Stephanie van Hoppe

138 Chapter 6 FVB genetic background, using a low-polysorbate 80 formulation to minimize possible inhibitory effects on Oatps (de Graan et al., 2012; Nieuweboer et al., 2014). After i.v. administration of docetaxel at 10 mg/kg, the plasma AUC was 2.9-fold higher in the Oatp1a/1b(-/-) mice (609 vs 212 µg x min/ml, P < 0.001). Similar to the findings of Lee et al. (2015), the liver exposure was not substantially altered in the Oatp1a/1b(-/-) mice, but the liver-to-plasma ratio was markedly lower at all except the earliest time points (at least 3-fold or more after 15 min). A limited pharmacokinetic study (15-60 min) of i.v. docetaxel (dosed at 10 mg/kg) in OATP1B1, OATP1B3, and OATP1A2 humanized mice indicated a 4-fold increase in docetaxel plasma AUC in Oatp1a/1b(-/-) compared to wild- type mice, which was largely reversed in both OATP1B1- and OATP1A2-transgenic mice (P < 0.001), and more modestly (P < 0.01) in OATP1B3-transgenic mice (Iusuf et al., 2015) ( Figure 3A and B) . In accordance with the unaltered liver AUC in the Oatp1a/1b(-/-) mice, the liver AUCs in all the humanized strains were not significantly different from those in the wild-type and Oatp1a/1b(-/-) mice. These unaltered liver AUC data are readily explained by a physiologically based pharmacokinetic model developed by Watanabe et al. (2009; 2010). This shows that a strong reduction in hepatic uptake of drugs that have little alternative extrahepatic clearance (e.g., renal clearance), will often result in markedly increased plasma levels of the drug, but only very small changes in the liver AUC. Accordingly, liver-to- plasma concentration ratios will decrease, but mainly due to the increased plasma concentrations of the drug. This is exactly the behavior that was observed for docetaxel in the studies of Iusuf et al. (2015) and Lee et al. (2015), but also earlier for rosuvastatin, another OATP substrate (Iusuf et al., 2013). Only the earlier data of De Graan et al. (2012), which appeared to show a >4-fold increase in liver AUC of docetaxel in Oatp1b2(-/-) mice are not yet adequately explained. Nonetheless, the collective data in Oatp knockout and various OATP1B-humanized strains provide strong support for the concept thatmouseOatp1b2 andhumanOATP1B1 and OATP1B3 in the sinusoidal membrane of the liver can contribute substantially to the liver uptake of docetaxel, and thus its plasma clearance as shown in Figure 3A and B . It is further noteworthy that the contribution to docetaxel clearance of OATP1B1 and OATP1B3 in the human liver will likely be at least additive. It could therefore be that coadministration of docetaxel with strong inhibitors of OATP1B1 and OATP1B3 might result in unwarranted overexposure of patients to docetaxel, which only has a narrow therapeutic window. 2 . 1 . 3 . Caba z i t a xe l The taxane cabazitaxel was recently introduced in the clinic as a second-line treatment of hormone-refractory prostate cancer. Amongst others this compound is less affected