Search the PBPK Model Repository

  Absorption Model

• First-Order

  Volume of Distribution

• Full PBPK (Method 2)
• Note: A Kp scalar (0.3) was used in the model

  Route of Elimination

• Biliary = 66%; Renal= 44%

  Perpetrator DDI

• None

  Validation

• Seven clinical studies describing single and multiple dose exposure of doxycycline were used to verify the PBPK model. The model predicted AUC values in 86% of studies within 2-fold (100% if one simulated/observed ratio is rounded down from 1.52 to 1.5), of which 57% were within 1.5-fold. 

  Limitations

• Model is not verified at doses below 100 mg or about 200 mg (dose-linearity of doxycycline is uncertain)
• Model assumes hyclate, monohydrate and hydrochloride formulations are bioequivalent
• Model is not developed for the prediction of IV doxycycline
• Model was developed and verified primarily in healthy volunteer studies (except Newton et al. 2005); appropriateness of extrapolation to acute malaria patients is unknown

  Updates in V19

• Updated in vitro­ data
  • fu: 0.142 -> 0.23
  • B:P: 1.5 -> 0.78
• Converted from minimal PBPK model to full PBPK model
• Elimination changed from user input IV clearance to retrograde clearance with biliary clearance and additional hepatic clearance

  Absorption Model

• First-Order

  Volume of Distribution

• Minimal PBPK (User input Vss)

  Route of Elimination

• Renal clearance (90%); non-specific hepatic metabolism (10%)

  Perpetrator DDI

• None

  Validation

• Four clinical studies describing single and multiple dose exposure of sulfadoxine were used to verify the PBPK model. In comparison of predicted vs. observed AUC, 100% of the studies were within 2-fold and 75% were within 1.5-fold. 

  Limitations

• In the absence of adequate data on the metabolism and excretion of sulfadoxine, it was assumed that 90% was cleared renally and 10% was metabolized by the liver.

  Updates in V19

• Updated in vitro­ data
  • LogP: 4.22 -> 0.54