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Jos H Beijnen - One of the best experts on this subject based on the ideXlab platform.

  • Quantitative analysis of the P‐glycoprotein inhibitor Elacridar (GF120918) in human and dog plasma using liquid chromatography with tandem mass spectrometric detection
    Journal of Mass Spectrometry, 2020
    Co-Authors: E Stokvis, Jan H M Schellens, Hilde Rosing, Roger C Causon, Jos H Beijnen
    Abstract:

    A liquid chromatographic/tandem mass spectrometric (LC/MS/MS) method for the determination of the P-glycoprotein and breast cancer resistance protein inhibitor Elacridar in human and dog plasma is described. The internal standard was stable isotopically labelled Elacridar. Sample pretreatment involved liquid–liquid extraction with tert-butyl methyl ether. Analysis of Elacridar and internal standard was performed by reversed-phase LC on a basic stable minibore analytical column with an eluent consisting of acetonitrile and aqueous ammonia. An API-2000 triple-quadrupole mass spectrometer with an electrospray ion source was used in the positive-ion multiple reaction monitoring mode. The run time per sample was only 6 min. The method is sensitive and specific, with a dynamic range from 1 to 500 ng ml−1 from 100 µl of human or dog plasma. The accuracy of the method was within 15% bias and the precision was lower than 15% for all tested concentration levels and in both matrices. The method is simple and the liquid–liquid extraction produces clean samples. This method was successfully applied to support the pharmacokinetics of a clinical trial in which orally applied Elacridar was used as a bioavailability enhancer. Copyright © 2004 John Wiley & Sons, Ltd.

  • P‐glycoprotein (MDR1/ABCB1) controls brain accumulation and intestinal disposition of the novel TGF‐β signaling pathway inhibitor galunisertib
    International Journal of Cancer, 2019
    Co-Authors: Wenlong Li, Jos H Beijnen, Hilde Rosing, Yaogeng Wang, Maria C Lebre, M. M. Tibben, Alfred H. Schinkel
    Abstract:

    Galunisertib (LY2157299), a promising small-molecule inhibitor of the transforming growth factor-beta (TGF-beta) 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.

  • oral coadministration of Elacridar and ritonavir enhances brain accumulation and oral availability of the novel alk ros1 inhibitor lorlatinib
    European Journal of Pharmaceutics and Biopharmaceutics, 2019
    Co-Authors: Wenlong Li, Jos H Beijnen, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Alfred H. Schinkel
    Abstract:

    Abstract Lorlatinib, a novel generation oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor with high membrane and blood-brain barrier permeability, recently received accelerated approval for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), and its further clinical development is ongoing. We previously found that the efflux transporter P-glycoprotein (MDR1/ABCB1) restricts lorlatinib brain accumulation and that the drug-metabolizing enzyme cytochrome P450-3A (CYP3A) limits its oral availability. Using genetically modified mouse models, we investigated the impact of targeted pharmacological inhibitors on lorlatinib pharmacokinetics and bioavailability. Upon oral administration of lorlatinib, the plasma AUC0-8h in CYP3A4-humanized mice was ∼1.8-fold lower than in wild-type and Cyp3a–/– mice. Oral coadministration of the CYP3A inhibitor ritonavir caused reversion to the AUC0-8h levels seen in wild-type and Cyp3a–/– mice, without altering the relative tissue distribution of lorlatinib. Moreover, simultaneous pharmacological inhibition of P-glycoprotein and CYP3A4 with oral Elacridar and ritonavir in CYP3A4-humanized mice profoundly increased lorlatinib brain concentrations, but not its oral availability or other relative tissue distribution. Oral lorlatinib pharmacokinetics was not significantly affected by absence of the multispecific Oatp1a/1b drug uptake transporters. The absolute oral bioavailability of lorlatinib over 8 h in wild-type, Cyp3a–/–, and CYP3A4-humanized mice was 81.6%, 72.9%, and 58.5%, respectively. Lorlatinib thus has good oral bioavailability, which is markedly restricted by human CYP3A4 but not by mouse Cyp3a. Pharmacological inhibition of CYP3A4 reversed these effects, and simultaneous P-gp inhibition with Elacridar boosted absolute brain levels of lorlatinib by 16-fold without obvious toxicity. These insights may help to optimize the clinical application of lorlatinib.

  • Oral coadministration of Elacridar and ritonavir enhances brain accumulation and oral availability of the novel ALK/ROS1 inhibitor lorlatinib
    European Journal of Pharmaceutics and Biopharmaceutics, 2019
    Co-Authors: Wenlong Li, Jos H Beijnen, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Alfred H. Schinkel
    Abstract:

    Abstract Lorlatinib, a novel generation oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor with high membrane and blood-brain barrier permeability, recently received accelerated approval for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), and its further clinical development is ongoing. We previously found that the efflux transporter P-glycoprotein (MDR1/ABCB1) restricts lorlatinib brain accumulation and that the drug-metabolizing enzyme cytochrome P450-3A (CYP3A) limits its oral availability. Using genetically modified mouse models, we investigated the impact of targeted pharmacological inhibitors on lorlatinib pharmacokinetics and bioavailability. Upon oral administration of lorlatinib, the plasma AUC0-8h in CYP3A4-humanized mice was ∼1.8-fold lower than in wild-type and Cyp3a–/– mice. Oral coadministration of the CYP3A inhibitor ritonavir caused reversion to the AUC0-8h levels seen in wild-type and Cyp3a–/– mice, without altering the relative tissue distribution of lorlatinib. Moreover, simultaneous pharmacological inhibition of P-glycoprotein and CYP3A4 with oral Elacridar and ritonavir in CYP3A4-humanized mice profoundly increased lorlatinib brain concentrations, but not its oral availability or other relative tissue distribution. Oral lorlatinib pharmacokinetics was not significantly affected by absence of the multispecific Oatp1a/1b drug uptake transporters. The absolute oral bioavailability of lorlatinib over 8 h in wild-type, Cyp3a–/–, and CYP3A4-humanized mice was 81.6%, 72.9%, and 58.5%, respectively. Lorlatinib thus has good oral bioavailability, which is markedly restricted by human CYP3A4 but not by mouse Cyp3a. Pharmacological inhibition of CYP3A4 reversed these effects, and simultaneous P-gp inhibition with Elacridar boosted absolute brain levels of lorlatinib by 16-fold without obvious toxicity. These insights may help to optimize the clinical application of lorlatinib.

  • 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, 2018
    Co-Authors: Wenlong Li, Jos H Beijnen, Els Wagenaar, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Alfred H. Schinkel
    Abstract:

    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.

Jan H M Schellens - One of the best experts on this subject based on the ideXlab platform.

  • Quantitative analysis of the P‐glycoprotein inhibitor Elacridar (GF120918) in human and dog plasma using liquid chromatography with tandem mass spectrometric detection
    Journal of Mass Spectrometry, 2020
    Co-Authors: E Stokvis, Jan H M Schellens, Hilde Rosing, Roger C Causon, Jos H Beijnen
    Abstract:

    A liquid chromatographic/tandem mass spectrometric (LC/MS/MS) method for the determination of the P-glycoprotein and breast cancer resistance protein inhibitor Elacridar in human and dog plasma is described. The internal standard was stable isotopically labelled Elacridar. Sample pretreatment involved liquid–liquid extraction with tert-butyl methyl ether. Analysis of Elacridar and internal standard was performed by reversed-phase LC on a basic stable minibore analytical column with an eluent consisting of acetonitrile and aqueous ammonia. An API-2000 triple-quadrupole mass spectrometer with an electrospray ion source was used in the positive-ion multiple reaction monitoring mode. The run time per sample was only 6 min. The method is sensitive and specific, with a dynamic range from 1 to 500 ng ml−1 from 100 µl of human or dog plasma. The accuracy of the method was within 15% bias and the precision was lower than 15% for all tested concentration levels and in both matrices. The method is simple and the liquid–liquid extraction produces clean samples. This method was successfully applied to support the pharmacokinetics of a clinical trial in which orally applied Elacridar was used as a bioavailability enhancer. Copyright © 2004 John Wiley & Sons, Ltd.

  • molecular imaging of abcb1 and abcg2 inhibition at the human blood brain barrier using Elacridar and 11c erlotinib pet
    The Journal of Nuclear Medicine, 2017
    Co-Authors: Remy B Verheijen, Emilia Sawicki, Jan H M Schellens, Jos H Beijnen, Bastiaan Nuijen, Maqsood Yaqub, Olaf Van Tellingen, Adriaan A Lammertsma
    Abstract:

    Transporters such as ABCB1 and ABCG2 limit the exposure of several anticancer drugs to the brain, leading to suboptimal treatment in the central nervous system. The purpose of this study was to investigate the effects of the ABCB1 and ABCG2 inhibitor Elacridar on brain uptake using 11C-erlotinib PET. Methods: Elacridar and cold erlotinib were administered orally to wild-type (WT) and Abcb1a/b;Abcg2 knockout mice. In addition, brain uptake was measured using 11C-erlotinib imaging and ex vivo scintillation counting in knockout and WT mice. Six patients with advanced solid tumors underwent 11C-erlotinib PET scans before and after a 1,000-mg dose of Elacridar. 11C-erlotinib brain uptake was quantified by pharmacokinetic modeling using volume of distribution (VT) as the outcome parameter. In addition, 15O-H2O scans to measure cerebral blood flow were acquired before each 11C-erlotinib scan. Results: Brain uptake of 11C-erlotinib was 2.6-fold higher in Abcb1a/b;Abcg2 knockout mice than in WT mice, measured as percentage injected dose per gram of tissue (P = 0.01). In WT mice, the addition of Elacridar (at systemic plasma concentrations of ≥200 ng/mL) resulted in an increased brain concentration of erlotinib, without affecting erlotinib plasma concentration. In patients, the VT of 11C-erlotinib did not increase after intake of Elacridar (0.213 ± 0.12 vs. 0.205 ± 0.07, P = 0.91). 15O-H2O PET showed no significant changes in cerebral blood flow. Elacridar exposure in patients was 401 ± 154 ng/mL. No increase in VT with increased Elacridar plasma exposure was found over the 271-619 ng/mL range. Conclusion: When Abcb1 and Abcg2 were disrupted in mice, brain uptake of 11C-erlotinib increased both at a tracer dose and at a pharmacologic dose. In patients, brain uptake of 11C-erlotinib was not higher after administration of Elacridar. The more pronounced role that ABCG2 appears to play at the human blood-brain barrier and the lower potency of Elacridar to inhibit ABCG2 may be an explanation of these interspecies differences.

  • Molecular Imaging of ABCB1 and ABCG2 Inhibition at the Human Blood–Brain Barrier Using Elacridar and 11C-Erlotinib PET
    The Journal of Nuclear Medicine, 2017
    Co-Authors: Remy B Verheijen, Emilia Sawicki, Jan H M Schellens, Jos H Beijnen, Bastiaan Nuijen, Maqsood Yaqub, Olaf Van Tellingen, Adriaan A Lammertsma, Alwin D. R. Huitema, N. Harry Hendrikse
    Abstract:

    Transporters such as ABCB1 and ABCG2 limit the exposure of several anticancer drugs to the brain, leading to suboptimal treatment in the central nervous system. The purpose of this study was to investigate the effects of the ABCB1 and ABCG2 inhibitor Elacridar on brain uptake using 11C-erlotinib PET. Methods: Elacridar and cold erlotinib were administered orally to wild-type (WT) and Abcb1a/b;Abcg2 knockout mice. In addition, brain uptake was measured using 11C-erlotinib imaging and ex vivo scintillation counting in knockout and WT mice. Six patients with advanced solid tumors underwent 11C-erlotinib PET scans before and after a 1,000-mg dose of Elacridar. 11C-erlotinib brain uptake was quantified by pharmacokinetic modeling using volume of distribution (VT) as the outcome parameter. In addition, 15O-H2O scans to measure cerebral blood flow were acquired before each 11C-erlotinib scan. Results: Brain uptake of 11C-erlotinib was 2.6-fold higher in Abcb1a/b;Abcg2 knockout mice than in WT mice, measured as percentage injected dose per gram of tissue (P = 0.01). In WT mice, the addition of Elacridar (at systemic plasma concentrations of ≥200 ng/mL) resulted in an increased brain concentration of erlotinib, without affecting erlotinib plasma concentration. In patients, the VT of 11C-erlotinib did not increase after intake of Elacridar (0.213 ± 0.12 vs. 0.205 ± 0.07, P = 0.91). 15O-H2O PET showed no significant changes in cerebral blood flow. Elacridar exposure in patients was 401 ± 154 ng/mL. No increase in VT with increased Elacridar plasma exposure was found over the 271-619 ng/mL range. Conclusion: When Abcb1 and Abcg2 were disrupted in mice, brain uptake of 11C-erlotinib increased both at a tracer dose and at a pharmacologic dose. In patients, brain uptake of 11C-erlotinib was not higher after administration of Elacridar. The more pronounced role that ABCG2 appears to play at the human blood-brain barrier and the lower potency of Elacridar to inhibit ABCG2 may be an explanation of these interspecies differences.

  • clinical pharmacokinetics of an amorphous solid dispersion tablet of Elacridar
    Drug Delivery and Translational Research, 2017
    Co-Authors: Emilia Sawicki, Jan H M Schellens, Jos H Beijnen, Bastiaan Nuijen, Remy B Verheijen, Olaf Van Tellingen, Alwin D. R. Huitema, Neeltje Steeghs
    Abstract:

    Elacridar is an inhibitor of the permeability glycoprotein (P-gp) and the breast cancer resistance protein (BCRP) and is a promising absorption enhancer of drugs that are substrates of these drug-efflux transporters. However, Elacridar is practically insoluble in water, resulting in low bioavailability which currently limits its clinical application. We evaluated the in vitro dissolution and clinical pharmacokinetics of a novel amorphous solid dispersion (ASD) tablet containing Elacridar. The dissolution from ASD tablets was compared to that from a crystalline powder mixture in a USP type II dissolution apparatus. The pharmacokinetics of the ASD tablet were evaluated in an exploratory clinical study at oral doses of 25, 250, or 1000 mg in 12 healthy volunteers. A target Cmax was set at ≥ 200 ng/mL based on previous clinical data. The in vitro dissolution from the ASD tablet was 16.9 ± 3.7 times higher compared to that from a crystalline powder mixture. Cmax and AUC0-∞ increased linearly with dose over the explored range. The target Cmax of ≥ 200 ng/mL was achieved at the 1000-mg dose level. At this dose, the Cmax and AUC0-∞ were 326 ± 67 ng/mL and 13.4 ± 8.6 · 103 ng · h/mL, respectively. In summary, the ASD tablet was well tolerated, resulted in relevant pharmacokinetic exposure, and can be used for proof-of-concept clinical studies.

  • pharmaceutical development of an amorphous solid dispersion formulation of Elacridar hydrochloride for proof of concept clinical studies
    Drug Development and Industrial Pharmacy, 2017
    Co-Authors: Emilia Sawicki, Jan H M Schellens, Jos H Beijnen, Bastiaan Nuijen
    Abstract:

    AbstractObjective: A novel tablet formulation containing an amorphous solid dispersion (ASD) of Elacridar hydrochloride was developed with the purpose to resolve the drug’s low solubility in water and to conduct proof-of-concept clinical studies.Significance: Elacridar is highly demanded for proof-of-concept clinical trials that study the drug’s suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with Elacridar were performed with a tablet containing Elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of Elacridar hydrochloride.Methods: Twenty four different ASDs were produced and dissolution was compared to crystalline Elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 m...

Alfred H. Schinkel - One of the best experts on this subject based on the ideXlab platform.

  • P‐glycoprotein (MDR1/ABCB1) controls brain accumulation and intestinal disposition of the novel TGF‐β signaling pathway inhibitor galunisertib
    International Journal of Cancer, 2019
    Co-Authors: Wenlong Li, Jos H Beijnen, Hilde Rosing, Yaogeng Wang, Maria C Lebre, M. M. Tibben, Alfred H. Schinkel
    Abstract:

    Galunisertib (LY2157299), a promising small-molecule inhibitor of the transforming growth factor-beta (TGF-beta) 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.

  • oral coadministration of Elacridar and ritonavir enhances brain accumulation and oral availability of the novel alk ros1 inhibitor lorlatinib
    European Journal of Pharmaceutics and Biopharmaceutics, 2019
    Co-Authors: Wenlong Li, Jos H Beijnen, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Alfred H. Schinkel
    Abstract:

    Abstract Lorlatinib, a novel generation oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor with high membrane and blood-brain barrier permeability, recently received accelerated approval for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), and its further clinical development is ongoing. We previously found that the efflux transporter P-glycoprotein (MDR1/ABCB1) restricts lorlatinib brain accumulation and that the drug-metabolizing enzyme cytochrome P450-3A (CYP3A) limits its oral availability. Using genetically modified mouse models, we investigated the impact of targeted pharmacological inhibitors on lorlatinib pharmacokinetics and bioavailability. Upon oral administration of lorlatinib, the plasma AUC0-8h in CYP3A4-humanized mice was ∼1.8-fold lower than in wild-type and Cyp3a–/– mice. Oral coadministration of the CYP3A inhibitor ritonavir caused reversion to the AUC0-8h levels seen in wild-type and Cyp3a–/– mice, without altering the relative tissue distribution of lorlatinib. Moreover, simultaneous pharmacological inhibition of P-glycoprotein and CYP3A4 with oral Elacridar and ritonavir in CYP3A4-humanized mice profoundly increased lorlatinib brain concentrations, but not its oral availability or other relative tissue distribution. Oral lorlatinib pharmacokinetics was not significantly affected by absence of the multispecific Oatp1a/1b drug uptake transporters. The absolute oral bioavailability of lorlatinib over 8 h in wild-type, Cyp3a–/–, and CYP3A4-humanized mice was 81.6%, 72.9%, and 58.5%, respectively. Lorlatinib thus has good oral bioavailability, which is markedly restricted by human CYP3A4 but not by mouse Cyp3a. Pharmacological inhibition of CYP3A4 reversed these effects, and simultaneous P-gp inhibition with Elacridar boosted absolute brain levels of lorlatinib by 16-fold without obvious toxicity. These insights may help to optimize the clinical application of lorlatinib.

  • Oral coadministration of Elacridar and ritonavir enhances brain accumulation and oral availability of the novel ALK/ROS1 inhibitor lorlatinib
    European Journal of Pharmaceutics and Biopharmaceutics, 2019
    Co-Authors: Wenlong Li, Jos H Beijnen, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Alfred H. Schinkel
    Abstract:

    Abstract Lorlatinib, a novel generation oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor with high membrane and blood-brain barrier permeability, recently received accelerated approval for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), and its further clinical development is ongoing. We previously found that the efflux transporter P-glycoprotein (MDR1/ABCB1) restricts lorlatinib brain accumulation and that the drug-metabolizing enzyme cytochrome P450-3A (CYP3A) limits its oral availability. Using genetically modified mouse models, we investigated the impact of targeted pharmacological inhibitors on lorlatinib pharmacokinetics and bioavailability. Upon oral administration of lorlatinib, the plasma AUC0-8h in CYP3A4-humanized mice was ∼1.8-fold lower than in wild-type and Cyp3a–/– mice. Oral coadministration of the CYP3A inhibitor ritonavir caused reversion to the AUC0-8h levels seen in wild-type and Cyp3a–/– mice, without altering the relative tissue distribution of lorlatinib. Moreover, simultaneous pharmacological inhibition of P-glycoprotein and CYP3A4 with oral Elacridar and ritonavir in CYP3A4-humanized mice profoundly increased lorlatinib brain concentrations, but not its oral availability or other relative tissue distribution. Oral lorlatinib pharmacokinetics was not significantly affected by absence of the multispecific Oatp1a/1b drug uptake transporters. The absolute oral bioavailability of lorlatinib over 8 h in wild-type, Cyp3a–/–, and CYP3A4-humanized mice was 81.6%, 72.9%, and 58.5%, respectively. Lorlatinib thus has good oral bioavailability, which is markedly restricted by human CYP3A4 but not by mouse Cyp3a. Pharmacological inhibition of CYP3A4 reversed these effects, and simultaneous P-gp inhibition with Elacridar boosted absolute brain levels of lorlatinib by 16-fold without obvious toxicity. These insights may help to optimize the clinical application of lorlatinib.

  • 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, 2018
    Co-Authors: Wenlong Li, Jos H Beijnen, Els Wagenaar, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Alfred H. Schinkel
    Abstract:

    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.

  • 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, 2018
    Co-Authors: Wenlong Li, Jos H Beijnen, Els Wagenaar, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Alfred H. Schinkel
    Abstract:

    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.

Severin Mairinger - One of the best experts on this subject based on the ideXlab platform.

  • for detection of P-glycoprotein-expressing murine breast cancer
    2020
    Co-Authors: Thomas Wanek, Severin Mairinger, Claudia Kuntner, Johann Stanek, Jens P. Bankstahl, Marion Bankstahl, Michael Sauberer, Sabine Strommer, Volker Wacheck, Wolfgang Löscher
    Abstract:

    Purpose One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphatebinding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. The aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [ 11 C]tariquidar and [ 11 C] Elacridar with the Pgp substrate radiotracer (R)-[ 11 C]

  • Assessment of cerebral P-glycoprotein expression and function with PET by combined ( 11 C)inhibitor and ( 11 C)substrate scans in rats
    2020
    Co-Authors: Julia Müllauer, Severin Mairinger, Thomas Wanek, Johann Stanek, Markus Müller, Rudolf Karch, Jens P. Bankstahl, Marion Bankstahl, Wolfgang Löscher, Oliver Langer
    Abstract:

    article i nfo 11 C)Elacridar ( 11 C)tariquidar (R)-( 11 C)verapamil P-glycoprotein Blood-brain barrier Introduction: The adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) protects the brain from accumulation of lipophilic compounds by active efflux transport across the blood-brain barrier. Changes in Pgp function/expression may occur in neurological disorders, such as epilepsy, Alzheimer's or Parkinson's disease. In this work we investigated the suitability of the radiolabeled Pgp inhibitors ( 11 C)

  • Assessment of cerebral P-glycoprotein expression and function with PET by combined [11C]inhibitor and [11C]substrate scans in rats
    Nuclear Medicine and Biology, 2013
    Co-Authors: Julia Müllauer, Severin Mairinger, Thomas Wanek, Johann Stanek, Markus Müller, Rudolf Karch, Jens P. Bankstahl, Marion Bankstahl, Wolfgang Löscher, Oliver Langer
    Abstract:

    Abstract Introduction The adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) protects the brain from accumulation of lipophilic compounds by active efflux transport across the blood–brain barrier. Changes in Pgp function/expression may occur in neurological disorders, such as epilepsy, Alzheimer’s or Parkinson’s disease. In this work we investigated the suitability of the radiolabeled Pgp inhibitors [ 11 C]Elacridar and [ 11 C]tariquidar to visualize Pgp density in rat brain with PET. Methods Rats underwent a first PET scan with [ 11 C]Elacridar ( n  = 5) or [ 11 C]tariquidar ( n  = 6) followed by a second scan with the Pgp substrate ( R )-[ 11 C]verapamil after administration of unlabeled tariquidar at a dose which half-maximally inhibits cerebral Pgp (3 mg/kg). Compartmental modeling using an arterial input function and Logan graphical analysis were used to estimate rate constants and volumes of distribution ( V T ) of radiotracers in different brain regions. Results Brain PET signals of [ 11 C]Elacridar and [ 11 C]tariquidar were very low (~ 0.5 standardized uptake value, SUV). There was a significant negative correlation between V T and K 1 (i.e. influx rate constant from plasma into brain) values of [ 11 C]Elacridar or [ 11 C]tariquidar and V T and K 1 values of ( R )-[ 11 C]verapamil in different brain regions which was consistent with binding of [ 11 C]inhibitors to Pgp and efflux of ( R )-[ 11 C]verapamil by Pgp. Conclusion The small Pgp binding signals obtained with [ 11 C]Elacridar and [ 11 C]tariquidar limit the applicability of these tracers to measure cerebral Pgp density. PET tracers with higher (i.e. subnanomolar) binding affinities will be needed to visualize the low density of Pgp in brain.

  • a comparative small animal pet evaluation of 11c tariquidar 11c Elacridar and r 11c verapamil for detection of p glycoprotein expressing murine breast cancer
    European Journal of Nuclear Medicine and Molecular Imaging, 2012
    Co-Authors: Thomas Wanek, Severin Mairinger, Claudia Kuntner, Johann Stanek, Jens P. Bankstahl, Marion Bankstahl, Michael Sauberer
    Abstract:

    Purpose One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. The aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [11C]tariquidar and [11C]Elacridar with the Pgp substrate radiotracer (R)-[11C]verapamil for discriminating tumours expressing low and high levels of Pgp using small-animal PET imaging in a murine breast cancer model.

  • Small-animal PET evaluation of [11C]MC113 as a PET tracer for P-glycoprotein
    BMC Pharmacology, 2010
    Co-Authors: Severin Mairinger, N. A. Colabufo, Thomas Wanek, Claudia Kuntner, Johann Stanek, Thomas Erker, Mariangela Cantore, F. Berardi, R. Perrone, Markus Müller
    Abstract:

    Background The radiolabelled inhibitor of the multidrug efflux transporter P-glycoprotein (P-gp) [C]Elacridar was developed as a positron emission tomography (PET) tracer to assess expression levels of P-gp at the blood-brain barrier (BBB) [1]. [C]Elacridar was shown to interact specifically with P-gp at the rodent BBB, but its brain PET signal was very low, which was possibly caused by transport of [C]Elacridar by P-gp [1]. In an attempt to gain a better understanding of the required properties of an effective P-gp PET tracer we evaluated C-labelled MC113, a structural analogue of Elacridar, which was characterised as an unambiguous non-transported P-gp inhibitor and which possesses lower molecular weight, lower lipophilicity and higher potency for P-gp inhibition than Elacridar (EC50 for inhibition of [ H]vinblastine transport in Caco-2 cell monolayers: 0.6 μM vs. 2.0 μM for Elacridar) [2].

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  • for detection of P-glycoprotein-expressing murine breast cancer
    2020
    Co-Authors: Thomas Wanek, Severin Mairinger, Claudia Kuntner, Johann Stanek, Jens P. Bankstahl, Marion Bankstahl, Michael Sauberer, Sabine Strommer, Volker Wacheck, Wolfgang Löscher
    Abstract:

    Purpose One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphatebinding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. The aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [ 11 C]tariquidar and [ 11 C] Elacridar with the Pgp substrate radiotracer (R)-[ 11 C]

  • P-Glycoprotein and Breast Cancer Resistance Protein at the Human Blood-Brain Barrier
    2020
    Co-Authors: Martin Bauer, Cecile Philippe, Wolfgang Wadsak, Markus Zeitlinger, Johann Stanek, Rudolf Karch, Markus Mitterhauser, Walter Jäger, Helmuth Haslacher, Oliver Langer
    Abstract:

    The adenosine triphosphate-binding cassette transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are 2 major gatekeepers at the blood-brain barrier (BBB) which restrict brain distribution of several clinically used drugs. In this study we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors 11 C-tariquidar and 11 C-Elacridar to assess Pgp density in human brain with PET. Methods—Healthy subjects underwent a first PET scan of 120 min duration with either 11 Ctariquidar (n = 6) or 11 C-Elacridar (n = 5) followed by a second PET scan of 60 min duration with (R)- 11 C-verapamil. During scan 1 (at 60 min after radiotracer injection) unlabeled tariquidar (3 mg/kg) was intravenously administered. Data was analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models using either metabolite-corrected or uncorrected arterial input functions. Results—Following injection of 11 C-tariquidar or 11 C-Elacridar, brain PET signal corrected for radioactivity in vasculature was very low (~0.1 standardized uptake value) with slow washout. In response to tariquidar injection, a moderate, but statistically significant rise in brain PET signal was observed for 11 C-tariquidar (+27 ± 15%, P = 0.014, paired t-test) and 11 C-Elacridar (+21 ± 15%, P = 0.014) without changes in plasma activity concentrations. Low levels of radiolabeled metabolites (

  • Assessment of cerebral P-glycoprotein expression and function with PET by combined ( 11 C)inhibitor and ( 11 C)substrate scans in rats
    2020
    Co-Authors: Julia Müllauer, Severin Mairinger, Thomas Wanek, Johann Stanek, Markus Müller, Rudolf Karch, Jens P. Bankstahl, Marion Bankstahl, Wolfgang Löscher, Oliver Langer
    Abstract:

    article i nfo 11 C)Elacridar ( 11 C)tariquidar (R)-( 11 C)verapamil P-glycoprotein Blood-brain barrier Introduction: The adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) protects the brain from accumulation of lipophilic compounds by active efflux transport across the blood-brain barrier. Changes in Pgp function/expression may occur in neurological disorders, such as epilepsy, Alzheimer's or Parkinson's disease. In this work we investigated the suitability of the radiolabeled Pgp inhibitors ( 11 C)

  • Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier
    Clinical Pharmacology & Therapeutics, 2016
    Co-Authors: Martin Bauer, Cecile Philippe, Johann Stanek, Rudolf Karch, Helmuth Haslacher, Kerstin Römermann, Beatrix Wulkersdorfer, Alexandra Maier-salamon, Christof Jungbauer, Wolfgang Wadsak
    Abstract:

    ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]Elacridar and [(11) C]tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]Elacridar and [(11) C]tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.

  • interaction of 11c tariquidar and 11c Elacridar with p glycoprotein and breast cancer resistance protein at the human blood brain barrier
    The Journal of Nuclear Medicine, 2013
    Co-Authors: Martin Bauer, Cecile Philippe, Wolfgang Wadsak, Markus Zeitlinger, Johann Stanek, Rudolf Karch, Markus Mitterhauser, Walter Jäger, Helmuth Haslacher
    Abstract:

    The adenosine triphosphate-binding cassette transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are 2 major gatekeepers at the blood-brain barrier (BBB) which restrict brain distribution of several clinically used drugs. In this study we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors 11C-tariquidar and 11C-Elacridar to assess Pgp density in human brain with PET. Methods Healthy subjects underwent a first PET scan of 120 min duration with either 11C-tariquidar (n = 6) or 11C-Elacridar (n = 5) followed by a second PET scan of 60 min duration with (R)-11C-verapamil. During scan 1 (at 60 min after radiotracer injection) unlabeled tariquidar (3 mg/kg) was intravenously administered. Data was analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models using either metabolite-corrected or uncorrected arterial input functions.