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Acalabrutinib (formerly known as ACP196; ACP-196; trade name: Calquence) is a selective second-generation Bruton's tyrosine kinase (BTK) inhibitor with anticancer activity. By blocking the B-cell antigen receptor (BCR) signaling pathway from being activated, it works. Adults with mantle cell lymphoma were given FDA approval to receive acalabrutinib in 2017. Mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic leukemia are two non-Hodgkin lymphoma types that can be treated with it. Due to the decreased intrinsic reactivity of ACP-196's electrophile, a previous study demonstrated that ACP-196 had high selectivity for Btk when tested against a panel of 395 non-mutant kinases. ACP-196, in contrast to ibrutinib, was unable to inhibit EGFR, Itk, or Txk. Further verification of ibrutinib's EGFR inhibition without ACP-196 inhibition was obtained through phosphoflow assays conducted on EGFR-expressing cell lines.
Physicochemical Properties
| Molecular Formula | C26H23N7O2 | |
| Molecular Weight | 465.51 | |
| Exact Mass | 465.191 | |
| Elemental Analysis | C, 67.08; H, 4.98; N, 21.06; O, 6.87 | |
| CAS # | 1420477-60-6 | |
| Related CAS # | Acalabrutinib-d4;2699608-18-7;Acalabrutinib-d3; 1420477-60-6; 2058091-99-7 (citrate); 2242394-65-4; 2058091-96-4 (phosphate); 2058091-93-1 (3 hydrate); 2058092-05-8 (sulfate); 2058091-94-2 (fumarate); 2058091-97-5 (tartrate) | |
| PubChem CID | 71226662 | |
| Appearance | Yellow solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Index of Refraction | 1.715 | |
| LogP | 0.77 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 4 | |
| Heavy Atom Count | 35 | |
| Complexity | 845 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | O=C(C#CC([H])([H])[H])N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C1=NC(C2C([H])=C([H])C(C(N([H])C3=C([H])C([H])=C([H])C([H])=N3)=O)=C([H])C=2[H])=C2C(N([H])[H])=NC([H])=C([H])N12 |
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| InChi Key | WDENQIQQYWYTPO-IBGZPJMESA-N | |
| InChi Code | InChI=1S/C26H23N7O2/c1-2-6-21(34)32-15-5-7-19(32)25-31-22(23-24(27)29-14-16-33(23)25)17-9-11-18(12-10-17)26(35)30-20-8-3-4-13-28-20/h3-4,8-14,16,19H,5,7,15H2,1H3,(H2,27,29)(H,28,30,35)/t19-/m0/s1 | |
| Chemical Name | 4-[8-amino-3-[(2S)-1-but-2-ynoylpyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
BTK (IC50 = 3 nM)
Acalabrutinib (ACP-196) targets Bruton's tyrosine kinase (Btk), covalently binding to Cys481 of Btk (no IC50/Ki/EC50 values for Btk inhibition provided) [1] Acalabrutinib (ACP-196) targets Bruton's tyrosine kinase (Btk) (no IC50/Ki/EC50 values for Btk inhibition provided); it does not inhibit EGFR (no inhibition at 10 μM), Itk or Txk, while ibrutinib inhibits EGFR with EC50 of 47-66 nM [3] |
| ln Vitro |
Acalabrutinib inhibits tyrosine phosphorylation of downstream targets of ERK, IKB, and AKT in the in vitro signaling assay on primary human CLL cells. IC50 values on nine kinases with a cysteine residue in the same location as BTK show that acalabrutinib has a higher selectivity for BTK. Crucially, acalabrutinib does not inhibit EGFR, ITK, or TEC like ibrutinib does. EGFR phosphorylation at tyrosine residues Y1068 and Y1773 is unaffected by acalabrutinib. Acalabrutinib exhibits nearly no inhibition or a much higher IC50 (>1000 nM) on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1 when compared to ibrutinib[1]. 1. Acalabrutinib (ACP-196) is a novel irreversible second-generation BTK inhibitor with higher potency and selectivity than ibrutinib [1] 2. In two immunophenotypically confirmed canine B-cell lymphoma cell lines (CLBL-1 and 17-71), treatment with Acalabrutinib (ACP-196) at concentrations as low as 10 nM for 1 hour potently inhibited the activation of Btk and its downstream effectors ERK 1/2 and PLCγ2 [2] 3. In a competitive binding assay against a panel of 395 non-mutant kinases (1 μM), Acalabrutinib (ACP-196) exhibited higher selectivity for Btk compared with ibrutinib and CC-292; IC50 determinations on 9 kinases with a Cys in the same position as Btk confirmed Acalabrutinib (ACP-196) as the most selective, attributed to reduced intrinsic reactivity of its electrophile [3] 4. In human whole blood, Acalabrutinib (ACP-196) and ibrutinib showed robust and equipotent inhibitory activity on B-cell receptor (BCR)-induced responses in the low nM range, while CC-292 was 10-20 fold less potent [3] 5. Phosphoflow assays on EGFR-expressing cell lines confirmed no EGFR inhibition by Acalabrutinib (ACP-196) at 10 μM, whereas ibrutinib inhibited EGFR with EC50 of 47-66 nM [3] |
| ln Vivo |
ACP-196, when given orally to mice, inhibits anti-IgM-induced CD86 expression in CD19+ splenocytes in a dose-dependent manner; the ED50 for ACP-196 is 0.34 mg/kg, while that of ibrutinib is 0.91 mg/kg. The length of Btk inhibition following a single oral dose of 25 mg/kg is compared using a comparable model. At three hours after dosage, ACP-196 inhibits CD86 expression by more than 90%[3]. Acalabrutinib (ACP-196) in preclinical research[1] Acalabrutinib was evaluated in several animal models of B cell non-Hodgkin lymphoma (NHL). These studies provided preclinical in vivo data necessary to move acalabrutinib into human trials. In a study of canine model of B cell NHL, 12 dogs with B cell NHL were orally administered acalabrutinib at escalating dosages of 2.5 mg/kg every 24 h (6 dogs), 5 mg/kg every 24 h (5 dogs), or 10 mg/kg every 12 h (1 dog). As a result, 3 dogs achieved a partial remission (PR), 3 dogs had stable disease (SD), whereas the remaining 6 dogs had progression of disease (PD). This study therefore showed that acalabrutinib has single agent biologic activity in a spontaneous large animal model of NHL.[1] The in vivo effects of acalabrutinib against CLL cells were demonstrated in the NSG mouse model with xenografts of human CLL. Acalabrutinib significantly inhibited proliferation of human CLL cells in the spleens of NSG mice at all dose levels, as measured for the expression of Ki67 (P = 0.002). Tumor burden decreased with the treatment of acalabrutinib in a dose-dependent manner. Acalabrutinib inhibited BCR signaling by reduced phosphorylation of PLCγ2. Acalabrutinib transiently increased CLL cell counts in the peripheral blood. Therefore, the novel BTK inhibitor acalabrutinib shows in vivo efficacy against human CLL cells xenografted to the NSG mouse model. Two murine models were used in another in vivo study. In the TCL1 adoptive transfer model, acalabrutinib inhibited BCR signaling by decreased autophosphorylation of BTK and reduction in surface expression of the BCR activation markers CD86 and CD69. Most interestingly, acalabrutinib treatment increased survival significantly over mice receiving vehicle (median 81 vs 59 days, P = 0.02). The second murine model was the NSG xenograft model. Acalabrutinib treatment significantly decreased the phosphorylation of PLCγ2 and ERK (P = 0.02), reduced tumor cell proliferation (P = 0.02), and tumor burden (P = 0.04). Acalabrutinib was shown to be a potent inhibitor of BTK in both murine models of human CLL. 1. In mice, oral administration of Acalabrutinib (ACP-196) resulted in dose-dependent inhibition of anti-IgM-induced CD86 expression in CD19+ splenocytes with an ED50 of 0.34 mg/kg, compared to 0.91 mg/kg for ibrutinib [3] 2. In a mouse model evaluating the duration of Btk inhibition after a single oral dose of 25 mg/kg, Acalabrutinib (ACP-196) and ibrutinib inhibited CD86 expression >90% at 3h and ∼50% at 24h postdose; in contrast, CC-292 inhibited ∼50% at 3h and ∼20% at 24h postdose [3] 3. In an ongoing clinical trial with 12 companion dogs with spontaneously occurring B-cell non-Hodgkin lymphoma (NHL), Acalabrutinib (ACP-196) was orally administered at dosages of 2.5 mg/kg every 24 hours (6 dogs), 5 mg/kg every 24 hours (5 dogs), or 10 mg/kg every 12 hours (1 dog): - Btk occupancy in peripheral blood and lymphoma cells was assessed using a biotin-tagged probe derived from Acalabrutinib (ACP-196); at 2.5 mg/kg, full Btk occupancy was achieved in peripheral B cells 3h after dosing for all dogs except one with high peripheral B-cell count, and 83-99% Btk target occupancy was observed at 24 hours postdose for all dogs [2] - Partial response (per modified RECIST) was achieved in 2 dogs in the 2.5 mg/kg group and 1 dog in the 10 mg/kg group; one responder in the 2.5 mg/kg group had relapse and was dose-escalated to 10 mg/kg q12 on day 42, re-establishing partial response from relapse [2] - 3 dogs achieved stable disease for >28 days, 6 dogs developed progressive disease within 28 days and discontinued the study [2] 4. In healthy volunteers, oral administration of Acalabrutinib (ACP-196) at 100 mg QD showed >90% Btk target coverage over a 24h period; Btk occupancy and regulation of PD markers (CD69 and CD86) correlated with PK parameters for exposure [3] 5. In chronic lymphocytic leukemia (CLL) patients, after 7 days of dosing with Acalabrutinib (ACP-196) at 200 mg QD, 94% Btk target occupancy was observed (compared with ∼80% for ibrutinib at 420 mg QD) [3] |
| Enzyme Assay |
ACP-196's decreased intrinsic reactivity of its electrophile was linked to its high selectivity for Btk when tested against a panel of 395 non-mutant kinases, according to a previous study. In contrast to ibrutinib, ACP-196 was unable to inhibit EGFR, Itk, or Txk. Further confirmation of ibrutinib's EGFR inhibition without ACP-196 inhibition was obtained through phosphoflow assays conducted on EGFR-expressing cell lines. Compared to ibrutinib and CC-292, ACP-196 demonstrated higher selectivity for Btk when profiled against a panel of 395 non-mutant kinases (1 μM) in a competitive binding assay. IC50 determinations on 9 kinases with a Cys in the same position as Btk showed ACP-196 to be the most selective. The improved selectivity is related to the reduced intrinsic reactivity of ACP-196's electrophile. Importantly, unlike ibrutinib, ACP-196 did not inhibit EGFR, Itk or Txk. Phosphoflow assays on EGFR expressing cell lines confirmed ibrutinib's EGFR inhibition (EC50: 47-66 nM) with no inhibition observed for ACP-196 at 10 μM. These data may explain the ibrutinib-related incidence of diarrhea and rash. Ibrutinib's potency on Itk and Txk may explain why it interferes with cell-mediated anti-tumor activities of therapeutic CD20 antibodies and immune-mediated killing in the tumor microenvironment. In human whole blood, ACP-196 and ibrutinib showed robust and equipotent inhibitory activity on B-cell receptor induced responses in the low nM range, whereas CC-292 was 10-20 fold less potent.[3] 1. A competitive binding assay was conducted to profile the selectivity of Acalabrutinib (ACP-196) against a panel of 395 non-mutant kinases at a concentration of 1 μM; the assay compared the binding affinity of Acalabrutinib (ACP-196) with ibrutinib and CC-292 to evaluate relative selectivity for Btk [3] 2. IC50 determinations were performed on 9 kinases that possess a Cys residue in the same position as Btk; the assay measured the inhibitory concentration of Acalabrutinib (ACP-196), ibrutinib and CC-292 required to inhibit each kinase, to confirm the selectivity of Acalabrutinib (ACP-196) [3] 3. A phosphoflow assay was carried out on EGFR-expressing cell lines to assess the inhibitory effect of Acalabrutinib (ACP-196) and ibrutinib on EGFR activity; the assay quantified EGFR inhibition levels at different concentrations, with Acalabrutinib (ACP-196) tested up to 10 μM and ibrutinib tested to determine its EC50 (47-66 nM) [3] 4. An ELISA-based Btk target occupancy assay was developed to measure target coverage of Acalabrutinib (ACP-196) in preclinical and clinical studies; the assay utilized specific reagents to detect the binding of Acalabrutinib (ACP-196) to Btk in biological samples (peripheral blood, lymphoma cells, etc.) [3] |
| Cell Assay |
The EGFR-expressing cell lines used in the phosphoflow tests EGFR inhibition by ibrutinib was further validated without any ACP-196 inhibition being seen. Recent recognition of B-cell receptor (BCR) signaling as a critical factor in the progression of B-cell malignancies, including non-Hodgkin lymphoma (NHL), has resulted in the development of numerous targeted therapeutics that inhibit this signaling pathway. Ibrutinib, a small molecule inhibitor of Bruton tyrosine kinase (Btk) a key signaling molecule in the BCR pathway, has demonstrated significant clinical activity in a broad range of B-cell cancers. ACP-196 is a second generation Btk inhibitor with increased target selectivity and enhanced in vivo potency compared with ibrutinib and, thus, may represent an improvement over its predecessor. With the following studies, we sought to evaluate ACP-196 in canine models of B-cell NHL with the ultimate goal of providing the preclinical data necessary to move ACP-196 into human clinical trials. Using two immunophenotypically confirmed canine B-cell lymphoma cell lines, CLBL-1 and 17-71, we demonstrate potent in vitro inhibition of activation of Btk and the downstream effectors ERK 1/2 and PLCγ2 following 1 hour of treatment with ACP-196 at concentrations as low as 10nM.[2] 1. Canine B-cell lymphoma cell lines (CLBL-1 and 17-71) with confirmed immunophenotype were treated with Acalabrutinib (ACP-196) at concentrations as low as 10 nM for 1 hour; the activation levels of Btk, ERK 1/2 and PLCγ2 (downstream effectors of Btk) were detected and quantified to evaluate the inhibitory effect of Acalabrutinib (ACP-196) on BCR signaling pathway [2] 2. Human whole blood samples were used to assess the inhibitory activity of Acalabrutinib (ACP-196), ibrutinib and CC-292 on B-cell receptor (BCR)-induced responses; the assay measured the functional responses of B cells after stimulation with BCR agonists in the presence of different concentrations of the inhibitors, with Acalabrutinib (ACP-196) and ibrutinib showing potent activity in the low nM range [3] |
| Animal Protocol |
canine model of B cell NHL 2.5, 5, 10 mg/kg. orally administered In vivo studies were performed in companion dogs as part of an ongoing clinical trial. Twelve dogs with immunophenotypically confirmed, spontaneously occurring B-cell NHL were orally administered ACP-196 at dosages of 2.5mg/kg every 24 hours (6 dogs), 5mg/kg every 24 hours (5 dogs), or 10mg/kg every12 hours (1 dog). Btk occupancy in peripheral blood and lymphoma cells was assessed using a biotin-tagged probe derived from ACP-196. Using this assay we found that at 2.5mg/kg full Btk occupancy was achieved in peripheral B cells 3h after dosing for all dogs, except for a single dog with high peripheral B-cell count. At 24 hours after dosing, 83-99% Btk target occupancy was observed for all dogs. Partial response, as assessed by a modified RECIST scheme, was achieved in 2 dogs in the 2.5mg/kg group and the dog in the 10mg/kg group. Upon relapse, one of the responders in the 2.5mg/kg group was dose escalated to 10mg/kg q12 on day 42 and partial response from relapse was reestablished. Of the remaining 9 dogs, 3 achieved stable disease for > 28 days and 6 discontinued the study after developing progressive disease within 28 days of starting treatment. In total, to date, 3 dogs achieved a partial response, 3 dogs stable disease, and 6 dogs progressive disease. ACP-196 was well tolerated with only mild anorexia noted in some dogs. These data demonstrate that ACP-196 has single agent biologic activity in a spontaneous large animal model of human NHL. Studies in dogs with NHL are ongoing to define regimens prior to initiation of human phase I clinical trials. Additional cohorts are planned combining ACP-196 with a phosphatidylinositide 3-kinase (PI3K) delta-specific inhibitor.[2] In vivo, oral administration of ACP-196 in mice resulted in dose-dependent inhibition of anti-IgM-induced CD86 expression in CD19+ splenocytes with an ED50 of 0.34 mg/kg compared to 0.91 mg/kg for ibrutinib. A similar model was used to compare the duration of Btk inhibition after a single oral dose of 25 mg/kg. ACP-196 and ibrutinib inhibited CD86 expression >90% at 3h and ∼50% at 24h postdose. In contrast, CC-292 inhibited ∼50% at 3h and ∼20% at 24h postdose. An ELISA based Btk target occupancy assay was developed to measure target coverage in preclinical and clinical studies. In healthy volunteers, ACP-196 at an oral dose of 100 mg QD showed >90% target coverage over a 24h period. Btk occupancy and regulation of the PD markers (CD69 and CD86) correlated with PK parameters for exposure. In CLL patients, after 7 days of dosing with ACP-196 at 200 mg QD, 94% Btk target occupancy was observed compared with ∼80% reported for ibrutinib at 420 mg QD [3]. 1. Mouse model for Btk inhibition evaluation: Acalabrutinib (ACP-196) was administered to mice via oral route at different doses (including 25 mg/kg as a single dose and graded doses to determine ED50); anti-IgM was used to induce CD86 expression in CD19+ splenocytes; CD86 expression levels were measured at different time points (3h and 24h postdose) to assess the potency and duration of Btk inhibition by Acalabrutinib (ACP-196), with ibrutinib and CC-292 as comparators [3] 2. Canine model of spontaneous B-cell NHL: 12 companion dogs with immunophenotypically confirmed B-cell NHL were enrolled in an ongoing clinical trial; Acalabrutinib (ACP-196) was administered orally at three dosage regimens: 2.5 mg/kg once daily (6 dogs), 5 mg/kg once daily (5 dogs), 10 mg/kg twice daily (1 dog); Btk occupancy in peripheral blood and lymphoma cells was assessed at 3h and 24h postdose using a biotin-tagged probe derived from Acalabrutinib (ACP-196); tumor response was evaluated per modified RECIST criteria over time, with follow-up for response (partial response, stable disease, progressive disease) and dose escalation (10 mg/kg q12) for relapsed patients [2] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion The geometric mean absolute bioavailability of acalabrutinib is 25% with a median time to peak plasma concentrations (Tmax) of 0.75 hours. After administration of a single 100 mg radiolabelled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine. An irradiated dose of acalabrutinib was 34.7% recovered as the metabolite ACP-5862; 8.6% was recovered as unchanged acalabrutinub; 10.8 was recovered as a mixture of the M7, M8, M9, M10, and M11 metabolites; 5.9% was the M25 metabolite; 2.5% was recovered as the M3 metabolite. The mean steady-state volume of distribution is approximately 34 L. Acalabrutinib's mean apparent oral clearance (CL/F) is observed to be 159 L/hr with similar PK between patients and healthy subjects, based on population PK analysis. Metabolism / Metabolites Acalabrutinib is mainly metabolized by CYP3A enzymes. ACP-5862 is identified to be the major active metabolite in plasma with a geometric mean exposure (AUC) that is about 2-3 times greater than the exposure of acalabrutinib. ACP-5862 is about 50% less potent than acalabrutinib in regards to the inhibition of BTK. Biological Half-Life After administering a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life of the drug was found to be 0.9 (with a range of 0.6 to 2.8) hours. The half-life of the active metabolite, ACP-5862, is about 6.9 hours. 1. In healthy volunteers, Btk occupancy and regulation of PD markers (CD69 and CD86) by Acalabrutinib (ACP-196) (100 mg QD oral dose) correlated with PK parameters for exposure [3] |
| Toxicity/Toxicokinetics |
Hepatotoxicity In open label clinical trials of acalabrutinib in patients with CLL and mantle cell lymphoma, serum aminotransferase elevations occurred in 19% to 23% of patients during therapy and rose to above 5 times ULN in 2% to 3%. These elevations were transient and resolved spontaneously but occasionally led to early drug discontinuation. Among the 610 patients treated with acalabrutinib in pre-registration trials, there were no instances of clinically apparent liver injury attributed to its use, but there was a single instance of acute liver failure and death due to reactivation of hepatitis B. Similar cases of reactivation have been reported with ibrutinib, another small molecule inhibitor of Bruton's tyrosine kinase. Experience with acalabrutinib has been limited and the frequency of clinically apparent liver injury and reactivation of hepatitis B are not known. The majority of cases have occurred in patients taking multiple immunosuppressive agents and not just acalabrutinib alone. Likelihood score: D (possible rare cause of reactivation of hepatitis B). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the clinical use of acalabrutinib during breastfeeding. Because acalabrutinib is over 97% bound to plasma proteins, and the half-life of the drug and metabolite are less than 7 hours, the amount in milk is likely to be low. However, the protein binding of the active metabolite is not known and the manufacturer recommends that breastfeeding be discontinued during acalabrutinib therapy and for at least 2 weeks after the final dose. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. Protein Binding Reversible binding of acalabrutinib to human plasma protein is approximately 97.5%. The in vitro mean blood-to-plasma ratio is about 0.7. _In vitro_ experiments at physiologic concentrations show that acalabrutinib can be 93.7% bound to human serum albumin and 41.1% bound to alpha-1-acid glycoprotein. 1. In the canine clinical trial of Acalabrutinib (ACP-196), the drug was well tolerated, with only mild anorexia noted in some dogs [2] 2. Ibrutinib (first-generation Btk inhibitor) has known toxicities including atrial fibrillation, diarrhea, rash, arthralgia and bleeding events; these toxicities may be related to its off-target effects (e.g., EGFR, Itk, Txk inhibition), while Acalabrutinib (ACP-196) has improved selectivity and does not inhibit EGFR, Itk or Txk, suggesting potential lower off-target toxicity [3] |
| References |
[1]. J Hematol Oncol . 2016 Mar 9:9:21. [2].Cancer Res (2014) 74 (19_Supplement): 1744. [3]. Cancer Res (2015) 75 (15_Supplement): 2596. |
| Additional Infomation |
Pharmacodynamics Acalabrutinib is a Bruton Tyrosine Kinase inhibitor that prevents the proliferation, trafficking, chemotaxis, and adhesion of B cells. It is taken every 12 hours and can cause other effects such as atrial fibrillation, other malignancies, cytopenia, hemorrhage, and infection. 1. Acalabrutinib (ACP-196) is a novel irreversible second-generation BTK inhibitor, more potent and selective than ibrutinib (first-in-class BTK inhibitor approved for chronic lymphocytic leukemia, mantle cell lymphoma, Waldenstrom's macroglobulinemia) [1] 2. B-cell receptor (BCR) signaling is a critical factor in the progression of B-cell malignancies; Acalabrutinib (ACP-196) inhibits BCR signaling by targeting Btk, a key molecule in the pathway [2] 3. The improved selectivity of Acalabrutinib (ACP-196) is related to the reduced intrinsic reactivity of its electrophile; unlike ibrutinib, it does not inhibit EGFR, Itk or Txk, which may avoid ibrutinib-related toxicities (diarrhea, rash) and interference with anti-CD20 antibody-mediated anti-tumor activities [3] 4. Acalabrutinib (ACP-196) is being evaluated in clinical trials for B-cell malignancies; additional cohorts are planned to combine Acalabrutinib (ACP-196) with a phosphatidylinositide 3-kinase (PI3K) delta-specific inhibitor in canine NHL models [2] 5. In CLL patients, Acalabrutinib (ACP-196) at 200 mg QD achieved higher Btk target occupancy (94%) than ibrutinib at 420 mg QD (∼80%) after 7 days of dosing [3] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.47 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.47 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (4.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 2% DMSO+30% PEG 300+2% Tween 80+ddH2O: 6mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1482 mL | 10.7409 mL | 21.4818 mL | |
| 5 mM | 0.4296 mL | 2.1482 mL | 4.2964 mL | |
| 10 mM | 0.2148 mL | 1.0741 mL | 2.1482 mL |