Pharmacology and pharmacokinetics of imatinib in pediatric patients

ABSTRACT

Introduction: The tyrosine kinase inhibitor (TKI) imatinib was rationally designed to target BCR-ABL1 which is constitutively activated in chronic myeloid leukemia (CML). Following the tremendous success in adults, imatinib also became licensed for treatment of CML in minors. The rarity of pediatric CML hampers the conduction of formal trials. Thus, imatinib is still the single TKI approved for CML treatment in childhood.

Areas covered: This review attempts to provide an overview of the literature on pharmacology, pharmacokinetic, and pharmacogenetic of imatinib concerning pediatric CML treatment. Articles were identified through a PubMed search and by reviewing abstracts from relevant hematology congresses. Additional information was provided from the authors’ libraries and expertise and from our own measurements of imatinib trough plasma levels in children. Pharmacokinetic variables (e.g. alpha 1-acid glycoprotein binding, drug–drug/food–drug interactions via cytochrome P450 3A4/5, cellular uptake mediated via OCT-1-influx variations and P-glycoprotein-mediated drug efflux) still await to be addressed in pediatric patients systematically.

Expert commentary: TKI response rates vary among different individuals and pharmacokinetic variables all can influence CML treatment success. Adherence to imatinib intake may be the most prominent factor influencing treatment outcome in teenagers thus pointing towards the potential benefits of regular drug monitoring.

KEYWORDS:

• Imatinib
• children
• dose
• infants
• teenagers
• pharmacokinetics
• alpha 1-acid glycoprotein
• cytochrome P450 3A4/5
• drug–drug/food–drug interactions
• OCT-1-influx
• P-glycoprotein-efflux
• compliance
• drug monitoring
• trough level
• generics

Acknowledgments

The expert technical assistance of Petra Lorenz, Laboratory Technician in determining drug plasma levels, Christina Nowasz, Study Nurse in maintenance of the patient registry and Jennifer Lawlor, Biologist, in editing the text of the manuscript is applaudably acknowledged.

Declaration of interest

M Suttorp discloses unrestricted research grant from Novartis Pharmaceuticals, Nuremberg, Germany; unrestricted funding of laboratory equipment by Sonnenstrahl e. V. Dresden, Germany (Parents support association for children with cancer); and unrestricted research funding by Stiftung Mitteldeutsche Kinderkrebsforschung, Leipzig, Germany (Foundation for support of children with cancer). M Bornhäuser discloses an unrestricted research grant from Novartis Pharmaceuticals, Nuremberg, Germany. M Metzler discloses an unrestricted research grant from Novartis Pharmaceuticals, Nuremberg, Germany. F Millot discloses speaker fees and unrestricted research grant from Novartis, Paris, France; speaker fees from Pfizer, Paris, France. E Schleyer discloses an unrestricted research grant from Novartis Pharmaceuticals, Nuremberg, Germany. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Generously continuous financial support was provided with unrestricted research grants from Novartis Pharmaceuticals, Nürnberg, Germany, Sonnenstrahl e. V. Dresden, Germany, and Stiftung Mitteldeutsche Kinderkrebsforschung, Leipzig, Germany.