title: Clinical pharmacokinetics of an amorphous solid dispersion tablet of elacridar.
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 Cmaxwas 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. Cmaxand AUC0-∞increased linearly with dose over the explored range. The target Cmaxof ≥ 200 ng/mL was achieved at the 1000-mg dose level. At this dose, the Cmaxand AUC0-∞were 326 ± 67 ng/mL and 13.4 ± 8.6 · 103ng · 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.
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands. e.sawicki@nki.nl.
authors.forename: Emilia
authors.identifier: 0000-0002-6473-1916
authors.initials: E
authors.lastname: Sawicki
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands.
authors.forename: Remy B
authors.initials: RB
authors.lastname: Verheijen
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands.|Department of Clinical Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Department of Clinical Chemistry/Preclinical Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.affiliation: Department of Clinical Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.|Department Medical Oncology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.|Utrecht Institute of Pharmaceutical Sciences (UIPS), David de Wied building, Universiteitsweg 99, 3584, CG, Utrecht, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands.
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Nuijen
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands.|Department of Clinical Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.|Utrecht Institute of Pharmaceutical Sciences (UIPS), David de Wied building, Universiteitsweg 99, 3584, CG, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Clinical Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.|Department Medical Oncology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
authors.forename: Neeltje
authors.initials: N
authors.lastname: Steeghs
mesh_terms: D000166:Acridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D000328:Adult; D001682:Biological Availability; D065546:Drug Liberation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011208:Powders; D013607:Tablets; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D000166:Acridines; D011208:Powders; D013607:Tablets; D044005:Tetrahydroisoquinolines; C083501:Elacridar
keywords: Absorption; Bioavailability; Breast cancer resistance protein; Dissolution; P-glycoprotein; Solid dispersion