The Experts below are selected from a list of 16827 Experts worldwide ranked by ideXlab platform
Alfred H. Schinkel - One of the best experts on this subject based on the ideXlab platform.
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p glycoprotein mdr1 abcb1 controls brain accumulation and intestinal disposition of the novel tgf β signaling pathway inhibitor galunisertib
International Journal of Cancer, 2020Co-Authors: M M Tibben, Yaogeng Wang, Hilde Rosing, Maria C Lebre, Jos H. Beijnen, Alfred H. SchinkelAbstract:Galunisertib (LY2157299), a promising small-molecule inhibitor of the transforming growth factor-beta (TGF-β) receptor, is currently in mono- and combination therapy trials for various cancers including glioblastoma, hepatocellular carcinoma and breast cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters and the drug-metabolizing CYP3A complex in galunisertib pharmacokinetics. In vitro, galunisertib was vigorously transported by human ABCB1, and moderately by mouse Abcg2. Orally administered galunisertib (20 mg/kg) was very rapidly absorbed. Galunisertib brain-to-plasma ratios were increased by ~24-fold in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type mice, but not in single Abcg2-/- mice, whereas galunisertib oral availability was not markedly affected. However, recovery of galunisertib in the small intestinal lumen was strongly reduced in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted galunisertib brain accumulation in wild-type mice to equal the levels seen in Abcb1a/1b;Abcg2-/- mice. Oatp1a/1b deficiency did not alter oral galunisertib pharmacokinetics or liver distribution. Cyp3a-/- mice showed a 1.9-fold higher plasma AUC0-1 hr than wild-type mice, but this difference disappeared over 8 hr. Also, transgenic human CYP3A4 overexpression did not significantly alter oral galunisertib pharmacokinetics. Abcb1 thus markedly restricts galunisertib brain penetration and affects its intestinal disposition, possibly through biliary excretion. Elacridar coadministration could fully inhibit both processes, without causing acute toxicity. Moreover, mouse Cyp3a, but not human CYP3A4, may eliminate galunisertib at high plasma concentrations. These insights may help to guide the further clinical development and application of galunisertib.
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p glycoprotein abcb1 mdr1 limits brain accumulation and cytochrome p450 3a cyp3a restricts oral availability of the novel fgfr4 inhibitor fisogatinib blu 554
International Journal of Pharmaceutics, 2020Co-Authors: Wenlong Li, Yaogeng Wang, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Mujtaba Ellari, Alfred H. SchinkelAbstract:Abstract Fisogatinib (BLU-554) is a highly selective and potent oral fibroblast growth factor receptor 4 (FGFR4) inhibitor currently in Phase I clinical trials for treatment of hepatocellular carcinoma (HCC). Using (male) genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in fisogatinib pharmacokinetics. In vitro, fisogatinib was modestly transported by hABCB1. Upon oral administration of 10 mg/kg fisogatinib, its brain accumulation was substantially increased in Abcb1a/1b−/− (6.3-fold) and Abcb1a/1b;Abcg2−/− mice (7.2-fold) compared to wild-type mice, but not in single Abcg2−/− mice. The oral plasma pharmacokinetics and liver distribution of fisogatinib were not significantly affected by the absence of Oatp1a/1b drug uptake transporters. We further found that plasma exposure of fisogatinib in Cyp3a−/− mice increased by 1.4-fold, and was subsequently 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. However, the relative tissue distribution of fisogatinib remained unaltered. In summary, in mice, fisogatinib brain accumulation is substantially limited by ABCB1 P-glycoprotein in the blood-brain barrier, and oral availability of fisogatinib is markedly restricted by CYP3A activity. The obtained insights may be useful for optimizing the clinical efficacy and safety of fisogatinib.
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p glycoprotein mdr1 abcb1 and breast cancer resistance protein bcrp abcg2 limit brain accumulation of the flt3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2019Co-Authors: Jing Wang, Irene A Retmana, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Alfred H. SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) limit brain accumulation of the FLT3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2018Co-Authors: Jing Wang, Irene A Retmana, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Alfred H. SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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p glycoprotein mdr1 abcb1 restricts brain accumulation and cytochrome p450 3a cyp3a limits oral availability of the novel alk ros1 inhibitor lorlatinib
International Journal of Cancer, 2018Co-Authors: Wenlong Li, Yaogeng Wang, Els Wagenaar, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Alfred H. SchinkelAbstract:Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small-cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains. In vitro, human ABCB1 and mouse Abcg2 modestly transported lorlatinib. Following oral lorlatinib administration (at 10 mg/kg), brain accumulation of lorlatinib, while relatively high in wild-type mice, was still fourfold increased in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice, but not in single Abcg2-/- mice. Lorlatinib plasma levels were not altered. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar increased the brain accumulation of lorlatinib in wild-type mice fourfold, that is, to the same level as in Abcb1a/1b;Abcg2-/- mice, without altering plasma exposure. Similar results were obtained for lorlatinib testis accumulation. In Cyp3a-/- mice, the plasma exposure of lorlatinib was increased 1.3-fold, but was then twofold reduced upon transgenic overexpression of human CYP3A4 in liver and intestine, whereas relative tissue distribution of lorlatinib remained unaltered. Our data indicate that lorlatinib brain accumulation is substantially limited by P-glycoprotein/ABCB1 in the blood-brain barrier, but this can be effectively reversed by elacridar coadministration. Moreover, oral availability of lorlatinib is markedly restricted by CYP3A4 activity. These insights may be used in optimizing the therapeutic application of lorlatinib.
Jos H. Beijnen - One of the best experts on this subject based on the ideXlab platform.
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p glycoprotein mdr1 abcb1 controls brain accumulation and intestinal disposition of the novel tgf β signaling pathway inhibitor galunisertib
International Journal of Cancer, 2020Co-Authors: M M Tibben, Yaogeng Wang, Hilde Rosing, Maria C Lebre, Jos H. Beijnen, Alfred H. SchinkelAbstract:Galunisertib (LY2157299), a promising small-molecule inhibitor of the transforming growth factor-beta (TGF-β) receptor, is currently in mono- and combination therapy trials for various cancers including glioblastoma, hepatocellular carcinoma and breast cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters and the drug-metabolizing CYP3A complex in galunisertib pharmacokinetics. In vitro, galunisertib was vigorously transported by human ABCB1, and moderately by mouse Abcg2. Orally administered galunisertib (20 mg/kg) was very rapidly absorbed. Galunisertib brain-to-plasma ratios were increased by ~24-fold in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type mice, but not in single Abcg2-/- mice, whereas galunisertib oral availability was not markedly affected. However, recovery of galunisertib in the small intestinal lumen was strongly reduced in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted galunisertib brain accumulation in wild-type mice to equal the levels seen in Abcb1a/1b;Abcg2-/- mice. Oatp1a/1b deficiency did not alter oral galunisertib pharmacokinetics or liver distribution. Cyp3a-/- mice showed a 1.9-fold higher plasma AUC0-1 hr than wild-type mice, but this difference disappeared over 8 hr. Also, transgenic human CYP3A4 overexpression did not significantly alter oral galunisertib pharmacokinetics. Abcb1 thus markedly restricts galunisertib brain penetration and affects its intestinal disposition, possibly through biliary excretion. Elacridar coadministration could fully inhibit both processes, without causing acute toxicity. Moreover, mouse Cyp3a, but not human CYP3A4, may eliminate galunisertib at high plasma concentrations. These insights may help to guide the further clinical development and application of galunisertib.
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p glycoprotein abcb1 mdr1 limits brain accumulation and cytochrome p450 3a cyp3a restricts oral availability of the novel fgfr4 inhibitor fisogatinib blu 554
International Journal of Pharmaceutics, 2020Co-Authors: Wenlong Li, Yaogeng Wang, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Mujtaba Ellari, Alfred H. SchinkelAbstract:Abstract Fisogatinib (BLU-554) is a highly selective and potent oral fibroblast growth factor receptor 4 (FGFR4) inhibitor currently in Phase I clinical trials for treatment of hepatocellular carcinoma (HCC). Using (male) genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in fisogatinib pharmacokinetics. In vitro, fisogatinib was modestly transported by hABCB1. Upon oral administration of 10 mg/kg fisogatinib, its brain accumulation was substantially increased in Abcb1a/1b−/− (6.3-fold) and Abcb1a/1b;Abcg2−/− mice (7.2-fold) compared to wild-type mice, but not in single Abcg2−/− mice. The oral plasma pharmacokinetics and liver distribution of fisogatinib were not significantly affected by the absence of Oatp1a/1b drug uptake transporters. We further found that plasma exposure of fisogatinib in Cyp3a−/− mice increased by 1.4-fold, and was subsequently 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. However, the relative tissue distribution of fisogatinib remained unaltered. In summary, in mice, fisogatinib brain accumulation is substantially limited by ABCB1 P-glycoprotein in the blood-brain barrier, and oral availability of fisogatinib is markedly restricted by CYP3A activity. The obtained insights may be useful for optimizing the clinical efficacy and safety of fisogatinib.
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p glycoprotein mdr1 abcb1 and breast cancer resistance protein bcrp abcg2 limit brain accumulation of the flt3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2019Co-Authors: Jing Wang, Irene A Retmana, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Alfred H. SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) limit brain accumulation of the FLT3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2018Co-Authors: Jing Wang, Irene A Retmana, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Alfred H. SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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p glycoprotein mdr1 abcb1 restricts brain accumulation and cytochrome p450 3a cyp3a limits oral availability of the novel alk ros1 inhibitor lorlatinib
International Journal of Cancer, 2018Co-Authors: Wenlong Li, Yaogeng Wang, Els Wagenaar, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Alfred H. SchinkelAbstract:Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small-cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains. In vitro, human ABCB1 and mouse Abcg2 modestly transported lorlatinib. Following oral lorlatinib administration (at 10 mg/kg), brain accumulation of lorlatinib, while relatively high in wild-type mice, was still fourfold increased in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice, but not in single Abcg2-/- mice. Lorlatinib plasma levels were not altered. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar increased the brain accumulation of lorlatinib in wild-type mice fourfold, that is, to the same level as in Abcb1a/1b;Abcg2-/- mice, without altering plasma exposure. Similar results were obtained for lorlatinib testis accumulation. In Cyp3a-/- mice, the plasma exposure of lorlatinib was increased 1.3-fold, but was then twofold reduced upon transgenic overexpression of human CYP3A4 in liver and intestine, whereas relative tissue distribution of lorlatinib remained unaltered. Our data indicate that lorlatinib brain accumulation is substantially limited by P-glycoprotein/ABCB1 in the blood-brain barrier, but this can be effectively reversed by elacridar coadministration. Moreover, oral availability of lorlatinib is markedly restricted by CYP3A4 activity. These insights may be used in optimizing the therapeutic application of lorlatinib.
Rolf W Sparidans - One of the best experts on this subject based on the ideXlab platform.
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p glycoprotein abcb1 mdr1 limits brain accumulation and cytochrome p450 3a cyp3a restricts oral availability of the novel fgfr4 inhibitor fisogatinib blu 554
International Journal of Pharmaceutics, 2020Co-Authors: Wenlong Li, Yaogeng Wang, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Mujtaba Ellari, Alfred H. SchinkelAbstract:Abstract Fisogatinib (BLU-554) is a highly selective and potent oral fibroblast growth factor receptor 4 (FGFR4) inhibitor currently in Phase I clinical trials for treatment of hepatocellular carcinoma (HCC). Using (male) genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in fisogatinib pharmacokinetics. In vitro, fisogatinib was modestly transported by hABCB1. Upon oral administration of 10 mg/kg fisogatinib, its brain accumulation was substantially increased in Abcb1a/1b−/− (6.3-fold) and Abcb1a/1b;Abcg2−/− mice (7.2-fold) compared to wild-type mice, but not in single Abcg2−/− mice. The oral plasma pharmacokinetics and liver distribution of fisogatinib were not significantly affected by the absence of Oatp1a/1b drug uptake transporters. We further found that plasma exposure of fisogatinib in Cyp3a−/− mice increased by 1.4-fold, and was subsequently 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. However, the relative tissue distribution of fisogatinib remained unaltered. In summary, in mice, fisogatinib brain accumulation is substantially limited by ABCB1 P-glycoprotein in the blood-brain barrier, and oral availability of fisogatinib is markedly restricted by CYP3A activity. The obtained insights may be useful for optimizing the clinical efficacy and safety of fisogatinib.
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p glycoprotein mdr1 abcb1 and breast cancer resistance protein bcrp abcg2 limit brain accumulation of the flt3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2019Co-Authors: Jing Wang, Irene A Retmana, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Alfred H. SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) limit brain accumulation of the FLT3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2018Co-Authors: Jing Wang, Irene A Retmana, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Alfred H. SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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p glycoprotein mdr1 abcb1 restricts brain accumulation and cytochrome p450 3a cyp3a limits oral availability of the novel alk ros1 inhibitor lorlatinib
International Journal of Cancer, 2018Co-Authors: Wenlong Li, Yaogeng Wang, Els Wagenaar, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Alfred H. SchinkelAbstract:Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small-cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains. In vitro, human ABCB1 and mouse Abcg2 modestly transported lorlatinib. Following oral lorlatinib administration (at 10 mg/kg), brain accumulation of lorlatinib, while relatively high in wild-type mice, was still fourfold increased in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice, but not in single Abcg2-/- mice. Lorlatinib plasma levels were not altered. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar increased the brain accumulation of lorlatinib in wild-type mice fourfold, that is, to the same level as in Abcb1a/1b;Abcg2-/- mice, without altering plasma exposure. Similar results were obtained for lorlatinib testis accumulation. In Cyp3a-/- mice, the plasma exposure of lorlatinib was increased 1.3-fold, but was then twofold reduced upon transgenic overexpression of human CYP3A4 in liver and intestine, whereas relative tissue distribution of lorlatinib remained unaltered. Our data indicate that lorlatinib brain accumulation is substantially limited by P-glycoprotein/ABCB1 in the blood-brain barrier, but this can be effectively reversed by elacridar coadministration. Moreover, oral availability of lorlatinib is markedly restricted by CYP3A4 activity. These insights may be used in optimizing the therapeutic application of lorlatinib.
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p glycoprotein mdr1 abcb1 restricts brain penetration of the bruton s tyrosine kinase inhibitor ibrutinib while cytochrome p450 3a cyp3a limits its oral bioavailability
Molecular Pharmaceutics, 2018Co-Authors: Stephanie Van Hoppe, Levi C M Buil, Els Wagenaar, Rolf W Sparidans, Johannes J M Rood, Jos H. BeijnenAbstract:Ibrutinib (Imbruvica), an oral tyrosine kinase inhibitor (TKI) approved for treatment of B-cell malignancies, irreversibly inhibits the Bruton’s tyrosine kinase (BTK). Its abundant metabolite, dihydrodiol-ibrutinib (ibrutinib-DiOH), which is primarily formed by CYP3A, has a 10-fold reduced BTK inhibitory activity. Using in vitro transport assays and genetically modified mouse models, we investigated whether the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug-metabolizing CYP3A enzyme family can affect the oral bioavailability and tissue disposition of ibrutinib and ibrutinib-DiOH. In vitro, ibrutinib was transported moderately by human ABCB1 and mouse Abcg2 but not detectably by human ABCG2. In mice, Abcb1 markedly restricted the brain penetration of ibrutinib and ibrutinib-DiOH, either alone or in combination with Abcg2, resulting in 4.5- and 5.9-fold increases in ibrutinib brain-to-plasma ratios in Abcb1a/1b–/– and Abcb1a/1b;Abcg2–/– mice relative to wild-type mice. Abcb1 and/or Abcg2 di...
Els Wagenaar - One of the best experts on this subject based on the ideXlab platform.
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p glycoprotein mdr1 abcb1 restricts brain accumulation and cytochrome p450 3a cyp3a limits oral availability of the novel alk ros1 inhibitor lorlatinib
International Journal of Cancer, 2018Co-Authors: Wenlong Li, Yaogeng Wang, Els Wagenaar, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Alfred H. SchinkelAbstract:Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small-cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains. In vitro, human ABCB1 and mouse Abcg2 modestly transported lorlatinib. Following oral lorlatinib administration (at 10 mg/kg), brain accumulation of lorlatinib, while relatively high in wild-type mice, was still fourfold increased in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice, but not in single Abcg2-/- mice. Lorlatinib plasma levels were not altered. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar increased the brain accumulation of lorlatinib in wild-type mice fourfold, that is, to the same level as in Abcb1a/1b;Abcg2-/- mice, without altering plasma exposure. Similar results were obtained for lorlatinib testis accumulation. In Cyp3a-/- mice, the plasma exposure of lorlatinib was increased 1.3-fold, but was then twofold reduced upon transgenic overexpression of human CYP3A4 in liver and intestine, whereas relative tissue distribution of lorlatinib remained unaltered. Our data indicate that lorlatinib brain accumulation is substantially limited by P-glycoprotein/ABCB1 in the blood-brain barrier, but this can be effectively reversed by elacridar coadministration. Moreover, oral availability of lorlatinib is markedly restricted by CYP3A4 activity. These insights may be used in optimizing the therapeutic application of lorlatinib.
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p glycoprotein mdr1 abcb1 restricts brain penetration of the bruton s tyrosine kinase inhibitor ibrutinib while cytochrome p450 3a cyp3a limits its oral bioavailability
Molecular Pharmaceutics, 2018Co-Authors: Stephanie Van Hoppe, Levi C M Buil, Els Wagenaar, Rolf W Sparidans, Johannes J M Rood, Jos H. BeijnenAbstract:Ibrutinib (Imbruvica), an oral tyrosine kinase inhibitor (TKI) approved for treatment of B-cell malignancies, irreversibly inhibits the Bruton’s tyrosine kinase (BTK). Its abundant metabolite, dihydrodiol-ibrutinib (ibrutinib-DiOH), which is primarily formed by CYP3A, has a 10-fold reduced BTK inhibitory activity. Using in vitro transport assays and genetically modified mouse models, we investigated whether the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug-metabolizing CYP3A enzyme family can affect the oral bioavailability and tissue disposition of ibrutinib and ibrutinib-DiOH. In vitro, ibrutinib was transported moderately by human ABCB1 and mouse Abcg2 but not detectably by human ABCG2. In mice, Abcb1 markedly restricted the brain penetration of ibrutinib and ibrutinib-DiOH, either alone or in combination with Abcg2, resulting in 4.5- and 5.9-fold increases in ibrutinib brain-to-plasma ratios in Abcb1a/1b–/– and Abcb1a/1b;Abcg2–/– mice relative to wild-type mice. Abcb1 and/or Abcg2 di...
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p glycoprotein mdr1 abcb1 restricts brain penetration of the bruton s tyrosine kinase inhibitor ibrutinib while cytochrome p450 3a cyp3a limits its oral bioavailability
Molecular Pharmaceutics, 2018Co-Authors: Stephanie Van Hoppe, Levi C M Buil, Els Wagenaar, Rolf W Sparidans, Johannes J M Rood, Jos H. Beijnen, Alfred H. SchinkelAbstract:Ibrutinib (Imbruvica), an oral tyrosine kinase inhibitor (TKI) approved for treatment of B-cell malignancies, irreversibly inhibits the Bruton's tyrosine kinase (BTK). Its abundant metabolite, dihydrodiol-ibrutinib (ibrutinib-DiOH), which is primarily formed by CYP3A, has a 10-fold reduced BTK inhibitory activity. Using in vitro transport assays and genetically modified mouse models, we investigated whether the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug-metabolizing CYP3A enzyme family can affect the oral bioavailability and tissue disposition of ibrutinib and ibrutinib-DiOH. In vitro, ibrutinib was transported moderately by human ABCB1 and mouse Abcg2 but not detectably by human ABCG2. In mice, Abcb1 markedly restricted the brain penetration of ibrutinib and ibrutinib-DiOH, either alone or in combination with Abcg2, resulting in 4.5- and 5.9-fold increases in ibrutinib brain-to-plasma ratios in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice relative to wild-type mice. Abcb1 and/or Abcg2 did not obviously restrict ibrutinib oral bioavailability, but Cyp3a deficiency increased the ibrutinib plasma AUC by 9.7-fold compared to wild-type mice. This increase was mostly reversed (5.1-fold reduction) by transgenic human CYP3A4 overexpression, with roughly equal contributions of intestinal and hepatic CYP3A4 metabolism. Our results suggest that pharmacological inhibition of ABCB1 during ibrutinib therapy might benefit patients with malignancies or (micro)metastases positioned behind an intact blood-brain barrier, or with substantial expression of this transporter in the malignant cells. Moreover, given the strong in vivo impact of CYP3A, inhibitors or inducers of this enzyme family will likely strongly affect ibrutinib oral bioavailability and, thus, its therapeutic efficacy, as well as its toxicity risks.
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P-glycoprotein (MDR1/ABCB1) restricts brain accumulation and cytochrome P450-3A (CYP3A) limits oral availability of the novel ALK/ROS1 inhibitor lorlatinib.
International Journal of Cancer, 2018Co-Authors: Wenlong Li, Yaogeng Wang, Els Wagenaar, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Alfred H. SchinkelAbstract:Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small-cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains. In vitro, human ABCB1 and mouse Abcg2 modestly transported lorlatinib. Following oral lorlatinib administration (at 10 mg/kg), brain accumulation of lorlatinib, while relatively high in wild-type mice, was still fourfold increased in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice, but not in single Abcg2-/- mice. Lorlatinib plasma levels were not altered. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar increased the brain accumulation of lorlatinib in wild-type mice fourfold, that is, to the same level as in Abcb1a/1b;Abcg2-/- mice, without altering plasma exposure. Similar results were obtained for lorlatinib testis accumulation. In Cyp3a-/- mice, the plasma exposure of lorlatinib was increased 1.3-fold, but was then twofold reduced upon transgenic overexpression of human CYP3A4 in liver and intestine, whereas relative tissue distribution of lorlatinib remained unaltered. Our data indicate that lorlatinib brain accumulation is substantially limited by P-glycoprotein/ABCB1 in the blood-brain barrier, but this can be effectively reversed by elacridar coadministration. Moreover, oral availability of lorlatinib is markedly restricted by CYP3A4 activity. These insights may be used in optimizing the therapeutic application of lorlatinib.
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breast cancer resistance protein bcrp abcg2 and p glycoprotein p gp abcb1 transport afatinib and restrict its oral availability and brain accumulation
Pharmacological Research, 2017Co-Authors: Stephanie Van Hoppe, Els Wagenaar, Rolf W Sparidans, Jos H. Beijnen, Alfred H. SchinkelAbstract:Afatinib is a highly selective, irreversible inhibitor of EGFR and HER-2. It is orally administered for the treatment of patients with EGFR mutation-positive types of metastatic NSCLC. We investigated whether afatinib is a substrate for the multidrug efflux transporters ABCB1 and ABCG2 and whether these transporters influence oral availability and brain and other tissue accumulation of afatinib. We used in vitro transport assays to assess human (h)ABCB1-, hABCG2- or murine (m)Abcg2-mediated transport of afatinib. To study the single and combined roles of Abcg2 and Abcb1a/1b in oral afatinib disposition, we used appropriate knockout mouse strains. Afatinib was transported well by hABCB1, hABCG2 and mAbcg2 in vitro. Upon oral administration of afatinib, Abcg2-/-, Abcb1a/1b-/- and Abcb1a/1b-/-;Abcg2-/- mice displayed a 4.2-, 2.4- and 7-fold increased afatinib plasma AUC0-24 compared with wild-type mice. Abcg2-deficient strains also displayed decreased afatinib plasma clearance. At 2h, relative brain accumulation of afatinib was not significantly altered in the single knockout strains, but 23.8-fold increased in Abcb1a/1b-/-;Abcg2-/- mice compared to wild-type mice. Abcg2 and Abcb1a/1b restrict oral availability and brain accumulation of afatinib. Inhibition of these transporters may therefore be of clinical importance for patients with brain (micro)metastases positioned behind an intact blood-brain barrier.
Maria C Lebre - One of the best experts on this subject based on the ideXlab platform.
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p glycoprotein mdr1 abcb1 controls brain accumulation and intestinal disposition of the novel tgf β signaling pathway inhibitor galunisertib
International Journal of Cancer, 2020Co-Authors: M M Tibben, Yaogeng Wang, Hilde Rosing, Maria C Lebre, Jos H. Beijnen, Alfred H. SchinkelAbstract:Galunisertib (LY2157299), a promising small-molecule inhibitor of the transforming growth factor-beta (TGF-β) receptor, is currently in mono- and combination therapy trials for various cancers including glioblastoma, hepatocellular carcinoma and breast cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters and the drug-metabolizing CYP3A complex in galunisertib pharmacokinetics. In vitro, galunisertib was vigorously transported by human ABCB1, and moderately by mouse Abcg2. Orally administered galunisertib (20 mg/kg) was very rapidly absorbed. Galunisertib brain-to-plasma ratios were increased by ~24-fold in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type mice, but not in single Abcg2-/- mice, whereas galunisertib oral availability was not markedly affected. However, recovery of galunisertib in the small intestinal lumen was strongly reduced in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar boosted galunisertib brain accumulation in wild-type mice to equal the levels seen in Abcb1a/1b;Abcg2-/- mice. Oatp1a/1b deficiency did not alter oral galunisertib pharmacokinetics or liver distribution. Cyp3a-/- mice showed a 1.9-fold higher plasma AUC0-1 hr than wild-type mice, but this difference disappeared over 8 hr. Also, transgenic human CYP3A4 overexpression did not significantly alter oral galunisertib pharmacokinetics. Abcb1 thus markedly restricts galunisertib brain penetration and affects its intestinal disposition, possibly through biliary excretion. Elacridar coadministration could fully inhibit both processes, without causing acute toxicity. Moreover, mouse Cyp3a, but not human CYP3A4, may eliminate galunisertib at high plasma concentrations. These insights may help to guide the further clinical development and application of galunisertib.
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p glycoprotein abcb1 mdr1 limits brain accumulation and cytochrome p450 3a cyp3a restricts oral availability of the novel fgfr4 inhibitor fisogatinib blu 554
International Journal of Pharmaceutics, 2020Co-Authors: Wenlong Li, Yaogeng Wang, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Mujtaba Ellari, Alfred H. SchinkelAbstract:Abstract Fisogatinib (BLU-554) is a highly selective and potent oral fibroblast growth factor receptor 4 (FGFR4) inhibitor currently in Phase I clinical trials for treatment of hepatocellular carcinoma (HCC). Using (male) genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in fisogatinib pharmacokinetics. In vitro, fisogatinib was modestly transported by hABCB1. Upon oral administration of 10 mg/kg fisogatinib, its brain accumulation was substantially increased in Abcb1a/1b−/− (6.3-fold) and Abcb1a/1b;Abcg2−/− mice (7.2-fold) compared to wild-type mice, but not in single Abcg2−/− mice. The oral plasma pharmacokinetics and liver distribution of fisogatinib were not significantly affected by the absence of Oatp1a/1b drug uptake transporters. We further found that plasma exposure of fisogatinib in Cyp3a−/− mice increased by 1.4-fold, and was subsequently 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. However, the relative tissue distribution of fisogatinib remained unaltered. In summary, in mice, fisogatinib brain accumulation is substantially limited by ABCB1 P-glycoprotein in the blood-brain barrier, and oral availability of fisogatinib is markedly restricted by CYP3A activity. The obtained insights may be useful for optimizing the clinical efficacy and safety of fisogatinib.
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p glycoprotein mdr1 abcb1 and breast cancer resistance protein bcrp abcg2 limit brain accumulation of the flt3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2019Co-Authors: Jing Wang, Irene A Retmana, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Alfred H. SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) limit brain accumulation of the FLT3 inhibitor quizartinib in mice
International Journal of Pharmaceutics, 2018Co-Authors: Jing Wang, Irene A Retmana, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Changpei Gan, Alfred H. SchinkelAbstract:Abstract Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b−/− and Abcb1a/1b;Abcg2−/− mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33–51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.
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p glycoprotein mdr1 abcb1 restricts brain accumulation and cytochrome p450 3a cyp3a limits oral availability of the novel alk ros1 inhibitor lorlatinib
International Journal of Cancer, 2018Co-Authors: Wenlong Li, Yaogeng Wang, Els Wagenaar, Maria C Lebre, Rolf W Sparidans, Jos H. Beijnen, Alfred H. SchinkelAbstract:Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small-cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains. In vitro, human ABCB1 and mouse Abcg2 modestly transported lorlatinib. Following oral lorlatinib administration (at 10 mg/kg), brain accumulation of lorlatinib, while relatively high in wild-type mice, was still fourfold increased in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice, but not in single Abcg2-/- mice. Lorlatinib plasma levels were not altered. Oral coadministration of the ABCB1/ABCG2 inhibitor elacridar increased the brain accumulation of lorlatinib in wild-type mice fourfold, that is, to the same level as in Abcb1a/1b;Abcg2-/- mice, without altering plasma exposure. Similar results were obtained for lorlatinib testis accumulation. In Cyp3a-/- mice, the plasma exposure of lorlatinib was increased 1.3-fold, but was then twofold reduced upon transgenic overexpression of human CYP3A4 in liver and intestine, whereas relative tissue distribution of lorlatinib remained unaltered. Our data indicate that lorlatinib brain accumulation is substantially limited by P-glycoprotein/ABCB1 in the blood-brain barrier, but this can be effectively reversed by elacridar coadministration. Moreover, oral availability of lorlatinib is markedly restricted by CYP3A4 activity. These insights may be used in optimizing the therapeutic application of lorlatinib.
