Population Pharmacokinetics of Intravenous and Intramuscular Streptomycin in Patients with Tuberculosis

Min Zhu, Ph.D., William J. Burman, M.D., George S. Jaresko, Pharm.D., Shaun E. Berning, Pharm.D., Roger W. Jelliffe, M.D.,and Charles A. Peloquin, Pharm.D.

Disclosures

Pharmacotherapy. 2001;21(9) 

In This Article

Methods

This prospective, unblinded clinical study was conducted at the National Jewish Medical and Research Center and the Denver Public Health Department, Denver, Colorado. From 1992-2000, all patients diagnosed with tuberculosis according to the American Thoracic Society and CDC criteria were eligible to participate. All signed an informed consent form before study participation. The study protocol was reviewed and approved by appropriate institutional review boards.

Medical history was recorded and physical examination was performed for each patient as part of routine care. Baseline laboratory test results were recorded for sodium, potassium, calcium, phosphorus, chloride, carbon dioxide, glucose, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, bilirubin, hemoglobin, hematocrit, and total counts of red blood cells, platelets, white blood cells, and differential. Changes in body weight, serum creatinine, and any other available laboratory data were recorded for patients at each follow-up visit. Patients were asked to report all concurrent drugs taken within 48 hours of a blood draw.

Two routes of administration and two sampling strategies were used. Patients in the intramuscular group underwent a more extensive pharmaco-kinetic evaluation after their doses were adminis-tered. For patients in the intravenous group, only two serum samples were collected after the intravenous doses were administered. Patients were scheduled to be sampled on at least two different dates.

All doses were prepared in a standardized fashion by each institution's pharmacy department. Patients in the intramuscular group were given multiple doses of streptomycin sulfate 400 mg/ml (Pfizer U.S. Pharmaceutical Group, New York, NY) Standardized intramuscular doses were given once/day or twice/week throughout the study. Patients in the intravenous group were given multiple doses of streptomycin dissolved in 100 ml dextrose 5% in water or normal saline and infused over a 30-minute period. Various catheters were used to administer intravenous streptomycin, including peripheral, central, and peripherally inserted central catheter lines. Unlike intramuscular doses, intravenous dosing regimens were adjusted to achieve targeted streptomycin serum concentrations (a calculated maximum concentration [Cmax] of 35-45 µg/ml for doses of approximately 12-15 mg/kg, and 65-80 µg/ml for doses of approximately 22-25 mg/kg).[10] Smaller intravenous doses were administered once/day or 5 times/week (Monday-Friday [M-F]); larger intravenous doses were administered 3 times/week, as requested by the attending physician.

Dose, dosing time, and blood sampling time were recorded for each subject on a study flow sheet during the visit. Blood was collected from intramuscular group patients through a 20-gauge angiocatheter inserted into a forearm vein. Catheters were maintained patent with a dilute heparin solution (10-15 U/ml). The first 1-2 ml of blood withdrawn was discarded in order to remove the heparin solution and prevent dilution of the serum sample. A total of 4 ml of blood was scheduled to be collected before dosing and at 0.5, 1, 2, 6, and 10 hours after dosing. In the intravenous group, a two-sample strategy was used. Blood samples were scheduled to be drawn at 2 and 6 hours after dosing by direct venipuncture. Blood samples collected were allowed to clot for 15-30 minutes and then were centrifuged at 2500-3000 g for 10 minutes to separate serum. Serum was promptly removed and frozen at -70°C until assay, typically within 7 days of collection for patients from the National Jewish Medical and Research Center. Samples from patients from the Denver Public Health Department were shipped to National Jewish for analysis each month. The number of doses examined for each subject depended on patient availability and time of visit.

Serum concentrations of streptomycin were measured using a validated high-performance liquid chromatography (HPLC) assay. The HPLC system consisted of a Waters 510 HPLC pump (Milford, MA), with a model 680 gradient controller and a solvent select valve, a Spectra Physics model 8875 fixed-volume autosampler (San Jose, CA), a Waters model 486 ultraviolet detector, a Macintosh 7100 computer (Apple Computer Inc., Cupertino, CA), and the Rainin Dynamax HPLC data management system (Woburn, MA). Concentrations of streptomycin were determined using peak height ratio of streptomycin to internal standard. Linear regression analysis using a weight of 1/Y[2] provided best fit over the approximately 2-log concentration range. Range of serum standard curves for streptomycin was 2.5-75 µg/ml, with linearity extending to at least 300 µg/ml. Samples determined to be above the high standard were diluted and reanalyzed. Absolute recovery of streptomycin from serum was 88%. Within-day precision of validation quality control samples (6, 30, 60 µg/ml) was 7.4-9.1% coefficient of variation (CV), and overall validation precision was 7.7-10.2% CV. Assay error pattern was determined from quality control samples assayed during the study. A line was fitted to the plot of standard deviation (SD) of quality control samples versus their mean concentrations (C) using linear regression. The resulting equation, SD = 1.1378 + 0.01446C, was used for subsequent pharmacokinetic analysis.

Patient data files were created using the PASTRX program in the USC*PACK software collection.[11] Information collected included patient demographics and treatment record (e.g., start date of therapy, dose, dosing frequency, sampling time, and serum concentrations measured). Creatinine clearance (Clcr) was calculated by the Cockcroft and Gault method.[12] Any streptomycin serum concentrations below the lower limit of quantification were removed from analysis.

A one-compartment model was selected for population pharmacokinetic analysis using USC*PACK software, Version 10.7.[11] The iterative two-stage Bayesian (IT2B) was run to define boundary ranges for the parameters. The Akaike information criterion and log-likelihood criterion were used to determine best fit of the test models. Fraction of dose absorbed (F) was arbitrarily fixed at 1. The assay error pattern described above was used for modeling. Additional nonassay variability was incorporated into the modeling process as "gamma," which is estimated by the software. The modeling process was started with relatively rich data sets obtained from patients in the intramuscular group. Elimination rate constant (Kel, hr-1) and apparent volume of distribution (V/F, L) were estimated for both groups; absorption rate constant (Ka, hr-1) was added for the intramuscular group's doses. Additional models were tested using volume of distribution adjusted for weight (Vs, L/kg), Kel slope (related to Clcr) plus a Kel intercept (nonrenal elimination), or total clearance (Cl/F).

Estimated medians and ranges for parameters obtained from IT2B analysis were used to define parameter ranges for nonparametric expectation maximization (NPEM) analysis. The log-likelihood criterion was used to determine best fit of the test models. The NPEM Bayesian posterior parameter joint densities of individual subjects were estimated starting from the population parameter joint density and continuing to analyze each subject's data. The Ka, Kel, and Vs estimates of each individual obtained from the NPEM model were used to compute additional pharmacokinetic parameters, including Cl/F (L/hr) and elimination half-life (hrs), using standard equations. Additional evaluations of models included correlation among parameters, and bias and precision of model-predicted concentrations compared with observed concentrations for the entire population.

Kinetic simulation was performed using streptomycin population median values of Ka, Kel, and Vs with WinNonlin pharmacokinetic software (Pharsight, Version 3).[13] Maximum serum concentration (Cmax, µg/ml), time to achieve Cmax (Tmax, hrs), and area under the concentration-time curve for one dosing interval at steady state (AUC0-t, µg

hr/ml) at given doses were estimated using a one-compartment open model. Pharmacokinetic-pharmacodynamic surrogate markers for antimicrobial effect were employed to evaluate commonly used streptomycin dosing regimens. These included ratio of Cmax:minimum inhibition concentration (MIC) of streptomycin against Mycobacterium tuberculosis, AUC above MIC (AUC>MIC), ratio of AUC:MIC, and time period with serum concentration above MIC (T>MIC). In the clinical setting, individual MIC values generally are not available. Susceptibility results usually are qualitative (susceptible or resistant at a single breakpoint concentration). Therefore, we used reported broth MIC of streptomycin against susceptible and moderately resistant M. tuber-culosis (ranges 1-2 and 8-12 µg/ml, respectively) to calculate pharmacodynamic parameter estimates. Representative MICs of 1 and 10 µg/ml were selected for the calculations.[14,15,16]

Statistical analyses were performed using JMP statistical software (Version 3.2.6, SAS Institute, Cary, NC), with supplemental analyses using IT2B, NPEM, and Excel (Microsoft Excel 97 SR-2, Seattle, WA). Frequency distributions, using JMP, included plots of the data, distribution curves to test for normality, and parametric and nonparametric measures of central tendency and dispersion. Mean ± SD was reported, and CV% was calculated as SD/mean

100%. Correlation analyses, using JMP, were performed across subject and outcome variables with nonparametric techniques. Dependence of pharmacokinetic variables on subject demographics was determined using Y by X analysis one parameter at a time. Significant findings were tested in multivariate analyses using stepwise addition and backward deletion. Differences among groups, or correlation between parameters and covariates, were considered statistically significant at a p value less than 0.05. Coefficient of determination was designated R2.

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