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

Results

Thirty patients (11 in the intramuscular group, 19 in the intravenous group) completed the study. Demographic variables of the patients, as well as their concurrent tuberculosis agents, are listed in Table 1. Nearly all patients in the intramuscular group had fully drug-susceptible tuberculosis and were seen at Denver Public Health. Nearly all intravenous group patients had multidrug-resistant tuberculosis that was susceptible to streptomycin; they were seen at the National Jewish Medical and Research Center. Most patients responded well to the prescribed drugs, but one patient in the intramuscular group relapsed during the study period. Patients in both groups tolerated streptomycin during the study regardless of route of administration or type of intravenous catheter used. The longest treatment period evaluated was 12 months; most patients could participate during the first 2 months after therapy began.

Fifteen predose serum concentrations were measured as 0 µg/ml; these values were not used in modeling data. These samples were all from patients in the intramuscular group. Pertinent pharmacokinetic parameter estimates of streptomycin generated from NPEM one-compartment analysis are in Table 2. For intramuscular doses, the most likely model was determined using Ka, Kel, and Vs, whereas for intravenous doses, the most likely model was determined using a Kel slope and intercept, plus V/F. Alternative parameter selections produced slightly less likely models. Sampling generally followed the planned schedule under clinical circumstances, and actual times of blood draw were always recorded (postdose range 0.42-9.67 hrs). With equivalent doses, the intravenous route produced modestly higher median Cmax values. With intramuscular streptomycin, Cmax tended to increase with mg/kg dose (p=0.075, R2=0.137). However, given the variability in Vs and Ka, which resulted in variability in Tmax, the mg/kg dose was not highly predictive of Cmax. For intramuscular doses, the highest Cmax (85.18 µg/ml) was achieved with the near-median dose of 17.74 mg/kg. Likewise, the mg/kg dose was not highly predictive of Tmax, with slightly earlier Tmax values seen after larger mg/kg doses (p=0.302, R2=0.048). Therefore, larger intra-muscular doses, with their larger volume to be absorbed, were not responsible for later Tmax values.

As intravenous doses were increased (range 500-1800 mg), proportional increases in Cmax (p=0.032) and AUC (p=0.001) were seen. In addition, Kel and Vs remained constant when the dose was altered, indicating linear kinetics. Variability (CV%) in parameter estimates was somewhat larger in the intravenous than intramuscular patient population: Kel (45% vs 27%), Vs (29% vs 22%), Cl/F (44% vs 30%). The CV for intramuscular Ka was 80%.

Similar median Vs estimates were obtained for intramuscular and intravenous streptomycin. The patients in the intravenous group were somewhat older and had lower Clcr values. Consistent with these facts, patients receiving the intravenous administration had somewhat lower Kel and Cl/F values and somewhat longer elimination half-life values. Estimated bio-availability of intramuscular streptomycin calculated with median dose and median AUC values of intravenous and intramuscular streptomycin (F = AUCintramuscular

Doseintravenous/ AUCintravenous

Doseintramuscular) was 0.84. Alternatively, F can be estimated using ratios of the Vs values (Vs-intramuscular:Vs-intravenous), resulting in an estimated F of 0.88.

Correlation between pharmacokinetic estimates of streptomycin and patients' demographic variables was examined. In the intramuscular group (11 patients), no specific associations were found between pharmaco-kinetic parameter estimates and age, race, or gender. Associations of Clcr and pharmacokinetic parameter estimates did not reach statistical significance.

In the intravenous group (19 patients), Kel and Cl/F estimates significantly decreased with lower Clcr. The V/F was positively associated with serum creatinine but negatively associated with Clcr. When volume was adjusted for weight, these relationships were no longer statistically significant. With the exception that AUC was somewhat lower in women than men, no specific associations were found between pharmacokinetic parameter estimates and age, race, or gender.

The 11 patients in the intramuscular group received injections 5 times/week (M-F) for 2 weeks, followed by twice/week for approximately 6 weeks. Models were created using 127 serum concentrations for these patients, who received approximately 26 total doses. In the intravenous group, models were created using 83 serum concentrations. Of these, 4% were associated with daily doses, 48% with M-F doses, 42% with MWF doses, and 6% with twice/week doses. Based on kinetic simulations using median doses for each regimen (Figures 1 and 2), Cmax:MIC, AUC:MIC, AUC>MIC, and T>MIC were calculated (Table 3). Using an MIC of 1 µg/ml for streptomycin, both intravenous and intramuscular administration showed a Cmax:MIC range of 37-56 µg/ml. For each route of administration, AUC>MIC values were similar regardless of frequency of dosing according to doses administered. The M-F regimen provided a T>MIC approximately 2-fold longer than that which followed the twice/week or MWF regimen. When MIC of 10 µg/ml for streptomycin was used, the M-F regimen showed a longer T>MIC than that which followed the intermittent regimens, regardless of route of administration. However, for intravenous doses, AUC>MIC for the M-F regimen was 40% smaller than that of the MWF regimen. All simulated trough concentrations were below 1 µg/ml.

Simulation plots of streptomycin administered 2 and 5 times/week after intramuscular injections.

Simulation plots of streptomycin administered 3 and 5 times/week after intravenous infusions.

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