BIOAVAIBILITY OF ACALABRUTINIB

FOR THE TREATMENT OF Chronic

lymphocytic leukaemia
Dosen Pengampu : Prof. Dr. apt. Budi
Suprapti, M.Si
AGUS PRATIWI
052024153008
Chronic Lymphocytic Leukemia (CLL)

Chronic lymphocytic leukemia is a chronic

lymphoproliferative disorder characterized by monoclonal
B cell proliferation (Mukkamalla et al., 2021).

 Most common leukemia of Western world.

 Less frequent in Asia and Latin America.
 Male to female ratio is 2:1.
 Median age at diagnosis is 65-70 years.
 In US population incidence is similar in different
races (Byrd et al., 2016). cervical lymphadenopathy in patient cll

Over time, you may have: Swollen lymph nodes in

your neck, armpits, stomach, or groin, shortness of
breath, pain or fullness in your stomach (spleen
bigger), fatigue, night sweats, fever and infections,
loss of appetite and weight (Byrd et al., 2016). Splenomegalie
A model for the cellular origin of CLL. CLL Treatment

(Gaidano et al., 2012) (Sood et al., 2021)

 Molecular weight 465.6
.
Solubility Freely soluble in water at pH values
below 3 but is practically insoluble in water at pH
values above 6.
LogP 0.49

Drug Action Acalabrutinib is a tyrosine kinase

inhibitor

Indications Chronic lymphocytic leukaemia

(BNF 81, 2021)

Dose 100 mg twice daily, doses should be

taken a approximately 12 hours apart, for dose adjustment,
interruption, or treatment discontinuation due
to side effects (BNF 81, 2021)
4-[8-amino-3-[(2S)-1-but-2-
ynoylpyrrolidin-2-yl]imidazo[1,5-
a]pyrazin-1-yl]-N-pyridin-2-ylbenzamide

(National Center for Biotechnology Information, 2021)

 Physicochemical Properties

Aqueous solubility Acalabrutinib has pH-dependent solubility (BCS Class

II compound). Acalabrutinib exposure is decreased by
gastric acid reducing agents.
Absorption

Bioavaibility The absolute bioavailability of acalabrutinib is

approximately 25% (range 20-30%).
Tmax Median TMAX = 0.75 h (acalabrutinib), 1.0-1.9 h
(ACP-5862).
Distribution

Volume of The mean volume of distribution at steady-state was

distribution 34 L, following a radiolabeled IV microtracer dose.
Acalabrutinib and ACP-5862 are approximately 98% and
99% bound to human plasma proteins, respectively

Elimination

Metabolism Acalabrutinib is primarily metabolized by CYP3A

Acalabrutinib enzymes, and to a lesser extent by glutathione

conjugation and amide hydrolysis. Active metabolite
ACP-5862 is formed via CYP3A metabolism of
acalabrutinib and is metabolized by CYP3A.

100 mg Excretion In the mass balance study, 84% of the dose was
received in the feces and 12% of the dose was
recovered in the urine, with less than 1% of the
dose excreted as unchanged acalabrutinib in urine

(National Center for Biotechnology Information, 2021)

 MECHANISM
OF ACTION
Calquence (acalabrutinib) is a small molecule Bruton tyrosine
kinase inhibitor. Acalabrutinib and its active metabolite, ACP-
5862, form a covalent bond with a cysteine residue in the BTK
active site, leading to inhibition of BTK enzymatic activity.
BTK is a signaling molecule of the B cell antigen receptor
(BCR) and cytokine receptor pathways. In B cells, BTK
signaling results in activation of pathways necessary for B-cell
proliferation, trafficking, chemotaxis, and adhesion. 

ACALABRUTINIB (Food and Drug Administration, 2021)

MECHANISM OF ACTION
Acalabrutinib
 Acalabrutinib (ACP-196) is a more selective,
irreversible BTK inhibitor that is specifically designed
to improve on the safety and efficacy of first-
generation BTK inhibitors (Byrd et al., 2016)

For patients with CLL or SLL, the recommended dose of

dose and
usage of
acalabrutinib monotherapy is 100 mg orally approximately
every 12 hours
(Khan & O'Brien, 2019)

For patients with previously untreated CLL or SLL receiving acalabrutinib

acalabrutinib
plus obinutuzumab, the recommended dose of acalabrutinib is 100 mg orally
approximately every 12 hours until disease progression or unacceptable
toxicity; acalabrutinib should be started at cycle 1 and obinutuzumab at
cycle 2 for a total of six 28-day cycles
(Khan & O'Brien, 2019)

Acalabrutinib is given before obinutuzumab when both are given on

the same day
(Khan & O'Brien, 2019)
Acalabrutinib pharmacokinetics
(Y. Miiao et al., 2021)

(Byrd et al., 2016)

 Calquence has clinically
meaningful drug–drug coadministration of
interactions (DDIs) with acid- decreased solubility at
Calquence with 40 mg of

reducing agents (ARAs) such as
proton pump inhibitors (PPIs),
the PPI omeprazole for 5
where concomitant use results
in reduced area under the
plasma drug concentration–time
curve (AUC) values (Patel et al.,
2020
background
the elevated gastric pH
levels that occur when
days decreased
ARAs are administered,
AUC by 43% in healthy
referred to here as the
subjects (Deisseroth,
“ARA effect”
2019)

Absorption across the To overcome the ARA

effect, a spray-dried ASD technologies are
intestinal membrane used to enhance
(Pepin et al., 2019). amorphous solid
dispersion (ASD) was solubilization and
developed and increase the
The extent of dose bioavailability of poorly
metabolized in humans formulated as an
immediate-release (IR) soluble drugs (Mooter,
(Zhang et al., 2014) 2012).
tablet.
The goal : to demonstrate mitigation of the ARA effect in
a beagle dog model using acalabrutinib ASD IR tablets at a
100 mg dose.

50/50 (%w/w) ASD containing acalabrutinib and

hydroxypropyl methylcellulose acetate succinate

In vivo tests were conducted in fasted beagle dogs

(1) pretreated with pentagastrin to increase gastric acid secretion and
lower stomach pH
(2) pretreated with famotidine (an ARA) to decrease gastric acid
secretion and elevate stomach pH

In vitro tests ; (1) multicompartment dissolution  average

gastrointestinal physiology in beagle dogs
(2) physical and chemical stability of the ASD
 Result in vitro
(ASD and API Characterization
Results)
PXRD diffractograms for the ASD and crystalline drug.

(a): SEMmicrograph of the ASD, panel

(b); SEMmicrograph of as-received acalabrutinib.
Physical and Chemical Stability Methods

Physical
Physical and Chemical Stability Methods

chemical
Tablet In Vitro Dissolution
Performance

 The crystalline solubility of

acalabrutinib is orders of
magnitude lower at pH 6 than at
pH 2.
 Resulting in a 3.4-fold
calculated enhancement in
duodenal AUC for the ASD tablet
relative to the Calquence
capsules,
Result in vivo - PK
Study o acalabrutinib is well absorbed when
administered to subjects with low stomach
pH.
o the famotidine pretreatment condition,
the ASD tablet achieved a 2.4-fold higher
AUC than the Calquence capsules,
o the performance of the Calquence capsules
suffered at high stomach pH, resulting in
roughly a 3-fold decrease in AUC compared
to the pentagastrin-treated dogs.
 Conclusion
1. Chronic lymphocytic leukemia is a chronic lymphoproliferative disorder
characterized by monoclonal B cell proliferation.
2. Acalabrutinib is a tyrosine kinase inhibitor for Chronic lymphocytic leukaemia
3. For Aqueous solubility, acalabrutinib has pH-dependent solubility (BCS Class II
compound). Acalabrutinib exposure is decreased by gastric acid reducing agents.
4. ASD tablets are an effective enabling technology for overcoming reduction in
AUC of the weakly basic drug acalabrutinib when co-administered with a gastric
ARA
5. In beagle dogs, ASD tablets achieved similar AUC values at low and high gastric
pH conditions and outperformed Calquence capsules 2.4-fold at high gastric pH
6. ASD had good physical stability and the ASD and ASD tablet showed good chemical
stability when stored refrigerated or at room temperature with a desiccant.
7. An ASD dosage form represents a useful strategy for improving patient
compliance and efficacy of acalabrutinib
8. This strategy can be extended to products other small molecule drugs with the
aim of increasing the bioavailability of promote improved performance in vivo
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Thank You