrob. Agents Chemother., 34,211421 17 (1990). 8. R. C. Erickson, A. R. Hildebrand, P. F. Hoffman and C. B. Gibson, A sensitive bioassay for teicoplanin in the presence or absence of other antibiotics. Diagn. Microbiol. Infect. Dis., 12,235-241 (1989). 9. Statistical Consultants, Inc., PCNONLIN and NONLIN84: Software for the statistical analysis of nonlinear models. Amer. Stat., 40,52 (1986). 10. H. G. Boxenbaum, S. Riegelman and R. M. Elashoff, Statistical estimations in pharmacokinetics. J. Pharmacokin. Biopharm., 2, 123-148 (1974). 11. M. Gibaldi and D. Perrier, Pharmacokinetics, 2nd edn, Marcel Dekker, New York, 1982. 12. J. G. Wagner, Linear pharmacokinetic equations allowing direct calculation of many needed
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pharmacokinetic parameters from the coefficient and exponents of polyexponential equations which have been fitted to the data. J. Pharmacokin. Biopharm., 4,443467 (1976). 13. W. J. Jusko, Guidelines for collection and analysis of pharmacokinetic data, in Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, 2nd edn, W. E. Evans, J. J. Schentag and W. J. Jusko (Eds), Applied Therapeutics, Inc., Spokane, WA, 1986, pp. 9-54, 14. D. J. Finney, Statistical Method in Biological Assay, 3rd edn, Charles Griffin and Company, Ltd, London, 1978. IS. SAS Institute Inc., SAS User’s Guide: Statistics, 5th edn, SAS Institute Inc., Cary, NC, 1985. 16. G. A. Thompson and R. C. Shumaker, MLTIDOSE: A multiple-dose simulation program for linear systems characterized by exponential functions. Drug Metabol. Rev.,21, 463469 ( 1989-90). 17. L. Verbist, T. B. Tjandramaga, B. Hendrickx, A. Van Hecken, P. Van Melle, R. Verbesselt, J. Verhaegen and P. J. DeSchepper, In vitro activity and human pharmacokinetics of teicoplanin. Antimicrobiol. Agents Chemother., 26,881-886 (1984). 18. G. L. Traina and M. Bonati, Pharmacokinetics of teicoplanin in man after intravenous administration. J. Pharmacokin. Biopharm., 12, 119-128 (1984). 19. K. K. Antony, E. W. Lewis, M. T. Kenny, J. K. Dulworth, M. B. Brackman, R. Kuzma, L. Yuh, M. G. Eller and G. A. Thompson, Phamacokinetics and bioavailability of a new formulation of teicoplanin following intravenous and intramuscular administration to humans. J . Pharm. Sci., 80,605-607 (1 99 I).
