Inhibitors | Dosing Regimen | SCr ↑ | CLcr↓ | GFR↓ | Markers for GFR | Cmax | fu | Cmax/IC50a | Cmax,u/IC50a | References | ||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
OCT2 | MATE1 | MATE2K | OCT2 | MATE1 | MATE2K | |||||||||
% | % | μM | ||||||||||||
Cimetidine | 400 mg (QDS) | 13–26 | 20 | NS | 51Cr–EDTA,inulin | 8–12 | 0.8 | 4.14 | 20.00 | 2.14 | 3.31 | 16.00 | 1.71 | Dutt et al., 1981; Hilbrands et al., 1991 |
Pyrimethamine | 50–100 mg SD | 18–26 | 25–27 | NS | inulin | 2.3a | 0.13 | 3.77 | 115.00 | 51.11 | 0.49 | 14.95 | 6.64 | Opravil et al., 1993; Kusuhara et al., 2011 |
Famotidine | 40 mg QD, 7days | NS | NS | — | — | 0.39 | 0.8 | 0.02 | 0.87 | 0.06 | 0.01 | 0.69 | 0.05 | Ishigami et al., 1989 |
Famotidine | 200 mg SD; 160 mg q4h | SI | SI | — | — | 1.25 | 0.8 | 0.06 | 2.78 | 0.19 | 0.05 | 2.22 | 0.15 | Hibma et al., 2015 |
Ranitidine | 300 mg QD | NS | NS | — | — | 3.72 | 0.85 | 0.32 | 0.45 | 0.18 | 0.27 | 0.39 | 0.15 | Motyl, 2004 |
Trimethoprim | 20 mg/kg/day (10 days); 200 mg BID | 31 | 16 | NS | 51Cr–EDTA iothalamate | 3.4–6.9 | 0.56 | 0.35 | 13.53 | 49.29 | 0.20 | 7.58 | 27.60 | Naderer et al., 1997; Arya et al., 2014 |
Dronedarone | 400 mg BID 7days | 10–15 | 18 | NS | Sinistrin, PAH | 0.30 | 0.02 | 0.16 | 0.65 | 0.03 | 0.003 | 0.013 | 0.001 | Tschuppert et al., 2007 |
DX-619 | 800 mg (QD) (4 days) | 30–40 | 26 | NS | Iohexol | 20.5–22 | 0.29–0.35b | 23.40 | 26.83 | 220.0 | 8.19 | 9.39 | 77.0 | Sarapa et al., 2007 |
Dolutegravir | 50 mg (QD or BID, 14 days) | 9–17 | 10 –14 | NS | Iohexol Cystatin C | 6.7–13.1 | 0.01 | 62.38 | 3.64 | 1.05 | 0.62 | 0.04 | 0.01 | Koteff et al., 2013 |
Cobicistat | 150 mg QD, 7 days, PO | 10.5, 23 | 8–14, 9 – 20 | NS | Iohexol | 1.55 | 0.03 | 0.04 | 1.58 | 0.08 | 0.001 | 0.05 | 0.002 | Cohen et al., 2011; German et al., 2012; Arya et al., 2014 |
Ritonavir | 100 mg QD | — | 25 | NS | Iohexol | 2.16 | 0.015 | 0.09 | 7.71 | 0.05 | 0.001 | 0.12 | 0.001 | Deray et al., 1998; German et al., 2012; Lepist et al., 2014 |
Ranolazine | 1000 mg BID, 5 days, PO | 12 | 10 | NS | Sinistrin | 6.01 | 0.38 | 0.13 | 0.36 | 0.12 | 0.05 | 0.14 | 0.05 | Arya et al., 2014 |
Rilpivirine | 25 mg (QD, 96 weeks) | 10 | — | NS | Cystatin C | 0.6 | 0.005 | 1.58 | 2.40 | 2.14 | 0.01 | 0.01 | 0.01 | Drug label; Maggi et al., 2014 |
Amiodarone | 400 mg QD | 11 | — | — | — | 0.8–2.3 | 0.04 | 0.49 | 2.30 | 0.05 | 0.02 | 0.09 | 0.002 | Pollak et al., 1993 |
Raltegravir | 400 mg BID | NS | NS | — | — | 3.38 | 0.17 | <0.03 | <0.03 | <0.03 | <0.01 | <0.01 | <0.01 | Drug label; Maggi et al., 2014; Rizk et al., 2014 |
Telaprevir | 750 mg q8h | SI | — | NS | Cystatin C, L–FABP, NAG | 5.82 | 0.04–0.24b | <0.06 | 0.09 | <0.06 | 0.01 | 0.02 | <0.01 | Suzuki et al., 2013; Matsui et al., 2015 |
Vandetanib | 300 mg QD | 15 | — | — | — | 0.33 | 0.1 | 0.83 | 5.50 | 8.25 | 0.08 | 0.55 | 0.83 | Shen et al., 2013 |
—, data are not reported or available; BID, twice daily; L-FABP, liver-type fatty acid binding protein; NAG, N-acetyl-β-Dglucosaminidase; NS, not significant (either statistically or clinically); PAH, para-amino-hippurate; PO, by mouth; QDS, four times a day; q4h, every 4 hours; q8h, every 8 hours; SD, single dose; SI, significantly increased compared with baseline level.
↵a IC50 values used were generated at Merck & Co. and shown in Table 1, except for DX-619, for which the lowest IC50 value obtained from the literature is used (see Table 1).
↵b Highest fu values are used to estimate Cmax,u/IC50 as the worst-case scenario.