[COVARIATE] input = {Weight, Genotype} Genotype = {type=categorical, categories= {Homozygous, Heterozygous}} EQUATION: logtWeight = log(Weight/70) [INDIVIDUAL] input = {V_pop, omega_V, Cl_pop, omega_Cl, Q_pop, omega_Q, V2_pop, omega_V2, logtWeight, beta_V_logtWeight, KD_pop, omega_KD, R0_pop, omega_R0, kint_pop, omega_kint, kon_pop, omega_kon, ksyn_pop, omega_ksyn, beta_Cl_logtWeight, beta_Q_logtWeight, beta_V2_logtWeight, Genotype, beta_KD_Genotype_Heterozygous} Genotype = {type=categorical, categories= {Homozygous, Heterozygous}} DEFINITION: V = {distribution=logNormal, typical=V_pop, covariate=logtWeight, coefficient=beta_V_logtWeight, sd=omega_V} Cl = {distribution=logNormal, typical=Cl_pop, covariate=logtWeight, coefficient=beta_Cl_logtWeight, sd=omega_Cl} Q = {distribution=logNormal, typical=Q_pop, covariate=logtWeight, coefficient=beta_Q_logtWeight, sd=omega_Q} V2 = {distribution=logNormal, typical=V2_pop, covariate=logtWeight, coefficient=beta_V2_logtWeight, sd=omega_V2} KD = {distribution=logNormal, typical=KD_pop, covariate=Genotype, coefficient={0, beta_KD_Genotype_Heterozygous}, sd=omega_KD} R0 = {distribution=logNormal, typical=R0_pop, sd=omega_R0} kint = {distribution=logNormal, typical=kint_pop, sd=omega_kint} kon = {distribution=logNormal, typical=kon_pop, sd=omega_kon} ksyn = {distribution=logNormal, typical=ksyn_pop, sd=omega_ksyn} [LONGITUDINAL] input={V, kint, kon, KD, ksyn, R0, Cl, Q, V2} PK: depot(target=L, p=1/V) ;p=1/V transforms the dose amount into a concentration added to the concentration L EQUATION: odeType=stiff ;Parameter transformation kel = Cl/V k12 = Q/V k21 = Q/V2 koff = KD*kon kdeg = ksyn/R0 ;Initial conditions t_0 = 0 L_0 = 0 R_0 = R0 P_0 = 0 A_0 = 0 ;Ordinary Differential Equations ddt_R = ksyn - kdeg*R - kon*L*R + koff*P ddt_P = kon*L*R - koff*P - kint*P ddt_L = -kel*L - kon*L*R + koff*P - k12*L + k21*A/V ddt_A = k12*L*V - k21*A ;Additional outputs Ltot = L+P ; total ligand concentration Rtot = R+P ; total receptor concentration TO = R/Rtot ; receptor occupancy RR = R/R0 ; ratio of free receptor to baseline value OUTPUT: output={L, TO}