Simcyp model input parameters for panobinostat

Parameter (Unit)ValueSource
Physical chemistry and blood binding
 Mol. wt, (g/mol)349.44
 LogP2.643Calculated logP (inhouse)
 Compound typeDiprotic acid
 pKa8.4 and 9Measured (internal data)
 Blood-to-plasma ratio1.4Measured (internal data)
fu,plasma0.104Measured (internal data)
 Model usedFirst order
fa (CV%)1 (30%, default)Clive et al. (2012)
 ka,(per h) (CV%)0.32 (30%, default)Savelieva et al. (2015)
fugut1Simcyp default and to minimize Fg value
Qgut, lit(CV%)2.8 (30%, default)Manually optimized for fit of clinical PK and DDI data
 Model usedMinimal PBPK
kin,(per h)1.42Savelieva et al. (2015)
kout(per h)0.04Savelieva et al. (2015)
 Vsac, l/kg10.5Manually optimized for fit of clinical PK data
Vss, l/kg (CV%)13 (15%)Estimate
 Model usedRetrograde modela
 CLint CYP3A4, µl/min per pmol P4500.3071Based on relative P450 contributions Determined in vitro
 CLint CYP2D6, µl/min per pmol P4501.578
 CLint CYP2C19, µl/min per pmol P4500.2254
  Additional HLM CL, µl/min per mg protein (CV%)35.96 (30%, default)Estimate of non-P450 mediated CL
 CLR, l/h (CV%)3.57 (30%, default)Clive et al. (2012)
 Ki, CYP2C19 (µM)17.5bMeasured
 Ki, CYP2D6 (µM)0.167Measured
 Ki, CYP3A4 (µM)7.5bMeasured
 kinact (per h)1.37 ± 0.187Measured
KI (µM)12.0 ± 4.47Measured
  • B/P, blood-to-plasma ratio.

  • a The P450 CLint and additional HLM CL was estimated using the Simcyp retrograde model, see Materials and Methods.

  • b IC50/2.