## ------------------------------------------------------------------------------ ## ## Shire HAE model ## Model parameter file (Default unit used in model: nM, h, L) ## Line 8 can be modified to define HAE subject cases or Healthy Control cases ## No need to change other parameter values unless the model is re-calibrated ## ------------------------------------------------------------------------------ ## CS_ksyn_C1Inh <- 11.883 ### [nM/h]. For HAE patients: 11.883; for Helathy Controls: 39.608 Max_Num_of_AA <- 150 ### [-]. Max number of acute attacks over simulation duration for virtual patients. Should not change. AA_AA_Fold_Max <- 12 ### [-]. Max fold increase for FXII auto-activation during acute attacks AA_AA_t_duration <- 12 ### [h]. Duration of elevated FXII auto-activation for acute attacks AA_Steepness <- 0.01 ### [-]. For controling the slope of increased FXII auto-activation. No need to change. CS_scaling_factor <- 1e+09 ### [-]. Scaling factor to convert M into nM unit. CS_Avogadro <- 6.02e+23 ### [number/mol]. Avogadro constant. CS_MW_FXII <- 80000 ### [g/mol]. Molecular weight for FXII CS_MW_preKAL <- 85000 ### [g/mol]. Molecular weight for preKAL CS_MW_C1Inh <- 105000 ### [g/mol]. Molecular weight for C1Inh CS_MW_HK <- 120000 ### [g/mol]. Molecular weight for HMWK CS_MW_BK <- 1060 ### [g/mol]. Molecular weight for BK CS_thalf_preKAL <- 24 ### [h]. Labcorp.com CS_thalf_KAL <- 5/60.0 ### [h]. Cumming et al. 1984 CS_thalf_HMWK <- 157 ### [h]. Weidmann et al. 2017 CS_thalf_cHMWK <- 157/14.0 ### [h]. Calibrated CS_thalf_C1Inh <- 42 ### [h]. Weidmann et al. 2017 CS_thalf_Bound_C1Inh <- 3/60.0 ### [h]. Assumed same rate as A2M to form covalent bond hence inactive, Jensen et al. 2004 CS_thalf_FXII <- 60 ### [h]. Weidmann et al. 2017 CS_thalf_FXIIa <- 5/60.0 ### [h]. Assumed same as t1/2 for KAL CS_thalf_BK <- 45/60.0/60.0 ### [h]. Cir et al. 2001 CS_thalf_gC1qR <- 2 ### [h]. Typical typical degradation rate for receptors: 3.5 hr for IL4Ra, Husain et al. 1996; 2 hr for gammaC receptor, Morelon and Dautry-Varsat 1998 CS_thalf_BDKRB2 <- 2 ### [h]. Typical typical degradation rate for receptors: 3.5 hr for IL4Ra, Husain et al. 1996; 2 hr for gammaC receptor, Morelon and Dautry-Varsat 1998 CS_gC1qR_per_Cell_Init <- 100000 ### [number/cell]. Mahdi et al. 2001, assumed limited by the CK1 cofactor CS_BDKRB2_per_Cell_Init <- 100000 ### [number/cell]. Estimated from Paquet et al. 1999 ### degradation rates below are determined from t1/2 above ### CS_kdeg_preKAL <- log(2)/CS_thalf_preKAL ### [1/h]. CS_kdeg_KAL <- log(2)/CS_thalf_KAL ### [1/h]. CS_kdeg_HMWK <- log(2)/CS_thalf_HMWK ### [1/h]. CS_kdeg_cHMWK <- log(2)/CS_thalf_cHMWK ### [1/h]. CS_kdeg_C1Inh <- log(2)/CS_thalf_C1Inh ### [1/h]. CS_kdeg_Bound_C1Inh <- log(2)/CS_thalf_Bound_C1Inh ### [1/h]. CS_kdeg_FXII <- log(2)/CS_thalf_FXII ### [1/h]. CS_kdeg_FXIIa <- log(2)/CS_thalf_FXIIa ### [1/h]. CS_kdeg_BK <- log(2)/CS_thalf_BK ### [1/h]. CS_kdeg_gC1qR <- log(2)/CS_thalf_gC1qR ### [1/h]. CS_kdeg_BDKRB2 <- log(2)/CS_thalf_BDKRB2 ### [1/h]. CS_kdeg_Lanadelumab_KAL_HMWK_gC1qR <- CS_kdeg_gC1qR ### [1/h]. CS_ksyn_preKAL <- 41.58883 ### [nM/h]. Calibrated CS_ksyn_FXII <- 10.83042 ### [nM/h]. Calibrated CS_ksyn_HMWK <- 39.93322 ### [nM/h]. Calibrated CS_ksyn_gC1qR <- CS_kdeg_gC1qR*CS_gC1qR_per_Cell_Init ### [nM/h]. Estimated from steady-state level data from Mahdi et al. 2001 CS_ksyn_BDKRB2 <- CS_kdeg_BDKRB2*CS_BDKRB2_per_Cell_Init ### [nM/h]. Estimated from steady-state level data from Paquet et al. 1999 CS_Kd_preKAL_HMWK <- 12 ### [nM]. Kd for preKAL binding with HMWK. Bock et al. 1985 CS_Kd_KAL_HMWK <- 15 ### [nM]. Kd for KAL binding with HMWK. Bock et al. 1985 CS_Kd_KAL_HK2Chain <- 72 ### [nM]. Kd for KAL binding with cHMWK. Kenniston et al. 2014 CS_Kd_C1Inh_KAL <- 150 ### [nM]. Kd for C1Inh binding with KAL. Estimated from immunosorbent assay data by Harpel et al. 1985 CS_Kd_C1Inh_FXIIa <- 1720 ### [nM]. Kd for C1Inh binding with FXIIa. Estimated from Biacore data by Björkqvist 2015 CS_Kd_HMWK_gC1qR <- 10.35 ### [nM]. Kd for HMWK binding with receptor complex. Fernando et al. 2003 CS_Kd_HK2Chain_gC1qR <- 10.35 ### [nM]. Kd for cHMWK binding with receptor complex. Assumed same as HMWK binding with receptor complex CS_Kd_FXII_gC1qR <- 144 ### [nM]. Kd for FXII bindind with receptor complex. Reddigari et al. 1993 CS_Kd_FXIIa_gC1qR <- 144 ### [nM]. Kd for FXIIa bindind with receptor complex. Assumed same as FXII bindind with receptor complex. CS_Kd_BK_BDKRB2 <- 0.5 ### [nM]. Kd for BK binding with BDKRB2 receptors. Paquet et al. 1999 CS_kon_HMWK_gC1qR <- 12.3e4*3600/CS_scaling_factor ### [1/(M*h)]. kon for HMWK binding with receptor complex. Pixley et al. 2011 CS_kon_HK2Chain_gC1qR <- 12.3e4*3600/CS_scaling_factor ### [1/(M*h)]. kon for cHMWK binding with receptor complex. Assumed same as HMWK binding with receptor complex. CS_kon_FXII_gC1qR <- CS_kon_HMWK_gC1qR ### [1/(M*h)]. kon for FXII binding with receptor complex. Assumed same as HMWK binding with receptor complex. CS_kon_FXIIa_gC1qR <- CS_kon_HMWK_gC1qR ### [1/(M*h)]. kon for FXIIa binding with receptor complex. Assumed same as HMWK binding with receptor complex. CS_kon_preKAL_HMWK <- 10*CS_kon_HMWK_gC1qR ### [1/(M*h)]. kon for preKAL binding with HMWK. Assuemd 10x of kon_HMWK_gC1qR, due to lower steric constraint CS_kon_KAL_HMWK <- 10*CS_kon_HMWK_gC1qR ### [1/(M*h)]. kon for KAL binding with HMWK. Assuemd 10x of kon_HMWK_gC1qR, due to lower steric constraint CS_kon_KAL_HK2Chain <- 10*CS_kon_HMWK_gC1qR ### [1/(M*h)]. kon for KAL binding with cHMWK. Assuemd 10x of kon_HMWK_gC1qR, due to lower steric constraint CS_kon_C1Inh_KAL <- 1.7e4*3600/CS_scaling_factor ### [1/(M*h)]. kon for C1Inh binding with KAL. Drouet et al. 2018 CS_kon_C1Inh_FXIIa <- 1*3.7e4*3600/CS_scaling_factor ### [1/(M*h)]. kon for C1Inh binding with FXIIa. Drouet et al. 2018 CS_kon_BK_BDKRB2 <- 1e7*3600/CS_scaling_factor ### [1/(M*h)]. kon for BK binding with BDKRB2 receptors. Assumed fast binding for BK due to its low MW CS_Km_FXII_AutoActivation <- 110 ### [nM]. Km for FXII auto-activation (S: FXII_gC1qR; E: FXII_gC1qR; P: FXIIa_gC1qR). Bernard et al. 1993 CS_kcat_FXII_AutoActivation <- 0.0475 ### [1/h]. kcat for FXII auto-activation (S: FXII_gC1qR; E: FXII_gC1qR; P: FXIIa_gC1qR). Calibrated CS_Km_FXII_Activation <- 510 ### [nM]. Km for FXII activation (S: FXII_gC1qR; E: KAL_HMWK_gC1qR; P: FXIIa_gC1qR). Tankersley & Finlayson 1984 CS_kcat_FXII_Activation <- 15 ### [1/h]. kcat for FXII activation (S: FXII_gC1qR; E: KAL_HMWK_gC1qR; P: FXIIa_gC1qR). Calibrated CS_Km_preKAL_Activation <- 91 ### [nM]. Km for preKAL activation (S: preKAL_HMWK_gC1qR; E: FXIIa_gC1qR; P: KAL_HMWK_gC1qR). Tankersley & Finlayson 1984 CS_kcat_preKAL_Activation <- 18 ### [1/h]. kcat for preKAL activation (S: preKAL_HMWK_gC1qR; E: FXIIa_gC1qR; P: KAL_HMWK_gC1qR). Calibrated CS_kcat_HMWK_cleavage <- 394.74 ### [1/h]. kcat for HMWK cleavage. Calibrated CS_Vproximal <- 8e-15 ### [L]. Proximal space volume near cell surface for each endothelial cell. 20 nm (height) x 400 um2 (surface area per endothelial cell) CS_Vmedium <- 1.23e-12 ### [L]. Per endothelial cell based plasma volume. Total plasma volume (3.126 L, Shah & Betts 2012) divided by the total number of endothelial cells (2.54E12, Bianconi 2013). CS_CLD <- 1e-2*CS_Vproximal*3600 ### [L/h]. Flux exchange rate in b/t proximal and vascular space for all unbound species (except for BK) CS_CLD_BK <- CS_CLD*30 ### [L/h]. Flux exchange rate in b/t proximal and vascular space for BK CS_Num_to_Conc_converter <- (1.0/CS_Avogadro/CS_Vproximal)*CS_scaling_factor ### [nM/number]. Convert number of surface receptor related species into concentrations CS_Num_of_Plasma_Rxn <- 23 ### [-]. Number of flux exchange reactions in vascular space CS_Num_of_Exchange_Rxn <- 10 ### [-]. Number of flux exchange reactions in b/t proximal and vascular space CS_Num_of_Surface_Rxn <- 29 ### [-]. Number of flux exchange reactions in proximal space parms <- c( INIT_Conc_Negligible = INIT_Conc_Negligible , PK_MW = PK_MW , CS_scaling_factor = CS_scaling_factor , CS_Avogadro = CS_Avogadro , CS_Vproximal = CS_Vproximal , CS_Vmedium = CS_Vmedium , CS_MW_FXII = CS_MW_FXII , CS_MW_preKAL = CS_MW_preKAL , CS_MW_C1Inh = CS_MW_C1Inh , CS_MW_HK = CS_MW_HK , CS_MW_BK = CS_MW_BK , CS_Num_to_Conc_converter = CS_Num_to_Conc_converter , CS_Num_of_Plasma_Rxn = CS_Num_of_Plasma_Rxn , CS_Num_of_Exchange_Rxn = CS_Num_of_Exchange_Rxn , CS_Num_of_Surface_Rxn = CS_Num_of_Surface_Rxn , CS_CLD = CS_CLD , CS_CLD_BK = CS_CLD_BK , CS_thalf_preKAL = CS_thalf_preKAL , CS_thalf_KAL = CS_thalf_KAL , CS_thalf_HMWK = CS_thalf_HMWK , CS_thalf_cHMWK = CS_thalf_cHMWK , CS_thalf_C1Inh = CS_thalf_C1Inh , CS_thalf_Bound_C1Inh = CS_thalf_Bound_C1Inh , CS_thalf_FXII = CS_thalf_FXII , CS_thalf_FXIIa = CS_thalf_FXIIa , CS_thalf_BK = CS_thalf_BK , CS_thalf_gC1qR = CS_thalf_gC1qR , CS_thalf_BDKRB2 = CS_thalf_BDKRB2 , CS_kdeg_preKAL = CS_kdeg_preKAL , CS_kdeg_KAL = CS_kdeg_KAL , CS_kdeg_HMWK = CS_kdeg_HMWK , CS_kdeg_cHMWK = CS_kdeg_cHMWK , CS_kdeg_C1Inh = CS_kdeg_C1Inh , CS_kdeg_Bound_C1Inh = CS_kdeg_Bound_C1Inh , CS_kdeg_FXII = CS_kdeg_FXII , CS_kdeg_FXIIa = CS_kdeg_FXIIa , CS_kdeg_BK = CS_kdeg_BK , CS_kdeg_gC1qR = CS_kdeg_gC1qR , CS_kdeg_BDKRB2 = CS_kdeg_BDKRB2 , CS_kdeg_Lanadelumab_KAL_HMWK_gC1qR = CS_kdeg_Lanadelumab_KAL_HMWK_gC1qR , CS_ksyn_C1Inh = CS_ksyn_C1Inh , CS_ksyn_preKAL = CS_ksyn_preKAL , CS_ksyn_FXII = CS_ksyn_FXII , CS_ksyn_HMWK = CS_ksyn_HMWK , CS_ksyn_gC1qR = CS_ksyn_gC1qR , CS_ksyn_BDKRB2 = CS_ksyn_BDKRB2 , CS_kon_preKAL_HMWK = CS_kon_preKAL_HMWK , CS_Kd_preKAL_HMWK = CS_Kd_preKAL_HMWK , CS_kon_KAL_HMWK = CS_kon_KAL_HMWK , CS_Kd_KAL_HMWK = CS_Kd_KAL_HMWK , CS_kon_KAL_HK2Chain = CS_kon_KAL_HK2Chain , CS_Kd_KAL_HK2Chain = CS_Kd_KAL_HK2Chain , CS_kon_C1Inh_KAL = CS_kon_C1Inh_KAL , CS_Kd_C1Inh_KAL = CS_Kd_C1Inh_KAL , CS_kon_C1Inh_FXIIa = CS_kon_C1Inh_FXIIa , CS_Kd_C1Inh_FXIIa = CS_Kd_C1Inh_FXIIa , CS_kon_HMWK_gC1qR = CS_kon_HMWK_gC1qR , CS_Kd_HMWK_gC1qR = CS_Kd_HMWK_gC1qR , CS_kon_HK2Chain_gC1qR = CS_kon_HK2Chain_gC1qR , CS_Kd_HK2Chain_gC1qR = CS_Kd_HK2Chain_gC1qR , CS_kon_FXII_gC1qR = CS_kon_FXII_gC1qR , CS_Kd_FXII_gC1qR = CS_Kd_FXII_gC1qR , CS_kon_FXIIa_gC1qR = CS_kon_FXIIa_gC1qR , CS_Kd_FXIIa_gC1qR = CS_Kd_FXIIa_gC1qR , CS_kon_BK_BDKRB2 = CS_kon_BK_BDKRB2 , CS_Kd_BK_BDKRB2 = CS_Kd_BK_BDKRB2 , CS_kon_KAL_Lanadelumab = CS_kon_KAL_Lanadelumab , CS_KD_KAL_Lanadelumab = CS_KD_KAL_Lanadelumab , CS_Km_FXII_AutoActivation = CS_Km_FXII_AutoActivation , CS_kcat_FXII_AutoActivation = CS_kcat_FXII_AutoActivation , CS_Km_FXII_Activation = CS_Km_FXII_Activation , CS_kcat_FXII_Activation = CS_kcat_FXII_Activation , CS_Km_preKAL_Activation = CS_Km_preKAL_Activation , CS_kcat_preKAL_Activation = CS_kcat_preKAL_Activation , CS_kcat_HMWK_cleavage = CS_kcat_HMWK_cleavage , CS_INIT_preKAL_in_plasma = CS_INIT_preKAL_in_plasma , CS_INIT_HMWK_in_plasma = CS_INIT_HMWK_in_plasma , CS_INIT_C1Inh_in_plasma = CS_INIT_C1Inh_in_plasma , CS_INIT_FXII_in_plasma = CS_INIT_FXII_in_plasma , CS_INIT_gC1qR = CS_INIT_gC1qR , CS_INIT_BDKRB2 = CS_INIT_BDKRB2 , CS_prct_HK2Chain_basal = CS_prct_HK2Chain_basal )