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Short description:

A simulation systems pharmacology model developed for the human endocannabinoid system which aimed to optimize any further clinical development of FAAH inhibitors. This is a simulation model which has been curated by EMBL-EBI. The model is available in the BioModels Database and simulation can be performed (via the BioModels Online Simulation tool) at: http://www.ebi.ac.uk/biomodels-main/BIOMD0000000512.

Format:	PharmML (0.6)
Related Publication:	A systems pharmacology perspective on the clinical development of Fatty Acid amide hydrolase inhibitors for pain. Benson N, Metelkin E, Demin O, Li GL, Nichols D, van der Graaf PH CPT: pharmacometrics & systems pharmacology, 1/2014, Volume 3, pages: e91 Affiliation: Xenologiq, Canterbury, Kent, UK. 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.
Contributors:	Phylinda Chan

Context of model development:	Mechanistic Understanding;
Long technical model description:	A systems pharmacology (physiologically based pharmacokinetic and systems biology) model describes the cannabinoid (CB) receptor anandamide binding, the fatty acid ethanolamide metabolism and distribution in the human body; the mutually exclusive binding of ethanolamides to FAAH.;
Model compliance with original publication:	Yes;
Model implementation requiring submitter’s additional knowledge:	No;
Modelling context description:	The model integrated physiological compartments; endocannabinoid production, degradation, and disposition data; PF-04457845 pharmacokinetics and pharmacodynamics, and cannabinoid receptor cannabinoid CB1-binding kinetics.;
Modelling task in scope:	simulation;
Nature of research:	Early clinical development (Phases I and II);
Therapeutic/disease area:	CNS;

Validation Status:	Annotations are correct.
Certification Comment:	This model is not certified.

Mandatory file
- PharmML_Benson_2014.xml

Additional Files

Model owner: Phylinda Chan
Submitted: Apr 7, 2016 4:48:48 PM
Last Modified: May 25, 2016 9:42:00 AM

Revisions

Version: 6
- Submitted on: May 25, 2016 9:42:00 AM
- Submitted by: Phylinda Chan
- With comment: Updated model annotations.
Version: 4
- Submitted on: Apr 7, 2016 4:48:48 PM
- Submitted by: Phylinda Chan
- With comment: Edited model metadata online.

Independent variable time

Structural Model sm

Variable definitions

vA_degr_b = \frac{((((BRAIN \times FAAH_b) \times kcat_FAAH) \times a_FAAH_A) \times A_b)}{(Km_FAAH_A \times FAAH_D_b)}

vO_degr_b = \frac{((((BRAIN \times FAAH_b) \times kcat_FAAH) \times a_FAAH_O) \times O_b)}{(Km_FAAH_O \times FAAH_D_b)}

vP_degr_b = \frac{((((BRAIN \times FAAH_b) \times kcat_FAAH) \times a_FAAH_P) \times P_b)}{(Km_FAAH_P \times FAAH_D_b)}

vL_degr_b = \frac{((((BRAIN \times FAAH_b) \times kcat_FAAH) \times a_FAAH_L) \times L_b)}{(Km_FAAH_L \times FAAH_D_b)}

vS_degr_b = \frac{((((BRAIN \times FAAH_b) \times kcat_FAAH) \times a_FAAH_S) \times S_b)}{(Km_FAAH_S \times FAAH_D_b)}

vNAPE_syn_b = ((((BRAIN \times Vmax_NAT) \times p_A) \times a_NAT_A) \times b_NAT_Brain)

vNOPE_syn_b = ((((BRAIN \times Vmax_NAT) \times p_O) \times a_NAT_O) \times b_NAT_Brain)

vNPPE_syn_b = ((((BRAIN \times Vmax_NAT) \times p_P) \times a_NAT_P) \times b_NAT_Brain)

vNLPE_syn_b = ((((BRAIN \times Vmax_NAT) \times p_L) \times a_NAT_L) \times b_NAT_Brain)

vNSPE_syn_b = ((((BRAIN \times Vmax_NAT) \times p_S) \times a_NAT_S) \times b_NAT_Brain)

vA_syn_b = \frac{\frac{(((BRAIN \times PLD_b) \times k_NA_PE) \times NAPE_b)}{Km_NA_PE}}{den_b}

vO_syn_b = \frac{\frac{(((BRAIN \times PLD_b) \times k_NO_PE) \times NOPE_b)}{Km_NO_PE}}{den_b}

vP_syn_b = \frac{\frac{(((BRAIN \times PLD_b) \times k_NP_PE) \times NPPE_b)}{Km_NP_PE}}{den_b}

vL_syn_b = \frac{\frac{(((BRAIN \times PLD_b) \times k_NL_PE) \times NLPE_b)}{Km_NL_PE}}{den_b}

vS_syn_b = \frac{\frac{(((BRAIN \times PLD_b) \times k_NS_PE) \times NSPE_b)}{Km_NS_PE}}{den_b}

vFAAH_syn_b = (((BRAIN \times FAAH_t) \times b_FAAH_Brain) \times k_deg_FAAH)

vFAAH_degr_b = ((BRAIN \times k_deg_FAAH) \times FAAH_b)

vFAAH_inh_b = (((BRAIN \times k_inh) \times FAAH_b) \times PF_b)

vFAAH_inh_degr_b = ((BRAIN \times k_deg_FAAH) \times FAAHinh_b)

vA_UE_b = (((BRAIN \times b_FAAH_Brain) \times kcl_A) \times A_b)

vO_UE_b = (((BRAIN \times b_FAAH_Brain) \times kcl_O) \times O_b)

vP_UE_b = (((BRAIN \times b_FAAH_Brain) \times kcl_P) \times P_b)

vL_UE_b = (((BRAIN \times b_FAAH_Brain) \times kcl_L) \times L_b)

vS_UE_b = (((BRAIN \times b_FAAH_Brain) \times kcl_S) \times S_b)

vA_degr_r = \frac{((((ROB \times FAAH_r) \times kcat_FAAH) \times a_FAAH_A) \times A_r)}{(Km_FAAH_A \times FAAH_D_r)}

vO_degr_r = \frac{((((ROB \times FAAH_r) \times kcat_FAAH) \times a_FAAH_O) \times O_r)}{(Km_FAAH_O \times FAAH_D_r)}

vP_degr_r = \frac{((((ROB \times FAAH_r) \times kcat_FAAH) \times a_FAAH_P) \times P_r)}{(Km_FAAH_P \times FAAH_D_r)}

vL_degr_r = \frac{((((ROB \times FAAH_r) \times kcat_FAAH) \times a_FAAH_L) \times L_r)}{(Km_FAAH_L \times FAAH_D_r)}

vS_degr_r = \frac{((((ROB \times FAAH_r) \times kcat_FAAH) \times a_FAAH_S) \times S_r)}{(Km_FAAH_S \times FAAH_D_r)}

vNAPE_syn_r = (((Vmax_NAT \times p_A) \times a_NAT_A) \times c_NAT_ROB)

vNOPE_syn_r = (((Vmax_NAT \times p_O) \times a_NAT_O) \times c_NAT_ROB)

vNPPE_syn_r = (((Vmax_NAT \times p_P) \times a_NAT_P) \times c_NAT_ROB)

vNLPE_syn_r = (((Vmax_NAT \times p_L) \times a_NAT_L) \times c_NAT_ROB)

vNSPE_syn_r = (((Vmax_NAT \times p_S) \times a_NAT_S) \times c_NAT_ROB)

vA_syn_r = \frac{\frac{(((ROB \times PLD_r) \times k_NA_PE) \times NAPE_r)}{Km_NA_PE}}{den_r}

vO_syn_r = \frac{\frac{(((ROB \times PLD_r) \times k_NO_PE) \times NOPE_r)}{Km_NO_PE}}{den_r}

vP_syn_r = \frac{\frac{(((ROB \times PLD_r) \times k_NP_PE) \times NPPE_r)}{Km_NP_PE}}{den_r}

vL_syn_r = \frac{\frac{(((ROB \times PLD_r) \times k_NL_PE) \times NLPE_r)}{Km_NL_PE}}{den_r}

vS_syn_r = \frac{\frac{(((ROB \times PLD_r) \times k_NS_PE) \times NSPE_r)}{Km_NS_PE}}{den_r}

vFAAH_syn_r = ((FAAH_t \times c_FAAH_ROB) \times k_deg_FAAH)

vFAAH_degr_r = ((ROB \times k_deg_FAAH) \times FAAH_r)

vFAAH_inh_r = (((ROB \times k_inh) \times FAAH_r) \times PF_r)

vFAAH_inh_degr_r = ((ROB \times k_deg_FAAH) \times FAAHinh_r)

vA_UE_r = ((c_NAAA_ROB \times kcl_A) \times A_r)

vO_UE_r = ((c_NAAA_ROB \times kcl_O) \times O_r)

vP_UE_r = ((c_NAAA_ROB \times kcl_P) \times P_r)

vL_UE_r = ((c_NAAA_ROB \times kcl_L) \times L_r)

vS_UE_r = ((c_NAAA_ROB \times kcl_S) \times S_r)

vA_degr_m = \frac{((((MEC \times FAAH_m) \times kcat_FAAH) \times a_FAAH_A) \times A_m)}{(Km_FAAH_A \times FAAH_D_m)}

vO_degr_m = \frac{((((MEC \times FAAH_m) \times kcat_FAAH) \times a_FAAH_O) \times O_m)}{(Km_FAAH_O \times FAAH_D_m)}

vP_degr_m = \frac{((((MEC \times FAAH_m) \times kcat_FAAH) \times a_FAAH_P) \times P_m)}{(Km_FAAH_P \times FAAH_D_m)}

vL_degr_m = \frac{((((MEC \times FAAH_m) \times kcat_FAAH) \times a_FAAH_L) \times L_m)}{(Km_FAAH_L \times FAAH_D_m)}

vS_degr_m = \frac{((((MEC \times FAAH_m) \times kcat_FAAH) \times a_FAAH_S) \times S_m)}{(Km_FAAH_S \times FAAH_D_m)}

vFAAH_syn_m = (((MEC \times FAAH_t) \times b_FAAH_MEC) \times k_deg_FAAH)

vFAAH_degr_m = ((MEC \times k_deg_FAAH) \times FAAH_m)

vFAAH_inh_m = (((MEC \times k_inh) \times FAAH_m) \times PF_m)

vFAAH_inh_degr_m = ((MEC \times k_deg_FAAH) \times FAAHinh_m)

vA_m_p = \frac{((MEC \times ktr_m_p_A) \times (A_m - (A_p \times Ktr_p_m_A)))}{((A_m + A_p) + Km_p_m_A)}

vo_m_p = ((MEC \times ktr_m_p_O) \times (O_m - (O_p \times Ktr_p_m_O)))

vP_m_p = ((MEC \times ktr_m_p_P) \times (P_m - (P_p \times Ktr_p_m_P)))

vL_m_p = ((MEC \times ktr_m_p_L) \times (L_m - (L_p \times Ktr_p_m_L)))

vS_m_p = ((MEC \times ktr_m_p_S) \times (S_m - (S_p \times Ktr_p_m_S)))

vA_b_m = \frac{((MEC \times ktr_m_p_A) \times (A_b - A_m))}{((A_b + A_b) + Km_p_m_A)}

vO_b_m = ((MEC \times ktr_m_p_O) \times (O_b - O_m))

vP_b_m = ((MEC \times ktr_m_p_P) \times (P_b - P_m))

vL_b_m = ((MEC \times ktr_m_p_L) \times (L_b - L_m))

vS_b_m = ((MEC \times ktr_m_p_S) \times (S_b - S_m))

vA_r_p = \frac{((PLASMA \times ktr_r_p) \times (A_r - (A_p \times Ktr_p_r_A)))}{((A_r + A_p) + Km_p_m_A)}

vO_r_p = ((PLASMA \times ktr_r_p) \times (O_r - (O_p \times Ktr_p_r_O)))

vP_r_p = ((PLASMA \times ktr_r_p) \times (P_r - (P_p \times Ktr_p_r_P)))

vL_r_p = ((PLASMA \times ktr_r_p) \times (L_r - (L_p \times Ktr_p_r_L)))

vS_r_p = ((PLASMA \times ktr_r_p) \times (S_r - (S_p \times Ktr_p_r_S)))

absorp = (kabs_PFM \times MD)

dist = ((kout_PFM \times PFM_p) - (kin_PFM \times PFM_r))

elim = ((klinear_PFM \times PFM_p) + \frac{\frac{(Vm_PFM \times PFM_p)}{(Km_PFM + \frac{PFM_p}{Vss_PFM})}}{Vss_PFM})

\frac{dA_b}{dtime} = ((((- 1 \times vA_degr_b) + (1 \times vA_syn_b)) + (- 1 \times vA_UE_b)) + (- 1 \times vA_b_m))

\frac{dO_b}{dtime} = ((((- 1 \times vO_degr_b) + (1 \times vO_syn_b)) + (- 1 \times vO_UE_b)) + (- 1 \times vO_b_m))

\frac{dP_b}{dtime} = ((((- 1 \times vP_degr_b) + (1 \times vP_syn_b)) + (- 1 \times vP_UE_b)) + (- 1 \times vP_b_m))

\frac{dL_b}{dtime} = ((((- 1 \times vL_degr_b) + (1 \times vL_syn_b)) + (- 1 \times vL_UE_b)) + (- 1 \times vL_b_m))

\frac{dS_b}{dtime} = ((((- 1 \times vS_degr_b) + (1 \times vS_syn_b)) + (- 1 \times vS_UE_b)) + (- 1 \times vS_b_m))

\frac{dNAPE_b}{dtime} = ((1 \times vNAPE_syn_b) + (- 1 \times vA_syn_b))

\frac{dNOPE_b}{dtime} = ((1 \times vNOPE_syn_b) + (- 1 \times vO_syn_b))

\frac{dNPPE_b}{dtime} = ((1 \times vNPPE_syn_b) + (- 1 \times vP_syn_b))

\frac{dNLPE_b}{dtime} = ((1 \times vNLPE_syn_b) + (- 1 \times vL_syn_b))

\frac{dNSPE_b}{dtime} = ((1 \times vNSPE_syn_b) + (- 1 \times vS_syn_b))

\frac{dFAAH_b}{dtime} = (((1 \times vFAAH_syn_b) + (- 1 \times vFAAH_degr_b)) + (- 1 \times vFAAH_inh_b))

\frac{dFAAHinh_b}{dtime} = ((1 \times vFAAH_inh_b) + (- 1 \times vFAAH_inh_degr_b))

\frac{dA_r}{dtime} = ((((- 1 \times vA_degr_r) + (1 \times vA_syn_r)) + (- 1 \times vA_UE_r)) + (- 1 \times vA_r_p))

\frac{dO_r}{dtime} = ((((- 1 \times vO_degr_r) + (1 \times vO_syn_r)) + (- 1 \times vO_UE_r)) + (- 1 \times vO_r_p))

\frac{dP_r}{dtime} = ((((- 1 \times vP_degr_r) + (1 \times vP_syn_r)) + (- 1 \times vP_UE_r)) + (- 1 \times vP_r_p))

\frac{dL_r}{dtime} = ((((- 1 \times vL_degr_r) + (1 \times vL_syn_r)) + (- 1 \times vL_UE_r)) + (- 1 \times vL_r_p))

\frac{dS_r}{dtime} = ((((- 1 \times vS_degr_r) + (1 \times vS_syn_r)) + (- 1 \times vS_UE_r)) + (- 1 \times vS_r_p))

\frac{dNAPE_r}{dtime} = ((1 \times vNAPE_syn_r) + (- 1 \times vA_syn_r))

\frac{dNOPE_r}{dtime} = ((1 \times vNOPE_syn_r) + (- 1 \times vO_syn_r))

\frac{dNPPE_r}{dtime} = ((1 \times vNPPE_syn_r) + (- 1 \times vP_syn_r))

\frac{dNLPE_r}{dtime} = ((1 \times vNLPE_syn_r) + (- 1 \times vL_syn_r))

\frac{dNSPE_r}{dtime} = ((1 \times vNSPE_syn_r) + (- 1 \times vS_syn_r))

\frac{dFAAH_r}{dtime} = (((1 \times vFAAH_syn_r) + (- 1 \times vFAAH_degr_r)) + (- 1 \times vFAAH_inh_r))

\frac{dFAAHinh_r}{dtime} = ((1 \times vFAAH_inh_r) + (- 1 \times vFAAH_inh_degr_r))

\frac{dA_m}{dtime} = (((- 1 \times vA_degr_m) + (- 1 \times vA_m_p)) + (1 \times vA_b_m))

\frac{dO_m}{dtime} = (((- 1 \times vO_degr_m) + (- 1 \times vo_m_p)) + (1 \times vO_b_m))

\frac{dP_m}{dtime} = (((- 1 \times vP_degr_m) + (- 1 \times vP_m_p)) + (1 \times vP_b_m))

\frac{dL_m}{dtime} = (((- 1 \times vL_degr_m) + (- 1 \times vL_m_p)) + (1 \times vL_b_m))

\frac{dS_m}{dtime} = (((- 1 \times vS_degr_m) + (- 1 \times vS_m_p)) + (1 \times vS_b_m))

\frac{dFAAH_m}{dtime} = (((1 \times vFAAH_syn_m) + (- 1 \times vFAAH_degr_m)) + (- 1 \times vFAAH_inh_m))

\frac{dFAAHinh_m}{dtime} = ((1 \times vFAAH_inh_m) + (- 1 \times vFAAH_inh_degr_m))

\frac{dA_p}{dtime} = ((1 \times vA_m_p) + (1 \times vA_r_p))

\frac{dO_p}{dtime} = ((1 \times vo_m_p) + (1 \times vO_r_p))

\frac{dP_p}{dtime} = ((1 \times vP_m_p) + (1 \times vP_r_p))

\frac{dL_p}{dtime} = ((1 \times vL_m_p) + (1 \times vL_r_p))

\frac{dS_p}{dtime} = ((1 \times vS_m_p) + (1 \times vS_r_p))

\frac{dPFM_gut}{dtime} = (\frac{1}{Default} \times (- 1 \times absorp))

\frac{dPFM_p}{dtime} = (((1 \times absorp) + (- 1 \times dist)) + (- 1 \times elim))

\frac{dPFM_r}{dtime} = (1 \times dist)

Initial conditions

A_b = 0.7493309

O_b = 20.77858

P_b = 6.541209

L_b = 2.319571

S_b = 3.427807

NAPE_b = 3.879041E-5

NOPE_b = 8.814287E-4

NPPE_b = 1.732296E-4

NLPE_b = 7.550331E-5

NSPE_b = 1.272629E-4

FAAH_b = 15.366

FAAHinh_b = 0.0

A_r = 0.5419204

O_r = 14.23822

P_r = 4.121915

L_r = 1.705466

S_r = 2.515968

NAPE_r = 4.241633E-6

NOPE_r = 9.638198E-5

NPPE_r = 1.894222E-5

NLPE_r = 8.256095E-6

NSPE_r = 1.391587E-5

FAAH_r = 2.165868

FAAHinh_r = 0.0

A_m = 0.97761

O_m = 16.3219

P_m = 5.809415

L_m = 0.0

S_m = 2.968774

FAAH_m = 10.686

FAAHinh_m = 0.0

A_p = 0.8740574

O_p = 5.085073

P_p = 4.849307

L_p = 1.916254

S_p = 0.273772

PFM_gut = 0.0

PFM_p = 0.0

PFM_r = 0.0

Parameter Model

Parameters

Cannot display simple parameters.

Simulation Steps

Simulation step ss

Observation

Type:Continuous

Variables:A_b O_b P_b L_b S_b NAPE_b NOPE_b NPPE_b NLPE_b NSPE_b FAAH_b FAAHinh_b A_r O_r P_r L_r S_r NAPE_r NOPE_r NPPE_r NLPE_r NSPE_r FAAH_r FAAHinh_r A_m O_m P_m L_m S_m FAAH_m FAAHinh_m A_p O_p P_p L_p S_p PFM_gut PFM_p PFM_r

Independent variable(time): 0.0:0.1:100.0