Population Pharmacokinetic Study of Teicoplanin in Severely

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1996, p. 1242–1247 Vol. 40, No. 5 0066-4804/96/$04.00ϩ0 Copyright ᭧ 1996, American Society for Microbiology

Population Pharmacokinetic Study of Teicoplanin in Severely Neutropenic Patients OLIVIER LORTHOLARY,1 MICHEL TOD,2* NATHALIE RIZZO,2 CHRISTOPHE PADOIN,2 OLIVIER BIARD,2 PHILIPPE CASASSUS,1 LOIC GUILLEVIN,1 2 AND OLIVIER PETITJEAN Service de Me´decine Interne1 and De´partement de Pharmacologie-Toxicologie,2 Centre de Recherche en Pathologie Infectieuse et Tropicale, Hoˆpital Avicenne, Universite´ Paris-Nord, 93000 Bobigny, France

Received 24 July 1995/Returned for modiﬁcation 1 November 1995/Accepted 28 February 1996

The teicoplanin pharmacokinetics (PK) of 30 febrile and severely neutropenic patients (polymorphonuclear count, <500/mm3) with hematologic malignancies were compared with those determined for five healthy volunteers (HV). Neutropenic patients were given piperacillin combined with amikacin, and teicoplanin was added to the regimen the day fever developed in patients suspected of having a staphylococcal infection or 48 h later. Teicoplanin was given intravenously at a dosage of 6 mg/kg of body weight at 0, 12, and 24 h and once a day thereafter. Five to eleven blood samples per patient were collected. Teicoplanin concentrations were measured by liquid chromatography. A bicompartmental model was fitted to the data by a nonlinear mixed- effect-model approach. Multiple-linear regression analysis was applied in an attempt to correlate PK parameters to nine covariates. The mean trough concentrations of teicoplanin 48 h after the onset of treatment and ,h after the last injection (last trough) ؎ standard deviations were 8.8 ؎ 4.1 and 17.5 ؎ 13.5 mg/liter 24 respectively. A significant increase was noted in the mean rate of elimination clearance of teicoplanin in as was the case with rates ,(0.002 ؍ neutropenic patients compared with that of HV (0.86 versus 0.73 liter/h, P the mean half-life of distribution was significantly ;(0.002 ؍ of distribution clearance (5.89 versus 4.94 liter/h, P In contrast, the volumes of the central .(0.002 ؍ shorter in patients than in HV (0.43 versus 0.61 h, P compartment (ca. 5.8 liters for both groups), the volumes of distribution at steady state (HV, 37.6 liters; patients, 55.9 liters), and the elimination half-lives (HV, 39.6 h; patients, 52.7 h) were not significantly different between HV and neutropenic patients. Interindividual variabilities of rates of clearance (coefficient of variation [CV], 43%) and elimination half-lives (CV, 56%) were mainly explained by the variabilities among rates of creatinine clearance. Interindividual variabilities of the volumes of the central compartment (CV, 33%) and the were correlated to interindividual variabilities among (%51 ؍ volumes of distribution at steady state (CV numbers of leukocytes and the ages of patients, respectively. On the basis of the population PK model of teicoplanin, simulations were made to optimize the dosing schedule. A supplemental 6 mg/kg dose of teicoplanin at 36 h resulted in a trough concentration at 48 h of 16.0 ؎ 4.5 mg/liter, with only 7% of patients having a trough concentration of less than 10 mg/liter, compared with 46% of patients on the usual schedule.

Infections remain the major cause of morbidity and mortal- tribution (V) of vancomycin for patients with cancer than for ity in neutropenic patients (3). Empirical wide-spectrum anti- healthy subjects. Teicoplanin pharmacokinetics have also been biotic regimens, most often containing a ␤-lactam antibiotic in studied for febrile neutropenic patients (13), but the lack of a combination with an aminoglycoside, have dramatically im- control group precluded assessment of the modifications of proved the outcome of febrile neutropenic patients. The in- pharmacokinetic parameters induced by hematologic malig- creasing prevalence of gram-positive infections observed in nancy. Considerable interindividual variability was observed recent years in neutropenic cancer patients (1) led to the infor teicoplanin and vancomycin pharmacokinetics, but rela- clusion of vancomycin (21) or teicoplanin (17) in the antibiotic tionships with demographic or biologic covariates were not regimen at the initial stage or 48 to 72 h later. Both glycopep- established. Therefore, the goal of our study was to compare tides demonstrated similar efficacies, but teicoplanin was asso- the teicoplanin pharmacokinetics of severely neutropenic fe- ciated with fewer side effects (14, 17). However, the optimal brile patients with those measured in healthy volunteers and to dosage of teicoplanin has been a matter of debate (2), in part examine the relationships between pharmacokinetic parame- because of insufficient data on its pharmacokinetics in some ters and several covariates by the methodology of population pathologic populations. Patients with cancer have shown al- pharmacokinetics (24). On the basis of the population phar- tered pharmacokinetics after taking some antibiotics, e.g., ami- macokinetic model, a proposal is made for supplementing noglycosides (28) and vancomycin. In the case of the latter teicoplanin dosages in order to achieve therapeutic drug levels drug, it was observed that most patients, including both adults in most of these neutropenic patients. (10) and children (7), required higher-than-expected vancomy- (Part of this research was presented at the 35th Interscience cin dosages to achieve desired concentrations in sera. This Conference on Antimicrobial Agents and Chemotherapy, San need for a higher dosage, in turn, was associated with higher Francisco, Calif., September 1995.) elimination clearance (CL) values and greater volumes of dis- MATERIALS AND METHODS Patients. Patients were eligible for this study if they had hematologic malig- * Corresponding author. Phone: 33 1 48 95 56 61. Fax: 33 1 48 95 56 59. nancies requiring antineoplasic chemotherapy (acute leukemia, myeloma, or

1242 VOL. 40, 1996 TEICOPLANIN IN SEVERELY NEUTROPENIC PATIENTS 1243

ing. For the group of neutropenic patients (n ϭ 30), a total number of 279 samples (5 to 11 samples per patient) was collected. For healthy volunteers, there were 20 samples per subject, i.e., 100 samples. Pharmacokinetic analysis. Bi- and triexponential models were fitted to the data. Selection of the most appropriate model was based on the Akaike information criterion (16) and the examination of residual plots. A bicompartmental model was finally fitted to teicoplanin concentration versus time data. To derive all the desired parameters, three alternative parameterizations were used: CL, Vc, K12, and K21; CL, Vc, t1/2␣, and t1/2␤;orCL,Vc,CLD, and Vss where Vc is the volume of the central compartment (which receives the dose), K12 and K21 are the central-to-peripheral and peripheral-to-central transfer rate constants, respectively, t1/2␣ and t1/2␤ are the half-lives of the first and the second exponential phases, respectively, Vss is the volume of distribution at steady state, and CLD is the distribution clearance. Since the sparse sampling schedule did not enable the estimation of individual pharmacokinetic parameters by usual methods for most patients, population pharmacokinetic methods based on a nonlinear mixed-effect-model approach were used (24). These methods separate explicitly the variability of drug concentrations in the population into two parts: interindividual variability charac- FIG. 1. Schematic description of the teicoplanin sampling schedule. terized by the distribution of pharmacokinetic parameters in the population and residual variability (e.g., measurement errors). First, a nonparametric maximum- likelihood method based on the expectation-maximization algorithm of Schu- mitzky (22), NPEM2, was applied to obtain the marginal probability-density lymphoma), neutropenia (a neutrophil count of Ͻ500/mm3) with an expected functions of the parameters CL, Vc, K12, and K21. Second, a parametric approach duration of Ͼ5 days, and fever (Ͼ38ЊC on two occasions or Ͼ38.5ЊC once). (11, 18) was used (with P-PHARM software; Simed, Cre´teil, France) to estimate Patients were excluded if they were under 18 years of age, their neutropenia was the mean and interindividual variance of each pharmacokinetic parameter in the not induced by chemotherapy, they had received systemic antibiotic therapy Ͻ3 population, to calculate the Bayesian maximum a posteriori estimates of indi- days before inclusion, they were HIV infected, or they were allergic to any of the vidual pharmacokinetic parameters, and to test relationships between these trial antibiotics (teicoplanin, piperacillin, and amikacin). Renal insufficiency was individual estimates and several covariates. not a cause for exclusion. Thirty patients were included in the study. In both population approaches, residual variability was assumed to be additive Healthy volunteers. The data from the work of Buniva et al. (4) were used. to the predicted concentration, with a Gaussian distribution with a mean differ- Five healthy male volunteers, who were 24 to 34 years old and weighed 72 to 84 ence of 0 and a variance proportional to the concentration. This choice was based kg, participated in the study. on the variance of concentration measurements. In the nonparametric method, Study design. On the inclusion of patients, hemocultures were established with no assumption had to be made about the form of the prior distributions of the three peripheral venous blood samples and one central (indwelling subclavian parameters. In the parametric approach, the form (normal or lognormal) of prior catheter) blood sample; urinalysis and a chest X ray were performed on each distributions of the parameters (CL, Vc, K12, and K21) was assigned from the patient. All patients were subjected to partial digestive decontamination with results of the nonparametric analysis, while the forms of the prior distributions nifuroxazide (400 mg three times a day) and amphotericin B (Fungizone, in the of the other parameters were determined by simulation with POPSIM software form of a mouthwash four times a day plus 500 mg in solution three times a day). (described below in the appendix). The model was validated by comparing the Piperacillin was given at a dosage of 4 g four times a day, in combination with 7.5 mean of the standardized residuals to 0 and by comparing their distribution to mg of amikacin per kg of body weight twice a day, from the first day of neutro- the normal distribution with the Kolmogorov-Smirnov test (with P-PHARM penia. Each antibiotic was dissolved in 0.9% saline and was administered intra- software). venously over 30 min. Teicoplanin was added to the regimen at a dosage of 6 An attempt was made to correlate individual maximum a posteriori estimates mg/kg administered intravenously over 1 min at 0, 12, and 24 h and once a day of the pharmacokinetic parameters of the patients with several covariates, which thereafter, as of the first day of febrile neutropenia in patients suspected of were measured every day (when relevant) during the study for each patient; these having a staphylococcal infection or 48 h later. For patients with a creatinine covariates included sex, age, weight, height, CLCR calculated according to the work of Cockroft and Gault (8), hematocrit count, polymorphonuclear count clearance (CLCR)ofϾ60 ml/min, the trough serum teicoplanin level was monitored at 24 h by means of a fluorescence polarization immunoassay (TDX; (PMN), leukocyte count, and status (healthy or neutropenic). In healthy volun- Abbott Laboratories, Rungis, France). When the teicoplanin level was Ͻ10 teers, the values for the hematocrit count, PMN, and the leukocyte count were mg/liter, the teicoplanin dose at 48 h was adjusted by increasing the dose by a unavailable. Multiple-linear regression analysis with stepwise inclusion between factor equal to the ratio of the desired trough level to the current trough level, maximum a posteriori estimates of all pharmacokinetic parameters and all co- and the trough level at 72 h was determined to further adapt the dose if variates was performed by analysis of variance to determine the relevant relationships (with P-PHARM software). The addition or deletion of each covariate necessary. For patients with a CLCR of Ͻ60 ml/min, no sample for drug monitoring was drawn at 24 h and the teicoplanin dosage from 96 h onwards was was based on an F test which in turn was based on the ratio of the mean square associated with adding or removing the covariate Xi in the regression equation, reduced to 3 mg/kg/day (CLCR, between 40 and 60 ml/min) or to 2 mg/kg/day to the mean square residual for the equation containing covariates X1 to Xi. The (CLCR, Ͻ40 ml/min). In all patients, peak (30 min after infusion) and trough (12 h) serum amikacin levels were monitored every 3 days to maintain a peak of Ͼ20 threshold value of the F statistics was 10 for the inclusion or deletion of a mg/liter and a trough of Ͻ5 mg/liter. When fever persisted 48 h after the addition covariate. No interaction between the covariates was allowed in the covariate of teicoplanin to the piperacillin-amikacin treatment, piperacillin was replaced model. Hence, the covariate model was as follows: Pj ϭ a0 ϩ a1 ⅐ X1j ϩ a2 ⅐ X2j by imipenem (1 g twice a day by intravenous infusion over 30 min). To patients ϩ ...ϩan ⅐Xnj where Pj is the value of a given parameter (P) of subject j, X1j with suspected or proven fungal infections, amphotericin B (1 mg/kg) was ad- to Xnj are the values of each covariate of subject j, and a0 to an are regression ministered daily by intravenous infusion over 6 h. Teicoplanin treatment was parameters. However, since there is often a linear relationship between the stopped for patients proven to have an allergy to the drug or when a resistant terminal rate constant and the CLCR value, the relationship between the values gram-positive bacterium was isolated from a pertinent clinical site. Patients were for t1/2␤ and CLCR was described as t1/2␤ ϭ (ln2)/(a0 ϩ a1 ⅐ CLCR) where considered to be cured of infection when fever and clinical signs of infection disappeared 72 h after the onset of teicoplanin treatment. Healthy volunteers received 400 mg of radiolabeled teicoplanin (41 ␮Ci) intravenously over 60 s. Pharmacokinetic study. Up to 12 blood samples were drawn from patients TABLE 1. Demographic and biologic data for the 30 patients from a peripheral vein as shown in Fig. 1 just before and after the first teicoplanin bolus injection, at 9, 12 (trough), 13, 24 (trough), 26, 48 (trough), and 51 h, and Value at mid-treatment for: at the trough preceding the last injection, the peak of the last injection, and 24 Age Weight Height No. of h after the peak of the last injection (last trough). Sera were separated by Value CL Hematocrit (yr) (kg) (cm) CR PMN/mm3 leukocytes centrifugation (1,000 ϫ g, 10 min) and stored at Ϫ20ЊC until analyzed. Teico- (ml/min) count (%) planin levels were measured by liquid chromatography as described by Jehl et al. (103/mm3) (12). The limit of quantification of the assay was 1 mg/liter, and the between-run coefficient of variation (CV) ranged from 11.5% at 3 mg/liter to 7.4% at 120 Mean 49.1 67.0 167 94.0 197 25.7 0.65 mg/liter. Results were expressed in total teicoplanin, but only the main compo- Median 49.0 66.0 169 101.0 80 25.2 0.38 nent A2-2 was used for the measurements. In healthy volunteers, blood samples SD 14.7 11.1 8 30.4 294 3.4 0.83 were drawn immediately before and 5 and 30 min and 1, 2, 4, 6, 8, 10, 12, 24, 36, Minimum 19 44 150 31 11 20.1 0.03 14 48, 60, 72, 96, 120, 144, 168, 192, and 240 h after administration. The [ C]teico- Maximum 73 93 188 146 1,269 34.2 3.30 planin concentration in each sample was measured by liquid scintillation count- 1244 LORTHOLARY ET AL. ANTIMICROB.AGENTS CHEMOTHER.

TABLE 2. Experimental teicoplanin concentrations and lognormal distributions for Vc, Vss, t1/2␣, and t1/2␤ were in the sera of the 30 patients used in the P-PHARM parametric population analysis of teico- Trough Trough Teicoplanin planin data. Peak concn Last concn at concn at treatment Results of the P-PHARM analysis are shown in Tables 4 and Value at 13 h trough 24 h 48 h duration (mg/liter) (mg/liter) 5. Table 4 shows that teicoplanin CL values were significantly (mg/liter) (mg/liter) (days) higher in neutropenic patients. There was also a trend to Mean 30.0 9.0 8.8 17.5 14.8 higher K12 values in neutropenic patients versus healthy vol- Median 27.2 9.3 8.2 12.8 11 unteers, which resulted in a significantly higher CLD value and SD 12.6 3.1 4.1 13.5 12.1 a significantly lower t1/2␣ value. Conversely, Vc values did not Minimum 12.0 4.4 3.2 5.5 3 differ appreciably between the two groups, while the increase

Maximum 72.6 14.6 16.7 56.5 49 in Vss values from neutropenic patients did not reach statistical significance. Table 4 shows that, among the nine covariates, a % 61 (41–77) 62 (44–80) 24 (1–42) only three were correlated with the pharmacokinetic parame- a Percentage of patients with trough concentrations of Ͻ10 mg/liter. Values in ters. The following relationships can be derived from the data Ϫ3 parentheses are 95% confidence intervals of the proportions. presented in Table 5: CL ϭ 7.99 ϫ 10 ϫ CLCR ϩ 0.135; Vc ϭ 0.260 ϫ leukocyte count ϩ 4.95; and Vss ϭ 0.965 ϫ age ϩ 4.2 where the units are those of Table 5. For example, for a a1 ⅐ CLCR and a0 are the renal and the nonrenal elimination rate constants, population of neutropenic patients with a CLCR value equal to respectively. 60 ml/min, the expected value of mean teicoplanin CL would Statistical analysis. Mean teicoplanin pharmacokinetic parameters of healthy be 0.616 liters/h with an interindividual standard deviation of volunteers and those of neutropenic patients were compared by using a categor- ical covariate in the population model, namely, status, whose value was set at 1 0.230 liter/h. By taking into account CLCR values, 40% of the for healthy volunteers and 2 for neutropenic patients. The status covariate was interindividual variability in teicoplanin CL values is explained. determined to be the only possible covariate (other than the relevant demo- Point estimates of the other parameters can be obtained in the graphic covariates found in the analysis described above, i.e., CLCR for CL and same way. For t1/2␤, a point estimate can be calculated accord- age for Vss) of each pharmacokinetic parameter. Significance was determined from the F value of the corresponding analysis of variance (i.e., regression mean ing to the following equation: square/residual mean square). A P value of Ͻ0.05 was considered to be significant. ln2 Simulations. The population pharmacokinetic parameters of teicoplanin in t1/2␤ ϭ Ϫ3 Ϫ3 2.40 ϫ 10 ϫ CLCR ϩ 3.35 ϫ 10 neutropenic patients (with relevant covariates: CLCR, age, and leukocyte count) were used to generate simulations of the mean concentrations Ϯ standard de- where the value for t is in hours and that for CL is in viation (SD) on the basis of data derived for 500 simulated individuals with 1/2␤ CR liters per hour. For neutropenic patients with CL values POPSIM software. CLCR was calculated according to the method of Cockroft CR and Gault (8), with simulated values for age, weight, sex, and creatinine concen- equal to 120 ml/min (i.e., 7.2 liters/h) or 10 ml/min (i.e., 0.6 trations in serum. These covariates were assumed to follow a normal distribution liter/h), the expected t1/2␤ are 34 and 202 h, respectively. with means and SDs corresponding to those of our patients. Since the experi- Last, a scatterplot of observed versus predicted data for mental distribution of leukocytes in our patients was very skewed, the leukocyte count was assumed to follow a lognormal distribution with a mean of 650 concentrations in serum after the Bayesian process is pre- leukocytes per mm3 and an SD of 200 leukocytes per mm3. No random error was sented in Fig. 2. added to the simulated concentrations. Because 62% of the patients had teicoplanin trough levels of Two dosing schedules were compared: the schedule used in this study, i.e., 6 Ͻ10 mg/liter, the impact of a supplemental 6 mg/kg dose of mg/kg bolus administrations of teicoplanin at 0, 12, and 24 h and once a day thereafter and the same schedule with a supplemental dose at 36 h. teicoplanin at 36 h was evaluated by the simulation of 500 The median concentrations and the percentages of concentration values less individuals with population pharmacokinetic parameters cor- than 10 mg/liter were calculated from the distribution of the 500 values at each responding to those of neutropenic patients. As shown in Ta- sampling time. ble 6, the addition of this supplemental dose indicated that only 7% of patients would have a trough level at 48 h below the RESULTS established threshold compared with the trough levels of patients on the dosing schedule used in this study. Thirty patients were included in the study (18 men and 12 women) and their major characteristics are shown in Table 1. Diagnoses were acute myeloblastic leukemia (10 patients), DISCUSSION non-Hodgkin’s lymphoma (9 patients), myeloma (5 patients), Hodgkin’s lymphoma (3 patients), acute lymphoblastic leuke- In most recent studies of teicoplanin pharmacokinetics, the mia (1 patient), and chronic myelogenous leukemia (1 patient). disposition of teicoplanin has been described by a triexponen- Trough teicoplanin concentrations measured in serum by tial model (23), indicating a very long terminal half-life (ca. 100 liquid chromatography for the 30 patients are shown in Table to 150 h). However, plasma or urine has to be collected for 21 2, along with the teicoplanin treatment durations. Trough con- days to ensure a precise determination of the parameters of the centrations at 48 h were Ͻ10 mg/liter in 62% of patients, but terminal elimination phase (5, 23). In our study, fitting a triex- the combined effect of dosage increase and accumulation of ponential model to the data was not statistically superior to the drug (the steady state has not yet been reached at 48 h) resulted in a lower proportion of too low trough levels (24%) at the end of teicoplanin treatment. TABLE 3. Nonparametric maximum-likelihood Results of NPEM2 nonparametric maximum-likelihood analysis of teicoplanin data analysis of teicoplanin data (30 patients) are shown in Table 3. Ϫ1 Ϫ1 Value CL (liter/h) Vc (liter) K12 h K21 h A comparison of the means and medians of the parameters and a visual examination of their marginal distribution indi- Mean 1.15 6.56 1.29 0.18 cated that CL, K , and K values had symmetrical distribu- Median 1.16 5.33 1.11 0.18 12 21 SD 0.56 4.01 0.62 0.075 tions whereas Vc values had an asymmetrical, long-tailed distribution. Consequently, owing to the relationships between CV (%) 48 61 48 42 the parameters, normal distributions for CL, CLD, K12, and K21 VOL. 40, 1996 TEICOPLANIN IN SEVERELY NEUTROPENIC PATIENTS 1245

TABLE 4. Parametric analysis of teicoplanin data

Mean (% CV) value for: Group Ϫ1 Ϫ1 CL (liter/h) Vc (liters) K12 h K21 h t1/2␣ (h) t1/2␤ (h) CLD (liters/h) Vss (liters) Healthy volunteers 0.73 (11) 5.59 (8) 0.86 (7) 0.15 (4) 0.61 (7) 39.6 (4) 4.94 (10) 37.6 (9) Patientsa 0.88 (43) 5.75 (33) 1.08 (34) 0.14 (30) 0.48 (27) 52.7 (56) 5.68 (25) 51.2 (51) All participantsa 0.88 (40) 5.81 (33) 1.03 (33) 0.14 (23) 0.50 (27) 50.1 (49) 5.72 (22) 48.8 (48) Patientsb 0.86 (32) 6.11 (29) 1.10 (36) 0.13 (23) 0.43 (18) —c 5.89 (23) 55.9 (42)

Pd 0.002 NSe 0.118 (NS) 0.142 (NS) 0.002 NS 0.002 0.142 (NS)

a Values were determined without taking covariates into account. b Values were determined with covariates. c t1/2␤ was expressed as a hyperbolic function of CLCR (see the text). d Comparison of mean pharmacokinetic parameters of healthy volunteers with those of patients (by the F test), taking the relevant demographic covariates into account. e NS, not signiﬁcant.

using a biexponential model, probably because teicoplanin tween the two groups had been considered, Vss values were treatment was discontinued after 2 weeks for most subjects similar for both groups. The most striking ﬁnding was the (Table 2). The use of a bicompartmental model instead of a correlation between the leukocyte count and some pharmaco- tricompartmental model results in a shorter estimated half-life. kinetic parameters. In particular, a low leukocyte count was

This explains why the teicoplanin half-life was about 40 to 50 h, associated with a low Vc. Table 4 shows that CLD values were similar to the values established in earlier teicoplanin disposi- significantly higher and t1/2␣ values were significantly lower for tion studies, for example that described in reference 26. How- neutropenic patients than for healthy subjects. Since CLD re- ever, Carver et al. (5) showed that the teicoplanin steady state flects the rate of transfer between the two compartments, this was achieved in about 10 days; i.e., for practical (clinical) increased rate of CL probably indicates that infection is asso- purposes, the relevant half-life for teicoplanin was about 60 h. ciated with a higher rate of teicoplanin exchange between Be that as it may, data from healthy volunteers were incorpo- plasma (the central compartment) and tissues (peripheral rated into our study and were treated in the same way, so as to compartments), possibly caused by modifications of vascular be able to compare neutropenic patients and healthy subjects. permeability. Also, it is interesting that PMN counts were Our experimental data (Table 2) are similar to those de- never selected as a significant covariate, once the number of scribed by Kureishi et al. (13), who found that the mean trough leukocytes had been taken into account. This means that all concentration at 24 h at steady state in febrile neutropenic the interindividual variability contained in PMN counts was patients Ϯ SD was 12.5 Ϯ 3.2 mg/liter. The interindividual also contained in leukocyte counts but that the latter were variability was higher in our study, but variabilities among better able to further account for interindividual variability in patients’ ages and CLCR values were also larger. This interin- teicoplanin disposition; i.e., from a pharmacokinetic point of dividual variability was also apparent in teicoplanin pharma- view, leukopenia was more meaningful than neutropenia. Like- cokinetic parameters (Table 4), especially in CL rates. Covari- wise, when all covariates were considered together, status (i.e., ate analysis revealed a high correlation between teicoplanin good health or the health of a cancer patient) was never se-

CL and CLCR, which is well known (20) and is explained by the lected as a significant covariate. This finding indicates that all elimination of teicoplanin almost entirely by glomerular filtra- the information contained in covariate status was accounted tion. As expected, CLCR was also negatively correlated with for by other covariates, probably by the number of leukocytes. the teicoplanin elimination half-life since the CL rate was Compared with vancomycin pharmacokinetic data reported reduced when the rate of CLCR was decreased. More interest- in the literature, the modifications of teicoplanin pharmacoki- ingly, age influenced teicoplanin Vss, which increased with age. This observation explains the apparent Vss differences between patients and healthy volunteers. Once the age difference be-

TABLE 5. Relationships between teicoplanin pharmacokinetic parameters and covariates by multivariate analysis

Slope (% SE of the estimate [CV])a of: Covariate CL (liter/h) Vc (liter) Vss (liter)

Ϫ3 CLCR (ml/min) 7.99 ϫ 10 (18) Age (yr) 9.65 ϫ 10Ϫ1 (20) Leukocyte count 2.60 ϫ 10Ϫ1 (16) (103/mm3) Interceptb 0.135 4.95 4.2 Residual SDb 0.248 2.17 15.3

r2 (P)c 0.53 (Ͻ0.001) 0.59 (Ͻ0.001) 0.46 (Ͻ0.001)

a Analysis is based on data from the 30 patients who participated in this study. b Units are those of the pharmacokinetic parameters. FIG. 2. Scatterplot of observed versus predicted concentrations in serum c Coefﬁcient of determination and P value of the F test. after individual Bayesian ﬁtting. 1246 LORTHOLARY ET AL. ANTIMICROB.AGENTS CHEMOTHER.

TABLE 6. Comparison of teicoplanin trough concentrations with two dosing schedules (simulation from 500 individuals)

Trough Mean trough Median Trough % of patients with Dosing schedule sampling concn (mg/ trough concn concn SD trough concn of time (h) liter) (mg/liter) (mg/liter) Ͻ10 mg/liter 6 mg/kg at 0, 12, 24, and 48 h 48 10.6 10.3 3.0 46 6 mg/kg once a day thereafter 240 14.3 13.2 6.0 24

6 mg/kg at 0, 12, 24, 36, and 48 h 48 16.0 15.7 4.5 7 6 mg/kg once a day thereafter 240 14.8 13.8 6.5 22

netic parameters of neutropenic patients compared with those APPENDIX of healthy volunteers were much less pronounced. Increased Principles of POPSIM. POPSIM is software written in Visual Basic CL values were found for both glycopeptides, but they 3.0 which is devoted to the simulation of concentration kinetics or amounted to ca. 20 to 30% for teicoplanin compared with ca. derived parameters in population models. The user must specify (i) the 100% for vancomycin (10). The increased Vss observed with structural pharmacokinetic (PK) model relating the concentration to vancomycin (10) was not found with teicoplanin, once age had dose, PK parameters, and time the drug is in an individual; (ii) the distribution (normal or lognormal) of each PK parameter in the pop- been taken into account. Finally, CLD was not measured in vancomycin studies of neutropenic patients (7, 10) and, there- ulation and its characteristics (mean vector and covariance matrix); fore, no comparison with teicoplanin can be made. (iii) the covariate model, i.e., the relationships between PK parameters Although teicoplanin’s bactericidal effect is time dependent, and the covariates; (iv) the distribution (uniform, normal, or lognormal) of each covariate in the population and its characteristics; (v) the it is not clear whether peak or trough teicoplanin levels are dosing schedule and the times at which concentrations have to be best correlated with clinical outcome. In one study with rabbits calculated, or the relationships between the known parameters and the

(6), high trough concentrations were more effective than high derived parameters (for example, if Vc and K12 distributions are peak concentrations in reducing bacterial titers in cardiac veg- known, the distribution of CLD can be simulated with the equation etations. But, in the study by Leport et al. (15) of endocarditis CLD ϭ K12 ⅐ Vc); and (vi) the number of sample vectors (subjects) in in humans, mean peak levels of teicoplanin in serum at 1 h the simulation. were lower, but not significantly so, in patients whose treat- This information is written in specific subroutines, which provide ment failed than in those who were cured (23.1 Ϯ 2.9 versus complete flexibility in the simulations. The algorithm proceeds as fol- 45.8 8.4 mg/liter), while no significant difference between lows: (i) generate a random vector of covariates according to the Ϯ specified distribution; (ii) calculate the corresponding adjusted popu- trough levels was found. However, the population sizes were lation PK parameters according to the covariate model; (iii) generate small (13 cures versus four failures). Moreover, endocarditis is a random vector of individual PK parameters according to the adjusted especially difficult to cure because antibiotic diffusion inside distribution; (iv) simulate the concentrations at desired sampling cardiac vegetations is heterogeneous (9). In fact, since teico- times, given the dosing schedule and the PK model, or compute the planin kinetics are linear, peak and trough levels are expected values of the derived parameters; and (v) store the simulated concen- to be highly correlated, and therefore clinical outcome could trations or the derived parameter values for descriptive statistics. be related to both. In a recent critical review of all available The generation of random deviates is based on a multiplicative clinical data (27), a trough level of Ͼ20 mg/liter was recom- congruential algorithm (subroutines ran 1 and gasdev) (19), after suit- mended as most effective when teicoplanin was given alone, able transformation in the case of lognormal distribution. Simulation of the concentrations follows the principle of superposition in the case but lower levels were effective when teicoplanin was combined of repeated dosing. Descriptive statistics include the use of means SDs, with aminoglycosides. Also, teicoplanin doses have to be high- percentiles (subroutine sort) (18), and histograms. er in immunocompromised hosts than in immunocompetent ones (25), i.e., teicoplanin levels have to be higher. In our ACKNOWLEDGMENTS study, teicoplanin was combined with piperacillin and amikacin and the minimal trough concentration to be reached was set at This study was funded by the Delegation` a la Recherche Clinique 10 mg/liter. from the Assistance Publique-Hoˆpitaux de Paris. The experimental results of our study showed that, in clinical We thank F. Jehl for his technical advice concerning teicoplanin measurements and Marion-Merrell-Dow Laboratories, Levallois, practice, the conventional dosing schedule may lead to a high France, for documentation support. proportion of patients with trough teicoplanin concentrations of Ͻ10 mg/liter at 48 h. Indeed, 62% of our patients had trough REFERENCES levels at 48 h below this established threshold. Simulation 1. Bodey, G. P. 1989. Evolution of antibiotic therapy for infection in neutro- experiments indicated that this deficiency could be largely penic patients: studies at MD Anderson Hospital. Rev. Infect. 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