Ibrutinib oral suspension bioavailability and compatibility for optimal enteral administration route

Abstract

Background:

Ibrutinib is the only Bruton tyrosine kinase inhibitor (BTKi) with once-daily oral capsule, tablet, and oral suspension formulations approved in the United States across indications of chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenström macroglobulinemia, and previously treated chronic graft-versus-host disease, and for mantle cell lymphoma in Europe. Patients with difficulty swallowing capsules or tablets may require alternative formulations or administration options to optimize treatment.

Objectives:

To evaluate the relative bioavailability of ibrutinib oral suspension relative to capsule or tablet formulations and to examine compatibility for optimal administration methods.

Methods:

Relative bioavailability of ibrutinib oral suspension was evaluated in healthy volunteers or patients in comparison to capsule or tablet formulations. Dose recovery and delivery, presence of impurities, particle size, and hold time were evaluated after in vitro mock oral suspension administration via syringe and nasogastric and percutaneous endoscopic gastrostomy (PEG) tubes.

Results:

Clinical bioavailability was comparable for ibrutinib oral suspension and capsules (420 mg/day) under the fasted state in healthy volunteers. Dose-normalized pharmacokinetic values were similar across ibrutinib formulations in patient studies. All evaluated enteral tubes achieved 90%–110% ibrutinib dose recovery regardless of tube type or syringe after 2 × 3 mL water rinses. Oral suspension preservative may be adsorbed into enteral tubes after a 60-minute hold time.

Conclusion:

Ibrutinib oral suspension bioavailability was comparable with ibrutinib tablet and capsule formulations. When dosed via standard enteral tube administration methods, ibrutinib oral suspension is stable and compatible with polyurethane, silicone, or polyvinyl nasogastric or PEG tubes. To ensure full dose recovery and prevent drug preservative adsorption into tubes, ibrutinib oral suspension should be administered immediately and followed by two rinses of 3 mL of water each. Ibrutinib oral suspension is a viable BTKi treatment option for patients requiring or preferring alternatives to oral capsules and tablets.

Plain language summary

Ibrutinib liquid oral suspension activity and best methods for giving ibrutinib to patients who have trouble swallowing pills

Ibrutinib is a once-a-day Bruton tyrosine kinase inhibitor treatment for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenström macroglobulinemia, mantle cell lymphoma, or chronic graft-versus-host disease. The drug comes in three formulations, a liquid oral suspension, tablet, and capsule. Across multiple studies, researchers studied the movement of ibrutinib into, through, and out of the body. They compared this movement in the three formulations and found that the ibrutinib liquid oral suspension worked the same as the tablets or capsules when taken on an empty stomach. In an in vitro mock administration analysis, researchers also tested different types of syringes and feeding tubes to find the best way to deliver ibrutinib oral suspension to patients who cannot or have trouble swallowing pills. They found that several common types of syringes and feeding tubes work well with ibrutinib oral suspension, and that liquid ibrutinib is delivered best when the drug is given immediately after being placed into the syringe. Based on this in vitro mock administration analysis, researchers recommend that the syringes and feeding tubes be rinsed twice with a small amount of water (3 mL for each rinse) after ibrutinib to make sure that patients receive the full dose. Because ibrutinib oral suspension works in a similar way to tablets or capsules and can be given with a feeding tube, ibrutinib oral suspension is a good treatment option for patients with who need or prefer an alternative to oral capsules and tablets.

Keywords

bioavailability Bruton tyrosine kinase inhibitor enteral tube ibrutinib Imbruvica nasogastric oral suspension percutaneous gastrostomy

Introduction

Ibrutinib is a once-daily Bruton tyrosine kinase inhibitor (BTKi) approved in the United States for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), and previously treated chronic graft-versus-host disease (cGVHD).¹ As a first-in-class medication, ibrutinib has the longest available follow-up period (up to 10 years in CLL/SLL) of any covalent BTKi.² Multiple randomized phase III studies have demonstrated both a significant progression-free survival^3–8 and overall survival benefit.^3,4,7,8 Ibrutinib is the only BTKi across all indications with oral capsule, tablet, and oral suspension formulations.¹ The approved ibrutinib dosage is 420 mg/day for adults across all indications and for patients with cGVHD who are aged ⩾12 years. Ibrutinib oral suspension is formulated at a concentration of 70 mg/mL¹ and was initially developed to allow once-daily dosing for pediatric patients aged ⩾1 to <12 years with cGVHD. Among pediatric patients with cGVHD, plasma concentrations for ibrutinib at the recommended pediatric dose were comparable with those observed in adults with cGVHD at the standard dose.⁹

Dysphagia, or difficulty swallowing, affects up to one in six adults and has an estimated global prevalence of 44%.^10,11 Older adults and patients with CLL with central nervous system involvement have a higher risk of swallowing difficulties.¹⁰ In addition, dysphagia has been reported in relation to Bing-Neel syndrome.¹² Difficulty swallowing solid formulations also may be physiological, caused by esophageal obstruction¹³ or neurologic disease,¹⁴ or may be nonphysiological (e.g., pill aversion).¹⁵ Dysphagia may negatively affect treatment outcomes and quality of life, potentially leading to additional health complications and reduced adherence to oral therapies.^16,17 Furthermore, real-world data analysis has shown that both all-cause healthcare-resource utilization per patient per month and all-cause costs per patient per month are significantly higher among patients with CLL and dysphagia compared with those without dysphagia. Similar results were observed among patients with WM with and without dysphagia.¹⁸ Therefore, a potentially broad patient population may benefit from the availability of an oral suspension formulation. Here, we evaluated relative bioavailability between oral suspension and capsule or tablet formulations in healthy adults and pediatric patients, and optimal administration of ibrutinib oral suspension via feeding tube to better understand pharmacokinetics (PK) and administration of ibrutinib oral suspension.

Methods

Relative bioavailability of ibrutinib suspension in healthy adults

Relative bioavailability of ibrutinib oral suspension versus capsules was evaluated through an open-label, randomized, parallel-group, three- or four-way crossover study of ibrutinib in healthy adults following single oral dose administration of ibrutinib oral suspension or capsules (NCT02390609; EudraCT 2015-000155-25). The single-center study was conducted from September 8, 2015, to November 30, 2015.

Healthy adults, aged 18–55 years (body mass index of 18 to ⩽30 kg/m², weighed ⩾50 kg), and in general good health were eligible to enroll in the study. The study was approved by the Institutional Review Board and was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Guidelines for Good Clinical Practice. All volunteers provided informed consent.

Participants were randomly assigned to receive ibrutinib oral suspension under a fed or fasted state versus ibrutinib capsule under a fasted state. Treatment A was single-dose ibrutinib 560 mg/day (4 × 140 mg capsules) administered after an overnight fast of ⩾10 h with no meal until 4 h after drug intake. Treatment B was single-dose ibrutinib 560 mg/day oral suspension after an overnight fast of ⩾10 h and no meal until 4 h after drug intake, and treatment C was the same oral suspension dose given 2 h after consuming a high-fat breakfast. Enrolled participants received one of six treatment sequences as follows: sequence 1: A/B/C; sequence 2: B/C/A; sequence 3: C/A/B; sequence 4: A/C/B; sequence 5: B/A/C; and sequence 6: C/B/A.

The duration of the study was approximately 67–83 days, including a screening period of 28 days and 3 × 4-day treatment periods, with a 7 (±2) day washout between treatment periods and a 10-day follow-up.

Pharmacokinetic and statistical analysis for healthy adults study

Serial intensive PK blood samples were collected over 48 h in each treatment period in the healthy adults. The following PK parameters were calculated using non-compartmental methods: maximum observed plasma concentration (C_max), time to reach maximum observed plasma concentration (t_max), half-life (t_1/2), area under the plasma concentration-time curve (AUC) from time 0 to 24 h after dosing (AUC₂₄), AUC from time 0 to time of the last observed quantifiable concentration (C_last (AUC_last)), AUC from time 0 to infinite time (AUC_∞), apparent volume of distribution under terminal phase after oral administration (Vz/F), and apparent total plasma or serum clearance of drug after oral administration (CL/F). All PK parameters were calculated using the actual times of blood sampling.

Assuming an intra-subject C_max coefficient of variation of 43%, a sample size of 18 subjects was determined to be sufficient for point estimates of the geometric mean (GM) ratios of C_max between test and reference to fall within 78%–128% of the true value with 90% confidence. Statistical analysis included subjects who completed reference treatment and ⩾1 test treatment. A mixed-effect model that included treatment, period, and treatment sequence as fixed effects, and subject as a random effect, was used to estimate the least squares mean and intra-subject variance. Ratios of C_max, AUC_last, and AUC_∞ with 90% CIs were constructed using estimated least squares mean and intra-subject variance from the mixed-effects model of log-transformed PK parameters.

Pharmacokinetics in patients with cGVHD and relapsed/refractory mature B-cell NHL

Dose-normalized PK of single- and multidose oral suspension formulations determined by population PK methods were compared with ibrutinib capsule and tablet formulations in pediatric and young adult patients with cGVHD (iMAGINE; NCT03790332)⁹ and relapsed/refractory (R/R) mature B-cell non-Hodgkin lymphoma (NHL; LYM3003; NCT02703272) in the fed state. Population PK methods were employed to determine PK parameters in patients since sparse samples (blood samples for PK were collected at pre-dose, 1, 2, 4, and 6 h) were collected in the iMAGINE and LYM3003 study, whereas in the healthy volunteers’ study, non-compartmental methods were used. These studies were approved by the Institutional Review Boards at each institution and were conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Guidelines for Good Clinical Practice. All volunteers provided informed consent. Relevant EQUATOR guidelines were followed for healthy adults and patients.

Enteral feeding tube testing: In vitro mock administration

Ibrutinib oral suspension was mock-administered by syringes through nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes and conducted in triplicate for each feeding tube and syringe type. The tube types included NG tubes made of polyurethane (PU), silicone (SIL), and polyvinyl chloride (PVC); and low-profile SIL PEG tubes with balloon and ENFit connectors. The syringes included in the study were polypropylene with SIL and high-density polyethylene seals (Supplemental Figure 1 and Supplemental Table 1).

The in vitro evaluation of mock administration through the four enteral feeding tube types was conducted using a low dose of 28 mg (0.4 mL) oral suspension ibrutinib; one 60-min holding sample was evaluated for each feeding tube and syringe type. To mimic the dosing of ibrutinib oral suspension in patients via enteral feeding tubes, syringes were first attached, breached, loaded, reassembled, and the dose administered, followed by water rinses. To mimic possible real-world conditions, a 60-min syringe hold time was evaluated with the maximal clinically relevant dose of 560 mg (8 mL) ibrutinib at the time of study. Recovery of ibrutinib and benzyl alcohol (preservative) was tested after the administration as a proxy for administration delivery. In addition, degradation and particle size differences were evaluated using laser diffraction and compared with a control sample with no enteral tube administration. These differences were measured after the 60-min hold in the enteral tube.

Results

Bioavailability in healthy adults

A total of 18 healthy participants received ibrutinib therapy and completed the study comparing oral suspension versus capsule or tablet formulations. All participants were White and of non-Hispanic/non-Latino ethnicity; 15 patients (83%) were men with a median age of 47 years (range, 29–55; Table 1). The relative bioavailability of ibrutinib oral suspension formulation under fasted state was comparable (treatment B; AUC_last GM: 236.2 ng*h/mL (90% CI: 94.2–124.9)) with that of ibrutinib capsule administered under fasted state (treatment A; AUC_last GM: 217.7 ng*h/mL; Table 2). Similar to what was observed previously with capsules or tablets, the relative bioavailability of oral suspension administered in the fed state was higher than oral suspension administered in the fasted state (AUC_last GM: 427.8 ng*h/mL (90% CI: 155.6–210.9) vs 236.2 ng /mL).¹⁹ Mean ibrutinib plasma concentration peaked approximately 3 h after oral administration for all three treatments, with the highest peak concentration observed with oral suspension administered in the fed state (Figure 1). A summary of plasma ibrutinib PK parameters in healthy adults from the bioavailability study is available in Supplemental Table 2.

Table 1.

Participant disposition and baseline characteristics.

Characteristic	Sequence 1^a A/B/Cn = 3	Sequence 2B/C/An = 3	Sequence 3C/A/Bn = 3	Sequence 4A/C/Bn = 3	Sequence 5B/A/Cn = 3	Sequence 6C/B/An = 3	TotalN = 18
Completed study, n (%)	3 (100)	3 (100)	3 (100)	3 (100)	3 (100)	3 (100)	18 (100)
Race, n (%)
White	3 (100)	3 (100)	3 (100)	3 (100)	3 (100)	3 (100)	18 (100)
Sex, n (%)
Male	3 (100)	3 (100)	2 (67)	2 (67)	2 (67)	3 (100)	15 (83)
Female	0	0	1 (33)	1 (33)	1 (33)	0	3 (17)
Ethnicity, n (%)
Non-Hispanic/non-Latino	3 (100)	3 (100)	3 (100)	3 (100)	3 (100)	3 (100)	18 (100)
Median age (range), years	48.0 (33–53)	31.0 (30–55)	53.0 (47–53)	39.0 (29–53)	47.0 (44–54)	46.0 (32–53)	47.0 (29–55)
Median body mass index (range), kg/m²	22.6 (22–29)	24.6 (21–25)	25.0 (24–26)	26.1 (23–29)	24.5 (23–29)	26.6 (22–27)	24.7 (21–29)

Treatments were as follows: (A) Ibrutinib, 560 mg administered as four capsules (140 mg each) after an overnight fast of ⩾10 h; (B) ibrutinib, 560 mg as a suspension, administered after an overnight fast of ⩾10 h; and (C) ibrutinib, 560 mg as a suspension, administered 2 h after completing a high-fat breakfast.

Table 2.

Relative bioavailability of ibrutinib oral suspension versus capsule formulation.

Parameter	N	Geometric mean	Ratio: Test/reference, %	90% CI, %	Intra-subject CV, %
Suspension treatment B or C (test) versus capsule (A) (reference)
C_max, ng/mL
Treatment A	18	29.6	NA		44.0
Treatment B	18	19.0	64.4	50.8–81.6
Treatment C	18	74.5	251.8	198.6–319.3
AUC_last, ng*h/mL
Treatment A	18	217.7	NA	NA	25.4
Treatment B	18	236.2	108.5	94.2–124.9
Treatment C	18	427.8	196.5	170–226.2
Suspension treatment C (test) versus suspension treatment B (reference)
C_max, ng/mL
Treatment B	18	19.0	NA	NA	46.5
Treatment C	18	74.5	391.3	302.2–506.6
AUC_last, ng h/mL
Treatment B	18	236.2	NA	NA	26.5
Treatment C	18	427.8	181.1	155.6–210.9

AUC_last, area under the curve from the time of dosing to the last measurable plasma concentration; C_max, maximum observed plasma concentration; CV, coefficient of variation; NA, not applicable.

Figure 1.

Mean plasma ibrutinib concentration-time profiles.

Pharmacokinetics in patients with cGVHD and R/R mature B-cell NHL

Among patients with cGVHD, dose-normalized AUC for 70 mg multidose oral suspension, 70 mg single-dose oral suspension, and tablet or capsule formulations were similar with GMs (90% CI) of 1432 (930–2205), 1319 (808–2153), and 1743 (1339–2270), respectively (Figure 2(a)). Results for dose-normalized C_max were also similar across the three dosing types, with GMs (90% CI) of 275 (168–448) for 70 mg multidose oral suspension, 302 (134–682) for 70 mg single-dose oral suspension, and 358 (261–491) for tablet or capsule formulations. Results followed a similar pattern among patients with R/R mature B-cell NHL; dose-normalized AUC for 70 mg multidose oral suspension, 70 mg single-dose oral suspension, and tablet or capsule formulations were similar with GMs (90% CI) of 469 (265–828), 363 (274–481), and 449 (380–531), respectively (Figure 2(b)). Values for dose-normalized C_max GMs (90% CI) were 72 (23–228) for 70 mg multidose oral suspension, 60 (39–92) for 70 mg single-dose oral suspension, and 73 (58–92) for tablet or capsule formulations.

Figure 2.

Comparison of dose-normalized PK of single- and multidose suspension formulations of ibrutinib versus capsule or tablet formulations in patients with (a) cGVHD and (b) R/R mature B-cell non-Hodgkin lymphoma. C_max and AUC at steady-state are normalized to 420 mg dose. Box plots show geometric means and 90% CI.

Real-world applicability: Dysphagia

A 62-year-old woman with a medical history notable for Hodgkin lymphoma treated with first-line doxorubicin-bleomycin-vinblastine-dacarbazine (ABVD) chemotherapy later experienced therapy-related complications of acute myeloid leukemia. After induction therapy, she underwent an allogeneic stem cell transplantation. During the early post-transplant period, the patient experienced grade 3 mucositis and acute gastrointestinal graft-versus-host disease (GVHD), responsive to steroid therapy. However, she later developed chronic skin GVHD that was refractory to initial treatment modalities.

Following resolution of mucositis and gastrointestinal GVHD, the patient reported persistent difficulty swallowing pills and/or tablets. Extensive evaluation did not reveal any evidence of functional dysphagia. Her aversion to pill and tablet ingestion persisted, posing challenges to the management of her cGVHD and other medical conditions. She demonstrated tolerability to liquid formulations, prompting a transition of her medications to liquid preparations whenever feasible.

In this case, the patient presented with nonphysiologic, pill-specific dysphagia. The prevalence of dysphagia in older-adult patients is estimated to be 50%,²⁰ with pill-swallowing difficulties affecting 10%–40% of these patients.^17,21 Therefore, shifting medication formulation to an oral suspension may be warranted in a large number of patients. The bioavailability and compatibility of ibrutinib oral suspension described in this manuscript support its use in patients with pill aversion.

Enteral feeding tube testing: In vitro mock administration

For some patients, administration of medications through NG or PEG tubes is necessary. Mock administration of ibrutinib oral suspension via enteral feeding tubes demonstrated that SIL and PVC NG tubes and SIL G-tube balloon tubes consistently delivered the desired dose with one water rinse of 3 mL when there was no syringe hold time (Table 3). The PU NG tube required a second 3 mL water rinse to deliver the desired dose. With a 60-min hold time, the SIL NG tube was the only tube type that delivered the desired dose with one 3 mL water rinse. All enteral tube types achieved the desired ibrutinib dose recovery (90%–110%) with two 3 mL water rinses (Figure 3(a)).

Table 3.

Ibrutinib percent recovery results.

Syringe hold time	Percent recovery (%)
	Assay + first rinse				Second rinse				Assay + rinses
	NG PU	NG SIL	NG PVC	PEG SIL	NG PU	NG SIL	NG PVC	PEG SIL	NG PU	NG SIL	NG PVC	PEG SIL
Control									100.0
Initial	83.8	90.9	93.6	90.7	8.2	3.8	1.1	4.2	92.0	94.7	94.7	94.9
60 min	88.2	95.0	88.0	87.3	3.1	0.9	2.4	4.2	91.3	95.9	90.4	91.5
	90.8	92.2	93.3	90.9	2.7	1.7	1.9	1.4	93.5	93.9	95.2	92.3
	87.7	95.0	90.8	89.5	3.4	0.8	3.1	3.1	91.1	95.8	93.9	92.6

NG, nasogastric; PEG, percutaneous endoscopic gastrostomy; PU, polyurethane; PVC, polyvinyl chloride; SIL, silicone.

Figure 3.

Ibrutinib dose recovery (a) and benzoyl alcohol recovery (b).

Benzyl alcohol is used as a preservative for multidose ibrutinib oral suspension. The recovery of benzyl alcohol, when there was no hold time, met the predefined acceptance criteria (80%–110%) with PVC and SIL G-tube balloon tubes administration, followed by the first water rinse. In contrast, the PU and SIL NG tubes needed a second 3 mL water rinse to meet the acceptance criteria. With a 60-min hold time, only the PVC NG tube met specification with a second 3 mL water rinse (Table 4). These results suggest that benzyl alcohol may be adsorbed into the tube during hold time, particularly with some enteral feeding tubes (Figure 3(b)); therefore, immediate dosing without hold time is recommended.

Table 4.

Benzyl alcohol percent recovery results.

Syringe hold time	Percent recovery (%)
	Assay + first rinse				Second rinse				Assay + rinses
	NG PU	NG SIL	NG PVC	PEG SIL	NG PU	NG SIL	NG PVC	PEG SIL	NG PU	NG SIL	NG PVC	PEG SIL
Control									102.3
Initial	70.1	78.7	96.8	92.9	10.5	5.5	2.3	7.1	80.6	84.2	99.1	100
60 min	25.3	63.9	77.4	61.7	5.4	2.5	3.3	7.9	30.7	66.4	80.7	69.6
	34.0	74.6	84.8	71.4	5.0	4.0	3.5	5.2	39.0	78.6	88.3	76.6
	24.9	58.0	81.4	71.3	4.1	3.0	4.2	7.2	29.0	61.0	85.6	78.5

NG, nasogastric; PEG, percutaneous endoscopic gastrostomy; PU, polyurethane; PVC, polyvinyl chloride; SIL, silicone.

No degradation of ibrutinib was observed after the 60-min hold time in any enteral tube type or in the fitting syringes tested in this analysis. Several tube and syringe types with various compositions of materials, including PU, PVC, SIL, or polypropylene/SIL, were tested (Supplemental Tables 3 and 4). In addition, when compared with the control sample, no significant change in particle size was observed, regardless of the tubing type used for ibrutinib administration samples (Supplemental Figure 2).

Analytical observations of the different tube types tested suggest that transparent tubes are the easiest to use. Other factors affecting ease of use include: (1) tube diameter, with wider tubes requiring less pressure and flushing to dislodge material that sticks to tube walls; and (2) presence or absence of a Y connector, where Y connectors may trap material.

Real-world applicability: Enteral tube use

A 55-year-old woman had a medical history notable for lower esophageal strictures due to longstanding, undiagnosed/untreated gastroesophageal reflux disease. During routine follow-up appointments with her primary care physician, persistent and progressive lymphocytosis was noted, prompting additional work-up and subsequently leading to the diagnosis of CLL. She started treatment with first-line ibrutinib upon meeting treatment initiation criteria.

The patient reported chronic mild to moderate dysphagia, primarily with solids, which was attributed to esophageal strictures that had persisted for at least 5 years prior to the CLL diagnosis, although the patient could swallow pills or tablets with liquids. Approximately 3 years after starting CLL-directed therapy, she experienced an acute exacerbation of dysphagia that necessitated hospitalization. An esophagogastroduodenoscopy performed after admission, including placement of an NG tube with direct visualization, revealed worsening of the esophageal stricture. Pending further evaluation and treatment, medications were administered via the NG tube when feasible and compatible, including ibrutinib oral suspension. In this case, the patient presented with physiologic dysphagia. Although postural adjustments and swallowing aids can be used to help make swallowing pills easier, these are not recommended for patients with physiologic swallowing dysfunction.¹⁷ Therefore, enteral tube administration of liquid medications is a feasible alternative to solid dosage formulations. As noted above, ibrutinib oral suspension is compatible with various materials used in the manufacturing of NG tubes and syringes, with no degradation noted even with prolonged hold times.

Discussion

Ibrutinib is the only BTKi approved as an oral suspension formulation, providing treatment options and flexibility for patients with CLL/SLL, WM, or cGVHD who have difficulty swallowing tablets or capsules.¹ The enteral tube use-optimization results presented here are also unique within the drug class. The real-world cases above highlight the importance of oral suspension formulations for patients with hematologic malignancy with both nonphysiologic and physiologic dysphagia. Despite the availability of different techniques or aids to facilitate pill swallowing,¹⁷ many patients and caregivers resort to manipulating or crushing tablets on a daily basis.²² However, crushing or chewing tablets or capsules can alter drug absorption and potentially cause harm.^23,24 Furthermore, many patients in hospitals and care facilities rely on enteral feeding, but crushing solid medication can lead to enteral tube blockages.²⁵ Thus, the availability of ibrutinib oral suspension may alleviate some medication administration challenges and support greater treatment adherence. In addition, the use of alternative dosing formulations for patients with CLL or WM may decrease healthcare-related costs.¹⁸ To reduce the number of patients crushing medication tablets, increased screening for dysphagia is warranted. Dysphagia screening is common among patients recovering from stroke, but is not routinely implemented in the care of other frail, older adults. A simple swallow screening tool may help healthcare providers identify patients with dysphagia more easily and provide them with appropriate medication formulations.²⁶

Regarding the effect of food intake on bioavailability, our results show an approximate doubling of ibrutinib exposure when taken after a high-fat breakfast compared with dosing under fasted conditions. As previously described for another predominantly CYP3A4-cleared drug, budesonide, this is thought to be caused by the stimulatory effect of food intake on intestinal blood flow, rather than enhanced solubilization of ibrutinib in the GI tract.²⁷ Because of the increased blood flow, ibrutinib diffusion from the enterocytes to the mesenteric vein and portal vein systems is increased, thus reducing the residence time in enterocytes and the first-pass metabolism mediated by CYP3A4. Additionally, the population PK analysis showed that the modified fasting condition (i.e., ibrutinib dosing ⩾30 min before or ⩾2 h after a meal), as applied throughout all studies in patients with B-cell malignancies, generated exposures that were not significantly lower than the fed condition. Furthermore, the coefficients of variation of AUC and C_max were approximately as high as 60% in healthy participants and up to twice as high in patients with B-cell malignancies. These differences in exposure between the fasted and fed states are not expected to be clinically relevant since a flat exposure-response relationship was noted for both safety and efficacy endpoints. However, conclusions across groups should be made with caution since population PK models were used to analyze sparse data from patients with cGVHD and NHL, whereas direct rich PK data were collected for healthy volunteers.

Regarding limitations for the enteral tube testing, in vitro testing was conducted once and was not repeated to test for consistency. Additionally, enteral tube testing was not conducted in patients.

Conclusion

Our results show that ibrutinib’s relative bioavailability is similar across formulations when administered under a fasted state and that ibrutinib oral suspension administration is compatible with multiple enteral tube and syringe types made of materials including polyurethane, PVC, SIL, or polypropylene/SIL. Dose-normalized AUC and C_max values were similar across ibrutinib formulations in the fasted state. In addition, the use-optimization results suggest that oral suspension administration with two 3 mL water rinses and no hold time ensures full dose delivery recovery without benzoyl alcohol preservative adsorption.

Analytical observations suggest that transparent tubes are the easiest to use and that tubes with wider diameters without Y connectors enhance usability. These findings form key clinical practice recommendations for ibrutinib oral suspension administration to ensure optimal dosing. Because the causes of dysphagia may be either physiologic^13,14,17 or nonphysiologic¹⁵ in nature, a broad spectrum of patients may benefit from the availability of ibrutinib oral suspension.

Clinical practice points

Ibrutinib has demonstrated both significant progression-free survival and overall survival benefits in multiple randomized phase III clinical trials and is the only BTKi with FDA-approved capsule, tablet, and oral suspension formulations.

Dysphagia affects approximately 44% of people worldwide, making an oral suspension formulation an important treatment option.

Our results show that the bioavailability of ibrutinib is similar across formulations and that the oral suspension is compatible with multiple enteral tube and syringe types.

To ensure targeted dose administration, immediate dosing without hold time, followed by two water rinses of 3 mL each, is recommended.

Supplemental Material

sj-docx-1-tah-10.1177_20406207251399466 – Supplemental material for Ibrutinib oral suspension bioavailability and compatibility for optimal enteral administration route

Supplemental material, sj-docx-1-tah-10.1177_20406207251399466 for Ibrutinib oral suspension bioavailability and compatibility for optimal enteral administration route by Jonas Paludo, Lisa Nodzon, Xavier Woot de Trixhe, Michelle Pacia, Heena Mavani, Harisha Atluri, Thomas J. Huemann, Jessica Shelly, Yemin Liu and Shayna Sarosiek in Therapeutic Advances in Hematology

Footnotes

Acknowledgements

The authors thank the volunteers and patients who participated in this study and their supportive families, as well as the investigators, subinvestigators, and coordinators at each of the study sites. The authors also thank James P. Dean, MD, PhD (employed with Pharmacyclics LLC, an AbbVie Company), for his contributions during the review of this manuscript. This study was sponsored by Pharmacyclics LLC, an AbbVie Company, and Janssen Pharmaceuticals. Editorial support was provided by Cindi A. Hoover, PhD, and funded by Pharmacyclics LLC, an AbbVie Company.

Author note

Presented in part at the Hematology/Oncology Pharmacy Association Annual Conference; April 2024; Tampa, FL. Encored at Oncology Nursing Society Congress (April 2024, Washington, DC) and NCODA Spring Forum (April 2024, Dallas, TX).

Declarations

ORCID iD

Lisa Nodzon

Supplemental material

Supplemental material for this article is available online.

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