JWS Online

Model

Name

benson1

Notes

The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000512) Biomodels notes: Figure 5 of the reference publication has been reproduced here. The plots shows cannabinoid receptor (CB1) occupancy (in percentage) in the brain with the increasing dosage of drug (0.1 to 40mg). The model as such reproduces the plot corresponding to 10mg dose. Other plots were obtained by varying the value of the parameter "Dose". JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes. No additional changes were made.

Substance units

None

Time units

None

Volume units

None

Area units

None

Length units

None

Reaction extent units

None

Manuscript information

A systems pharmacology perspective on the clinical development of Fatty Acid amide hydrolase inhibitors for pain.

N Benson
E Metelkin
O Demin
GL Li
D Nichols
Piet H van der Graaf

CPT Pharmacometrics Syst Pharmacol 2014; 3 :

PubMed: 24429592
PubMed Central: PMC3910012
DOI: 10.1038/psp.2013.72
ISSN: 2163-8306
URL: https://ncbi.nlm.nih.gov/pubmed/24429592

Abstract

The level of the endocannabinoid anandamide is controlled by fatty acid amide hydrolase (FAAH). In 2011, PF-04457845, an irreversible inhibitor of FAAH, was progressed to phase II clinical trials for osteoarthritic pain. This article discusses a prospective, integrated systems pharmacology model evaluation of FAAH as a target for pain in humans, using physiologically based pharmacokinetic and systems biology approaches. The model integrated physiological compartments; endocannabinoid production, degradation, and disposition data; PF-04457845 pharmacokinetics and pharmacodynamics, and cannabinoid receptor CB1-binding kinetics. The modeling identified clear gaps in our understanding and highlighted key risks going forward, in particular relating to whether methods are in place to demonstrate target engagement and pharmacological effect. The value of this modeling exercise will be discussed in detail and in the context of the clinical phase II data, together with recommendations to enable optimal future evaluation of FAAH inhibitors.CPT: Pharmacometrics Systems Pharmacology (2014) 3, e91; doi:10.1038/psp.2013.72; published online 15 January 2014.

Simulations using this model 7

Simulation
benson2014_Fig5	SED-ML COMBINE Archive
benson2014_Fig5	SED-ML COMBINE Archive
benson2014_Fig5	SED-ML COMBINE Archive
benson2014_Fig5	SED-ML COMBINE Archive
benson2014_Fig5	SED-ML COMBINE Archive
benson2014_Fig5	SED-ML COMBINE Archive
benson2014_Fig5	SED-ML COMBINE Archive

Unit definitions 0

Unit definitions have no effect on the numerical analysis of the model. It remains the responsibility of the modeler to ensure the internal numerical consistency of the model. If units are provided, however, the consistency of the model units will be checked.

Name	Definition

Compartments 5

Id	Name	Spatial dimensions	Size
BRAIN	—	3.0	1.45000004768372
Default	—	3.0	1.0
MEC	—	3.0	0.0000149999996210681
PLASMA	—	3.0	2.6489999294281
ROB	—	3.0	65.3000030517578

Species 39

Id	Name	Initial quantity	Compartment	Fixed
A_b	A_b	0.7493309	BRAIN	✘
A_m	A_m	0.97761	MEC	✘
A_p	A_p	0.8740574	PLASMA	✘
A_r	A_r	0.5419204	ROB	✘
FAAH_b	FAAH_b	15.366	BRAIN	✘
FAAH_m	FAAH_m	10.686	MEC	✘
FAAH_r	FAAH_r	2.165868	ROB	✘
FAAHinh_b	FAAHinh_b	0.0	BRAIN	✘
FAAHinh_m	FAAHinh_m	0.0	MEC	✘
FAAHinh_r	FAAHinh_r	0.0	ROB	✘
L_b	L_b	2.319571	BRAIN	✘
L_m	L_m	0.0	MEC	✘
L_p	L_p	1.916254	PLASMA	✘
L_r	L_r	1.705466	ROB	✘
NAPE_b	NAPE_b	0.00003879041	BRAIN	✘
NAPE_r	NAPE_r	0.000004241633	ROB	✘
NLPE_b	NLPE_b	0.00007550331	BRAIN	✘
NLPE_r	NLPE_r	0.000008256095	ROB	✘
NOPE_b	NOPE_b	0.0008814287	BRAIN	✘
NOPE_r	NOPE_r	0.00009638198	ROB	✘
NPPE_b	NPPE_b	0.0001732296	BRAIN	✘
NPPE_r	NPPE_r	0.00001894222	ROB	✘
NSPE_b	NSPE_b	0.0001272629	BRAIN	✘
NSPE_r	NSPE_r	0.00001391587	ROB	✘
O_b	O_b	20.77858	BRAIN	✘
O_m	O_m	16.3219	MEC	✘
O_p	O_p	5.085073	PLASMA	✘
O_r	O_r	14.23822	ROB	✘
PFM_gut	PFM_gut	0.0	Default	✘
PFM_p	PFM_p	0.0	Default	✘
PFM_r	PFM_r	0.0	Default	✘
P_b	P_b	6.541209	BRAIN	✘
P_m	P_m	5.809415	MEC	✘
P_p	P_p	4.849307	PLASMA	✘
P_r	P_r	4.121915	ROB	✘
S_b	S_b	3.427807	BRAIN	✘
S_m	S_m	2.968774	MEC	✘
S_p	S_p	0.273772	PLASMA	✘
S_r	S_r	2.515968	ROB	✘

Initial assignments 0

Initial assignments are expressions that are evaluated at time=0. It is not recommended to create initial assignments for all model entities. Restrict the use of initial assignments to cases where a value is expressed in terms of values or sizes of other model entities. Note that it is not permitted to have both an initial assignment and an assignment rule for a single model entity.

Definition

Reactions 75

Id	Name	Reaction Equation and Kinetic Law
absorp	absorp	PFM_gut > PFM_p kabs_PFM * MD
dist	dist	PFM_p > PFM_r kout_PFM * PFM_p - kin_PFM * PFM_r
elim	elim	PFM_p > ∅ klinear_PFM * PFM_p + Vm_PFM * PFM_p / (Km_PFM + PFM_p / Vss_PFM) / Vss_PFM
vA_UE_b	vA_UE_b	A_b > ∅ BRAIN * b_FAAH_Brain * kcl_A * A_b
vA_UE_r	vA_UE_r	A_r > ∅ c_NAAA_ROB * kcl_A * A_r
vA_b_m	vA_b_m	A_b > A_m MEC * ktr_m_p_A * (A_b - A_m) / (A_m + A_b + Km_p_m_A)
vA_degr_b	vA_degr_b	A_b > ∅ BRAIN * FAAH_b * kcat_FAAH * a_FAAH_A * A_b / (Km_FAAH_A * FAAH_D_b)
vA_degr_m	vA_degr_m	A_m > ∅ MEC * FAAH_m * kcat_FAAH * a_FAAH_A * A_m / (Km_FAAH_A * FAAH_D_m)
vA_degr_r	vA_degr_r	A_r > ∅ ROB * FAAH_r * kcat_FAAH * a_FAAH_A * A_r / (Km_FAAH_A * FAAH_D_r)
vA_m_p	vA_m_p	A_m > A_p MEC * ktr_m_p_A * (A_m - A_p * Ktr_p_m_A) / (A_m + A_p + Km_p_m_A)
vA_r_p	vA_r_p	A_r > A_p PLASMA * ktr_r_p * (A_r - A_p * Ktr_p_r_A) / (A_r + A_p + Km_p_m_A)
vA_syn_b	vA_syn_b	NAPE_b > A_b BRAIN * PLD_b * k_NA_PE * NAPE_b / Km_NA_PE / den_b
vA_syn_r	vA_syn_r	NAPE_r > A_r ROB * PLD_r * k_NA_PE * NAPE_r / Km_NA_PE / den_r
vFAAH_degr_b	vFAAH_degr_b	FAAH_b > ∅ BRAIN * k_deg_FAAH * FAAH_b
vFAAH_degr_m	vFAAH_degr_m	FAAH_m > ∅ MEC * k_deg_FAAH * FAAH_m
vFAAH_degr_r	vFAAH_degr_r	FAAH_r > ∅ ROB * k_deg_FAAH * FAAH_r
vFAAH_inh_b	vFAAH_inh_b	FAAH_b > FAAHinh_b BRAIN * k_inh * FAAH_b * PF_b
vFAAH_inh_degr_b	vFAAH_inh_degr_b	FAAHinh_b > ∅ BRAIN * k_deg_FAAH * FAAHinh_b
vFAAH_inh_degr_m	vFAAH_inh_degr_m	FAAHinh_m > ∅ MEC * k_deg_FAAH * FAAHinh_m
vFAAH_inh_degr_r	vFAAH_inh_degr_r	FAAHinh_r > ∅ ROB * k_deg_FAAH * FAAHinh_r
vFAAH_inh_m	vFAAH_inh_m	FAAH_m > FAAHinh_m MEC * k_inh * FAAH_m * PF_m
vFAAH_inh_r	vFAAH_inh_r	FAAH_r > FAAHinh_r ROB * k_inh * FAAH_r * PF_r
vFAAH_syn_b	vFAAH_syn_b	∅ > FAAH_b BRAIN * FAAH_t * b_FAAH_Brain * k_deg_FAAH
vFAAH_syn_m	vFAAH_syn_m	∅ > FAAH_m MEC * FAAH_t * b_FAAH_MEC * k_deg_FAAH
vFAAH_syn_r	vFAAH_syn_r	∅ > FAAH_r FAAH_t * c_FAAH_ROB * k_deg_FAAH
vL_UE_b	vL_UE_b	L_b > ∅ BRAIN * b_FAAH_Brain * kcl_L * L_b
vL_UE_r	vL_UE_r	L_r > ∅ c_NAAA_ROB * kcl_L * L_r
vL_b_m	vL_b_m	L_b > L_m MEC * ktr_m_p_L * (L_b - L_m)
vL_degr_b	vL_degr_b	L_b > ∅ BRAIN * FAAH_b * kcat_FAAH * a_FAAH_L * L_b / (Km_FAAH_L * FAAH_D_b)
vL_degr_m	vL_degr_m	L_m > ∅ MEC * FAAH_m * kcat_FAAH * a_FAAH_L * L_m / (Km_FAAH_L * FAAH_D_m)
vL_degr_r	vL_degr_r	L_r > ∅ ROB * FAAH_r * kcat_FAAH * a_FAAH_L * L_r / (Km_FAAH_L * FAAH_D_r)
vL_m_p	vL_m_p	L_m > L_p MEC * ktr_m_p_L * (L_m - L_p * Ktr_p_m_L)
vL_r_p	vL_r_p	L_r > L_p PLASMA * ktr_r_p * (L_r - L_p * Ktr_p_r_L)
vL_syn_b	vL_syn_b	NLPE_b > L_b BRAIN * PLD_b * k_NL_PE * NLPE_b / Km_NL_PE / den_b
vL_syn_r	vL_syn_r	NLPE_r > L_r ROB * PLD_r * k_NL_PE * NLPE_r / Km_NL_PE / den_r
vNAPE_syn_b	vNAPE_syn_b	∅ > NAPE_b BRAIN * Vmax_NAT * p_A * a_NAT_A * b_NAT_Brain
vNAPE_syn_r	vNAPE_syn_r	∅ > NAPE_r Vmax_NAT * p_A * a_NAT_A * c_NAT_ROB
vNLPE_syn_b	vNLPE_syn_b	∅ > NLPE_b BRAIN * Vmax_NAT * p_L * a_NAT_L * b_NAT_Brain
vNLPE_syn_r	vNLPE_syn_r	∅ > NLPE_r Vmax_NAT * p_L * a_NAT_L * c_NAT_ROB
vNOPE_syn_b	vNOPE_syn_b	∅ > NOPE_b BRAIN * Vmax_NAT * p_O * a_NAT_O * b_NAT_Brain
vNOPE_syn_r	vNOPE_syn_r	∅ > NOPE_r Vmax_NAT * p_O * a_NAT_O * c_NAT_ROB
vNPPE_syn_b	vNPPE_syn_b	∅ > NPPE_b BRAIN * Vmax_NAT * p_P * a_NAT_P * b_NAT_Brain
vNPPE_syn_r	vNPPE_syn_r	∅ > NPPE_r Vmax_NAT * p_P * a_NAT_P * c_NAT_ROB
vNSPE_syn_b	vNSPE_syn_b	∅ > NSPE_b BRAIN * Vmax_NAT * p_S * a_NAT_S * b_NAT_Brain
vNSPE_syn_r	vNSPE_syn_r	∅ > NSPE_r Vmax_NAT * p_S * a_NAT_S * c_NAT_ROB
vO_UE_b	vO_UE_b	O_b > ∅ BRAIN * b_FAAH_Brain * kcl_O * O_b
vO_UE_r	vO_UE_r	O_r > ∅ c_NAAA_ROB * kcl_O * O_r
vO_b_m	vO_b_m	O_b > O_m MEC * ktr_m_p_O * (O_b - O_m)
vO_degr_b	vO_degr_b	O_b > ∅ BRAIN * FAAH_b * kcat_FAAH * a_FAAH_O * O_b / (Km_FAAH_O * FAAH_D_b)
vO_degr_m	vO_degr_m	O_m > ∅ MEC * FAAH_m * kcat_FAAH * a_FAAH_O * O_m / (Km_FAAH_O * FAAH_D_m)
vO_degr_r	vO_degr_r	O_r > ∅ ROB * FAAH_r * kcat_FAAH * a_FAAH_O * O_r / (Km_FAAH_O * FAAH_D_r)
vO_r_p	vO_r_p	O_r > O_p PLASMA * ktr_r_p * (O_r - O_p * Ktr_p_r_O)
vO_syn_b	vO_syn_b	NOPE_b > O_b BRAIN * PLD_b * k_NO_PE * NOPE_b / Km_NO_PE / den_b
vO_syn_r	vO_syn_r	NOPE_r > O_r ROB * PLD_r * k_NO_PE * NOPE_r / Km_NO_PE / den_r
vP_UE_b	vP_UE_b	P_b > ∅ BRAIN * b_FAAH_Brain * kcl_P * P_b
vP_UE_r	vP_UE_r	P_r > ∅ c_NAAA_ROB * kcl_P * P_r
vP_b_m	vP_b_m	P_b > P_m MEC * ktr_m_p_P * (P_b - P_m)
vP_degr_b	vP_degr_b	P_b > ∅ BRAIN * FAAH_b * kcat_FAAH * a_FAAH_P * P_b / (Km_FAAH_P * FAAH_D_b)
vP_degr_m	vP_degr_m	P_m > ∅ MEC * FAAH_m * kcat_FAAH * a_FAAH_P * P_m / (Km_FAAH_P * FAAH_D_m)
vP_degr_r	vP_degr_r	P_r > ∅ ROB * FAAH_r * kcat_FAAH * a_FAAH_P * P_r / (Km_FAAH_P * FAAH_D_r)
vP_m_p	vP_m_p	P_m > P_p MEC * ktr_m_p_P * (P_m - P_p * Ktr_p_m_P)
vP_r_p	vP_r_p	P_r > P_p PLASMA * ktr_r_p * (P_r - P_p * Ktr_p_r_P)
vP_syn_b	vP_syn_b	NPPE_b > P_b BRAIN * PLD_b * k_NP_PE * NPPE_b / Km_NP_PE / den_b
vP_syn_r	vP_syn_r	NPPE_r > P_r ROB * PLD_r * k_NP_PE * NPPE_r / Km_NP_PE / den_r
vS_UE_b	vS_UE_b	S_b > ∅ BRAIN * b_FAAH_Brain * kcl_S * S_b
vS_UE_r	vS_UE_r	S_r > ∅ c_NAAA_ROB * kcl_S * S_r
vS_b_m	vS_b_m	S_b > S_m MEC * ktr_m_p_S * (S_b - S_m)
vS_degr_b	vS_degr_b	S_b > ∅ BRAIN * FAAH_b * kcat_FAAH * a_FAAH_S * S_b / (Km_FAAH_S * FAAH_D_b)
vS_degr_m	vS_degr_m	S_m > ∅ MEC * FAAH_m * kcat_FAAH * a_FAAH_S * S_m / (Km_FAAH_S * FAAH_D_m)
vS_degr_r	vS_degr_r	S_r > ∅ ROB * FAAH_r * kcat_FAAH * a_FAAH_S * S_r / (Km_FAAH_S * FAAH_D_r)
vS_m_p	vS_m_p	S_m > S_p MEC * ktr_m_p_S * (S_m - S_p * Ktr_p_m_S)
vS_r_p	vS_r_p	S_r > S_p PLASMA * ktr_r_p * (S_r - S_p * Ktr_p_r_S)
vS_syn_b	vS_syn_b	NSPE_b > S_b BRAIN * PLD_b * k_NS_PE * NSPE_b / Km_NS_PE / den_b
vS_syn_r	vS_syn_r	NSPE_r > S_r ROB * PLD_r * k_NS_PE * NSPE_r / Km_NS_PE / den_r
vo_m_p	vo_m_p	O_m > O_p MEC * ktr_m_p_O * (O_m - O_p * Ktr_p_m_O)

Parameters 0 155

Global parameters

Id	Value
AG2_b	0.0
AG_p	0.0
CB1_b	0.0
Dose	10.0
ED50	0.53
Emax_PFM	0.773
FAAH_D_b	0.0
FAAH_D_m	0.0
FAAH_D_r	0.0
FAAH_t	78.0
F_PFM	0.0
F_r	0.0
Gut	1.65
H	0.48
Heart	0.31
Kd_AG2	3424.0
Kd_CB1_A	239.2
Ki_A	230.0
Ki_L	1000.0
Ki_O	240.0
Ki_P	6700.0
Ki_S	840.0
Kidney	0.28
Km_FAAH_A	8200.0
Km_FAAH_L	10800.0
Km_FAAH_O	52200.0
Km_FAAH_P	543000.0
Km_FAAH_S	10000.0
Km_NA_PE	2800.0
Km_NL_PE	1000.0
Km_NO_PE	2900.0
Km_NP_PE	3300.0
Km_NS_PE	3400.0
Km_PFM	26.1
Km_p_m_A	1.0
Kp_b_PF	1.3
Kp_m_PF	1.3
Kp_r_PF	1.5
Ktr_p_m_A	1.89
Ktr_p_m_L	2.77
Ktr_p_m_O	9.07
Ktr_p_m_P	2.65
Ktr_p_m_S	30.01
Ktr_p_r_A	0.62
Ktr_p_r_L	0.89
Ktr_p_r_O	2.8
Ktr_p_r_P	0.85
Ktr_p_r_S	9.19
LEU	0.025
LG_p	0.0
LIVER	1.69
Leucocytes	0.025
Lungs	1.172
MD	0.0
M_A	347.5
M_L	323.5
M_O	325.5
M_P	299.5
M_PF	455.4
M_S	321.5
Muscles	35.0
OG_p	0.0
PFG_p	0.0
PF_b	0.0
PF_m	0.0
PF_p	0.0
PF_r	0.0
PG_p	0.0
PLD_b	10000000.0
PLD_r	10000000.0
Pancreas	0.077
R_PF	0.6
SG_p	0.0
Spleen	0.192
Testis	0.036
Thymus	0.029
Vm_PFM	1511.0
Vmax_NAT	300.0
Vss_PFM	58.328
a_FAAH_A	1.0
a_FAAH_L	1.15
a_FAAH_O	5.7
a_FAAH_P	37.8
a_FAAH_S	1.0
a_NAT_A	1.0
a_NAT_L	8.6
a_NAT_O	13.0
a_NAT_P	0.42
a_NAT_S	1.0
b_FAAH_Brain	0.197
b_FAAH_Gut	0.034
b_FAAH_Kidney	0.069
b_FAAH_Leucocytes	0.0
b_FAAH_Liver	1.0
b_FAAH_Lungs	0.032
b_FAAH_MEC	0.137
b_FAAH_Spleen	0.03
b_FAAH_Testis	0.126
b_NAAA_Brain	0.6
b_NAAA_Gut	0.2
b_NAAA_Heart	0.2
b_NAAA_Kidney	0.6
b_NAAA_Liver	1.0
b_NAAA_Lungs	14.0
b_NAAA_Spleen	8.0
b_NAAA_Testis	0.6
b_NAAA_Thymus	4.0
b_NAT_Brain	1.667
b_NAT_Heart	1.0
b_NAT_Kidney	0.667
b_NAT_Leucocytes	0.0
b_NAT_Lungs	0.033
b_NAT_Muscles	0.333
b_NAT_Pancreas	0.333
b_NAT_Testis	0.667
c_FAAH_ROB	0.0
c_NAAA_ROB	0.0
c_NAT_ROB	0.0
den_b	0.0
den_r	0.0
e1	0.0
k_NA_PE	202.0
k_NL_PE	100.0
k_NO_PE	230.0
k_NP_PE	270.0
k_NS_PE	280.0
k_deg_FAAH	0.0051
k_inh	1.1
kabs_PFM	2.2
kcat_FAAH	18000.0
kcl_A	1.74
kcl_L	1.25
kcl_O	2.5
kcl_P	2.61
kcl_S	1.2
kin_PFM	0.117
klinear_PFM	0.0803
kout_PFM	0.18
ktr_m_p_A	150.0
ktr_m_p_L	0.0
ktr_m_p_O	10.0
ktr_m_p_P	10.0
ktr_m_p_S	10.0
ktr_r_p	100.0
p_A	0.051
p_L	0.016
p_O	0.098
p_P	0.615
p_S	0.191
slag1_b	0.0
slag1_r	0.0
slag2_b	0.0
slag2_r	0.0
t	0.0
tid	0.0

Local parameters

Id	Value	Reaction

Rules 0 0 27

Assignment rules

Definition
tid = t / 2.400000e+01
CB1_b = (A_b / Kd_CB1_A + AG2_b / Kd_AG2) / (1.000000e+00 + A_b / Kd_CB1_A + AG2_b / Kd_AG2)
SG_p = 1.000000e-03 * S_p * M_S
LG_p = 1.000000e-03 * L_p * M_L
PG_p = 1.000000e-03 * P_p * M_P
PFG_p = 1.000000e-03 * PFM_p / Vss_PFM
F_r = 1.500000e+03 * FAAH_r / (FAAHinh_r + FAAH_r)
FAAH_D_b = 1.000000e+00 + A_b / Km_FAAH_A + O_b / Km_FAAH_O + P_b / Km_FAAH_P + L_b / Km_FAAH_L + S_b / Km_FAAH_S
PF_m = PF_p * Kp_m_PF
PF_r = PF_p * Kp_r_PF
den_b = 1.000000e+00 + slag1_b + slag2_b
MD = PFM_gut + 1.000000e+06 * Dose * F_PFM
PF_b = PF_p * Kp_b_PF
FAAH_D_r = 1.000000e+00 + A_r / Km_FAAH_A + O_r / Km_FAAH_O + P_r / Km_FAAH_P + L_r / Km_FAAH_L + S_r / Km_FAAH_S
den_r = 1.000000e+00 + slag1_r + slag2_r
c_FAAH_ROB = LIVER * b_FAAH_Liver + Gut * b_FAAH_Gut + Spleen * b_FAAH_Spleen + Kidney * b_FAAH_Kidney + Lungs * b_FAAH_Lungs + Testis * b_FAAH_Testis + Leucocytes * b_FAAH_Leucocytes
AG_p = 1.000000e-03 * A_p * M_A
OG_p = 1.000000e-03 * O_p * M_O
FAAH_D_m = 1.000000e+00 + A_m / Km_FAAH_A + O_m / Km_FAAH_O + P_m / Km_FAAH_P + L_m / Km_FAAH_L + S_m / Km_FAAH_S
c_NAAA_ROB = LIVER * b_NAAA_Liver + Gut * b_NAAA_Gut + Spleen * b_NAAA_Spleen + Kidney * b_NAAA_Kidney + Heart * b_NAAA_Heart + Lungs * b_NAAA_Lungs + Thymus * b_NAAA_Thymus + Testis * b_NAAA_Thymus * Testis
slag2_r = A_r / Ki_A + O_r / Ki_O + P_r / Ki_P + L_r / Ki_L + S_r / Ki_S
slag1_r = NAPE_r / Km_NA_PE + NOPE_r / Km_NO_PE + NPPE_r / Km_NP_PE + NLPE_r / Km_NL_PE + NSPE_r / Km_NS_PE
c_NAT_ROB = Pancreas * b_NAT_Pancreas + Kidney * b_NAT_Kidney + Heart * b_NAT_Heart + Lungs * b_NAT_Lungs + Muscles * b_NAT_Muscles + Testis * b_NAT_Testis + Leucocytes * b_NAT_Leucocytes
slag2_b = A_b / Ki_A + O_b / Ki_O + P_b / Ki_P + L_b / Ki_L + S_b / Ki_S
slag1_b = NAPE_b / Km_NA_PE + NOPE_b / Km_NO_PE + NPPE_b / Km_NP_PE + NLPE_b / Km_NL_PE + NSPE_b / Km_NS_PE
PF_p = 1.000000e+00 / M_PF * PFM_p / Vss_PFM
F_PFM = Emax_PFM * Dose / (ED50 + Dose)

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Trigger	Assignments