- Email: [email protected]
What next? Preferably development of drugs that are no longer transported by the ABCB1 and ABCG2 efflux transporters
G Model
ARTICLE IN PRESS
YPHRS-3598; No. of Pages 1
Pharmacological Research xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Letter to the Editor What next? Preferably development of drugs that are no longer transported by the ABCB1 and ABCG2 efflux transporters We appreciate the comments of Dr. Srinivas. In general we agree with his assessments. In fact, we often emphasize in our publications that mouse studies are useful to establish basic principles governing pharmacokinetic behavior, but should not be used in a simplistic one-to-one way to predict what is going to happen in humans. Ultimately, this can only be done in trials in humans, optimally designed with a basic understanding of the underlying principles in mind. There is always scope for additional experimentation in any experimental study. The primary reason we did not include a separate study arm adding a strong P-gp/ABCB1 and BCRP/ABCG2 inhibitor to afatinib (we would have used elacridar) is that we and others have done this in the past for a range of other shared P-gp and BCRP substrates in mice, and this always worked in our hands [see 1, 2, and references therein]. The same is true for analogous studies by the research groups of, for instance, Dr. Elmquist and Dr. Van Tellingen. This means that at sufficiently high dose elacridar can virtually completely inhibit P-gp and BCRP in the blood-brain barrier of mice, making the results for afatinib predictable. Afatinib is not unique in being strongly affected by both P-gp and BCRP, especially with respect to brain accumulation. Many of the targeted anticancer drugs that we (and other groups) have tested so far are strongly affected by both transporters, albeit to variable relative extents [see 1, 2, and citations in our original paper]. From this perspective, perhaps the use of P-gp inhibitors instead of highly effective dual inhibitors of both P-gp and BCRP may also have contributed to failure of some clinical inhibitor trials. However, the real-life clinical treatment of tumors is complicated, and there can be many additional reasons why application of P-gp inhibitors has so far failed to substantially improve therapy response, as also alluded to by Dr. Srinivas. What next? It is fair to say that we don’t think the longer-term future is for chronic clinical administration of strong P-gp and BCRP inhibitors together with targeted anticancer drugs, especially when it concerns improving brain (tumor) access. It is risky to completely inhibit P-gp and BCRP in the blood-brain barrier of patients in a chronic setting, as would be required for clinical treatment with most targeted anticancer drugs. Unpredictable (CNS) toxicity of drugs, pesticides and even some food components to which such patients will inevitably be exposed might emerge. Indeed, we have observed severe and even lethal toxicity of otherwise well tolerated drugs, pesticides, and food compounds in P-gp and/or Bcrp knockout mouse strains due to highly increased availability of these compounds [3, 4, and unpublished data]. In our view, the future lies in the development of effective targeted anticancer drugs that are no longer transported substrates of P-gp and BCRP. This appears to be difficult to achieve, likely related
to the many other constraints of developing efficacious new drugs − we estimate that at least 90% of targeted anticancer drugs that have been registered over the past 10 years are significantly transported by either or both of these transporters. However, it does appear to be feasible if a dedicated effort is made [e.g.,5]. Such “untransported” drugs would combine the advantages of being no longer susceptible to multidrug resistance mediated by P-gp and BCRP present in tumor cells, and of having relatively enhanced access to brain (tumor) tissue. Obtaining such compounds should therefore be a main goal for pharmaceutical companies developing new anticancer drugs, especially those targeting tumors or metastases positioned in whole or in part behind the blood-brain barrier. References [1] S.C. Tang, et al., Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar, Int. J. Cancer 134 (6) (2014) 1484–1494. [2] S. Durmus, et al., Oral availability and brain penetration of the B-RAFV600E inhibitor vemurafenib can be enhanced by the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar, Mol. Pharm. 9 (11) (2012) 3236–3245. [3] A.H. Schinkel, et al., Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs, Cell 77 (4) (1994) 491–502. [4] J.W. Jonker, et al., The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria, Proc. Natl. Acad. Sci. USA 99 (24) (2002) 15649–15654. [5] L. Salphati, et al., Targeting the PI3K pathway in the brain − efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier, Clin. Cancer Res. 18 (22) (2012) 6239–6248.
Stéphanie van Hoppe Alfred H. Schinkel ∗ Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands ∗ Corresponding
author. E-mail address: [email protected] (A.H. Schinkel) 16 May 2017 Available online xxx
http://dx.doi.org/10.1016/j.phrs.2017.05.015 1043-6618/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: S. van Hoppe, A.H. Schinkel, What next? Preferably development of drugs that are no longer transported by the ABCB1 and ABCG2 efflux transporters, Pharmacol Res (2017), http://dx.doi.org/10.1016/j.phrs.2017.05.015
ARTICLE IN PRESS
YPHRS-3598; No. of Pages 1
Pharmacological Research xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Letter to the Editor What next? Preferably development of drugs that are no longer transported by the ABCB1 and ABCG2 efflux transporters We appreciate the comments of Dr. Srinivas. In general we agree with his assessments. In fact, we often emphasize in our publications that mouse studies are useful to establish basic principles governing pharmacokinetic behavior, but should not be used in a simplistic one-to-one way to predict what is going to happen in humans. Ultimately, this can only be done in trials in humans, optimally designed with a basic understanding of the underlying principles in mind. There is always scope for additional experimentation in any experimental study. The primary reason we did not include a separate study arm adding a strong P-gp/ABCB1 and BCRP/ABCG2 inhibitor to afatinib (we would have used elacridar) is that we and others have done this in the past for a range of other shared P-gp and BCRP substrates in mice, and this always worked in our hands [see 1, 2, and references therein]. The same is true for analogous studies by the research groups of, for instance, Dr. Elmquist and Dr. Van Tellingen. This means that at sufficiently high dose elacridar can virtually completely inhibit P-gp and BCRP in the blood-brain barrier of mice, making the results for afatinib predictable. Afatinib is not unique in being strongly affected by both P-gp and BCRP, especially with respect to brain accumulation. Many of the targeted anticancer drugs that we (and other groups) have tested so far are strongly affected by both transporters, albeit to variable relative extents [see 1, 2, and citations in our original paper]. From this perspective, perhaps the use of P-gp inhibitors instead of highly effective dual inhibitors of both P-gp and BCRP may also have contributed to failure of some clinical inhibitor trials. However, the real-life clinical treatment of tumors is complicated, and there can be many additional reasons why application of P-gp inhibitors has so far failed to substantially improve therapy response, as also alluded to by Dr. Srinivas. What next? It is fair to say that we don’t think the longer-term future is for chronic clinical administration of strong P-gp and BCRP inhibitors together with targeted anticancer drugs, especially when it concerns improving brain (tumor) access. It is risky to completely inhibit P-gp and BCRP in the blood-brain barrier of patients in a chronic setting, as would be required for clinical treatment with most targeted anticancer drugs. Unpredictable (CNS) toxicity of drugs, pesticides and even some food components to which such patients will inevitably be exposed might emerge. Indeed, we have observed severe and even lethal toxicity of otherwise well tolerated drugs, pesticides, and food compounds in P-gp and/or Bcrp knockout mouse strains due to highly increased availability of these compounds [3, 4, and unpublished data]. In our view, the future lies in the development of effective targeted anticancer drugs that are no longer transported substrates of P-gp and BCRP. This appears to be difficult to achieve, likely related
to the many other constraints of developing efficacious new drugs − we estimate that at least 90% of targeted anticancer drugs that have been registered over the past 10 years are significantly transported by either or both of these transporters. However, it does appear to be feasible if a dedicated effort is made [e.g.,5]. Such “untransported” drugs would combine the advantages of being no longer susceptible to multidrug resistance mediated by P-gp and BCRP present in tumor cells, and of having relatively enhanced access to brain (tumor) tissue. Obtaining such compounds should therefore be a main goal for pharmaceutical companies developing new anticancer drugs, especially those targeting tumors or metastases positioned in whole or in part behind the blood-brain barrier. References [1] S.C. Tang, et al., Increased oral availability and brain accumulation of the ALK inhibitor crizotinib by coadministration of the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar, Int. J. Cancer 134 (6) (2014) 1484–1494. [2] S. Durmus, et al., Oral availability and brain penetration of the B-RAFV600E inhibitor vemurafenib can be enhanced by the P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) inhibitor elacridar, Mol. Pharm. 9 (11) (2012) 3236–3245. [3] A.H. Schinkel, et al., Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs, Cell 77 (4) (1994) 491–502. [4] J.W. Jonker, et al., The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria, Proc. Natl. Acad. Sci. USA 99 (24) (2002) 15649–15654. [5] L. Salphati, et al., Targeting the PI3K pathway in the brain − efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier, Clin. Cancer Res. 18 (22) (2012) 6239–6248.
Stéphanie van Hoppe Alfred H. Schinkel ∗ Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands ∗ Corresponding
author. E-mail address: [email protected] (A.H. Schinkel) 16 May 2017 Available online xxx
http://dx.doi.org/10.1016/j.phrs.2017.05.015 1043-6618/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: S. van Hoppe, A.H. Schinkel, What next? Preferably development of drugs that are no longer transported by the ABCB1 and ABCG2 efflux transporters, Pharmacol Res (2017), http://dx.doi.org/10.1016/j.phrs.2017.05.015