Electronic Supplementary Material I: Glossary10.1208/s12248... · Web viewTransfer from vascular to interstitial compartment via lymphatic flow 0.054 0.03 0.042 k VAS - EL Organ (hr-1)

Electronic Supplementary Material I: Glossary

Table 1. Rate constants for GIT and spleen

Rate constant(Unit)

Formula Process GIT Spleen Splanchnic

Vascular space

kVAS−circul .Organ (hr-1) QOrgan−LOrgan

V VASOrgan

Transfer from vascular compartment to plasma

538.9 299.4 419.2

(1−σVAS)∗k LY VAS− ISFOrgan

(hr-1)(1−σVAS)∗LOrgan

V VASOrgan

Transfer from vascular to interstitial compartment via lymphatic flow

0.054 0.03 0.042

kVAS−ELOrgan (hr-1) CLUptake

Organ

V VASOrgan

Elimination from vascular compartment

1.87E-05 5.43E-06 1.21E-05

kVAS−VASOrgan (hr-1) CLUptake

Organ

V ENDOrgan ∗k 1

Input from vascular compartment to itself. Reflect endosomal contribution to vascular compartment

1.73E-05 5.30E-06 1.13E-05

kVAS−ISFOrgan (hr-1) (1−FR)∗CLUptake

Organ

V ENDOrgan ∗k1

Transfer from vascular to interstitial compartment

4.92E-06 1.51E-06 3.22E-06

k ISF−VASOrgan (hr-1) FR∗CLUptake

Organ

V ENDOrgan ∗k2

Transfer from interstitial to vascular compartment

2.06E-06 1.89E-06 1.98E-06

Interstitial space(1−σVAS)∗k LY VAS− ISF

Organ (hr-1)

(1−σVAS)∗LOrgan

V VASOrgan

Transfer from vascular to interstitial compartment via lymphatic flow

0.054 0.03 0.042

(1−σ LY)∗kLY ISF−lnOrgan (hr-

1)(1−σ LY)∗LOrgan

V ISFOrgan

Transfer from interstitial compartment to lymph node via lymphatic flow

0.14 0.24 0.192

k ISF−ELOrgan (hr-1) CLUptake

Organ

V ISFOrgan

Elimination from interstitial compartment

3.1E-06 2.7E-06 2.91E-06


Organ

V ENDOrgan ∗k1

Transfer from vascular to interstitial compartment

4.92E-06 1.51E-06 3.22E-06

k ISF−ISFOrgan (hr-1) CLUptake

Organ

V ENDOrgan ∗k 2

Input from interstitial compartment to itself. Reflect endosomal contribution to interstitial compartment

2.88E-06 2.65E-06 2.76E-06


Organ

V ENDOrgan ∗k2

Transfer from interstitial to vascular compartment

2.06E-06 1.89E-06 1.98E-06

** The difference in rate constants governing transfer of species in GIT and spleen is less than 5 folds (Table 1). Transfer rates for the lumped compartment k XXX−XXX

Splanchnic are calculated as the average of those for GIT and spleen.

Table 2. Rate constants for heart, kidney, skin, and muscle

Rate constant(Unit)

Formula Heart Kidney skin Muscle Visceral

Vascular space


V VASOrgan

2395.2 1596.8 362.3 319.4 1168.4



V VASOrgan

0.24 0.16 0.036 0.032 0.12


Organ

V VASOrgan

1.03E-05 5.39E-06 7.98E-06 2.87E-05 1.31E-05


Organ

V ENDOrgan ∗k 1

1.01E-05 5.33E-06 7.88E-06 2.71E-05 1.26E-05


Organ

V ENDOrgan ∗k1

2.87E-06 1.52E-06 2.25E-06 7.71E-06 3.59E-06


Organ

V ENDOrgan ∗k2

2.66E-06 1.13E-06 1.13E-06 2.81E-06 1.93E-06


Organ (hr-1)


V VASOrgan

0.24 0.16 0.036 0.032 0.12



V ISFOrgan

1.41 0.76 0.12 0.074 0.59


Organ

V ISFOrgan

3.8E-06 1.6E-06 1.6E-06 4.17E-06 2.79E-06


Organ

V ENDOrgan ∗k1

2.87E-06 1.52E-06 2.25E-06 7.71E-06 3.59E-06


Organ

V ENDOrgan ∗k 2

3.71E-06 1.58E-06 1.58E-06 3.93E-06 2.70E-06


Organ

V ENDOrgan ∗k2

2.66E-06 1.13E-06 1.13E-06 2.81E-06 1.93E-06

** The difference in rate constants governing transfer of species in heart, kidney, skin, and muscle is less than 8 folds (Table 1). An exception is the transfer rate from the interstitial compartment to the LN which is 12 and 19 folds higher for heart than skin and muscle. For simplicity, these rates are considered close and rate for the lumped compartment k XXX−XXX

Visceral are calculated as the median of those for heart, kidney, skin, and muscle.

Table 3. Rate constants for splanchnic and visceral

Rate constant(Unit)

Formula Splanchnic Visceral Peripheral

Vascular space


V VASOrgan

419.2 1168.4 793.8



V VASOrgan

0.042 0.12 0.08


Organ

V VASOrgan

1.21E-05 1.31E-05 1.26E-05


Organ

V ENDOrgan ∗k 1

1.13E-05 1.26E-05 1.19E-05


Organ

V ENDOrgan ∗k1

3.22E-06 3.59E-06 3.40E-06


Organ

V ENDOrgan ∗k2

1.98E-06 1.93E-06 1.95E-06


Organ (hr-1)


V VASOrgan

0.042 0.12 0.08



V ISFOrgan

0.192 0.59 0.39


Organ

V ISFOrgan

2.91E-06 2.79E-06 2.85E-06


Organ

V ENDOrgan ∗k1

3.22E-06 3.59E-06 3.40E-06


Organ

V ENDOrgan ∗k 2

2.76E-06 2.70E-06 2.73E-06


Organ

V ENDOrgan ∗k2

1.98E-06 1.93E-06 1.95E-06

** The difference in rate constants governing transfer of species in splanchnic and visceral compartments is less than 3 folds (Table 1). Transfer rates are considered close and rate for the lumped compartment k XXX−XXX

Peripheral are calculated as the average of those for splanchnic and visceral compartments.

Table 4. Rate constants for central, peripheral and lymph node compartments

Rate constant(Unit)

Formula Process Value

Vascular space

k ELCentral (hr-1) k VAS−EL

Peripheral

(1+kVAS−circul .

Peripheral

QPeripheral

V Plasma

)

Elimination rate from the central compartment

6.1E-06

(1−σVAS)∗k LY−ISFCentral (hr-

1)(1−σVAS)∗kLY VAS− ISF

Perip h eral

(1+kVAS−circul .

Periph eral

QPeriph eral

V Plasma

)

Transfer rate from the central to interstitial (i.e. peripheral) compartment via lymphatic flow

0.018

kCentralCentral (hr-1) k VAS−VAS

Peripheral

(1+kVAS−circul .

Peripheral

QPeripheral

V Plasma

)

First order input from central compartment to itself which reflects the impact of recycled drug from endosomal compartment

5.8E-06

kCe ntral− ISFCentral (hr-1) kVAS− ISF

Peripheral

(1+kVAS−circul .

Perip h eral

QPeriph eral

V Plasma

)

First order input from central to interstitial (i.e. peripheral) compartment

1.6E-06

k ISF−CentralPeriph eral (hr-1) k ISF−VAS

Peripheral Transfer from interstitial (i.e. peripheral) to central compartments

1.95E-06

(1−σ LY)∗kLY ISF−lnPerip h eral

(hr-1)(1−σ LY)∗LPeripheral

V ISFPeripheral

Transfer from interstitial (i.e. peripheral) compartment to lymph node via lymphatic flow

0.39

k ISF−ISFPeriph eral (hr-1) CLUptake

Peripheral

V ENDPeripheral ∗k2

Input from Peripheral compartment to itself. Reflect endosomal contribution to interstitial compartment

2.73E-06

k ISF−CentralPeriph eral (hr-1) FR∗CLUptake

Perip heral

V ENDPeripheral ∗k2

Transfer from Peripheral to Central compartment

1.95E-06

1Tauln

(hr-1)Transfer from lymph node to Central compartment

0.11

Electronic Supplementary Material II: Supplementary Figures

Supplementary Figure 1. Impact of F1 and F2 reflecting the non-FcRn dependent tissue uptake on mAb plasma PK. The figure shows some deviations upon removing the 2 coefficients. These deviations may be explained by mAb-specific processes such as surface charge and target binding.

Supplementary Figure 2. Simulation using full model showing amounts of free and bound mAb in different endosomal subcompartments. Muscle is used as an example. Free mAb is 4 to 8 log-folds lower thanKDEND and thus are considered negligible compared toKDEND.

Supplementary Figure 3. Simulations from the full PBPK Model. A, amounts of mAb in plasma and lymph node. Lymph compartment shows high contribution to the mass of mAb in the body. Amounts in vascular and interstitial compartments of heart shown as an example of tissue PK. B, concentrations of mAb in plasma showing biexponential profile. Vascular compartment rapidly equilibrates with plasma.

Supplementary Figure 4. Simulations from the full PBPK Model showing amounts in endosomal compartments of representative organs.

Supplementary Figure 5. Simulations from the full PBPK Model showing steady-state concentrations (achieved by

continuous IV infusion)

Supplementary Figure 6. Diagnostic plots for assessment of models fit to the data: (a) observations vs. population prediction, (b) observations vs. individual prediction (c) conditional weighted residuals vs. predicted concentration, and (d) conditional weighted residuals vs. time

Supplementary Figure 7. Simulations from the simple physiological model, A, and the two compartmental model, B. Concentration in peripheral compartment in two compartment model is over predicted by assuming equilibrium with central compartment.

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Electronic Supplementary Material I: Glossary10.1208/s12248... · Web viewTransfer from vascular to interstitial compartment via lymphatic flow 0.054 0.03 0.042 k VAS - EL Organ (hr-1)