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Drug Deliv Transl Res. 2017 Feb;7(1):125-131. doi: 10.1007/s13346-016-0346-3.

Clinical pharmacokinetics of an amorphous solid dispersion tablet of elacridar.

Author information

1
Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands. e.sawicki@nki.nl.
2
Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Louwesweg 6, 1066, EC, Amsterdam, The Netherlands.
3
Department of Clinical Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
4
Department of Clinical Chemistry/Preclinical Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
5
Department Medical Oncology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
6
Utrecht Institute of Pharmaceutical Sciences (UIPS), David de Wied building, Universiteitsweg 99, 3584, CG, Utrecht, The Netherlands.

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.

KEYWORDS:

Absorption; Bioavailability; Breast cancer resistance protein; Dissolution; P-glycoprotein; Solid dispersion

PMID:
27864786
DOI:
10.1007/s13346-016-0346-3
[Indexed for MEDLINE]

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