Elacridar

Elacridar is a potent inhibitor of P-glycoprotein with IC50 values of 193 nM. [1]

P-glycoprotein (permeability glycoprotein) is an important membrane protein. It pumps many foreign substances out of cells. P-glycoprotein belongs to the MDR/TAP subfamily. P-glycoprotein is transmembrane glycoprotein which is about 170 kDa. It is expressed in certain cell types primarily in the pancreas, liver, colon and kidney. It contains 6 transmembrane domains in the N-terminal half of the molecule. It also contains an ATP-binding site in the large cytoplasmic domain. P-glycoprotein binds to the substrate at the cytoplasmic side of the protein. When ATP binds to the cytoplasmic side, the substrate was excreted from the cell. P-glycoprotein can pump toxins or drugs back into the intestinal lumen, pumps them into bile ducts in liver cells.In some cancer cells, P-glycoprotein is overexpressed. It is involved in multidrug resistance of cancer cells.[2]

Elacridar can significantly inhibit the activity of P-glycoprotein at 1μM in MDCKII cells which overexpress P-glycoprotein.[3] In the parental MDCK-II cells, elacridar at 5μM completely inhibit the polarized sunitinib transport.[4] Elacridar did not inhibit the activity of several human cytochromeP450 enzymes in vitro. The absolute bioavailability was about 0.47 and 1.3 respectively, when elacridar was given in the orally and microemulsion, intraperitoneally at 10 mg/kg in mice.[3] Elacridar also can significantly increase sunitinib brain accumulation levels in mice at 10 mg/kg.[4]

References:
[1].  Bankstahl JP, Bankstahl M, Romermann K, Wanek T, Stanek J, Windhorst AD, Fedrowitz M, Erker T, Muller M, Loscher W et al: Tariquidar and elacridar are dose-dependently transported by P-glycoprotein and Bcrp at the blood-brain barrier: a small-animal positron emission tomography and in vitro study. Drug Metab Dispos, 41(4):754-762.
[2].  Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL et al: Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 2009, 323(5922):1718-1722.
[3].  Sane R, Mittapalli RK, Elmquist WF: Development and evaluation of a novel microemulsion formulation of elacridar to improve its bioavailability. J Pharm Sci, 102(4):1343-1354.
[4].  Tang SC, Lagas JS, Lankheet NA, Poller B, Hillebrand MJ, Rosing H, Beijnen JH, Schinkel AH: Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration. Int J Cancer, 130(1):223-233.

Whole-Body Distribution and Radiation Dosimetry of 11C-Elacridar and 11C-Tariquidar in Humans.[Pubmed:27081167]

J Nucl Med. 2016 Aug;57(8):1265-8.

UNLABELLED: (11)C-Elacridar and (11)C-tariquidar are new PET tracers to assess the transport activity of P-glycoprotein (adenosine triphosphate-binding cassette subfamily B, member 1 [ABCB1]) and breast cancer resistance protein (adenosine triphosphate-binding cassette subfamily G, member 2 [ABCG2]). This study investigated the whole-body distribution and radiation dosimetry of both radiotracers in humans. METHODS: Twelve healthy volunteers (6 women, 6 men) underwent whole-body PET/CT imaging over the 90 min after injection of either (11)C-Elacridar or (11)C-tariquidar. Radiation doses were calculated with OLINDA/EXM software using adult reference phantoms. RESULTS: Biodistribution was consistent with a major elimination route of hepatobiliary excretion, which may be mediated by ABCB1 and ABCG2. High radioactivity uptake was seen in liver, followed by spleen and kidneys, whereas brain uptake was lowest. Effective doses were 3.41 +/- 0.06 muSv/MBq for (11)C-elacidar and 3.62 +/- 0.11 muSv/MBq for (11)C-tariquidar. CONCLUSION: Our data indicate that both (11)C-Elacridar and (11)C-tariquidar are safe radiotracers, for which an injected activity of 400 MBq corresponds to a total effective dose of approximately 1.5 mSv.

Liposomes Coloaded with Elacridar and Tariquidar To Modulate the P-Glycoprotein at the Blood-Brain Barrier.[Pubmed:26390138]

Mol Pharm. 2015 Nov 2;12(11):3829-38.

This study prepared three liposomal formulations coloaded with Elacridar and tariquidar to overcome the P-glycoprotein-mediated efflux at the blood-brain barrier. Their pharmacokinetics, brain distribution, and impact on the model P-glycoprotein substrate, loperamide, were compared to those for the coadministration of free Elacridar plus free tariquidar. After intravenous administration in rats, Elacridar and tariquidar in conventional liposomes were rapidly cleared from the bloodstream. Their low levels in the brain did not improve the loperamide brain distribution. Although Elacridar and tariquidar in PEGylated liposomes exhibited 2.6 and 1.9 longer half-lives than free Elacridar and free tariquidar, respectively, neither their Kp for the brain nor the loperamide brain distribution was improved. However, the conjugation of OX26 F(ab')2 fragments to PEGylated liposomes increased the Kps for the brain of Elacridar and tariquidar by 1.4- and 2.1-fold, respectively, in comparison to both free P-gp modulators. Consequently, the Kp for the brain of loperamide increased by 2.7-fold. Moreover, the plasma pharmacokinetic parameters and liver distribution of loperamide were not modified by the PEGylated OX26 F(ab')2 immunoliposomes. Thus, this formulation represents a promising tool for modulating the P-glycoprotein-mediated efflux at the blood-brain barrier and could improve the brain uptake of any P-glycoprotein substrate that is intended to treat central nervous system diseases.

Clinical pharmacokinetics of an amorphous solid dispersion tablet of elacridar.[Pubmed:27864786]

Drug Deliv Transl Res. 2017 Feb;7(1):125-131.

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-infinity 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-infinity were 326 +/- 67 ng/mL and 13.4 +/- 8.6 . 10(3) 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.[Pubmed:28010129]

Drug Dev Ind Pharm. 2017 Apr;43(4):584-594.

OBJECTIVE: 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 months at +15-25 degrees C, +2-8 degrees C and -20 degrees C. RESULTS: The ASD powder was composed of freeze dried Elacridar hydrochloride-povidone K30-sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline Elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25 mg Elacridar hydrochloride and were stable for at least 12 months at -20 degrees C. CONCLUSIONS: The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such.