ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 1991, p. 2551-2557 0066-4804/91/122551-07$02.00/0 Copyright C 1991, American Society for Microbiology
Vol. 35, No. 12
Pharmacokinetics and Tolerability of Teicoplanin in Healthy Volunteers after Single Increasing Doses A. DEL FAVERO,l* L. PATOIA,1 R. ROSINA,2 G. BUNIVA,2 A. DANESE,2 A. BERNAREGGI,2 E. MOLINI,3 AND L. CAVENAGHI2 Department of Internal Medicine' and Department of Otorhinolaryngology,3 University of Perugia, Perugia, and Marion Merrell Dow Research and Development, Lepetit Center, Gerenzano (Varese),2 Italy
Received 4 February 1991/Accepted 23 September 1991 In this double-blind, randomized study, five healthy subjects per group received doses of 15, 20, or 25 mg of teicoplanin per kg of body weight, and one subject per group received a 0.9% NaCl placebo as single intravenous infusion over 30 min. Serial blood samples and urine were collected for 13 days postadministration, and concentrations of teicoplanin were determined by microbiological assay. The pharmacokinetic data were analyzed by noncompartmental and compartmental analyses. Laboratory safety tests, audiometry, and serum creatinine clearance measurements were done prior to day 1 and on days 2 and 14. In the three groups, peak levels at the end of the infusion averaged 194, 197, and 253 mg/liter, respectively. Mean concentrations in plasma 24 h after the administration were 10.5, 13.6, and 19.8 mg/liter, respectively. Mean values of volume of distribution at steady state were 0.80, 0.87, and 0.87 liters/kg, respectively. Terminal half-lives averaged 88, 83, and 92 h. Mean total clearance values were 10.9, 11.0, and 11.3 mg/h/kg, respectively, with renal clearance accounting for 75, 81, and 78%, respectively, of the total. The 13-day cumulative mean urinary recovery ranged from 71 to 78% of the dose within the groups. The pharmacokinetics of teicoplanin appears to be linear in the range of administered doses. Teicoplanin was generally well tolerated. Side effects, appearing in five subjects, were represented by fevers, chills, and skin reactions; these adverse reactions were mild, but one episode of rash necessitated the interruption of infusion, and one episode of chills necessitated treatment with corticosteroids. There was no indication of drug-related modifications of laboratory test results.
The pharmacokinetics of teicoplanin has been extensively investigated in numerous studies (17) carried out with both healthy volunteers and patients, with a range of doses from 2 to 6 mg/kg of body weight. In healthy volunteers, teicoplanin shows a triexponential plasma kinetic profile. Concentrations of around 70 mg/liter have been observed 5 min after the intravenous (i.v.) administration of 6 mg/kg (4, 5, 17). The apparent terminal half-life ranged in different studies from 34 to 163 h after a single dose, depending on the length of sampling (4-6, 13, 16-19, 21). A preliminary analysis of experience in the United States of the treatment of endocarditis due to Staphylococcus aureus, mainly in drug addicts, indicates that dosages of less than 12 mg/kg/ day did not approach the anticipated efficacy for this patient population, thus suggesting that the daily dose of teicoplanin for this specific condition would have to be increased. Since earlier studies on the tolerability of increasing doses of teicoplanin among normal volunteers did not include such a high dose, this study was carried out in order to obtain information on the tolerability and pharmacokinetics of teicoplanin among volunteers in a dose range of 15 to 25 mg/kg. (This work has been previously presented in part at the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy [9]).
weight tables of the Metropolitan Life Insurance Company (1). Criteria for exclusion included a history of allergies or allergic reactions to any drug, of hearing loss or abnormal vestibular function, of renal or hepatic impairment, of alcohol or drug abuse, of immunological disorders, and of acute illness within 2 weeks prior to the study. Subjects taking chronic medication or any medication within 5 days prior to the study and smoking more than 20 cigarettes a day were also excluded. All subjects were in good health, as indicated by a complete medical evaluation, which included a medical history, physical examination, electrocardiogram, baseline audiometry, and routine laboratory tests. All subjects gave informed consent in writing. The study was approved by the Local Ethical Review Committee. Study design. This was a double-blind, randomized study in which subjects received either teicoplanin or a placebo. Three groups with six subjects per group, corresponding to doses of 15 (group 1), 20 (group 2), and 25 (group 3) mg/kg, respectively, were treated. Five subjects per group were given the study drug, and one subject per group received a placebo infusion of 0.9% sodium chloride. Each subject was monitored for 14 days postadministration. All subjects within one group completed the follow-up before the next group was studied. The study was carried out at the Day Hospital facilities of the Institute of the Clinica Medica Generale e Terapia Medica of the Medical School of the University of Perugia, Perugia, Italy. The subjects were kept under observation from the evening before administration to 48 h following the injection of the study drug or placebo and returned daily to the Day Hospital as outpatients for the collection of blood and urine until the samples for pharmacokinetics were completed. Drug administration. Each teicoplanin vial was reconsti-
MATERIALS AND METHODS
Subjects. A total of 18 (6 per group) normal healthy adult male volunteers were selected. Criteria for inclusion were as follows: age, between 18 and 40 years; body weight, within 15% of ideal weight, as reported by the 1983 height and *
Corresponding author. 2551
2552
ANTIMICROB. AGENTS CHEMOTHER.
DEL FAVERO ET AL.
tuted with 3 ml of sterile water for injection. An adequate volume of reconstituted teicoplanin was further diluted with 0.9% sodium chloride, to a final volume of 130 ml, in order to provide the nominal dose in 100 ml of the final infusion solution. The actual doses administered were calculated from the teicoplanin concentrations of the infusion solutions, as determined by the microbiological assay. These solutions were prepared in the afternoon of the day before administration and were stored overnight at 4°C. They were returned to room temperature about 1 h before the start of administration. The containers of i.v. solution were wrapped in aluminum foil to mask any differences in the teicoplanin and placebo solutions. A constant-rate infusion pump (Terufusion infusion pump model STC-503, Terumo), which delivered 100 ml over 30 min, was used to administer the solutions. The placebo infusion consisted of 100 ml of O.9o sodium chloride solution for injection. Both the investigator and the subject remained blinded to the study drugs administered throughout the study. Sample collection. (i) Blood samples. Blood samples (about 5 mL each) were obtained prior to the infusion; at the end of the infusion (0 time); 5, 15, and 30 min and 1, 2, 4, 6, 8, 12, 24, 36, and 48 h after the completion of the infusion; and every 24 h thereafter for a total of 13 days, or 312 h. Heparinized tubes were used for blood collection and after separation from red blood cells by centrifugation for 10 min at 800 to 1,000 x g at room temperature, each plasma sample was transferred to a prelabelled polypropylene tube and stored at or below -20°C until assayed. (ii) Urine samples. From the start of the intravenous infusion, total urine output was collected at 24-h intervals, as pooled collections, daily for a total of 13 days. Urine was stored at 4°C until each collection was complete. Urine volumes were measured, and 10-ml aliquots were transferred into polypropylene tubes and stored at or below -20°C until assayed. (iii) Samples for 24-h creatinine clearance measurements. The 24-h creatinine clearance was measured prior to drug administration, on the basis of two initial 24-h urine collections. A 24-h creatinine clearance measurement was obtained on the 2nd and 13th days. Creatininuria for each 24-h collection sample was measured following the infusion. Safety monitoring. Vital signs (supine blood pressure, pulse, respiration, and oral temperature) were recorded immediately prior to administration of the teicoplanin or placebo infusion, at 10 and 20 min after the beginning of the infusion, and at the end of the infusion. Following the infusion, vital signs were taken at 1, 4, 8, 12, and 24 h, immediately after the blood sample had been obtained. During the study, subjects were observed daily to detect any evidence of adverse experiences. When an adverse event appeared, vital signs were measured at appropriate times.
For each teicoplanin dose, a physical examination and a panel of laboratory tests were performed 24 h after the infusion and on the 14th day postadministration. Evaluation of the auditory function was carried out by pure-tone audiometry in a soundproof room, twice before the study and 24 h and 14 days after the administration of study drug or placebo. The equipment used was an AMPLAID 455 audiometer with TDH49 earphones. Hearing thresholds were assessed by air conduction bilaterally at 250, 500, 1,000, 2,000, 3,000, 4,000, 6,000, and 8,000 Hz. Every increase of signal intensity was of 5 dB. Significant hearing change was defined as a permanent auditory threshold change greater than 15 dB at any two consecutive frequencies in either ear (14). No subjects had significant hearing loss according to the baseline audiogram (i.e., an air conduction pure-tone speech frequency threshold average of greater than 30 dB [mean of threshold value at 500, 1,000, and 2,000 Hz] for either ear or both ears) or pronounced preexisting tinnitus or dizziness problems. Concentrations of beta-2 microglobulin, a low-molecularweight protein used to test renal-tubular damage (22), in plasma and in 24-h urine samples of the group of volunteers treated with the highest dosage of teicoplanin (25 mg/kg) were determined prestudy and at days 2, 5, 7, and 12 postadministration. The immunoenzymatic method, with the Enzygnost beta-2 microglobulin kit, (Behring), was used. Drug assay. Teicoplanin concentrations in plasma and urine were determined by agar diffusion microbiological assay (7). The method was carried out according to the parallel-line design (standard versus sample curves for the same petri dish), as described in the British and European Pharmacopoeias and also as reported in the USP in the section Biological Assay. With this design, the validation (evaluation of specificity, precision, and recovery) is performed every time an assay is done. The method uses Bacillus subtilis ATCC 6633 as the test organism and has a limit of detection of 0.05 mg/liter and a confidence interval (95%) of 5%. The linearity of the log (dose)-response curve was assessed within the range of concentrations (from 0.05 to 0.8 mg/liter) adopted. Pharmacokinetic data analysis. Three- and four-exponential models were fitted to postinfusion plasma concentration data by the PCNONLIN program (20). The best fit was obtained by using 1/C2 as weighting factor, where c' is the teicoplanin concentration in plasma predicted at each sampling time. The goodness of fit of exponential models to experimental data was judged according to the Gallant test (11), the F-ratio test (3), and the Akaike information criteria (23). The method of residuals was used to obtain initial estimates of macroconstants. The pharmacokinetic parameters associated with the exponential equations were calculated in the standard manner (12). ±
TABLE 1. Subject demographics and teicoplanin doses' Group (n)
Age (yr)
Ht (cm)
Wt (kg)
1 (5) 2 (4) 3 (5)
26 ± 5 26 ± 2 24 ± 4
172 ± 4 177 ± 3 176 ± 5
73.2 ± 2 64.5 t 7 70.4 ± 10
Nominal dose (mg)
1,095 ± 41 1,275 ± 150 1,775 ± 271
Dose solution
(mg/ml) 11.3 ± 0.6 12.5 + 2.3 18.7 ± 2.7
a Data are given as means ± standard deviation. The infused volume was 100 ml for all groups.
Measured dose
Total (mg)
1,126 ± 64 1,249 ± 229
1,870
± 268
Fractional (mg/kg) 15.4 ± 0.5 19.3 ± 1.4 26.6 ± 0.8
VOL. 35, 1991
PHARMACOKINETICS AND TOLERABILITY OF TEICOPLANIN
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a repre-
For noncompartmental analysis, the terminal dispositionwas estimated by log-linear least-square fit of the terminal phase (72 to 312 h); terminal half-life was obtained as (ln2)/Iz, and the area under the serum concentration-time curve (AUC) was obtained by the trapezoidal rule, from time zero to the last sampling time, adding the term CjAZ to extrapolate the AUC to infinity, where CZ is the concentration of drug measured at the last sampling time. Total clearance (CL) was calculated as the ratio of dose to AUC; renal clearance (CLR) was calculated as the ratio of the cumulative amount of drug excreted in the urine in the interval 0 to 312 h postadministration to the plasma AUCO312. The urinary elimination half-lives were calculated by log-linear fit of urinary excretion rates in the apparent terminal phase (72 to 312 h). The volumes of distribution in the central compartment, during the elimination phase, and at steady state and the mean residence time were calculated according to usual relationships (12). Statistical analysis. The Student t test for paired data was used to analyze laboratory test values before and after teicoplanin administration and to compare pharmacokinetic parameters obtained with the three- and four-exponential models. Tukey's multiple comparison test (10) was used for the analysis of the pharmacokinetic parameters obtained with a noncompartmental and a triexponential model for the three groups of subjects. A type one experimentwise error rate of less than 0.05 was considered statistically significant. The statistical analysis was performed by using the package SAS. The correlation between AUC and dose was evaluated by linear regression and analysis of variance for linear regression (2). rate constant XZ
RESULTS Clinical results. All subjects but one received the full projected dose of teicoplanin. For one subject of group 2, the drug infusion was stopped 18 min after the start because of an adverse reaction to teicoplanin, consisting of four urticarial spots (two on the trunk and one each on a cheek and a leg), accompanied by itching. The first (2 cm in diameter) appeared 5 min after the beginning of teicoplanin infusion; the other three (0.5, 4, and 5 cm in diameter) were present after another 10 min of infusion. Drug treatment was interrupted, and signs and symptoms disappeared spontaneously
within 1 h of the end of infusion. This subject received a reduced dose of teicoplanin and was consequently not considered in the pharmacokinetic analysis. Another five subjects suffered mild adverse events after the infusion of teicoplanin. Three subjects had a slight, transient increase in body temperatures within 2 h following the end of infusion. The body temperatures rose to 37.1, 37.3, and 37.8°C in one subject of group 2 and in two subjects of group 3, respectively. In the subject with a 37.8°C fever, the increase in temperature was preceded by shaking chills, which required the administration of 100 mg of hydrocortisone i.v., with prompt recovery from symptoms. The increased body temperature lasted for a short time (30 to 240 min) in all subjects. Furthermore, two subjects of the first group, on the third and sixth days of follow-up, each had a single, small, short-lived, noninfiltrative, nonitching erythematous skin lesion on the limb, of doubtful significance. No adverse reactions were experienced by the subjects given placebo. No significant changes in vital signs or in laboratory test results were noted. In particular, creatinine clearance values and (for subjects treated with 25 mg/kg) the values of beta-2 microglobulin in plasma and urine were in the normal range, with no changes or trends of clinical relevance evident in any subject. No clinically significant changes in audiometry parameters were found in any subject when individual hearing thresholds registered before and 24 h and 14 days after treatment were compared. Pharmacokinetics analysis. The demographic characteristics of the subjects and the actual doses administered are illustrated in Table 1, showing good agreement between the nominal and the measured doses. Figure 1 shows semilogarithmic plots of mean plasma concentration-time curves after i.v. administration of teicoplanin. For each subject, most of the experimental datum points lay on the best-fit curves (Fig. 2). Mean values of pharmacokinetic parameters obtained with the three groups of subjects with compartmental analyses of plasma data by using both three- and four-exponential models and noncompartmental analysis and those values calculated from urinary data are reported in Table 2. The four-exponential term equation seemed to improve most of the curve fittings, according to the Gallant test, the F-ratio test, and the Akaike information criteria. However, the values of the main pharmacokinetics parameters calculated after the fitting of three- or four-exponential-term models to data did not differ significantly, as reported by Danese et al. (8). Thus, we concluded that the slight improvement of curve fitting obtained with the four-exponential-term model did not justify the increased complexity introduced into the structural model, and the results of the three-exponential-term equation, also utilized in previous pharmacokinetic studies, are discussed here. Mean peak levels in plasma at the end of the 30-min constant-rate infusions were 194 mg/liter (range, 139 to 257 mg/liter) in group 1, 197 mg/liter (range, 157 to 242 mg/liter) in group 2, and 253 mg/liter (range, 181 to 315mg/liter) in group 3, whereas levels at 24 h after the administration (trough) were 10.5 mg/liter (range, 9 to 13 mg/liter) 13.6 mg/liter (range, 12 to 16 mg/liter), and 19.8 mg/liter (range, 14 to 23 mg/liter), respectively. By three-compartment analysis, the values of the volumes of distribution in the central compartment averaged 0.07, 0.09, and 0.11 liters/kg in the three groups, whereas the mean steady-state volumes of distribution were 0.80, 0.87, and
VOL. 35, 1991
PHARMACOKINETICS AND TOLERABILITY OF TEICOPLANIN
2555
0
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Vol. 35, No. 12
Pharmacokinetics and Tolerability of Teicoplanin in Healthy Volunteers after Single Increasing Doses A. DEL FAVERO,l* L. PATOIA,1 R. ROSINA,2 G. BUNIVA,2 A. DANESE,2 A. BERNAREGGI,2 E. MOLINI,3 AND L. CAVENAGHI2 Department of Internal Medicine' and Department of Otorhinolaryngology,3 University of Perugia, Perugia, and Marion Merrell Dow Research and Development, Lepetit Center, Gerenzano (Varese),2 Italy
Received 4 February 1991/Accepted 23 September 1991 In this double-blind, randomized study, five healthy subjects per group received doses of 15, 20, or 25 mg of teicoplanin per kg of body weight, and one subject per group received a 0.9% NaCl placebo as single intravenous infusion over 30 min. Serial blood samples and urine were collected for 13 days postadministration, and concentrations of teicoplanin were determined by microbiological assay. The pharmacokinetic data were analyzed by noncompartmental and compartmental analyses. Laboratory safety tests, audiometry, and serum creatinine clearance measurements were done prior to day 1 and on days 2 and 14. In the three groups, peak levels at the end of the infusion averaged 194, 197, and 253 mg/liter, respectively. Mean concentrations in plasma 24 h after the administration were 10.5, 13.6, and 19.8 mg/liter, respectively. Mean values of volume of distribution at steady state were 0.80, 0.87, and 0.87 liters/kg, respectively. Terminal half-lives averaged 88, 83, and 92 h. Mean total clearance values were 10.9, 11.0, and 11.3 mg/h/kg, respectively, with renal clearance accounting for 75, 81, and 78%, respectively, of the total. The 13-day cumulative mean urinary recovery ranged from 71 to 78% of the dose within the groups. The pharmacokinetics of teicoplanin appears to be linear in the range of administered doses. Teicoplanin was generally well tolerated. Side effects, appearing in five subjects, were represented by fevers, chills, and skin reactions; these adverse reactions were mild, but one episode of rash necessitated the interruption of infusion, and one episode of chills necessitated treatment with corticosteroids. There was no indication of drug-related modifications of laboratory test results.
The pharmacokinetics of teicoplanin has been extensively investigated in numerous studies (17) carried out with both healthy volunteers and patients, with a range of doses from 2 to 6 mg/kg of body weight. In healthy volunteers, teicoplanin shows a triexponential plasma kinetic profile. Concentrations of around 70 mg/liter have been observed 5 min after the intravenous (i.v.) administration of 6 mg/kg (4, 5, 17). The apparent terminal half-life ranged in different studies from 34 to 163 h after a single dose, depending on the length of sampling (4-6, 13, 16-19, 21). A preliminary analysis of experience in the United States of the treatment of endocarditis due to Staphylococcus aureus, mainly in drug addicts, indicates that dosages of less than 12 mg/kg/ day did not approach the anticipated efficacy for this patient population, thus suggesting that the daily dose of teicoplanin for this specific condition would have to be increased. Since earlier studies on the tolerability of increasing doses of teicoplanin among normal volunteers did not include such a high dose, this study was carried out in order to obtain information on the tolerability and pharmacokinetics of teicoplanin among volunteers in a dose range of 15 to 25 mg/kg. (This work has been previously presented in part at the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy [9]).
weight tables of the Metropolitan Life Insurance Company (1). Criteria for exclusion included a history of allergies or allergic reactions to any drug, of hearing loss or abnormal vestibular function, of renal or hepatic impairment, of alcohol or drug abuse, of immunological disorders, and of acute illness within 2 weeks prior to the study. Subjects taking chronic medication or any medication within 5 days prior to the study and smoking more than 20 cigarettes a day were also excluded. All subjects were in good health, as indicated by a complete medical evaluation, which included a medical history, physical examination, electrocardiogram, baseline audiometry, and routine laboratory tests. All subjects gave informed consent in writing. The study was approved by the Local Ethical Review Committee. Study design. This was a double-blind, randomized study in which subjects received either teicoplanin or a placebo. Three groups with six subjects per group, corresponding to doses of 15 (group 1), 20 (group 2), and 25 (group 3) mg/kg, respectively, were treated. Five subjects per group were given the study drug, and one subject per group received a placebo infusion of 0.9% sodium chloride. Each subject was monitored for 14 days postadministration. All subjects within one group completed the follow-up before the next group was studied. The study was carried out at the Day Hospital facilities of the Institute of the Clinica Medica Generale e Terapia Medica of the Medical School of the University of Perugia, Perugia, Italy. The subjects were kept under observation from the evening before administration to 48 h following the injection of the study drug or placebo and returned daily to the Day Hospital as outpatients for the collection of blood and urine until the samples for pharmacokinetics were completed. Drug administration. Each teicoplanin vial was reconsti-
MATERIALS AND METHODS
Subjects. A total of 18 (6 per group) normal healthy adult male volunteers were selected. Criteria for inclusion were as follows: age, between 18 and 40 years; body weight, within 15% of ideal weight, as reported by the 1983 height and *
Corresponding author. 2551
2552
ANTIMICROB. AGENTS CHEMOTHER.
DEL FAVERO ET AL.
tuted with 3 ml of sterile water for injection. An adequate volume of reconstituted teicoplanin was further diluted with 0.9% sodium chloride, to a final volume of 130 ml, in order to provide the nominal dose in 100 ml of the final infusion solution. The actual doses administered were calculated from the teicoplanin concentrations of the infusion solutions, as determined by the microbiological assay. These solutions were prepared in the afternoon of the day before administration and were stored overnight at 4°C. They were returned to room temperature about 1 h before the start of administration. The containers of i.v. solution were wrapped in aluminum foil to mask any differences in the teicoplanin and placebo solutions. A constant-rate infusion pump (Terufusion infusion pump model STC-503, Terumo), which delivered 100 ml over 30 min, was used to administer the solutions. The placebo infusion consisted of 100 ml of O.9o sodium chloride solution for injection. Both the investigator and the subject remained blinded to the study drugs administered throughout the study. Sample collection. (i) Blood samples. Blood samples (about 5 mL each) were obtained prior to the infusion; at the end of the infusion (0 time); 5, 15, and 30 min and 1, 2, 4, 6, 8, 12, 24, 36, and 48 h after the completion of the infusion; and every 24 h thereafter for a total of 13 days, or 312 h. Heparinized tubes were used for blood collection and after separation from red blood cells by centrifugation for 10 min at 800 to 1,000 x g at room temperature, each plasma sample was transferred to a prelabelled polypropylene tube and stored at or below -20°C until assayed. (ii) Urine samples. From the start of the intravenous infusion, total urine output was collected at 24-h intervals, as pooled collections, daily for a total of 13 days. Urine was stored at 4°C until each collection was complete. Urine volumes were measured, and 10-ml aliquots were transferred into polypropylene tubes and stored at or below -20°C until assayed. (iii) Samples for 24-h creatinine clearance measurements. The 24-h creatinine clearance was measured prior to drug administration, on the basis of two initial 24-h urine collections. A 24-h creatinine clearance measurement was obtained on the 2nd and 13th days. Creatininuria for each 24-h collection sample was measured following the infusion. Safety monitoring. Vital signs (supine blood pressure, pulse, respiration, and oral temperature) were recorded immediately prior to administration of the teicoplanin or placebo infusion, at 10 and 20 min after the beginning of the infusion, and at the end of the infusion. Following the infusion, vital signs were taken at 1, 4, 8, 12, and 24 h, immediately after the blood sample had been obtained. During the study, subjects were observed daily to detect any evidence of adverse experiences. When an adverse event appeared, vital signs were measured at appropriate times.
For each teicoplanin dose, a physical examination and a panel of laboratory tests were performed 24 h after the infusion and on the 14th day postadministration. Evaluation of the auditory function was carried out by pure-tone audiometry in a soundproof room, twice before the study and 24 h and 14 days after the administration of study drug or placebo. The equipment used was an AMPLAID 455 audiometer with TDH49 earphones. Hearing thresholds were assessed by air conduction bilaterally at 250, 500, 1,000, 2,000, 3,000, 4,000, 6,000, and 8,000 Hz. Every increase of signal intensity was of 5 dB. Significant hearing change was defined as a permanent auditory threshold change greater than 15 dB at any two consecutive frequencies in either ear (14). No subjects had significant hearing loss according to the baseline audiogram (i.e., an air conduction pure-tone speech frequency threshold average of greater than 30 dB [mean of threshold value at 500, 1,000, and 2,000 Hz] for either ear or both ears) or pronounced preexisting tinnitus or dizziness problems. Concentrations of beta-2 microglobulin, a low-molecularweight protein used to test renal-tubular damage (22), in plasma and in 24-h urine samples of the group of volunteers treated with the highest dosage of teicoplanin (25 mg/kg) were determined prestudy and at days 2, 5, 7, and 12 postadministration. The immunoenzymatic method, with the Enzygnost beta-2 microglobulin kit, (Behring), was used. Drug assay. Teicoplanin concentrations in plasma and urine were determined by agar diffusion microbiological assay (7). The method was carried out according to the parallel-line design (standard versus sample curves for the same petri dish), as described in the British and European Pharmacopoeias and also as reported in the USP in the section Biological Assay. With this design, the validation (evaluation of specificity, precision, and recovery) is performed every time an assay is done. The method uses Bacillus subtilis ATCC 6633 as the test organism and has a limit of detection of 0.05 mg/liter and a confidence interval (95%) of 5%. The linearity of the log (dose)-response curve was assessed within the range of concentrations (from 0.05 to 0.8 mg/liter) adopted. Pharmacokinetic data analysis. Three- and four-exponential models were fitted to postinfusion plasma concentration data by the PCNONLIN program (20). The best fit was obtained by using 1/C2 as weighting factor, where c' is the teicoplanin concentration in plasma predicted at each sampling time. The goodness of fit of exponential models to experimental data was judged according to the Gallant test (11), the F-ratio test (3), and the Akaike information criteria (23). The method of residuals was used to obtain initial estimates of macroconstants. The pharmacokinetic parameters associated with the exponential equations were calculated in the standard manner (12). ±
TABLE 1. Subject demographics and teicoplanin doses' Group (n)
Age (yr)
Ht (cm)
Wt (kg)
1 (5) 2 (4) 3 (5)
26 ± 5 26 ± 2 24 ± 4
172 ± 4 177 ± 3 176 ± 5
73.2 ± 2 64.5 t 7 70.4 ± 10
Nominal dose (mg)
1,095 ± 41 1,275 ± 150 1,775 ± 271
Dose solution
(mg/ml) 11.3 ± 0.6 12.5 + 2.3 18.7 ± 2.7
a Data are given as means ± standard deviation. The infused volume was 100 ml for all groups.
Measured dose
Total (mg)
1,126 ± 64 1,249 ± 229
1,870
± 268
Fractional (mg/kg) 15.4 ± 0.5 19.3 ± 1.4 26.6 ± 0.8
VOL. 35, 1991
PHARMACOKINETICS AND TOLERABILITY OF TEICOPLANIN
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DEL FAVERO ET AL.
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14
Time (days)
FIG. 2. Polyexponential fittings of datum points of sentative subject. exp, exponential.
a repre-
For noncompartmental analysis, the terminal dispositionwas estimated by log-linear least-square fit of the terminal phase (72 to 312 h); terminal half-life was obtained as (ln2)/Iz, and the area under the serum concentration-time curve (AUC) was obtained by the trapezoidal rule, from time zero to the last sampling time, adding the term CjAZ to extrapolate the AUC to infinity, where CZ is the concentration of drug measured at the last sampling time. Total clearance (CL) was calculated as the ratio of dose to AUC; renal clearance (CLR) was calculated as the ratio of the cumulative amount of drug excreted in the urine in the interval 0 to 312 h postadministration to the plasma AUCO312. The urinary elimination half-lives were calculated by log-linear fit of urinary excretion rates in the apparent terminal phase (72 to 312 h). The volumes of distribution in the central compartment, during the elimination phase, and at steady state and the mean residence time were calculated according to usual relationships (12). Statistical analysis. The Student t test for paired data was used to analyze laboratory test values before and after teicoplanin administration and to compare pharmacokinetic parameters obtained with the three- and four-exponential models. Tukey's multiple comparison test (10) was used for the analysis of the pharmacokinetic parameters obtained with a noncompartmental and a triexponential model for the three groups of subjects. A type one experimentwise error rate of less than 0.05 was considered statistically significant. The statistical analysis was performed by using the package SAS. The correlation between AUC and dose was evaluated by linear regression and analysis of variance for linear regression (2). rate constant XZ
RESULTS Clinical results. All subjects but one received the full projected dose of teicoplanin. For one subject of group 2, the drug infusion was stopped 18 min after the start because of an adverse reaction to teicoplanin, consisting of four urticarial spots (two on the trunk and one each on a cheek and a leg), accompanied by itching. The first (2 cm in diameter) appeared 5 min after the beginning of teicoplanin infusion; the other three (0.5, 4, and 5 cm in diameter) were present after another 10 min of infusion. Drug treatment was interrupted, and signs and symptoms disappeared spontaneously
within 1 h of the end of infusion. This subject received a reduced dose of teicoplanin and was consequently not considered in the pharmacokinetic analysis. Another five subjects suffered mild adverse events after the infusion of teicoplanin. Three subjects had a slight, transient increase in body temperatures within 2 h following the end of infusion. The body temperatures rose to 37.1, 37.3, and 37.8°C in one subject of group 2 and in two subjects of group 3, respectively. In the subject with a 37.8°C fever, the increase in temperature was preceded by shaking chills, which required the administration of 100 mg of hydrocortisone i.v., with prompt recovery from symptoms. The increased body temperature lasted for a short time (30 to 240 min) in all subjects. Furthermore, two subjects of the first group, on the third and sixth days of follow-up, each had a single, small, short-lived, noninfiltrative, nonitching erythematous skin lesion on the limb, of doubtful significance. No adverse reactions were experienced by the subjects given placebo. No significant changes in vital signs or in laboratory test results were noted. In particular, creatinine clearance values and (for subjects treated with 25 mg/kg) the values of beta-2 microglobulin in plasma and urine were in the normal range, with no changes or trends of clinical relevance evident in any subject. No clinically significant changes in audiometry parameters were found in any subject when individual hearing thresholds registered before and 24 h and 14 days after treatment were compared. Pharmacokinetics analysis. The demographic characteristics of the subjects and the actual doses administered are illustrated in Table 1, showing good agreement between the nominal and the measured doses. Figure 1 shows semilogarithmic plots of mean plasma concentration-time curves after i.v. administration of teicoplanin. For each subject, most of the experimental datum points lay on the best-fit curves (Fig. 2). Mean values of pharmacokinetic parameters obtained with the three groups of subjects with compartmental analyses of plasma data by using both three- and four-exponential models and noncompartmental analysis and those values calculated from urinary data are reported in Table 2. The four-exponential term equation seemed to improve most of the curve fittings, according to the Gallant test, the F-ratio test, and the Akaike information criteria. However, the values of the main pharmacokinetics parameters calculated after the fitting of three- or four-exponential-term models to data did not differ significantly, as reported by Danese et al. (8). Thus, we concluded that the slight improvement of curve fitting obtained with the four-exponential-term model did not justify the increased complexity introduced into the structural model, and the results of the three-exponential-term equation, also utilized in previous pharmacokinetic studies, are discussed here. Mean peak levels in plasma at the end of the 30-min constant-rate infusions were 194 mg/liter (range, 139 to 257 mg/liter) in group 1, 197 mg/liter (range, 157 to 242 mg/liter) in group 2, and 253 mg/liter (range, 181 to 315mg/liter) in group 3, whereas levels at 24 h after the administration (trough) were 10.5 mg/liter (range, 9 to 13 mg/liter) 13.6 mg/liter (range, 12 to 16 mg/liter), and 19.8 mg/liter (range, 14 to 23 mg/liter), respectively. By three-compartment analysis, the values of the volumes of distribution in the central compartment averaged 0.07, 0.09, and 0.11 liters/kg in the three groups, whereas the mean steady-state volumes of distribution were 0.80, 0.87, and
VOL. 35, 1991
PHARMACOKINETICS AND TOLERABILITY OF TEICOPLANIN
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