Table 2.
Summary of PBPK models published for narrow therapeutic index substrates
| Main Clearance Enzyme | Compound | Application | Model Type | IV or Oral | Clearancea | Simulated genotype specified? | Population matched?b | Verificationc | Acceptance Criteriad | Software | Citation |
|---|---|---|---|---|---|---|---|---|---|---|---|
| CYP1A2 | Theophylline | Pregnancy | Full | Oral | BC | No | Sex | B, D | 2 | Simcyp, Matlab | (Ke et al., 2013b) |
| Theophylline | DDI | Minimal | Both | In vitro | No | N.S. | B, E | 1 | Matlab | (Pan et al., 2011) | |
| CYP2C9 | Phenytoin | Clinical PK | Minimal | Oral | In vitro | Yes | Age, Sex, PGX | B | 1 | Simcyp | (Polasek et al., 2009) |
| Warfarin | DDI | Full | Oral | PE | No | Age, Sex, PGX | A | 4 | Berkeley Madonna | (Brantley et al., 2014) | |
| CYP3A4 | Cyclosporine | Pediatrics | Full | IV | In vivo, SF | No | Age | C | 1 | AdaptII | (Gérard et al., 2010) |
| Cyclosporine | DDI | Full | Oral | In vitro | No | N.S. | E | 5 | WinNonlin | (Guo et al., 2013) | |
| Cyclosporine | DDI | Full | Both | PE | No | N.S. | C, E | 5 | Matlab | (Gertz et al., 2013) | |
| Cyclosporine | Allometry | Full | Oral | SF | No | N.S | A, D | 1 | PK Sim | (Thiel et al., 2014) | |
| Quinidine | DDI | Full | Oral | In vitro | No | N.S. | E | 5 | WinNonlin | (Guo et al., 2013) | |
| Sirolimus | Clinical PK | Full | Oral | In vitro, PE | No | Age, Sex | B, D, E | 1 | Simcyp | (Emoto et al., 2013) | |
| Tacrolimus | DDI | Full | Oral | In vitro | No | N.S. | E | 5 | WinNonlin | (Guo et al., 2013) | |
| Tacrolimus | Clinical PK | Minimal | Oral | BC | Yes | Age, Sex, PGX | D, E | 1 | PKquest | (Gérard et al., 2014) |
a
BC = back-calculated from in vivo data, PE = parameter estimate, SF = scaling factor.
b
PGX = genotype, N.S. = not specified.
c
Data sets used in model verification included: (A) Single dose PK, (B) alternative dosing regimen, (C) alternative formulation, (D) alternative population, (E) DDI.
d
Acceptance criteria fell into 5 categories: (1) Not specified, (2) Ratio of PK parameter(s) must be within 30% of observed ratio, (3) Ratio of PK parameter(s) must be within 2 fold of observed ratio, (4) PK parameters must be within 30% of observed parameters, (5) PK parameters must be within 2 fold of observed parameters.