Table 5.
Summary of the PBPK models published for transporter substrates, inhibitors and inducers
| Compound Modeled (Relevant Transporter) | Application | Minimal or Full | Oral or IV | Clearancea | Simulated genotype specified? | Population matched?b | Verificationc | Acceptance Criteriad | Software | Citation |
|---|---|---|---|---|---|---|---|---|---|---|
| Inducers | ||||||||||
| Rifampin (P-gP) | Transport | Minimal | Oral | BC | No | A,S | A, E | 1 | Simcyp | (Neuhoff et al., 2013b) |
| Inhibitors | ||||||||||
| Cyclosporine ( OATP1B1) | Transport | Full | Oral | In vivo | Yes | N.S. | A, E | 1 | Simcyp | (Varma et al., 2012) |
| Cyclosporine (OATP1B1, OATP1B3 BCRP) | Transport | Full | Oral | BC | No | Age, sex, PGX | B | 1 | Simcyp | (Jamei et al., 2014) |
| Cyclosporine (OATP1B1, OATP1B3 BCRP) | DDI | Full | Both | PE | No | N.S. | C, E | 5 | Matlab | (Gertz et al., 2013) |
| Gemfibrozil ( OATP1B1) | DDI | Minimal | Oral | PE | No | N.S. | A, B, E | 1 | Napp | (Kudo et al., 2013) |
| Gemfibrozil (OATP1B1) | Transport | Full | Oral | BC | Yes | N.S. | E | 1 | Simcyp | (Varma et al., 2015a)* updated Varma et al 2012 |
| Probenecid (OAT1, OAT3) | DDI | Full | Both | BC | No | N.S. | C | 1 | Simcyp | (Hsu et al., 2014) |
| Verapamil (P-gp) | DDI | Full | Oral | BC | No | Age, sex | A, E | 1 | Simcyp | (Neuhoff et al., 2013b) |
| Substrates | ||||||||||
| Atorvastatin (OATP1B1) | Absorption | Full | Oral | In vitro | No | Age, sex | D | 1 | Simcyp | (Darwich et al., 2013) |
| Bosentan (OATP1B1) | Transport | Full | IV | In vitro, SF | No | N.S. | None | 1 | Berkeley Madonna | (Jones et al., 2012) |
| Dabigatran (P-gp) | DDI | Full | Both | In vitro | No | N.S. | A, B, E | 1 | PK Sim | (Zhao and Hu, 2014) |
| Digoxin (P-gp) | Transport | Full | Both | BC | No | Age, sex | A, B | 4 | Simcyp | (Neuhoff et al., 2013b) |
| Fluvastatin (OATP1B1) | Transport | Full | IV | In vitro, SF | No | N.S. | None | 1 | Berkeley Madonna | (Jones et al., 2012) |
| Glyburide (OATP1B1) | DDI | Full | Both | In vitro | Yes | PDX | B, C, E | 1 | Simcyp | (Varma et al., 2014) |
| Glyburide (OATP1B1) | Pregnancy | Full | Oral | BC | No | sex | B, D, E | 2 | Simcyp, Matlab | (Ke et al., 2013a) |
| Pravastatin (OATP1B1, OAT3) | Clinical PK | Full | Both | In vitro, SF | No | N.S. | C | 1 | Matlab, PK Sim | (Meyer et al., 2012) |
| Pravastatin (OATP1B1) | Transport | Full | Both | In vitro, SF | No | N.S. | A, B, E | 1 | Simcyp | (Varma et al., 2012) |
| Repaglinide (OATP1B1) | Transport | Full | IV | In vitro, SF | No | N.S. | None | 1 | Berkeley Madonna | (Jones et al., 2012) |
| Repaglinide (OATP1B1) | RI | Full | Oral | BC | Yes | N.S. | D | 1 | Simcyp | (Zhao et al., 2012a) |
| Repaglinide (OATP1B1) | DDI | Minimal | Oral | In vivo | No | N.S. | E | 1 | Napp | (Kudo et al., 2013) |
| Repaglinide (OATP1B1) | DDI | Full | Both | BC | No | N.S. | C, E | 1 | Simcyp | (Varma et al., 2013) |
| Rosuvastatin (BCRP OATP1B1, OATP1B3) | Transport | Full | Oral | BC, PE, SA | No | Age, sex | B, E | 1 | Simcyp | (Jamei et al., 2014) |
| Rosuvastatin (OATP1B1, OATP1B3) | Transport | Full | Both | In vitro, SF | No | N.S. | C | 1 | ASCLX | (Bosgra et al., 2014) |
| Telmisartan (OATP1B3) | Transport | Full | Both | In vitro, SF | No | N.S. | C | 1 | Matlab | (Li et al., 2014c) |
a
BC = back calculated from in vivo data, PE = parameter estimation, SA= sensitivity analysis, 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.