## ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ##
## Shire HAE model simulation condition file for Lanadelumab (Default unit used in model: nM, h, L)
## ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ##
##
## Use the following block to set up dose amount, total number of dose, dose interval, and virtual patient file name
##

Dose_amount <- 150.0										### [mg]. Dose amount in mg unit
N_dose <- 13												### [-]. Total number of dose
Dose_interval <- 24*7*2										### [h]. Dose interval
inputFileName <- 'Param_Sampling_pt100.csv'					### Input file name for sampled PK & acute attack variations for virtual patients
num_of_patients_to_run <- 100 								### Number of virtual patients to simulate (must be no more than the total number of virtual patients in the input file)
random_patients_selection <- FALSE							### Use TRUE or FALSE to specify whether randomly pick over virtual population or pick sequentially
outputDir <- './Output'                 					### Output directory name (if the directory already exists, all the files in there will be deleted before running new simulations)
CS_KD_KAL_Lanadelumab <- 0.12 								### [nM]. Kd for Lanadelumab binding with KAL. Shire measurements as in Kenniston et al. 2014
CS_kon_KAL_Lanadelumab <- 12.096 							### [1/(M*h)]. kon for Lanadelumab binding with KAL. Sexton et al. 2013
PK_MW <- 150000 											### [g/mol]. Molecular weight for the drug (150 kDa for Lanadelumab)
CS_prct_HK2Chain_basal <- 35.6								### [%]. Basal percentage for %2Chain

## No need to change the following parameters for most cases
basal_equilibrium_duration <- 1000 							### [h]. Allow 1,000 hours for the contact system to reach baseline equilibrium
run_in_period <- 24*28*3 									### [h]. Three-month run-in period for Study 03 trials
duration_post_last_dose <- 24*7*12 							### [h]. Addational duration of 12 weeks post last dose

time_interval <- 0.5 										### [h]. The reporting time interval to be used in the output CSV files
time_start <- 0												### [h]. The starting time for the simulation
time_end <- basal_equilibrium_duration + run_in_period + N_dose * Dose_interval + duration_post_last_dose	### [h]. The time for the end of simulation

target_vars <- c('PK_Conc_Central_in_ugml', 'CS_BK_in_plasma', 'CS_prct_HK2Chain')							### [-]. Target variables for statistics
percentiles <- c(25, 50, 75)																				### [-]. Percentiles for target variables
BK_threshold <- 0.020																						### [nM]. BK threshold for detecting acute attacks

## ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ##
##
## Use the following block to set up sampling paramters such as total number of virtual patients to sample, PK parameters, acute attack frequency, and percentage of missing dose
##

num_patients <- 100																												### [-]. Total number of virtual patients to sample
weight_Param_info <- data.frame(name = 'WT', mean = 81.1, stdev = 0.281*81.1, min = 36.7, max = 178, normal = 70, digits = 2)															### [kg]. Body weight of virtual patients
popPK_Param_info <- rbind(data.frame(name = 'PK.V_F', mean = 12.8, stdev = 2.24, min = 7.52, max = 32.7, Eta_Mean = 0, Eta_Cov = 0.08399, WT_exponent = 0.717, digits = 2)				### [L]. Volume of the central compartment
						, data.frame(name = 'PK.CL_F', mean = 0.0249, stdev = 6.18E-3, min = 0.0123, max = 0.0879, Eta_Mean = 0, Eta_Cov = 0.09575, WT_exponent = 0.891, digits = 4)	### [L/h]. Drug clearance rate
						, data.frame(name = 'PK.ka', mean = 0.0179, stdev = 2.96E-3, min = 6.13E-3, max = 0.0395, Eta_Mean = 0, Eta_Cov = 0.58041, WT_exponent = 0, digits = 4))		### [1/h]. Drug absorption rate

AA_quarterly_freq_info <- data.frame(mean = 10.5, stdev = 9.04, min = 3, max = 35)												### [-]. Acute attack quarterly frequency
min_num_events <- 10																											### [-]. Minimum number of acute attacks
min_event_interval <- 48																										### [h]. Minimum time interval between two attack events
max_event_interval <- 24*90																										### [h]. Maximum time interval between two attack events
Fold_normalized_info <- data.frame(mean = 0.35, stdev = 0.1, min = 0.2, max = 1.0)												### [-]. Fold increase of FXII auto-activation of acute attack

missing_dose_prct <- 30																						### [%]. Percentage of occurance of not taking treament as scheduled. Assume makeup dose occured 1 week after occurance
Missing_dose_freq_info <- data.frame(mean = N_dose*missing_dose_prct/100.0, stdev = 2.0, min = 1, max = 6)						### [-]. Standard deviation of missing dose

##
## ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ##