Table 2.
Effect of CKD on pharmacokinetics of model substrate drugs
| Enzyme or transporter | Substrate drug | CKD populations | f u a (%) | AUCR (total) | R value | AUCR (unbound) | R value | |||
|---|---|---|---|---|---|---|---|---|---|---|
| HV | CKD | Simulated | Observeda | Simulated | Observeda | |||||
| CYP2C8 | Rosiglitazone | Simcyp (CYP2C8 47%) | 0.16 | 0.22 | 1.44 | 0.81 | 1.78 | 2.47 | 1.11 | 2.23 |
| Modified (CYP2C8 100%)b | 0.16 | 0.22 | 0.93 | 0.81 | 1.14 | 1.58 | 1.11 | 1.42 | ||
| Pioglitazone | Simcyp (CYP2C8 47%) | 3 | 3.5 c | 1.58 | 0.78 | 2.03 | 2.40 | 0.92 c | 2.61 c | |
| Modified (CYP2C8 100%)b | 3 | 3.5 c | 0.90 | 0.78 | 1.15 | 1.36 | 0.92 c | 1.48 c | ||
| OATP | Pitavastatin | Simcyp (CYP2C8 47%, OATP100%) | 0.6 | 0.6 | 0.85 | 1.36 | 0.63 | 1.05 | 1.36 | 0.77 |
| Simcyp (CYP2C8 47%, OATP 60%)d | 0.6 | 0.6 | 1.28 | 1.36 | 0.94 | 1.59 | 1.36 | 1.17 | ||
| Modified (CYP2C8 100%, OATP100%) | 0.6 | 0.6 | 0.84 | 1.36 | 0.62 | 1.04 | 1.36 | 0.77 | ||
| Modified (CYP2C8 100%, OATP60%)d | 0.6 | 0.6 | 1.28 | 1.36 | 0.94 | 1.59 | 1.36 | 1.17 | ||
| CYP2C8/OATP | Repaglinide | Simcyp (CYP2C8 47%, OATP100%) | 3.6 | 3.6 | 1.37 | 2.72 | 0.51 | 1.72 | 2.72 | 0.63 |
| Simcyp (CYP2C8 47%, OATP 50%)d | 3.6 | 3.6 | 2.55 | 2.72 | 0.94 | 3.18 | 2.72 | 1.17 | ||
| Modified (CYP2C8 100%, OATP100%) | 3.6 | 3.6 | 1.08 | 2.72 | 0.40 | 1.35 | 2.72 | 0.50 | ||
| Modified (CYP2C8 100%, OATP60%) | 3.6 | 3.6 | 1.72 | 2.72 | 0.63 | 2.14 | 2.72 | 0.79 | ||
| Modified (CYP2C8 100%, OATP45%) | 3.6 | 3.6 | 2.20 | 2.72 | 0.81 | 2.75 | 2.72 | 1.01 | ||
| Modified (CYP2C8 100%, OATP40%)d | 3.6 | 3.6 | 2.43 | 2.72 | 0.89 | 3.03 | 2.72 | 1.11 | ||
Simcyp default and modified “Sim‐RenalGFR_less30” severe renal impairment populations were used in the simulations with dosing regimen, GFR, average age, and gender matched to the corresponding clinical CKD studies. Simcyp: V16 default “Sim‐RenalGFR_less30” population where the CYP2C8 abundance was reduced to 47% of the HVs. Modified: the CYP2C8 abundance was set back to 100% of HVs in the V16 default “Sim‐RenalGFR_less30” population. The OATP1B abundance was adjusted in the simulations when needed as indicated in parenthesis.
AUCR, area under the concentration‐time curves ratio; CKD, chronic kidney disease; CYP, cytochrome P450; f u, unbound fraction; HV, healthy volunteer; OATP, organic anion‐transporting polypeptide.
aObserved f u and AUCR values were from the dedicated clinical CKD studies: rosiglitazone,51 pitavastatin28 and repaglinide.35 bCYP2C8 abundance as in HV. cPioglitazone f u for patients with CKD were not reported in the clinical study,52 thus predicted f u was used in the simulations. Prediction of f u was based on changes in albumin content reported in severe CKD, assuming that albumin was the main plasma protein involved in binding of this drug, as detailed in ref.13 The “observed” unbound AUCR of 0.92 was calculated based on the estimated fu and the corresponding R values were estimated, shown as italic numbers. dOATP1B function was optimized to reproduce the observed AUCR for pitavastatin and repaglinide.