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Zhejiang Kanglaite Pharmaceutical Co., Ltd. Pharmacokinetic Report for Protocol KN-001-01 CONFIDENTIAL

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Pharmacokinetic Report (DRAFT)

Phase I Study of KLT in Patients with Solid Tumors Refractory to Standard

Therapy

PROTOCOL NUMBER: KN-001-01 Name of Drug: Kanglaite Injection (KLT) (Semen Coicis Oil) Study Design: Open-label, sequential cohort, dose-escalation

study Sponsor: Zhejiang Kanglaite

Pharmaceutical Company, Ltd. Sponsor Contact: Hong Farling, Ph.D. Kanglaite-USA, Inc. 50 West Broadway, 300 South Suite 1125 Salt Lake City, Utah, 84101 Drug Development Phase: Phase I Dosing Dates: Sample Analysis Dates: 17 October 2001 to 12 December 2002 Clinical Study Site: Huntsman Cancer Institute 2000 Circle of Hope Salt Lake City, UT 84112 Analytical Study Site: PPD Development Analytical Laboratory 2244 Dabney Rd. Richmond, Virginia 23230 Principal Investigator: Richard Wheeler, MD Report Date: 19 March 2003



TABLE OF CONTENTS 1. BACKGROUND................................................................................................................ 5

2. PHARMACOKINETIC OBJECTIVES ............................................................................... 5

3. DRUG TREATMENTS ...................................................................................................... 5

4. PHARMACOKINETIC ANALYSIS .................................................................................... 5

5. RESULTS......................................................................................................................... 8

6. DATA DISPLAYS ........................................................................................................... 12

7. CONCLUSIONS ............................................................................................................. 12

LIST OF TABLES Table 1: Patient Randomization Providing KLT Doses ............................................................................... 13 Table 2 : Draw Times (hours) for Individual Doses..................................................................................... 14 Table 3: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Palmitic Acid

(Noncompartmental analysis) .............................................................................................................. 15 Table 4: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Monoalkylene Stearic Acid

(Noncompartmental analysis) .............................................................................................................. 16 Table 5: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Dialkylene Stearic Acid

(Noncompartmental analysis) .............................................................................................................. 17 Table 6 : Modeling Diagnostics for One compartmental Analysis of Palmitic Acid ..................................... 18 Table 7 : Modeling Diagnostics for Two compartmental Analysis of Palmitic Acid ..................................... 19 Table 8: Modeling Diagnostics for One Compartmental Analysis of Monoalkylene Stearic Acid................ 20 Table 9: Modeling Diagnostics for Two-compartmental Analysis of Monoalkylene Stearic Acid ................ 21 Table 10 : Modeling Diagnostics for One compartmental Analysis of Dialkylene Stearic Acid ................... 22 Table 11 : Modeling Diagnostics for Two compartmental Analysis of Dialkylene Stearic Acid ................... 23 Table 12: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Palmitic Acid (Compartmental

analysis) ............................................................................................................................................... 24 Table 13: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Monoalkylene Stearic Acid

(Compartmental analysis) .................................................................................................................... 25 Table 14: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Dialkylene Stearic Acid

(Compartmental analysis) .................................................................................................................... 26 Table 15: Comparison of Pharmacokinetic Parameters – Compartmental versus

Noncompartmental............................................................................................................................... 27



LIST OF FIGURES Figure 1: Baseline Corrected Palmitic Acid Mean Plasma Concentration Profiles ..................................... 28 Figure 2: Baseline Corrected Palmitic Acid Mean Plasma Concentration Profiles (Semi-log).................... 29 Figure 3: Baseline Corrected Monoalkylene Stearic Acid Mean Plasma Concentration Profiles................ 30 Figure 4: Baseline Corrected Monoalkylene Stearic Acid Mean Plasma Concentration Profiles

(Semi-log) ............................................................................................................................................ 31 Figure 5: Baseline Corrected Dialkylene Stearic Acid Mean Plasma Concentration Profiles ..................... 32 Figure 6: Baseline Corrected Dialkylene Stearic Acid Mean Plasma Concentration Profiles (Semi-

log) ....................................................................................................................................................... 33 Figure 7: Baseline Corrected Cmax versus Dose ......................................................................................... 34 Figure 8: Baseline Corrected AUC(0-t) versus Dose .................................................................................. 35



LIST OF ABBREVIATIONS AND TERMS AC Akaike criteria AUC Area under the plasma concentration time curve AUC (0-inf) or AUC(0-�)

Area under the concentration versus time curve from 0 to infinity

AUC (0-t) Area under the concentration versus time curve from 0 to t hours where t is the last measured concentration

AUMC (0-t) Area under the moment curve from 0-t AUMC (0-inf) or AUMC (0-�)

Area under the moment curve from 0 to infinity

CL or CL/F Plasma clearance Cmax Maximum plasma concentration observed Ct Concentration at LQCT Kel or �z Elimination rate constant LQCT Last quantifiable concentration time MRT Mean Residence time, the average time that each drug molecule remains

in the body PD Pharmacodynamic R2 Correlation coefficient SC Schwartz criteria SSR Sum of square residuals T½ Half-life Tmax Sampling time at which Cmax occurred Vc Volume of the central compartment Vdss or Vss Volume of distribution at steady state Vd Volume of distribution WSSR Weighted sum of square residuals



1. BACKGROUND

KLT is a botanical product developed in China for the treatment of cancer. The active ingredient in KLT is a neutral oil extracted and isolated from coix seed (a member of the grass family known as Coicis Semen Yokuinin), a traditional Chinese medicine. The extraction process yields a neutral oil, which is combined with a natural emulsifier and an iso-osmotic agent to produce the microgranular oil/water emulsion, KLT. The drug is administered by intravenous (IV) or intra-arterial (ia) infusion.

2. PHARMACOKINETIC OBJECTIVES To determine the pharmacokinetics of KLT in patients with refractory solid tumors. The pharmacokinetic parameters of palmitic acid, dialkylene stearic acid, and monoalkylene stearic acid were computed.

3. DRUG TREATMENTS

Cohorts of three patients were treated at each dose level. The initial dose of 10,000 mg Semen Coicis oil (100 mL) was administered as a daily intravenous infusion for 21 consecutive days followed by a seven-day rest period. This treatment cycle was repeated until disease progression or until unacceptable toxicity occurred. Once three patients have completed at least two weeks of treatment at each dose level, the next dose level was administered to the next cohort of patients. Doses were escalated to 20,000 mg (200 mL), 30,000 mg (300 mL), 40,000 mg (400 ml), and 50,000 mg (500 mL). All doses were administered at the following rate: 60 mL/hr during the initial 10 minutes and 100 mL/hr thereafter. In this open-label, sequential cohort, dose-escalation study, all patients received KLT. One cycle of treatment consisted of an IV infusion given daily for 21 consecutive days, followed by a seven-day rest period. The KLT doses administered to the 16 patients are shown in Table 1.

4. PHARMACOKINETIC ANALYSIS

During the first treatment cycle, blood was drawn for pharmacokinetic analysis of plasma KLT levels. On Day 1, between 12-14 blood draws occurred depending on the dose administered. On Day 2, blood was obtained immediately before infusion, and then at 8 and 16 hours after the start of the infusion. On Days 3, 4, and 21 blood was obtained immediately before the infusion. On Days 22, 23, and 24,



blood was obtained at time points that were 24 hours, 48 hours, and 72 hours after the start of the Day 21 infusion, respectively. The Days 22, 23, and 24 blood draws were repeated at the same time points in Cycles 2, 4, and 6. The individual draw times are given in Table 2. Noncompartmental Analysis Pharmacokinetic parameters for palmitic acid, dialkylene stearic acid, and monoalkylene stearic acid in plasma after the first dose of Cycle 1 were calculated using non-compartmental analysis. Non-compartmental pharmacokinetic parameters were determined for the plasma concentration-time data from 0-24 hours for Cycle 1 only, using SAS (version 8.02, SAS Institute, Cary, North Carolina).

The following non-compartmental pharmacokinetic parameters were estimated from the baseline corrected plasma concentrations of each patient for all three analytes.

Cmax Maximum plasma concentration over the entire

sampling phase, directly obtained from the experimental plasma concentration time data, without interpolation.

Tmax Sampling time at which Cmax occurred, directly

obtained from the experimental plasma concentration time data, without interpolation.

�z The terminal elimination rate constant obtained from

the terminal phase of the log concentration versus time plot.

T1/2 The half-life was only calculated when a meaningful

estimate of elimination rate (�z) could be calculated for a given set of data.

AUC(0-t) Area under the concentration versus time curve

calculated using the linear trapezoidal rule from time 0 to last quantifiable concentration time (LQCT).

AUC(0-�) Area from the time of the dose to infinity is the sum of

AUC(0-t) and the residual area calculated as Ct /�z where Ct is the observed concentration at LQCT. This parameter was only calculated when estimate of

z(2) logT e

1/2�

�



elimination rate could be calculated for given set of data.

AUMC(0-�) Area under the moment curve from zero to infinity.

Where AUMC(0-t) was the area under the moment curve from zero to last quantifiable concentration time. CL Plasma clearance was dose divided by AUC(0-�).

Vd Terminal exponential volume of distribution for IV

dose administration based on the terminal phase, calculated as

Vss Volume of distribution at steady state for IV dose

administration, calculated as the product of clearance (CL) and MRT:

Vss = CL x MRT

Where MRT was the mean residence time calculated as ratio:

Compartmental Analysis The purpose of compartmental modeling was to determine the volume of distribution of the central compartment (Vc), Volume of distribution at steady state (Vss) and clearance (CL). For a one compartmental model the volume of the central compartment and the volume of distribution at steady state are identical.

zCt t)-AUC(0 )-AUC(0�

��

)0( ��AUCdose

)-AUC(0 *z

DoseVd�

�

�

2)-AUC(0)-AUMC(0MRT meInfusionti�

�

�

�

2zCt*t t)-AUMC(0 )-AUMC(0

zCt��

��



Plasma concentration profiles for Cycle 1 (0-24 hours) were examined to determine the appropriate models. WinNonlin Professional Version 3.2 (Pharsight Inc.,Cary, NC) was used for compartmental modeling. Both 1- and 2-compartment models were investigated. WinNonlin default models “2” and “9” were modified to model the baseline along with other pharmacokinetic parameters. In comparing 1- and 2- compartment models, the following criteria were used:

a. correlation coefficients b. observed versus predicted plots c. sum of square residuals (SSR) or weighted sum of square

residuals (WSSR) (for weight = 1; SSR = WSSR) d. Akaike criteria (AC) e. Schwartz criteria (SC)

A larger correlation coefficient is indicative of better fit. A smaller Akaike criteria and Schwartz criteria are also indicative of better fits. The sum of square residuals or weighted sum of square residuals is a measure of how much of the data is not explained by the model. Lower SSR and WSSR values are indicative of better fits. The better model from the two was then modeled using three different weighting schemes (uniform, 1/concentration and 1/concentration2 ). Each weighting scheme was evaluated based on the following criteria:

a. correlation coefficients b. observed versus predicted plots c. weighted sum of square residuals

5. RESULTS The plasma data from the 16 patients dosed with the 5 different doses of KLT was analyzed by compartmental and noncompartmental methods. The mean content of palmitic acid, monoalkylene stearic acid, and dialkylene stearic acid in the semen coicis oil was 12.48%, 45.9%, and 38.5%, respectively. These percentages were used to calculate the dose of each component and were used to compute the pharmacokinetic parameters. Noncompartmental Analysis Patients with missing/ insufficient data: For many patients, concentrations fluctuated around the baseline. Elimination rate constants could not be calculated for some of these



patients. Consequently, parameters that depend on the elimination constant (terminal half-life, clearance, volume of distribution and mean residence time) could not be calculated for these patients. These patients were: �� For palmitic acid: patients 1, 2, 3 (Dose = 10,000 mg), 4 (Dose =

20,000 mg). �� For monoalkylene stearic acid: patient 13 (Dose = 50,000 mg). Patient 14 (Dose 50,000 mg) had palmitic acid concentrations from 2.5 to 13 hours missing. The infusion for this patient goes up to 5.12 hours. These missing samples would cause AUC to be underestimated, thus yielding incorrect pharmacokinetic parameters. Hence for this patient, no pharmacokinetic analysis was done and only the available concentration data have been displayed (Attachment 1, Section 1.2). Pharmacokinetic profiles: The mean baseline corrected concentration time profiles up to 24 hours are shown in Figures 1 - 6. For days 22 to 24 ( 24 to 72 hours after last dose), the uncorrected concentration values across cycles were compared (Attachments 8 and 9). The 24, 48 and 72 hour concentrations did not show a clear trend across cycles. The values fluctuate. The mean plots indicate that the standard deviation associated with the mean concentration values were large and overlapping. There is no clear trend to suggest that these values are different across the cycles 1, 2, 4 and 6. These results suggest that there is no accumulation from Cycle 1 to Cycle 6. Pharmacokinetic parameters Mean pharmacokinetic parameters for the three analytes are displayed in Tables 3 to 5. The median Tmax for all the three analytes were at the end of infusion as expected. The content of monoalkylene stearic acid in KLT used was the highest at 45.9%, followed by dialkylene stearic acid (38.5%) and palmitic acid (12.48%). Accordingly, the mean Cmax was highest for monoalkylene stearic acid followed by dialkylene stearic acid and palmitic acid. For monoalkylene stearic acid, patient number 9 had an extrapolated area between AUC(0-t) and AUC(0-inf) greater than 20%. For dialkylene stearic acid, in addition to patient number 9, patients 5 and 24 also have the extrapolated area between AUC(0-t) and AUC(0-inf) greater than 20%. The AUC(0-inf) values should therefore be interpreted with caution.



Dose proportionality assessments were done by plotting mean Cmax vs. dose and mean AUC(0-t) vs. dose (Figures 7 and 8). AUC(0-t) was used for comparison instead of AUC(0-inf) as the number of patients for which AUC(0-inf) could be computed were lower that that for AUC(0-t). The plots indicate that while Cmax appears to increase proportionately with dose (for mono and dialkylene stearic acids), AUC appears to increase disproportionately with dose. For palmitic acid, both Cmax and AUC appear to level off as dose increases. These results should be interpreted with caution since the number of number of patients used to develop this relationship is very small (n = 1 to 4). The mean half-life for palmitic acid ranged from 1.5 to 7.5 hours. For monoalkylene stearic acid and dialkylene stearic acid the mean half-lives were from 1 to 4.7 hours and 2.3 to 9.6 hours, respectively. Mean clearance values were from 0.6 to 2.8 L/hr for the 3 analytes across all the five doses. The variability in half-lives and clearances are reflective of the variability seen in the terminal elimination constant.

Compartmental Analysis

The modeling diagnostics for the three analytes are shown in tables 6 through 11. The volume of distribution and clearance values for the final model are displayed in tables 12 to 14.

One Compartment versus Two Compartment

The data were modeled using 1-compartment and 2-compartment models. Observed vs. predicted plots for non-weighted 1-compartment and 2-compartment models are displayed in Appendix 1. The model diagnostics are provided in Tables 6 - 11. The observed vs. predicted fits indicate that the data fits both the one and the two compartment models adequately. The correlation coefficients and the weighted sum of square residuals are also comparable between the two models. The model diagnostics vs. the Akaike and Schwartz criteria indicate that for all 3 analytes, the one compartmental model is better (lower Akaike and Schwartz criteria) for most patients. For palmitic acid and monoalkylene stearic acid, 15 out of 16 patients have a lower Akaike and Schwartz value for the one compartment fit. For dialkylene stearic acid, 11 out of 16 patients have a smaller Akaike and Schwartz value for the 1- compartment model as compared to the 2 compartmental model. The other 5 patients showed only a marginal improvement in Akaike and Schwartz. The estimation errors (%CV) for the parameters of the two compartment model are extremely high, indicating that the data does not support a second compartment (see the WinNonlin text output in



Appendix 1). Hence, a 1-compartment model was the appropriate model for all the three analytes.

Weighting

Weighting schemes of concentration–1 (Y-1) and concentration–2 (Y-2) were used to determine the model that best fit the individual profiles.

For palmitic acid, the uniform weight (or no weight) model showed comparable correlation coefficients and weighted sum of squares residuals as compared to a weighting factor of Y-1. Weighting factor of Y-2

was hence not attempted for this analyte. A one compartment model with uniform weighting was hence chosen as the final model for palmitic acid.

For the dialkylene and monoalkylene stearic acids, weighting factor of Y-1

gave lower weighted sum of squares residuals as compared to the uniform weighting fits. Hence, for these analytes, a Y-2 weighting was also attempted. The weighted sum of squares residuals was lower for the weighting factor, Y-2, as compared to uniform and Y-1 weighting. This was seen with 13 patients for monoalkylene stearic acid and 11 out of 16 patients for dialkylene stearic acid. The correlation coefficients were comparable for all the three weighting schemes. The observed versus predicted plots were also comparable and showed good fits. However, based on the lower weighted sum of squares residuals seen with the Y-2 weighting scheme, a one compartmental model with a weight of Y-2 was chosen as the final model.

Comparison of Volume of Distribution and Clearance: Compartmental Versus Noncompartmental Table 15 displays the mean and %CV for compartmental and noncompartmental parameters. For a one compartmental model, volume of the central compartment and volume at steady state are identical. For all three analytes, most of the doses show that the mean Vd from the non-compartmental analysis is greater than the mean Vc from the compartmental analysis. Conversely, the mean clearance values are generally lower for the noncompartmental analysis as compared to the compartmental analysis. Though the difference in volume of distribution cannot be explained, the difference in clearance can be attributed to the lower AUC observed for the compartment model as compared to the noncompartmental model. The difference is greatest with dialkylene stearic acid and lowest with palmitic acid. However, in all cases, the sample size is small and %CV is high, indicating that these results must be interpreted with caution.



6. DATA DISPLAYS

All graphs and statistical listings are provided in Attachments 1 through 9 of Appendix 1 of this report. The noncompartmental analyses for palmitic acid, monoalkylene stearic acid and dialkylene stearic acid are presented in Attachment 1, 2 and 3 respectively. Attachments 4 through 6 display the compartmental analyses for palmitic acid, monoalkylene stearic acid and dialkylene stearic acid. The uncorrected concentration data for all the three analytes are given in attachment 7. Attachment 8 gives the individual plots and attachment 9 gives the mean plots comparing day 22-24 concentrations for cycles 1 through 6. Sampling deviations are provided in Attachment 10 of Appendix 1.

7. CONCLUSIONS

�� Intravenous Administration of KLT results in highest levels for monoalkylene stearic acid, followed by dialkylene stearic acid and palmitic acid.

�� The pharmacokinetic parameters, AUC(0-t), AUC(0-inf) and Cmax of palmitic acid, monoalkylene stearic acid and dialkylene stearic acid do not show dose proportionality in the dose range studied. The small sample size (n=1-4) and high variability however, suggest that this result should be interpreted with caution.

�� A one-compartment model with uniform weighting appears to be the optimal pharmacokinetic model for palmitic acid.

�� A one-compartment model with weight of concentration-2 appears to be the optimal pharmacokinetic model for monoalkylene stearic acid and dialkylene stearic acid.

�� Noncompartment analysis gives higher volumes and lower clearances as compared to compartment analysis. The sample size for this comparison is however small (n=1-4).



Table 1: Patient Randomization Providing KLT Doses

Equivalent to:

Patient Numbers

Dose (mg)

Infusion Rate (all doses)

Total Infusion Time

(minutes) Dose (mL)

Approximate Dose in an Average 70 kg

Adult (mg/kg) 1, 2, 3 10,000 1st 10 minutes: 64 100 143

4, 5, 6 20,000 60 mL/hr 124 200 286

7, 8, 9, 24 30,000 184 300 429

10, 11, 12 40,000 After the 1st 10 minutes: 244 400 572

13, 14, 15 50,000 100 mL/hr 304 500 714



Table 2 : Draw Times (hours) for Individual Doses

Dose Cycle Day 10,000

(mg) 20,000 (mg)

30,000 (mg)

40,000 (mg)

50,000 (mg)

1 1 0.00 0.00 0.00 0.00 0.00 1 1 0.17 0.17 0.17 0.17 0.17 1 1 0.67 0.75 1.00 1.00 1.00 1 1 1.07* 1.50 2.00 2.00 2.50 1 1 1.25 2.07* 3.07* 3.00 4.00 1 1 1.50 2.25 3.25 4.07* 5.07* 1 1 2.00 2.50 3.50 4.25 5.25 1 1 3.00 3.00 4.00 4.50 5.50 1 1 4.00 4.00 5.00 5.00 6.00 1 1 8.00 6.00 7.00 6.00 7.00 1 1 12.00 10.00 11.00 8.00 9.00 1 1 16.00 14.00 15.00 12.00 13.00 1 1 NA** 18.00 19.00 16.00 17.00 1 1 NA** NA** NA** 20.00 21.00 1 2 24.00 24.00 24.00 24.00 24.00 1 2 32.00 32.00 32.00 32.00 32.00 1 2 40.00 40.00 40.00 40.00 40.00 1 3 48.00 48.00 48.00 48.00 48.00 1 4 72.00 72.00 72.00 72.00 72.00 1 21 480.00 480.00 480.00 480.00 480.00

1, 2, 4, 6 22 504.00 504.00 504.00 504.00 504.00 1, 2, 4, 6 23 528.00 528.00 528.00 528.00 528.00 1, 2, 4, 6 24 552.00 552.00 552.00 552.00 552.00

* samples drawn immediately upon termination of infusion. ** NA Not applicable



Table 3: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Palmitic Acid (Noncompartmental analysis)

10,000 mg Dose* 20,000 mg Dose* 30,000 mg Dose* 40,000 mg Dose* 50,000 mg Dose* Pharmacokinetic Parameters N Mean %CV N Mean %CV N Mean %CV N Mean %CV N Mean %CV

AUC(0-inf) (mg.hr/mL) 0 . . 2 1.95 35 4 3.97 37 3 6.90 56 2 5.98 74

AUC(0-t) (mg.hr/mL) 3 0.94 64 3 1.40 48 4 3.86 38 3 6.50 51 2 5.91 75

AUMC 0 . . 2 20.99 44 4 24.38 16 3 50.34 91 2 32.79 69

CL (L/hr) 0 . . 2 1.36 35 4 1.06 44 3 0.97 70 2 1.44 74

Cmax (mg/mL) 3 0.222 37 3 0.400 26 4 0.844 34 3 1.163 25 2 1.124 56

T1/2 (hr) 0 . . 2 7.50 108 4 2.39 115 3 2.99 93 2 1.49 77

Kel (1/hr) 0 . . 2 0.2212 108 4 0.7074 89 3 0.37 61 2 0.6640 77

MRT (hr) 0 . . 2 9.53 11 4 5.23 48 3 4.29 67 2 3.08 12

Tmax ** (hr) 3 1.25 1.07-

2.02 3 2.07 1.50-2.07 4 3.07 2.90-

3.25 3 4.07 4.05-4.14 2 5.16 5.07-

5.25 Vss (L) 0 . . 2 12.73 24 4 6.40 93 3 3.16 27 2 4.63 82

Vd (L) 0 . . 2 11.96 90 4 2.71 85 3 3.00 47 2 2.20 4

* Dose is for KLT; Palmitic Acid was 12.48% of the Semen Coicis Oil dose. ** Median and range are reported for Tmax



Table 4: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Monoalkylene Stearic Acid (Noncompartmental analysis)


AUC(0-inf) (mg.hr/mL) 3 3.26 84 3 4.64 77 4 10.74 42 3 18.22 32 2 44.46 58

AUC(0-t) (mg.hr/mL) 3 3.15 88 3 4.01 66 4 9.28 31 3 17.99 32 3 32.13 86

AUMC 3 30.25 96 3 47.69 133 4 58.23 50 3 98.46 38 2 325.15 80

CL (L/hr) 3 2.65 96 3 2.82 60 4 1.51 50 3 1.10 38 2 0.62 58

Cmax (mg/mL) 3 0.864 56 3 1.397 33 4 2.550 36 3 3.546 21 3 4.265 61

T1/2 (hr) 3 0.99 84 3 4.67 137 4 1.49 93 3 2.01 37 2 2.49 7

Kel (1/hr) 3 1.0495 61 3 0.5412 91 4 0.7710 67 3 0.3741 32 2 0.279 7

MRT (hr) 3 6.81 76 3 6.29 92 4 4.17 49 3 3.28 11 2 4.20 45

Tmax ** (hr) 3 1.07 1.07-

1.15 3 2.07 2.05-2.07 4 3.06 2.90-

3.07 3 4.07 4.05-4.14 3 5.07 5.07-

7.00 Vss (L) 3 9.85 70 3 11.33 28 4 7.08 97 3 3.50 27 2 2.27 15

Vd (L) 3 3.32 75 3 9.39 82 4 2.45 52 3 2.95 19 2 2.19 53

* Dose is for KLT; Monoalkylene Stearic Acid was 45.9% of the Semen Coicis Oil dose. ** Median and range are reported for Tmax



Table 5: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Dialkylene Stearic Acid (Noncompartmental analysis)


AUC(0-inf) (mg.hr/mL) 3 3.53 102 3 6.88 40 4 12.11 12 3 17.63 33 3 30.97 78

AUC(0-t) (mg.hr/mL) 3 2.96 98 3 5.61 33 4 9.62 26 3 17.36 33 3 29.56 76

AUMC 3 41.76 142 3 91.65 73 4 126.73 96 3 105.82 47 3 258.61 109

CL (L/hr) 3 1.94 65 3 1.30 51 4 0.96 11 3 0.94 34 3 1.00 81

Cmax (mg/mL) 3 0.870 46 3 1.348 23 4 2.301 34 3 3.256 19 3 3.680 47

T1/2 (hr) 3 4.43 102 3 9.57 57 4 6.46 123 3 2.87 56 3 2.25 75

Kel (1/hr) 3 0.3257 89 3 0.1002 76 4 0.2524 79 3 0.2868 44 3 0.4223 55

MRT (hr) 3 7.64 79 3 10.77 63 4 9.28 119 3 3.80 23 3 4.54 57

Tmax ** (hr) 3 1.07 1.07-

1.15 3 2.07 2.05-2.07 4 3.07 2.90-

3.25 3 4.07 4.05-4.14 3 5.13 5.07-

5.25 Vss (L) 3 10.17 75 3 11.33 41 4 9.25 125 3 3.45 24 3 3.59 58

Vd (L) 3 6.96 38 3 14.73 31 4 9.28 128 3 3.55 32 3 2.41 59

* Dose is for KLT; Dialkylene Stearic Acid was 38.5% of the Semen Coicis Dose. ** Median and range are reported for Tmax



Table 6 : Modeling Diagnostics for One compartmental Analysis of Palmitic Acid

No. of compartments = 1 No. of compartments = 1 Weight = 1 Weight =1/Y Patient

Number AC SC R2 WSSR AC SC R2 WSSR 1 -30.6 -28.9 0.63 0.06 -26.8 -24.0 0.64 0.059 2 -23.5 -21.8 0.80 0.103 -19.5 -16.7 0.80 0.103 3 -23.6 -21.9 0.74 0.103 -20.9 -18.0 0.77 0.093 4 -34.4 -32.5 0.86 0.056 -30.9 -27.7 0.87 0.054 5 -45.0 -43.1 0.95 0.026 -41.8 -38.6 0.95 0.025 6 -63.4 -61.4 0.99 0.007 -66.4 -63.2 1.00 0.004 7 -6.6 -4.7 0.93 0.407 -2.6 0.6 0.93 0.407 8 -26.1 -24.2 0.96 0.101 -22.9 -19.7 0.96 0.096 9 -15.0 -13.1 0.96 0.223 -11.0 -7.8 0.96 0.223 10 -10.9 -8.8 0.97 0.325 -6.9 -3.3 0.97 0.325 11 -31.3 -29.1 0.97 0.083 -27.3 -23.7 0.97 0.083 12 -30.1 -28.0 0.99 0.09 -26.5 -22.9 0.99 0.088 13 -22.9 -20.8 0.94 0.146 -19.0 -15.5 0.94 0.145 14 -4.1 -4.8 0.71 0.184 -0.1 -1.2 0.71 0.184 15 -31.4 -29.3 0.99 0.083 -27.4 -23.9 0.99 0.083 24 -32.9 -31.0 0.92 0.062 -32.2 -29.0 0.94 0.049

For weight = 1; SSR = WSSR



Table 7 : Modeling Diagnostics for Two compartmental Analysis of Palmitic Acid

No. of compartments = 2 Weight = 1

Patient Number AC SC R2 WSSR 1 -26.8 -24.0 0.64 0.059 2 -19.5 -16.7 0.80 0.103 3 -20.9 -18.0 0.77 0.093 4 -30.9 -27.7 0.87 0.054 5 -41.8 -38.6 0.95 0.025 6 -66.4 -63.2 1.00 0.004 7 -2.6 0.6 0.93 0.407 8 -22.9 -19.7 0.96 0.096 9 -11.0 -7.8 0.96 0.223 10 -6.9 -3.3 0.97 0.325 11 -27.3 -23.7 0.97 0.083 12 -26.5 -22.9 0.99 0.088 13 -19.0 -15.5 0.94 0.145 14 -0.1 -1.2 0.71 0.184 15 -27.4 -23.9 0.99 0.083 24 -32.2 -29.0 0.94 0.049



Table 8: Modeling Diagnostics for One Compartmental Analysis of Monoalkylene Stearic Acid

No. of compartments = 1 No. of compartments = 1 No. of compartments = 1 Weight = 1 Weight =1/Y Weight =1/Y^2

Patient Number AC SC R2 WSSR AC SC R2 WSSR AC SC R2 WSSR 1 -28.3 -26.6 0.95 0.071 -27.4 -25.7 0.95 0.076 -27.0 -25.3 0.95 0.079 2 -8.8 -7.1 0.86 0.321 -7.0 -5.3 0.86 0.367 -7.6 -5.9 0.86 0.352 3 4.5 6.2 0.89 0.889 2.2 3.9 0.89 0.744 -1.1 0.6 0.89 0.58 4 -23.1 -21.2 0.98 0.125 -22.1 -20.2 0.98 0.135 -21.1 -19.2 0.98 0.144 5 -25.2 -23.2 0.98 0.108 -25.2 -23.3 0.98 0.108 -25.3 -23.4 0.97 0.107 6 -18.8 -16.8 0.99 0.171 -19.9 -18.0 0.99 0.157 -21.6 -19.7 0.99 0.139 7 7.7 9.7 0.98 1.133 5.9 7.8 0.98 0.991 3.5 5.4 0.98 0.837 8 -5.8 -3.9 0.98 0.431 -12.5 -10.6 0.98 0.266 -20.4 -18.5 0.98 0.152 9 -3.4 -1.5 0.99 0.511 1.6 3.6 0.99 0.732 4.2 6.2 0.99 0.882 10 5.7 7.9 0.99 0.983 4.2 6.3 0.98 0.888 1.6 3.7 0.98 0.745 11 -15.8 -13.7 0.99 0.233 -17.4 -15.3 0.99 0.21 -18.0 -15.8 0.99 0.202 12 -7.0 -4.9 0.99 0.42 -13.3 -11.2 0.99 0.276 -21.7 -19.6 0.99 0.158 13 -13.7 -11.5 0.98 0.27 -12.8 -10.7 0.98 0.285 -11.9 -9.8 0.98 0.302 14 38.4 40.5 0.96 8.648 35.2 37.3 0.95 6.99 26.7 28.8 0.94 3.966 15 -12.6 -10.5 1.00 0.289 -14.7 -12.6 1.00 0.251 -19.6 -17.5 1.00 0.182 24 -15.5 -13.5 0.97 0.216 -16.5 -14.6 0.97 0.201 -18.7 -16.8 0.97 0.172



Table 9: Modeling Diagnostics for Two-compartmental Analysis of Monoalkylene Stearic Acid

No. of compartments = 2 Weight = 1

Patient Number AC SC R2 WSSR 1 -24.3 -21.50 0.95 0.071 2 -4.8 -1.95 0.86 0.321 3 6.9 9.73 0.90 0.788 4 -19.1 -15.90 0.98 0.125 5 -23.3 -20.15 0.98 0.092 6 -23.2 -19.98 0.99 0.094 7 11.8 14.95 0.98 1.133 8 -2.3 0.85 0.98 0.414 9 -2.5 0.66 0.99 0.408 10 9.7 13.28 0.99 0.983 11 -12.0 -8.47 0.99 0.230 12 -3.7 -0.21 0.99 0.400 13 -9.7 -6.11 0.98 0.270 14 42.4 45.90 0.96 8.648 15 -8.6 -5.10 1.00 0.289 24 -14.2 -11.02 0.97 0.177



Table 10 : Modeling Diagnostics for One compartmental Analysis of Dialkylene Stearic Acid

No. of compartments = 1 No. of compartments = 1 No. of compartments = 1 Weight = 1 Weight =1/Y Weight =1/Y2

Patient Number AC SC R2 WSSR AC SC R2 WSSR AC SC R2 WSSR

1 -24.9 -23.2 0.94 0.093 -23.2 -21.5 0.94 0.106 -21.9 -20.2 0.94 0.117 2 -26.1 -24.4 0.95 0.084 -24.8 -23.1 0.95 0.094 -23.8 -22.1 0.95 0.101 3 -8.5 -6.8 0.94 0.327 -8.2 -6.5 0.94 0.335 -8.5 -6.8 0.94 0.329 4 -22.1 -20.2 0.97 0.134 -21.0 -19.1 0.97 0.145 -20.1 -18.2 0.97 0.155 5 -22.3 -20.4 0.97 0.132 -23.3 -21.4 0.97 0.123 -24.7 -22.8 0.96 0.112 6 -21.8 -19.9 0.99 0.137 -21.9 -20.0 0.99 0.136 -22.5 -20.6 0.98 0.131 7 2.5 4.5 0.98 0.781 0.5 2.4 0.98 0.675 -1.7 0.2 0.98 0.577 8 -3.7 -1.7 0.97 0.502 -7.5 -5.6 0.97 0.381 -12.3 -10.3 0.97 0.271 9 -1.9 0.0 0.98 0.567 0.6 2.5 0.98 0.678 2.1 4.0 0.98 0.756 10 -4.1 -2.0 0.99 0.509 -8.9 -6.8 0.99 0.37 -13.9 -11.8 0.99 0.266 11 -11.6 -9.5 0.99 0.309 -17.1 -15.0 0.99 0.215 -22.1 -19.9 0.99 0.154 12 -5.4 -3.3 0.99 0.468 -10.8 -8.7 0.99 0.325 -17.8 -15.7 0.99 0.204 13 -26.5 -24.4 0.99 0.115 -26.4 -24.3 0.99 0.115 -26.4 -24.2 0.99 0.116 14 26.8 28.9 0.97 3.989 23.4 25.5 0.96 3.195 16.1 18.2 0.96 1.962 15 -8.2 -6.0 1.00 0.389 -8.9 -6.8 1.00 0.37 -11.8 -9.7 1.00 0.304 24 -20.4 -18.4 0.97 0.152 -21.5 -19.6 0.97 0.141 -22.6 -20.7 0.97 0.129



Table 11 : Modeling Diagnostics for Two compartmental Analysis of Dialkylene Stearic Acid

No. of compartments = 2 Weight = 1 Patient

Number AC SC R2 WSSR 1 -20.9 -18.1 0.94 0.093 2 -22.1 -19.3 0.95 0.084 3 -9.9 -7.1 0.96 0.216 4 -24.5 -21.3 0.98 0.085 5 -24.4 -21.2 0.98 0.086 6 -29.8 -26.6 0.99 0.058 7 6.5 9.7 0.98 0.781 8 -1.7 1.5 0.97 0.433 9 2.1 5.3 0.98 0.567 10 -0.1 3.4 0.99 0.509 11 -8.7 -5.1 0.99 0.288 12 -3.0 0.5 0.99 0.42 13 -22.6 -19.1 0.99 0.114 14 30.8 34.3 0.97 3.989 15 -4.2 -0.6 1.00 0.389 24 -24.8 -21.6 0.98 0.083



Table 12: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Palmitic Acid (Compartmental analysis)

Vd CL Patient Dose of KLT (L) %CV* (L/hr) %CV*

1 10000 5.23 57 4.77 67 2 10000 3.22 29 1.38 55 3 10000 2.27 53 3.30 40

Mean 3.57 3.15 %CV 42 54

4 20000 4.15 32 3.49 24 5 20000 3.43 19 2.99 14 6 20000 2.76 7 1.93 6

Mean 3.45 2.81 %CV 20 28

7 30000 1.94 16 0.66 21 8 30000 3.34 12 0.85 18 9 30000 2.41 12 0.61 20 24 30000 4.48 24 2.47 18

Mean 3.04 1.15 %CV 37 77

10 40000 2.02 11 0.55 14 11 40000 3.22 13 1.34 11 12 40000 2.69 5 0.46 10

Mean 2.64 0.78 %CV 23 62

13 50000 3.14 20 1.56 12 14 50000 0.44 221 2.59 63 15 50000 1.88 6 0.60 5

Mean 1.82 1.59 %CV 74 63

* estimation %CV For one compartment model Vd = Vss



Table 13: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Monoalkylene Stearic Acid (Compartmental analysis)


1 10000 3.53 25 5.44 18 2 10000 4.17 27 1.97 39 3 10000 1.55 34 2.39 24

Mean 3.08 3.27 %CV 44 58

4 20000 3.42 17 3.27 11 5 20000 3.83 19 3.91 11 6 20000 2.60 14 2.29 9

Mean 3.29 3.16 %CV 19 26

7 30000 1.99 14 0.91 13 8 30000 3.86 11 1.61 9 9 30000 2.52 20 0.98 17 24 30000 4.13 21 3.48 12

Mean 3.12 1.75 %CV 33 69

10 40000 2.27 15 0.97 11 11 40000 3.20 11 1.62 7 12 40000 2.93 5 0.77 5

Mean 2.80 1.12 %CV 17 40

13 50000 3.91 15 2.37 8 14 50000 2.17 13 0.41 17 15 50000 2.10 9 0.88 6

Mean 2.73 1.22 %CV 38 84




Table 14: Arithmetic Mean (%CV) Pharmacokinetic Parameters for Dialkylene Stearic Acid (Compartmental analysis)


1 10000 3.03 28 4.35 21 2 10000 4.57 16 1.89 26 3 10000 1.75 26 2.23 20

Mean 3.12 2.82 %CV 45 47

4 20000 4.08 16 2.60 13 5 20000 4.93 15 2.79 14 6 20000 2.86 13 1.94 10

Mean 3.96 2.45 %CV 26 18

7 30000 2.17 11 0.83 11 8 30000 4.07 11 1.11 13 9 30000 2.48 16 0.91 15 24 30000 4.81 18 3.10 11

Mean 3.38 1.49 %CV 37 73

10 40000 2.53 9 0.90 7 11 40000 3.69 8 1.33 7 12 40000 3.01 5 0.63 6

Mean 3.07 0.95 %CV 19 37

13 50000 4.54 8 1.76 5 14 50000 2.57 10 0.38 13 15 50000 2.20 8 0.73 6

Mean 3.10 0.96 %CV 41 75




Table 15: Comparison of Pharmacokinetic Parameters – Compartmental versus Noncompartmental Noncompartmental analysis Compartmental analysis CL (L/hr) Vd (L) CL (L/hr) Vd (L) N Mean %CV Mean %CV N Mean %CV Mean %CV Palmitic acid KLT Dose = 10000 mg 0 . . . . 3 3.15 54 3.57 42 KLT Dose = 20000 mg 2 1.36 35 11.96 90 3 2.81 28 3.45 20 KLT Dose = 30000 mg 4 1.06 44 2.71 85 4 1.15 77 3.04 37 KLT Dose = 40000 mg 3 0.97 70 3.00 47 3 0.78 62 2.64 23 KLT Dose = 50000 mg 2 1.44 74 2.20 4 3 1.59 63 1.82 74 Monoalkylene stearic acid KLT Dose = 10000 mg 3 2.65 96 3.32 75 3 3.27 58 3.08 44 KLT Dose = 20000 mg 3 2.82 60 9.39 82 3 3.16 26 3.29 19 KLT Dose = 30000 mg 4 1.51 50 2.45 52 4 1.75 69 3.12 33 KLT Dose = 40000 mg 3 1.1 38 2.95 19 3 1.12 40 2.80 17 KLT Dose = 50000 mg 2 0.62 58 2.19 53 3 1.22 84 2.73 38 Dialkylene stearic acid KLT Dose = 10000 mg 3 1.94 65 6.96 38 3 2.82 47 3.12 45 KLT Dose = 20000 mg 3 1.3 51 14.73 31 3 2.45 18 3.96 26 KLT Dose = 30000 mg 4 0.96 11 9.28 128 4 1.49 73 3.38 37 KLT Dose = 40000 mg 3 0.94 34 3.55 32 3 0.95 37 3.07 19 KLT Dose = 50000 mg 3 1.00 81 2.41 59 3 0.96 75 3.10 41



Figure 1: Baseline Corrected Palmitic Acid Mean Plasma Concentration Profiles



Figure 2: Baseline Corrected Palmitic Acid Mean Plasma Concentration Profiles (Semi-log)



Figure 3: Baseline Corrected Monoalkylene Stearic Acid Mean Plasma Concentration Profiles



Figure 4: Baseline Corrected Monoalkylene Stearic Acid Mean Plasma Concentration Profiles (Semi-log)



Figure 5: Baseline Corrected Dialkylene Stearic Acid Mean Plasma Concentration Profiles



Figure 6: Baseline Corrected Dialkylene Stearic Acid Mean Plasma Concentration Profiles (Semi-log)



Figure 7: Baseline Corrected Cmax versus Dose

Dose in mg

0 10000 20000 30000 40000 50000 60000

Cm

ax in

mg/

mL

0

1

2

3

4

5

Palmitic acid Monoalkylene stearic acid Dialkylene stearic acid



Figure 8: Baseline Corrected AUC(0-t) versus Dose

Dose in mg

0 10000 20000 30000 40000 50000 60000

AUC

(0-t)

in m

g*hr

/mL

0

5

10

15

20

25

30

35

Palmitic acid Monoalkylene stearic acid Dialkylene stearic acid

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Pharmacokinetic Report (DRAFT) Phase I Study of … Kanglaite Pharmaceutical Co., Ltd. Pharmacokinetic Report for Protocol KN-001-01 CONFIDENTIAL G:\Group\Pk\BIOSTAT\Kanglaite\KN00101\Report\PK