Pharmacokinetics of RheothRx Injection in Healthy Male Volunteers

Pharmacokinetics of RheothRx Injection in Healthy Male Volunteers R. C. JEWELLX, S. P. KHOR, D. F. KISOR, K. A. K. LACROIX*,

AND

W. A. WARGIN

Received November 29, 1996, from the Glaxo Wellcome Inc., Five Moore Drive, Research Triangle Park, NC 27709. publication March 13, 1997X . * Present address: Quintiles Inc., 1007 Slater Road, Durham, NC 27703. Abstract 0 The objectives of this study were to evaluate the safety and tolerability of RheothRx (poloxamer 188) Injection administered as an intravenous (iv) infusion to healthy male volunteers and to determine the pharmacokinetic profile of poloxamer 188. Thirty-six healthy male volunteers were enrolled in a randomized, double-blind, placebo-controlled, dose-escalation trial for RheothRx Injection. The volunteers were randomized to three treatment groups (12 per treatment group, with eight receiving active therapy and four receiving placebo). In each treatment group, volunteers received RheothRx Injection or placebo as an iv infusion on two occasions at least 3 weeks apart to make a total of six doses being studied (10, 30, and 45 mg/kg/h for 72 h, 60 mg/kg/h for 43.3 to 72 h, 60 and 90 mg/kg/h for 24 h). Serial plasma samples were collected during and up to 36 h after the end of the infusions; urine was collected over intervals from the start of the infusion until 36 h after the infusions were terminated. Plasma and urine samples were assayed for poloxamer 188 by gel-permeation chromatography. Pharmacokinetic parameter values were calculated by noncompartmental and compartmental methods. Poloxamer 188 was eliminated primarily by renal excretion. Estimates of clearance, elimination rate constant, and apparent volume of distribution at steady state values were independent of infusion rate. Poloxamer 188 displayed no apparent infusion rate dependence in its pharmacokinetics.

Introduction RheothRx1 Injection is a sterile aqueous solution of poloxamer 188 (150 mg/mL) intended for intravenous (iv) administration. Poloxamer 188, NF, is a nonionic block copolymer comprised of a single chain of hydrophobic polyoxypropylene connected to two chains of hydrophilic polyoxyethylene and has an average molecular weight of 8400 Da. The structure of poloxamer 188 is given in Figure 1. The active component of RheothRx Injection, poloxamer 188, was first synthesized in the 1950s and has been used as a food additive, a stool softener, a topical wound cleanser, an emulsifying agent in iv fat emulsions, and an additive in cardiopulmonary bypass perfusion solutions.2-5 As an emulsifying agent, poloxamer 188 is present at 2.72% (w/v) in Fluosol, which is approved for the prevention or diminution of myocardial ischemia during coronary angioplasty in patients at high risk of ischemic complications. More recently, pharmacology studies have shown that poloxamer 188 is a hemorheologic agent that enhances microvascular blood flow and reduces blood viscosity, particularly under low shear conditions.6 In addition, poloxamer 188 possesses antithrombotic and cytoprotective actions.6 A preliminary study of the pharmacokinetics of poloxamer 188 after a single 15-min iv administration in humans at 0, 25, 50, 100, 200, and 400 mg/kg was conducted with a different formulation and a different (colorimetric) assay.7 MacLeod et al. stated that the maximum concentration (Cmax) and area under the concentration-time curve (AUC) increased dose dependently, detailed pharmacokinetic information was pubX

Abstract published in Advance ACS Abstracts, May 1, 1997.

808 / Journal of Pharmaceutical Sciences Vol. 86, No. 7, July 1997

Accepted for

Figure 1sStructure of poloxamer 188 (where average value of a ) 80 and average value of b ) 27).

lished. Therefore, more rigorous assessment of the pharmacokinetics of poloxamer 188, formulated as RheothRx Injection, was needed. The objectives of this study were to evaluate the safety and tolerability of RheothRx Injection administered as an iv infusion in healthy male volunteers and to determine the pharmacokinetic profile of poloxamer 188. The current work will focus primarily on the pharmacokinetics of poloxamer 188.

Experimental Section Clinical Study DesignsThirty-six healthy male volunteers (nonsmokers, 19 to 35 years of age inclusive, weighing between 122 and 230 pounds, and not deviating by more than 27% from their ideal body weights) were enrolled in a randomized, double-blind, placebocontrolled, dose-escalation trial. The use of prescription and nonprescription drugs, caffeine, and alcohol was not permitted in the study. The study was conducted in accordance with the 1964 Declaration of Helsinki and was approved by the Institutional Review Board. Written informed consent was obtained from all volunteers prior to their participation in the study. The study consisted of six dosing periods. Each subject was assigned to one of three treatment groups (12 subjects per treatment group). Each group underwent dosing in two dosing periods at least 3 weeks apart, as follows: Group I, Periods 1 and 4; Group II, Periods 2 and 5; and Group III, Periods 3 and 6. One Group II subject received treatment with doses for Periods 2 and 6 instead of Periods 2 and 5 to increase the number of volunteers receiving the Period 6 dose. Periods 1 through 6 were conducted in numerical sequence at weekly intervals, and the dose was escalated with each dosing period based on assessment of safety and tolerance of the previous dose. Within each group, subjects were randomized in a 2:1 fashion, such that eight received RheothRx Injection and four received placebo; the placebo treatment was an infusion of the vehicle for RheothRx Injection at the same rate as the active treatment. All infusions were administered into a peripheral arm vein; blood samples were collected from the vein in the opposite arm. The treatment groups, planned infusion rates, and the number of subjects who participated in each dosing period are presented in Table 1. Each infusion consisted of a 15-min loading infusion followed by a maintenance infusion. After Period 4, the protocol was amended to decrease the planned dosing regimens in terms of infusion rates (Period 5) and total infusion duration (Periods 5 and 6) in response to adverse experiences (primarily muscle pain in the legs and back); details of the dosing regimens after amendment are provided in Table 1. Safety was evaluated by physical examinations and by monitoring vital signs, clinical laboratory tests, electrocardiograms, and adverse experiences. Serial blood samples of 7 mL each were collected prior to beginning the infusion and at 0.5, 1, 2, 6, 9, 12, and 24 h during the infusion; for longer infusions, samples were also collected at 48 and 72 h during the infusion. In addition, serial blood samples were collected at 1, 2, 3, 4, 6, 9, 12, 24, 28, and 36 h after the termination of the infusion. If the infusion was terminated early, a blood sample was collected at the time of infusion termination.

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Table 1sSubject Numbers, Treatment Groups, and Dosing Schedules Number of Subjects Period

Group

Scheduled Regimen

1

I

2

II

3

III

4

I

5

II

6

III

10 mg/kg (0.067 mL/kg) over 15 min, followed by 10 mg/kg/h (0.067 mL/kg/h) for 71.75 h 30 mg/kg (0.20 mL/kg) over 15 min, followed by 30 mg/kg/h (0.20 mL/kg/h) for 71.75 h 45 mg/kg (0.30 mL/kg) over 15 min, followed by 45 mg/kg/h (0.30 mL/kg/h) for 71.75 h 60 mg/kg (0.40 mL/kg) over 15 min, followed by 60 mg/kg/h (0.40 mL/kg/h) for 71.75 ha 60 mg/kg (0.40 mL/kg) over 15 min, followed by 60 mg/kg/h (0.40 mL/kg/h) for 23.75 hb 90 mg/kg (0.60 mL/kg) over 15 min, followed by 90 mg/kg/h (0.60 mL/kg/h) for 23.75 hc

RheothRx Injection

Placebo

8

4

8

4

8

4

7

3

5

4

3

4

The amount of drug eliminated in the urine, Ae(∞), was determined from the start of the infusion until the end of the urine collection period (36 h after termination of the infusion). The percent of the dose excreted unchanged was calculated based on Ae(∞) and the total administered dose. Renal clearance, CLR, was calculated as follows:

CLR ) Ae(∞)/AUC0f∞

(3)

Compartmental pharmacokinetic analysis using a two-compartment model was also performed on the poloxamer 188 concentrationtime data using NONLIN10; the model subroutine contained provisions for both loading and maintenance infusions. The model equation is shown in eq 4:

C)

a Terminated early (43.3−43.5 h) in 6/7 subjects due to adverse experiences. Modified by protocol amendment from 75 mg/kg (0.50 mL/kg) over 15 min, followed by 75 mg/kg/h (0.50 mL/kg/h) for 71.75 h. c Modified by protocol amendment from 90 mg/kg (0.60 mL/kg) over 15 min, followed by 90 mg/kg/h (0.60 mL/kg/h) for 71.75 h. b

Urine was collected over the intervals 0-12 and 12-24 h during the infusion; for longer infusions, additional collection intervals were 24-48 and 48-72 h during the infusion. In addition, urine was collected at 0-2, 2-4, 4-6, 6-10, 10-14, 14-24, 24-28, and 28-36 h after the termination of the infusion. If the infusion was terminated early, the urine collection interval ended at the time of infusion termination. Analytical MethodssThe gel-permeation chromatography methods used for the analysis of poloxamer 188 concentrations in plasma and urine samples were developed and validated at Glaxo Wellcome Inc.8 Briefly, plasma samples were processed by protein precipitation with acetone, and urine samples were extracted with tetrahydrofuran after the addition of sodium chloride before subjecting the samples to gel-permeation chromatography with refractive index detection. Two 5-µm PLgel (1000 Å, 300 × 7 mm) columns, thermostatted at 40 °C, were used in series. The mobile phase consisted of a 95:5 solution of tetrahydrofuran:water and was pumped at a rate of 1 mL/min. The limit of quantification for poloxamer 188 in plasma was 0.05 mg/mL, with inter- and intraday coefficients of variation of <10% and bias of <3%. The limit of quantification for poloxamer 188 in urine was 0.25 mg/mL, with inter- and intraday coefficients of variation of 12% and bias of <4%. Pharmacokinetic AnalysissBoth noncompartmental and compartmental pharmacokinetic methods were used to calculate pharmacokinetic parameters. In the noncompartmental analysis, the elimination rate constant, λz, was determined by log-linear regression of the terminal phase of the concentration-time curve after each administration, and the corresponding half-life, t1/2, was calculated. The area under the curve of concentration versus time from time zero to infinity (AUC0f∞) was determined by the linear trapezoidal rule, with extrapolation to infinity based on the actual concentration at the last measurable timepoint and the elimination rate constant. The steady-state plasma poloxamer 188 concentration, Css, was determined as the average of all available plasma poloxamer 188 concentration data collected between 24 and 72 h during the infusion. Clearance was determined in two ways:

CLAUC ) dose/AUC0f∞

(1)

CLCss ) infusion rate/Css

(2)

The apparent volume of distribution at steady state, Vdss, and mean residence time, MRT, were determined by the method of Watari and Benet.9

k0(k21 - λ1)(1 - e-λ1T)e-λ1t Vdcλ1(λ1 - λz)

k0(k21 - λz)(1 - e-λzT)e-λzt +

Vdcλz(λz - λ1)

(4)

where C is the plasma concentration at time t, k0 is the infusion rate, k21 is the intercompartmental transfer rate constant from compartment 2 to compartment 1, Vdc is the volume of distribution of compartment 1 (central compartment), λ1 is the hybrid rate constant describing the rapid phase of drug disposition, λz is the hybrid rate constant describing the slow phase of drug disposition, T is the duration of the infusion (T ) t during infusion; T < t after end of infusion), and t is the time from the beginning of the infusion. Then, Vdss was calculated as:

Vdss ) Vdc (1 + k12/k21)

(5)

Using NONLIN, various weighting schemes were evaluated for their ability to accommodate the heteroscedasticity of the data, and a weighting factor of 1/concentration was selected to minimize optimally the sum of squares. Goodness-of-fit was assessed using Akaike’s Information Criterion.11 Statistical AnalysissSafety data were summarized in tabular form. Summary tables and individual subject listings were reviewed. Statistical analyses were performed on the noncompartmental pharmacokinetic parameter values with SAS for Windows, Version 6.08.12 If the distributions of the pharmacokinetic parameter values were non-normal, the values were natural log-transformed if this transformation normalized the distribution; in this case, only clearance values required log-transformation. Point estimates and 95% confidence intervals for the parameters were generated. Linear regression analysis was used to explore the relationships between the infusion rate (k0) of RheothRx Injection and the poloxamer 188 Css, CL, λz, and Vdss. The linear regression analyses were performed as if the observations were independent (i.e., as if the data came from different subjects); the validity of the assumption of independence cannot be verified for these analyses. Analysis of variance (ANOVA) with model terms for maintenance infusion rate and subject was performed to examine the relationship between the k0 of RheothRx Injection and the same four variables of Css (in an infusion rate-normalized fashion), CL, λz, and Vdss. If k0 was determined to have a significant effect on the parameter value, comparisons were constructed and tested by the two one-sided tests procedure with an acceptance range of (0.80, 1.25) and a reference infusion rate of 30 mg/kg/h (the lowest infusion rate with values for all parameters).

Results Thirty-six volunteers were enrolled in the study. Twenty subjects (nine RheothRx Injection-treated and 11 placebotreated) completed two dosing periods as scheduled; 16 subjects (15 RheothRx Injection-treated and one placebotreated) did not. Eight RheothRx Injection-treated subjects had their infusions stopped prematurely because of adverse events (e.g., back pain, leg pain, headache, nausea). One RheothRx Injection-treated subject had his infusion stopped early because of withdrawal of consent for personal reasons. Four subjects (three RheothRx Injection-treated and one placebo-treated) did not receive their second scheduled infusions because of persistent laboratory abnormalities (elevated liver enzymes) after the first dosing period. Three RheothRx

Journal of Pharmaceutical Sciences / 809 Vol. 86, No. 7, July 1997

Figure 2sPlot of mean plasma poloxamer 188 concentrations against time for all six dosing periods. Key: (0) 10 mg/kg/h (n ) 7); (4) 30 mg/kg/h (n ) 7); (O) 45 mg/kg/h (n ) 7); (9) 60 mg/kg/h (43.3−72 h; n ) 6); (2) 60 mg/kg/h (24 h; n ) 5); (b) 90 mg/kg/h (n ) 3).

Figure 3sPlot of Css against infusion rate. The line shows the results of linear regression analysis.

Injection-treated subjects did not receive their second infusion because of withdrawal of consent. All pharmacokinetic data from all subjects were analyzed and are included. The most frequent adverse experiences in the study were pain, injection site abnormality (redness, swelling, tenderness, pain and/or discomfort), and nausea. Clinical chemistry, hematology, urinalysis, and electrocardiographic results were essentially unchanged during the study, with the exception of some laboratory assessments. Mild-to-moderate, reversible elevations in hepatic enzymes (primarily ALT and AST) were observed more commonly in RheothRx Injection-treated subjects than in placebo-treated subjects and were generally resolved within 1 week of the end of the infusion. A reversible proteinuria was observed in some subjects receiving RheothRx Injection infusions. A plot of the mean plasma poloxamer 188 concentrations against time for all six dosing periods is given in Figure 2. Because of the use of a loading infusion, plasma poloxamer 188 concentrations approached steady state early in the course of treatment, although the calculation of steady-state concentrations only used data at hour 24 or later. The summary statistics for the noncompartmental pharmacokinetic parameters during all six dosing periods are presented in Table 2. The extrapolated AUC did not exceed 3% of the total AUC0f∞ in any case. Estimates of AUC0f∞ could not be obtained for any subject during Period 1 or for two subjects during Period 2 because of insufficient post810 / Journal of Pharmaceutical Sciences Vol. 86, No. 7, July 1997

Figure 4sPlot of Vss against infusion rate. The line shows the results of linear regression analysis.

infusion concentration-time data. Summary statistics for AUC0f∞ were not calculated for any dosing period because of differences in the infusion duration for some of the dosing periods and subjects. Estimates of CLAUC were similar to those of CLCss; because CLCss values were available for all infusions, statistical analyses were performed only on the CLCss data. Figures 3 and 4 are plots of Css and Vdss against infusion rate, respectively. Linear regression analysis showed that Css increased linearly with increasing infusion rate (r2 ) 0.849; p < 0.0001). There was no apparent infusion-rate dependence in CL (r2 ) 0.0002; p ) 0.9345) or λz (r2 ) 0.045; p ) 0.2678). The Vdss increased slightly with increasing infusion rate (r2 ) 0.330; p ) 0.0011). The results of the analysis of variance procedures, which took subject drop-out into account, are summarized in Table 3. The λz and Vdss values did not show a statistically significant dependence on either infusion rate or subject. Both infusion rate-normalized steady-state plasma concentrations (Css/k0) and natural log-transformed clearance [ln(CLCss)] values showed a small but statistically significant dependence on both k0 and subject. Further examinations of comparisons by the two one-sided tests procedure for Css/k0 and ln(CLCss) values showed no statistically significant differences for Css/ k0. The 90% confidence intervals for the comparison of ln(CLCss) at 45 and 90 mg/kg/h against 30 mg/kg/h were not contained within the (0.80, 1.25) interval, although the ratios for all four k0 comparisons were included in the interval. The slopes associated with the effect of k0 on Css/k0 and CLCss were very small (0.0000273 and -0.00202, respectively); these small effects were of no clinical significance. Because of the lack of a clinically significant effect of k0 on plasma CL, data from all k0 values were combined in the calculation of the mean and 95% confidence interval for CLCss (based on natural log-transformed data). The mean CLCss value was 1.06 mL/min/kg, with a 95% confidence interval of 0.99 to 1.14 mL/min/kg. Similarly, all λz data were combined to calculate an overall mean λz of 0.148 h-1, with a 95% confidence interval of 0.137 to 0.159 h-1. The average amount of the administered dose that was eliminated in the urine ranged from 72 to 94% across the dosing periods. Estimates of CLR were, on average, 78% of the corresponding systemic CL estimates. The results of the compartmental pharmacokinetic analysis, which were similar to the results of the noncompartmental analysis, are shown in Table 4. The two-compartment model as described by eq 4 provided excellent agreement between the predicted and the actual poloxamer 188 plasma concentration-time data, as shown by the example in Figure 5.

Table 2sSummary Statistics for Noncompartmental Pharmacokinetic Parameters for Poloxamer 188a Parameter (units)

10 mg/kg/h

30 mg/kg/h

45 mg/kg/h

60 mg/kg/h (43.3−72 h)

60 mg/kg/h (24 h)

90 mg/kg/hr

N λz (h-1) t1/2 (h)b CLAUC (mL/min/kg) CLCss (mL/min/kg) Css (mg/mL) Vdss (L/kg) MRT (h) % Excreted unchanged CLR (mL/min/kg)

7 NC NC NC 1.14 ± 0.19 0.16 ± 0.03 NC NC 72.2 ± 9.1 NC

6 0.170 ± 0.039 4.08 0.98 ± 0.18 0.98 ± 0.19c 0.56 ± 0.10d 0.151 ± 0.020 2.65 ± 0.63 83.4 ± 17.7e 0.76 ± 0.22

8 0.143 ± 0.016 4.86 0.96 ± 0.13 0.97 ± 0.13 0.85 ± 0.11 0.125 ± 0.046 2.17 ± 0.74 79.4 ± 13.7 0.72 ± 0.20

7 0.124 ± 0.012 5.60 1.00 ± 0.14 1.02 ± 0.15 1.07 ± 0.16 0.158 ± 0.016 2.68 ± 0.47 88.3 ± 10.0 0.80 ± 0.07

5 0.163 ± 0.034 4.25 1.11 ± 0.30 1.07 ± 0.27 1.05 ± 0.24 0.187 ± 0.026 2.90 ± 0.53 81.5 ± 20.3 0.87 ± 0.41

3 0.150 ± 0.023 4.62 1.34 ± 0.34 1.27 ± 0.26 1.31 ± 0.25 0.230 ± 0.044 2.89 ± 0.35 94.0 ± 3.3 1.18 ± 0.29

a Values are means ± standard deviations; NC, not calculated. b Harmonic mean. c Including all subjects (n ) 8), CL d Css ) 1.15 ± 0.34 mL/min/kg. Including all subjects (n ) 8), Css ) 0.51 ± 0.14 mg/mL. e Including all subjects (n ) 8), % excreted unchanged ) 78.3 ± 18.3.

Table 3sResults of Analysis of Variance of Noncompartmental Pharmacokinetic Parameter Values Parameter

Overall p Value

Effects

Slope

p Value for Effects

Comparison

Ratio

90% Confidence Interval

Power (%)

Normalized Css (mg/mL/mg/kg/h)

0.0001

Infusion rate Subject

0.0000273 s

0.0044 0.0001

Clearance (ln-transformed)

0.0001

Infusion rate Subject

−0.00202 s

0.0026 0.0001

λz (h-1)

0.2549

Vdss (L/kg)

0.2655

Infusion rate Subject Infusion rate Subject

−0.000363 s 0.00126 s

0.3682 0.2579 0.0701 0.4637

10−30 45−30 60−30 90−30 10−30 45−30 60−30 90−30 s s s s

0.999 1.002 1.001 1.002 1.086 0.908 0.953 0.907 s s s s

0.997−1.000 0.999−1.005 0.999−1.002 0.999−1.005 0.983−1.200 0.737−1.118 0.883−1.029 0.765−1.075 s s s s

100 100 100 100 95.2 9.7 99.5 41.1 s s s s

Table 4sSummary Statistics for Compartmental Pharmacokinetic Parameters for Poloxamer 188a Parameter (units)

N λ1 (h-1) t1/2λ1, (h)b λz (h-1) t1/2 (h)b CL (mL/min/kg) Vdc (L/kg) Vdss (L/kg) Css,pred (mg/mL) a

10 mg/kg/h 7 NC NC NC NC NC NC NC NC

30 mg/kg/h 6

1.67 ± 0.28 0.42 0.173 ± 0.021 4.01 0.99 ± 0.18 0.058 ± 0.014 0.163 ± 0.023 0.56 ± 0.10

45 mg/kg/h

60 mg/kg/h (43.3−72 h)

60 mg/kg/h (24 h)

90 mg/kg/h

1.48 ± 0.34 0.47 0.156 ± 0.033 4.45 0.96 ± 0.14 0.061 ± 0.014 0.161 ± 0.020 0.85 ± 0.11

7 1.52 ± 0.22 0.46 0.148 ± 0.023 4.04 1.01 ± 0.13 0.056 ± 0.011 0.175 ± 0.024 1.08 ± 0.16

5 1.76 ± 0.40 0.39 0.171 ± 0.047 4.69 1.12 ± 0.31 0.058 ± 0.011 0.172 ± 0.020 1.02 ± 0.27

3 1.62 ± 0.39 0.43 0.153 ± 0.035 4.52 1.34 ± 0.33 0.071 ± 0.005 0.208 ± 0.027 1.26 ± 0.29

8

Values are means ± standard deviations; NC, not calculated. b Harmonic mean.

Discussion Steady-state plasma concentrations increased linearly with increasing infusion rate (k0) values up to 90 mg/kg/h. Figure 3 could be interpreted to show a slight tendency toward nonlinearity at the 90-mg/kg/h infusion rate; however, this apparent lack of linearity may be an artifact due to the failure of all subjects to complete two dosing periods. Comparison of the Css values for the three subjects who received both 90mg/kg/h infusions and lower infusion rates showed that the Css values were approximately proportional to the values of k0. The analysis of variance revealed a statistically significant but very small effect of k0 on infusion rate-normalized Css values that is not clinically significant. The comparisons of infusion rate-normalized Css values by the two one-sided tests procedure showed no statistically significant differences. Linear regression analysis indicated that the plasma CL of poloxamer 188 was independent of k0. The analysis of variance showed a statistically significant but very small effect of k0 on CL that is not clinically significant. The comparisons between plasma CL values showed that the 90% confidence intervals were not contained within the (0.80, 1.25) interval for the 45- and 90-mg/kg/h groups; however, the 60-mg/kg/h

group was not statistically significantly different from the 30mg/kg/h group. It is worth noting that the subjects in the 45- and 90-mg/kg/h groups were generally the same subjects and were a different group of subjects from the reference 30mg/kg/h group, suggesting that the two one-sided tests procedure may have resulted in wider confidence intervals when using intersubject variability. The finding that the 60mg/kg/h group (which shares some members with the 30-mg/ kg/h group and is intermediate in k0 between the 45- and 90mg/kg/h groups) is not different from the 30-mg/kg/h group is consistent with this suggestion. The elimination rate constant, λz, did not change with k0, as shown by both linear regression and analysis of variance procedures. There was an increase in the Vdss with increasing k0 from a mean of 0.15 L/kg at 30 mg/kg/h to a mean of 0.23 L/kg at 90 mg/kg/h when examined by linear regression analysis. The analysis of variance procedure, which included a model term for subject as well as k0, revealed no effect of k0 on Vdss. These CL, λz, Css, and Vdss data are supportive of linear pharmacokinetics (i.e., no infusion rate-dependence in pharmacokinetics). In the earlier publication with a different

Journal of Pharmaceutical Sciences / 811 Vol. 86, No. 7, July 1997

on filtration because of its size. As a result, the finding that the CLR of poloxamer 188 is 71% of the calculated creatinine clearance is not inconsistent with a primarily glomerular filtration mechanism of renal elimination.

Conclusions Poloxamer 188 was eliminated primarily by renal excretion. After iv infusions at increasing infusion rate (k0) values from 10 to 90 mg/kg/h in healthy young male volunteers, Css values of poloxamer 188 were linearly related to k0. The plasma CL, λz, and Vdss were independent of k0, with a mean plasma CL of 1.06 mL/min/kg. Poloxamer 188 displayed no apparent infusion rate dependence in its pharmacokinetics.

References and Notes Figure 5sExample fit of two-compartment model to plasma poloxamer 188 concentration−time data (Subject 8; 60 mg/kg/h).

formulation as well as a different assay, MacLeod et al.7 found that Cmax and AUC increased dose-dependently, which is consistent with the current results. Poloxamer 188 elimination is primarily by renal excretion. The renal pharmacokinetic data in Table 2 could be interpreted to suggest an increase in percent excreted unchanged and CLR with k0, which is again likely because of the failure of all subjects to complete both dosing periods. The CLR values within the same subjects who received two infusions did not show any dose dependence. The mechanism of CLR for poloxamer 188 is unknown; however, given its lack of electrical charge and macromolecular nature, it is reasonable to hypothesize that poloxamer 188 is cleared via glomerular filtration.13,14 Consistent with this hypothetical mechanism, poloxamer 188 shares some of the characteristics (no electrical charge and relatively large size) of the neutral dextrans that are cleared by glomerular filtration. The CLR of poloxamer 188 in this study was a median of 71% of the estimated glomerular filtration rate (calculated creatinine clearance based on the equation of Cockroft and Gault15). Glomerular filtration becomes restricted at molecular weights greater than ∼5000 Da, as was demonstrated in a series of experiments with neutral dextrans.13 The average molecular weight of poloxamer 188 is 8400 Da, suggesting that it may experience some restriction

812 / Journal of Pharmaceutical Sciences Vol. 86, No. 7, July 1997

1. RheothRx is a trademark of CytRx Corporation, Norcross, GA. 2. May, L. E. J. Am. Geriatrics Soc. 1958, 6, 814-817. 3. Rodeheaver, G. T.; Kurtz, L.; Kircher, B. J.; Edlich, R. F. Ann. Emerg. Med. 1980, 9, 572-576. 4. Waddell, W. R.; Geyer, R. P.; Olsen, F. R.; Stare, F. J. Metab. Clin. Exp. 1957, 6, 815-821. 5. Miyauchi, Y.; Inoue, T.; Paton, B. C. Circulation 1966, 33/34 (Suppl.), I71-I77. 6. Glaxo Wellcome Inc., data on file. 7. MacLeod, C. M.; McKenna, R.; Emanuele, R. M. Clin. Pharmacol. Ther. 1993, 53, 211. 8. Foss, R. G.; Hubbell, J. P., unpublished results. 9. Watari, N.; Benet, L. Z. J. Pharmacokinet. Biopharm. 1989, 17, 593-599. 10. Metzler, C. M.; Elfring, G. L.; McEwen, A. J. Biometrics 1974, 30, 562-563. 11. Akaike, H. Ann. Inst. Stat. Math. 1969, 21, 243-247. 12. SAS System for Windows, Version 6.08 [computer program], SAS Institute, Cary, NC, 1993. 13. Chang, R. L. S.; Ueki, I. F.; Troy, J. L.; Deen, W. M.; Robertson, C. R.; Brenner, B. M. Biophys. J. 1975, 15, 887-906. 14. Chang, R. L. S.; Deen, W. M.; Robertson, C. R.; Brenner, B. M. Kidney Int. 1975, 8, 212-218. 15. Cockroft, D. W.; Gault, M. H. Nephron 1976, 16, 31-41.

Acknowledgments The authors acknowledge R. Foss, V. Otto, T. Allsup, and J. Hubbell for their performance of the sample analyses for this study and Y. Yin for her statistical advice. This work was presented in part at the Ninth Annual Meeting of the American Association of Pharmaceutical Scientists.

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