Merge pull request #72 from nlmixr2/phenylalanine_charbonneau_2021-v2

Add phenylalanine_charbonneau_2021 model; allow models not to have estimated parameters

R/modeldb.R

@@ -132,6 +132,9 @@ addFileToModelDb <- function(dir, file, modeldb) {
   if ("rxLinCmt" %in% paramErr) {
     paramErr[paramErr %in% "rxLinCmt"] <- "linCmt()"
   }
+  if (is.null(paramErr)) {
+    paramErr <- ""
+  }
 
   ret <-
     data.frame(

inst/modeldb/endogenous/phenylalanine_charbonneau_2021.R

@@ -0,0 +1,52 @@
+phenylalanine_charbonneau_2021 <- function() {
+  description <- "Phenylalanine model for absorption and metabolism in healthy subjects and patients with PKU"
+  reference <- "Charbonneau, M.R., Denney, W.S., Horvath, N.G. et al. Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria. Commun Biol 4, 898 (2021). https://doi.org/10.1038/s42003-021-02183-1"
+  covariates <-
+    list(
+      WT = "Body weight in kg",
+      time = "Time in hours",
+      f_pah = "Fraction of healthy PAH activity (healthy = 1; PKU patient = 0 to 0.03)",
+      bl_phe = "Typical values are about 0.075 mmol/L in healthy subjects and 1.18 mmol/L in patients"
+    )
+  # parameters come from Table 4 in paper
+  ini({
+    bl_phe <- 1.18; label("Baseline Phenylalanine (Phe) concentration (mmol/L)")
+    bl_gut <- 0; label("Baseline Phe in the gut (mg)")
+
+    ka_gut <- 0.25; label("Absorption rate from gut to plasma")
+    v_npd <- 0.015; label("Rate of net protein breakdown ((mmol/L)/hr)")
+
+    vmax_pah <- 0.9; label("Maximum rate of Phe breakdown by PAH in a healthy subject ((mmol/L)/hr)")
+    f_pah <- 0; label("Fraction of healthy PAH activity (PKU patient = 0 to 0.02)")
+    km_pah <- 0.51; label("Michaelis-Menten constant for Phe with PAH (mmol/L)")
+    kact_pah <- 0.54; label("Phe activation constant for PAH")
+
+    vmax_trans <- 0.063; label("Maximum rate of Phe breakdown by transaminase ((mmol/L)/hr)")
+    km_trans <- 1.37; label("Michaelis-Menten constant for Phe with transaminase (mmol/L)")
+
+    cl_renal <- 5.696e-4; label("Renal clearance of Phe per body weight ((L/kg)/hr)")
+
+    vd <- 0.5; label("Body-weight normalized volume distribution of Phe (L/kg)")
+  })
+  model({
+    # Molecular weight of Phe (g/mol)
+    mw_phe <- 165.19
+    # Unit conversion adjustment from Gut to Plasma concentrations (mmol/L)/mg
+    f_gut_plasma <- 1/(mw_phe * vd_phe * WT)
+
+    v_pah <- vmax_pah*f_pah / (1 + km_pah/phe + km_pah*kact_pah/(phe^2)) # units: (mmol/L)/hr
+    v_trans <- vmax_trans / (1 + km_trans/phe) # units: (mmol/L)/hr
+    v_renal <- phe * cl_renal * vd # units: (mmol/L)/hr
+
+    d/dt(gut) <- -ka_gut*gut
+    d/dt(phe) <- ka*gut*f_gut_plasma + v_npd - v_pah - v_trans - v_renal
+    gut(0) <- bl_gut
+    phe(0) <- bl_phe
+    phe_umol <- phe * 1000 # units: umol/L (more commonly used in clinical laboratories)
+
+    # The following is an augmentation of the model reported in the paper.  It
+    # indicates the approximate daily Phe intake (in mg) to achieve
+    # steady-state.
+    daily_phe_intake <- 24 * vd * (v_pah + v_trans + v_renal - v_npd) / f_gut_plasma
+  })
+}