APPENDIX F

A. Drug Model Report

Drug Model Details

PK Model

    Absorption Compartment: Abs

        Receives Formulation PPG

        Absorption Flow [Ka] to Compartment Plasma

    Central Compartment: Plasma

        Flow [CL0] to Compartment Elim

    Elimination Compartment: Elim

Model Blocks

 1. Abs: Absorption Compartment

        Amount Variable: A1

        Initial Amount: 0

        Outputs:

            A1 {unit}

 

 2. CL0: Flow

        From: Central Cpt. Plasma

        To: Elimination Cpt. Elim

        Forward Rate CL0 = K10_variability   default(0)

        Inputs:

            F = 1

            CL0 = K10_variability  default(0) {1/h}

 

 3. Concentration: Response

        Adherence model: One-coin

        Inputs:

            i = C  default(0)

            Dt = 0 {h}

            P = 0

        Outputs:

            Concentration

 

 4. Elim: Elimination Compartment

        Amount Variable: A0

        Initial Amount: 0

        Outputs:

            A0 {unit}

 

 5. K10_variability: Continuous Distribution

        Units: {1/h}

        Type: Lognormal

        Level: Subject Parameter

        True Mean(x): 

        sd(x):

        Inputs:

            mean = 2.8516 {1/h}

            sd = 1.7321 {1/h}

            mult = 1

            lo = -2.34496 {1/h}

            hi = 8.04812 {1/h}

        Outputs:

            K10_variability {1/h}

        Comment:

            Low and High are plus or minus 3 SD

 

 6. Ka: Flow

        From: Absorption Cpt. Abs

        To: Central Cpt. Plasma

        Forward Rate Ka = Ka_variability   default(1)

        Inputs:

            F = 1

            Ka = Ka_variability  default(1) {1/h}

 

 7. Ka_variability: Continuous Distribution

        Units: {1/h}

        Type: Lognormal

        Level: Subject Parameter

        True Mean(x): 

        sd(x):

        Inputs:

            mean = 0.113197 {1/h}

            sd = 0.049678 {1/h}

            mult = 1

            lo = -0.0367128 {1/h}

            hi = 0.261356 {1/h}

        Outputs:

            Ka_variability {1/h}

        Comment:

            Low and High are plus or minus 3 SD

 

 8. Plasma: Central Compartment

        Concentration Variable: C

        Initial Concentration: 0

        Volume V = Vd_Kg   default(1000)

        Inputs:

            V = Vd_Kg  default(1000) {mL}

            PlasmaIRate = 0 {unit/h}

        Outputs:

            A {unit}

            C {unit/mL}

 

 9. population: Covariate Distribution Model

        Covariates:

            Weight: Units {kg}

        Sub-Population: Default1

            Distribution: Weight

                    Type: Normal

                    Mean(x):  100

                    cv(x)%: 5

                    Low: 96

                    High: 104

 

10. PPG: Formulation

        Dose into compartment: Abs

        Adherence model: One-coin

        Inputs:

            Dt = 0 {h}

            P = 0

        Outputs:

            PPG

 

11. Vd_Kg: Expression

         Vd_variability* Weight

        Outputs:

            Vd_Kg {mL}

 

12. Vd_variability: Continuous Distribution

        Units: {mL/kg}

        Type: Lognormal

        Level: Subject Parameter

        True Mean(x): 

        sd(x):

        Inputs:

            mean = 438.443 {mL/kg}

            sd = 186.483 {mL/kg}

            mult = 1

            lo = -121.006 {mL/kg}

            hi = 997.892 {mL/kg}

        Outputs:

            Vd_variability {mL/kg}

        Comment:

            Low and High are plus or minus 3 SD

Model Parameters

Parameter {Units}	Default Value
CL0_F	1
Concentration_Dt {h}	0
Concentration_P	0
K10_variability_hi {1/h}	8.04812
K10_variability_lo {1/h}	-2.34496
K10_variability_mean {1/h}	2.8516
K10_variability_mult	1
K10_variability_sd {1/h}	1.7321
Ka_F	1
Ka_variability_hi {1/h}	0.261356
Ka_variability_lo {1/h}	-0.0367128
Ka_variability_mean {1/h}	0.113197
Ka_variability_mult	1
Ka_variability_sd {1/h}	0.049678
PlasmaIRate {unit/h}	0
PPG_Dt {h}	0
PPG_P	0
Vd_variability_hi {mL/kg}	997.892
Vd_variability_lo {mL/kg}	-121.006
Vd_variability_mean {mL/kg}	438.443
Vd_variability_mult	1
Vd_variability_sd {mL/kg}	186.483

Model Equations

  1. if(iSubPop==0) then Weight = normal1(1,100,(100)*(5)/1d2,96,104){kg} endif

  2. Temp_00 = lgnMeanSD(1, Vd_variability_mean, Vd_variability_sd, Vd_variability_lo, Vd_variability_hi){mL/kg}

  3. Vd_variability = Vd_variability_mult*Temp_00

  4. Vd_Kg = Vd_variability*Weight

  5. Temp_01 = lgnMeanSD(1, Ka_variability_mean, Ka_variability_sd, Ka_variability_lo, Ka_variability_hi){1/h}

  6. Ka_variability = Ka_variability_mult*Temp_01

  7. Temp_02 = lgnMeanSD(1, K10_variability_mean, K10_variability_sd, K10_variability_lo, K10_variability_hi){1/h}

  8. K10_variability = K10_variability_mult*Temp_02

  9. V = Vd_Kg

 10. Ka = Ka_variability

 11. CL0 = K10_variability

 12. C = A/V

 13. A1' = -(A1*Ka)

 14. A0' = C*V*CL0

 15. Concentration_i = C

 16. A' = A1*Ka-C*V*CL0

B. Protocol Report

Study Objectives

Learn TS2 1-cmpt model

Investigation Plan

Study Population and Subject Selection

Total number of subjects: 1000

.Number of centers: 1.

Center sizes:

Center Number	Center Name	Center Size
1	Center 1	1000

 

Each center has same population: Default1.

Inclusion Criteria

None.

 

Exclusion Criteria

None.

Study Design

Lead-in Phase

No lead-in phase.

 

Study Type: Parallel.

Treatments:

·        Treatment Arm 1

Randomization Procedures

Block Randomized allocation.

Include	Treatment Arm	Allocation Ratio	Subject Count
Yes	Treatment Arm 1	1	1000
Block Size:		2
Total Subject Count:			1000

Treatments and Observations

Treatments used in the study:

Treatment Arm	Drug/Formulation	Dose	Schedule
Treatment Arm 1	PPG	15000 unit / kg	Dose(s) at 0, 12, 24, 36, 48, 60, 72 Hours

 

Observations in the study:

Response(s)	Measurement Schedule
Concentration	Every hr for 84 hours: Sample(s) at: 0Hr every 1 Hours for 85 Hours.

 

Follow-up Phase

No follow-up phase.

Active Phase Timeline

Table of Events

	Treatments / Observations				Treatment Arm 1	Observations
Time / Event	Week	Day	Hour	Minute	PPG 15000 unit / kg	Concentration
Dosing/ Sampling Times	1	1	0	0	X	X
	1	1	1	0		X
	1	1	2	0		X
	1	1	3	0		X
	1	1	4	0		X
	1	1	5	0		X
	1	1	6	0		X
	1	1	7	0		X
	1	1	8	0		X
	1	1	9	0		X
	1	1	10	0		X
	1	1	11	0		X
	1	1	12	0	X	X
	1	1	13	0		X
	1	1	14	0		X
	1	1	15	0		X
	1	1	16	0		X
	1	1	17	0		X
	1	1	18	0		X
	1	1	19	0		X
	1	1	20	0		X
	1	1	21	0		X
	1	1	22	0		X
	1	1	23	0		X
	1	2	0	0	X	X
	1	2	1	0		X
	1	2	2	0		X
	1	2	3	0		X
	1	2	4	0		X
	1	2	5	0		X
	1	2	6	0		X
	1	2	7	0		X
	1	2	8	0		X
	1	2	9	0		X
	1	2	10	0		X
	1	2	11	0		X
	1	2	12	0	X	X
	1	2	13	0		X
	1	2	14	0		X
	1	2	15	0		X
	1	2	16	0		X
	1	2	17	0		X
	1	2	18	0		X
	1	2	19	0		X
	1	2	20	0		X
	1	2	21	0		X
	1	2	22	0		X
	1	2	23	0		X
	1	3	0	0	X	X
	1	3	1	0		X
	1	3	2	0		X
	1	3	3	0		X
	1	3	4	0		X
	1	3	5	0		X
	1	3	6	0		X
	1	3	7	0		X
	1	3	8	0		X
	1	3	9	0		X
	1	3	10	0		X
	1	3	11	0		X
	1	3	12	0	X	X
	1	3	13	0		X
	1	3	14	0		X
	1	3	15	0		X
1	3	16	0		X
1	3	17	0		X
1	3	18	0		X
1	3	19	0		X
1	3	20	0		X
1	3	21	0		X
1	3	22	0		X
1	3	23	0		X
1	4	0	0	X	X
1	4	1	0		X
1	4	2	0		X
1	4	3	0		X
1	4	4	0		X
1	4	5	0		X
1	4	6	0		X
1	4	7	0		X
1	4	8	0		X
1	4	9	0		X
1	4	10	0		X
1	4	11	0		X
1	4	12	0		X

 

C. Mean time-concentration-SD profile for the simulation. 

 

 

D. Plot of mean time-concentration profile for the simulation