Abstract
Alectinib, approved as 150 mg capsules for the treatment of adults with advanced ALK‐positive non‐small cell lung cancer, is being assessed in children with ALK‐positive solid and central nervous system tumors. An ad hoc pediatric‐friendly suspension of alectinib, prepared from capsule contents, is under investigation as an alternative formulation for children who cannot swallow capsules. This randomized, crossover, relative bioavailability, and food effect study evaluated alectinib administered as an oral suspension versus capsule formulation following conventional venipuncture and capillary microsampling. A total of 28 healthy adult subjects received a 600 mg single dose of alectinib in two groups: fasted (n = 14) and mixed fed (n = 14; seven receiving high‐fat meal and seven receiving low‐fat meal). Combined alectinib + M4 (active metabolite) exposure was higher for suspension versus capsule, with geometric mean ratio (GMR) of 2.6 for area under the concentration–time curve extrapolated to infinity (AUC0‐∞) and 3.0 for maximum observed concentration (C max) under fasted conditions, and 1.7 for both parameters for mixed fed. The suspension showed increased alectinib + M4 AUC0‐∞ following a high‐fat meal versus fasted conditions (GMR 1.7 [90% confidence interval 1.4–2.2]). Alectinib AUC0‐∞ and C max measured in venous and capillary samples were generally similar for the suspension and capsule. Single oral doses of 600 mg alectinib suspension and capsule were well tolerated, with no safety concerns. Based on these findings, the oral suspension of alectinib appears suitable for use in pediatric studies after appropriate dose adjustment relative to the capsule.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Alectinib, approved as 150 mg capsules for the treatment of advanced ALK‐positive non‐small cell lung cancer in adults, is being investigated in children with ALK‐positive solid and central nervous system tumors. A formulation for children who are unable to swallow capsules is essential.
WHAT QUESTION DID THIS STUDY ADDRESS?
This study evaluated the relative bioavailability and pharmacokinetics (PK) of alectinib and M4 (active metabolite) following administration of oral suspension versus capsule formulation of alectinib.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The oral suspension showed significantly higher exposure than the capsule under fed and fasted conditions. Alectinib exposure increased in the presence of food, irrespective of formulation. Fat content may impact alectinib PK, although this is not considered clinically relevant. Microsampling techniques did not meaningfully impact PK parameters for alectinib compared with venipuncture methods.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
Our results indicate that the oral suspension of alectinib is suitable for use in pediatric studies following appropriate dose adjustment, and that microsampling is a feasible alternative collection method to venipuncture for alectinib bioanalysis.
INTRODUCTION
Although rare, cancer is one of the leading causes of death in children globally. 1 Due to the low incidence of disease and physical limitations (i.e., lower blood volume and risk for developmental toxicities), clinical trials in children are challenging, bringing complexities to the traditional drug development framework from ethical and statistical perspectives. 2 , 3
Generating adequate pediatric clinical data for dose optimization is difficult across such a heterogeneous population. Pharmacokinetic (PK) sampling with conventional venipuncture blood collection is often unfeasible in children due to the need for repeated sampling, and blood sample volume constraints in younger children. 2 , 3 , 4 Thus, there is growing interest from pharmaceutical companies in the integration of less invasive, microsampling techniques for quantitative PK bioanalysis in clinical drug development, particularly in studies enrolling special patient populations, such as pediatrics. 5 In addition, orally administered pharmaceuticals susceptible to prominent food effect on drug exposure face additional challenges related to the uncertainty of potential impact from various child diets on drug PK. These types of drugs, where prescribing information specifies dosing administration in relation to meals, may also benefit from food effect testing beyond the standard high‐fat meal to study more practical pediatric‐friendly (low‐fat) meals.
Alectinib is a potent anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of adult patients with advanced ALK‐positive non‐small cell lung cancer at a recommended dosing regimen of 600 mg orally twice daily (b.i.d.) with food. 6 Alectinib is commercially available as 150 mg capsules. A phase I/II study is currently investigating the safety, PK, and efficacy of alectinib in children and adolescents (birth to ≤17 years) with solid or central nervous system tumors harboring ALK fusions (NCT04774718).
Development of an age‐appropriate formulation of alectinib for children who cannot swallow capsules is critical for use in the pediatric setting. An ad hoc pediatric‐friendly alectinib formulation is being explored by mixing the contents from the 150 mg capsules in water to create an extemporaneous suspension (hereafter referred to as an oral suspension). Alectinib is predominantly metabolized by cytochrome P450 3A (CYP3A) to its similarly active metabolite, M4, which has shown equipotent activity to alectinib. 7 , 8 Alectinib demonstrates poor solubility and high permeability with a prominent food effect; an approximate three‐fold increase in the combined exposure of alectinib and M4 was observed following administration of a single 600 mg dose of alectinib (administered as capsules) to healthy adults with a high‐fat, high‐calorie meal. 9
Here, we present the results of a phase I healthy adult volunteer study using venipuncture and microsampling collection techniques to determine the relative bioavailability and PK of alectinib and M4 (equipotent active metabolite) administered as a pediatric‐friendly oral suspension compared to the commercially approved adult formulation (150 mg capsule) in healthy subjects. As the pediatric population would likely ingest smaller meals than adults, with a more moderate fat content, the study also assessed the effects of meal type (i.e., high‐ and low‐fat) on the PK of alectinib and M4 following oral suspension administration.
METHODS
Study design and treatment
The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on/Council for Harmonisation E6 Guideline for Good Clinical Practice. All subjects provided written informed consent.
This was a phase I, crossover, open‐label, randomized, single‐dose, single‐center, two‐sequence, two‐period relative bioavailability and food effect study (EudraCT No: 2020‐003891‐42) conducted in healthy male and female volunteers of non‐childbearing potential under fasted and mixed‐fed conditions. The study schema is shown in Figure 1. A washout period of at least 14 days was required between doses to prevent carryover effects of treatment. Replacement subjects could be enrolled, if necessary, to ensure that at least 24 subjects completed the study, 12 under fasted conditions and 12 under mixed‐fed conditions.
FIGURE 1.
Study schematic of crossover design. Treatment A is 600 mg alectinib administered orally as a capsule formulation (150 mg capsules; reference) and Treatment B is 600 mg alectinib administered orally as an extemporaneous suspension formulation (water mixed 1:1 with apple juice; test).
All subjects received the following two single‐dose treatments in a randomized sequence: 600 mg alectinib administered orally as a capsule (using 150 mg capsules); 600 mg alectinib administered orally as an oral suspension. The oral suspension was prepared by adding the contents of four 150 mg alectinib capsules to 20 mL water and stirring on a magnetic plate (10 min stirring at 600 rpm, 1 min rest) to yield a drug concentration suspension of 30 mg/mL. This suspension was gently mixed (1:1) with apple juice and ingested within 2 h of preparation.
For treatments in the fasted state, alectinib was administered in the morning after at least a 10‐h fast. For treatments in the mixed‐fed state, alectinib was administered in the morning (after at least a 10‐h fast) within 30 min after a standard high‐fat (800–1000 total calories; 50% of calories from fat) or low‐fat (400–500 total calories; 25% of calories from fat) meal.
Subjects
Eligible subjects were healthy males or females of non‐childbearing potential, aged 18–60 years, with a body mass index (BMI) of 18–32 kg/m2. Key exclusion criteria included: history of significant hypersensitivity, intolerance, or allergy to any drug compound (or to any of the additives in the alectinib formulation), food, or other substance or drug‐induced hepatotoxicity; history of stomach/intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (except appendectomy and hernia repair); use of any prescription medicine within 2 weeks prior to day 1; use of biologic therapy within 6 months of study entry; use of moderate/strong CYP3A inhibitors/inducers within 4 weeks or five half‐lives, whichever was longer, prior to day 1; participation in an investigational drug study within 90 days or five half‐lives, whichever was longer.
Objectives
The primary objective was to determine the relative bioavailability of alectinib following administration of the oral suspension or capsule in healthy subjects under fasted and fed conditions, separately. Secondary objectives were to evaluate the PK of alectinib, M4, and the combined exposure of alectinib and M4, following administration of the oral suspension or capsule under fasted and fed conditions, separatelyand to determine the safety and tolerability of single oral doses of alectinib following administration of the oral suspension or capsule under fasted and fed conditions. Exploratory objectives included a comparison of the PK of alectinib and M4 following venipuncture and capillary microsampling techniques as well as an evaluation of the effects of a high‐fat versus low‐fat meal on the PK of the oral suspension.
Assessments
PK samples were collected for determination of alectinib and M4 plasma concentrations using venous catheter and capillary fingerstick sampling techniques. Venous samples (1 mL) were taken predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60, 72, 96, and 120 h postdose. Capillary microsamples (0.2 mL) were taken at 0.5, 2, 4, 6, 16, 24, 48, 72, 96, and 120 h postdose.
Alectinib and M4 concentrations were measured using a validated liquid chromatography–tandem mass spectrometry method. 10 The calibration range was 1.50–1500 ng/mL using 50 μL plasma sample volume. Several capillary microsamples were received with insufficient sample volume prior to analysis; these were diluted 5‐fold (10 μL sample/40 μL control matrix) or 10‐fold (5 μL sample/45 μL control matrix), resulting in a raised lower limit of quantification (LLOQ) for alectinib and M4 in these particular diluted samples of 7.50 ng/mL (5‐fold dilution) or 15.0 ng/mL (10‐fold dilution).
Safety was assessed through adverse events (AEs) recording, vital signs, clinical laboratory analyses, 12‐lead electrocardiograms (ECGs), and physical examinations. AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.
Pharmacokinetic analysis
The geometric mean ratio (GMR) and associated 90% confidence intervals (CIs) of the following alectinib PK parameters were calculated as the primary endpoint: single‐dose area under the concentration–time curve (AUC) from time 0 to the last measurable concentration (AUC0‐t ); AUC extrapolated to infinity (AUC0‐∞); and maximum observed concentration (C max), by formulation under fasted and mixed‐fed conditions, separately.
Additional PK parameters were assessed as secondary endpoints for each formulation and food condition individually for both alectinib and M4 metabolite: time to C max (t max), last measurable concentration (C t), percentage of AUC due to extrapolation from C t to infinity (AUC%extrap), apparent terminal elimination rate constant (λz), apparent terminal elimination half‐life (t 1/2), apparent systemic clearance (CL/F), apparent volume of distribution during the terminal elimination phase (V z/F), and time to C t (t last). Additional secondary M4 PK parameters included AUC0‐t , AUC0‐∞, and the metabolic ratio based on C max (MR_C max), metabolic ratio based on AUC0‐t (MR_AUC0‐t ), and metabolic ratio based on AUC0‐∞ (MR_AUC0‐∞). Combined alectinib + M4 molar exposure PK parameters included: C max, AUC0‐t , AUC0‐∞, and AUC%extrap, where individual concentrations were converted from nanograms per milliliter (ng/mL) to nanomoles (nM) for both alectinib (482.625 g/mol) and M4 (456.587 g/mol) and then summed. The PK parameters of alectinib and/or M4 were calculated from venous blood concentrations, using noncompartmental analysis (NCA) methods within the validated software program Phoenix WinNonlin (Certara, Version 8.1). For the calculations of AUC and terminal rate constant, subjects with samples that are below the limit of quantification (BLQ) for the pre‐dose PK sample or occurring before T max, the result was set to 0. For subsequent timepoints, the result was set to missing.
For the microsampling comparison, venous and capillary samples were time‐matched for NCA analysis and paired based on subject, analyte, formulation, meal type, period, sequence, and timepoint for paired ratio percent differences. The ratio was calculated as follows: capillary/venous *100. Subjects with missing samples or samples BLQ were excluded from the analysis.
Statistical analysis
The safety population comprised all subjects who received at least one dose of study drug. The PK population consisted of all subjects who received at least one dose of study drug and had at least one evaluable post‐dose PK sample.
The relative bioavailability of alectinib was analyzed by comparing oral suspension to capsule for AUC0‐t , AUC0‐∞, and C max of all analytes (alectinib, M4, and combined alectinib + M4) under fasted, mixed (high‐ and low‐fat) fed, high‐fat fed, and low‐fat fed conditions. The natural log‐transformed PK parameters were analyzed using a mixed‐effect analysis of variance (ANOVA) model. The model included treatment sequence, period, and formulation as fixed effects and subject within treatment sequence as a random effect (predefined model).
An exploratory analysis of food effect on alectinib was investigated for AUC0‐t , AUC0‐∞, and C max of all analytes (alectinib, M4, and combined alectinib + M4) from venous samples by comparing the relative bioavailability of mixed (high‐ and low‐fat) fed, high‐fat fed, and low‐fat fed conditions with fasted condition. The natural log‐transformed PK parameters were analyzed using an ANOVA model with dietary condition added as a fixed effect to the predefined model.
An exploratory analysis of collection technique (capillary microsampling and venipuncture) effect on alectinib was performed by comparing AUC0‐t , AUC0‐∞, and C max for alectinib and M4, separately. The natural log‐transformed PK parameters were analyzed using an ANOVA model with collection technique and meal type added as fixed effects to the predefined model.
RESULTS
Subjects
As of April 1, 2021, a total of 28 subjects (22 males, 6 females) were enrolled and completed the study, of whom 14 were randomized to the fasted group and 14 to the mixed‐fed group (seven subjects were given a high‐fat meal and seven subjects a low‐fat meal). The median subject age was 38 (range 23–60) years and mean BMI (standard deviation) was 25.4 (3.5) kg/m2. All subjects were White.
Pharmacokinetics
Alectinib and M4 plasma concentration–time profiles by formulation in the mixed‐fed and fasted states are illustrated in Figure 2 and Figure S1, respectively. A summary of alectinib and M4 PK parameters following single‐dose administration of oral suspension and capsule in the fasted, mixed‐fed state, and by meal type, are provided in Table 1 and Table S1, respectively. The oral suspension resulted in higher individual alectinib and M4 peak and overall systemic exposure than the capsule under both mixed‐fed (Figure 2) and fasted (Figure S1) conditions. A delay in reaching C max was observed for the capsule compared with the oral suspension under mixed‐fed conditions (median t max of 6.0 and 3.5 h, respectively), but time to C max was similar for both formulations under fasted conditions (median t max of 3.0 and 2.5 h, respectively). The geometric mean metabolic ratio of M4 to alectinib for C max (MR_C max) ranged from 0.148 (fasted) to 0.244 (mixed fed) for capsule and 0.171 (fasted) to 0.337 (mixed fed) for the suspension. The corresponding geometric mean metabolic ratio for AUC0‐∞ (MR_AUC0‐∞) ranged from 0.302 (fasted) to 0.410 (mixed fed) for the capsule and 0.374 (fasted) to 0.552 (mixed fed) for the suspension, under fasted and fed conditions. The t 1/2 of alectinib was similar for the oral suspension and capsule in the different groups (15.9–22.9 h).
FIGURE 2.
Mean (standard deviation) alectinib (a) and M4 (active metabolite) (b) plasma concentration–time profiles following administration of single‐dose 600 mg alectinib oral suspension or capsules under mixed‐fed conditions.
TABLE 1.
Summary of alectinib pharmacokinetic parameters following single‐dose administration of oral suspension or capsule: fasted and mixed‐fed conditions, and by meal type, separately.
| Parameter | Fasted (n = 14) | Mixed fed (n = 14) | High‐fat meal (n = 7) | Low‐fat meal (n = 7) | ||||
|---|---|---|---|---|---|---|---|---|
| Capsule | Suspension | Capsule | Suspension | Capsule | Suspension | Capsule | Suspension | |
| AUC0‐t (h*ng/mL) | 2200 (45.0) | 5530 (34.9) | 4850 (68.0) | 7520 (32.2) | 7570 (37.1) | 9010 (30.1) | 3110 (51.0) | 6280 (22.9) |
| AUC0‐∞ (h*ng/mL) | 2320 (44.5) | 5640 (34.5) | 4950 (66.6) | 7660 (32.2) | 7660 (37.4) | 9120 (30.6) | 3200 (49.5) | 6440 (23.6) |
| %AUCextrap (%) | 4.14 (73.8) | 1.66 (61.1) | 1.43 (97.6) | 1.11 (105.6) | 0.901 (76.2) | 0.903 (84.2) | 2.26 (80.5) | 1.35 (130.3) |
| C max (ng/mL) | 133 (47.4) | 391 (31.5) | 286 (53.1) | 462 (19.5) | 397 (34.6) | 460 (22.3) | 206 (43.4) | 464 (18.1) |
| t max (h) | 3.0 (2.0–5.0) | 2.5 (1.0–3.5) | 6.0 (3.5–12.0) | 3.5 (1.0–6.0) | 8.0 (3.5–12.0) | 4.0 (3.5–6.0) | 5.0 (4.0–6.0) | 2.0 (1.0–4.0) |
| C t (ng/mL) | 2.91 (44.8) | 3.17 (43.4) | 2.87 (54.5) | 3.46 (77.4) | 2.85 (73.4) | 3.17 (78.6) | 2.89 (37.7) | 3.79 (82.3) |
| t last (h) | 96 (72–120) | 120 (72–120) | 120 (72–120) | 120 (72–120) | 120 (96–120) | 120 (96–120) | 96 (72–120) | 96 (72–120) |
| t lag (h) | 0.5 (0.0–1.0) | 0 (0–0) | 2.0 (0.50–3.50) | 0 (0–0) | 2.0 (0.5–3.5) | 0 (0–0) | 2.0 (1.5–2.5) | 0 (0–0) |
| t 1/2 (h) | 22.9 (37.8) | 20.4 (28.7) | 17.1 (28.5) | 16.9 (34.7) | 16.8 (19.9) | 18.0 (19.2) | 17.4 (37.2) | 15.9 (47.2) |
| CL/F (L/h) | 258.0 (44.5) | 106.0 (34.5) | 121 (66.6) | 78.3 (32.2) | 78.3 (37.4) | 65.8 (30.6) | 188 (49.5) | 93.1 (23.6) |
| V z/F (L) | 8540 (47.0) | 3130 (50.8) | 2980 (69.9) | 1910 (33.7) | 1890 (26.3) | 1710 (21.7) | 4700 (60.6) | 2140 (41.3) |
| MR_C max | 0.148 (36.8) | 0.171 (29.2) | 0.244 (20.7) | 0.337 (33.6) | 0.240 (27.5) | 0.298 (39.7) | 0.248 (13.4) | 0.381 (22.5) |
| MR_AUC0‐∞ | 0.302 (37.1) | 0.374 (22.9) | 0.410 (22.3) | 0.552 (31.5) | 0.381 (24.0) | 0.453 (23.5) | 0.442 (19.3) | 0.671 (25.0) |
Note: Data are presented as geometric mean (CV) or median (minimum–maximum).
Abbreviations: AUC0‐∞, area under the concentration–time curve extrapolated to infinity; AUC0‐t , area under the concentration–time curve from time 0 to the last measurable concentration; %AUCextrap, percentage of area under the concentration–time curve that is due to extrapolation from the last measurable concentration to infinity; CL/F, apparent systemic clearance; C max, maximum observed concentration; C t, last measurable concentration; CV, coefficient of variation (%); MR, metabolic ratio; PK, pharmacokinetic; t 1/2, apparent terminal elimination half‐life; t lag, time immediately prior to the first measurable concentration; t last, time of the last measurable concentration; t max, time to maximum observed concentration; V z/F, apparent volume of distribution during the terminal elimination phase.
The relative bioavailability of alectinib and M4 increased significantly following administration of the oral suspension compared with the capsule, under both fasted and mixed‐fed conditions (Table 2; Table S2). Under fasted conditions, the single‐dose AUC0‐∞ for alectinib, M4, and combined alectinib + M4 increased by 2.4‐, 2.7‐, and 2.6‐fold, respectively, when alectinib was administered as an oral suspension compared with the capsule. Corresponding single‐dose C max values increased by 2.9‐, 3.4‐, and 3.0‐fold, respectively. Under mixed‐fed conditions, the single‐dose AUC0‐∞ for alectinib, M4, and combined alectinib + M4 increased by 1.6‐, 2.1‐, and 1.7‐fold, respectively, when alectinib was administered as an oral suspension compared with the capsule. Corresponding single‐dose C max values increased by 1.6‐, 2.2‐, and 1.7‐fold, respectively.
TABLE 2.
Relative bioavailability of combined alectinib + M4 (active metabolite) pharmacokinetic parameters under fasted and mixed‐fed conditions.
| Parameter | Formulation | n | GLSM | Oral suspension vs capsule GMR (90% CI) |
|---|---|---|---|---|
| Alectinib + M4, fasted | ||||
| AUC0‐t (h*nmol/L) | Capsule | 14 | 5870 | 2.67 (2.28–3.10) |
| Suspension | 14 | 15,600 | ||
| AUC0‐∞ (h*nmol/L) | Capsule | 14 | 6180 | 2.60 (2.23–3.04) |
| Suspension | 14 | 16,100 | ||
| C max (nmol/L) | Capsule | 14 | 299 | 2.97 (2.61–3.37) |
| Suspension | 14 | 887 | ||
| Alectinib + M4, mixed fed | ||||
| AUC0‐t (h*nmol/L) | Capsule | 14 | 14,000 | 1.72 (1.40–2.11) |
| Suspension | 14 | 24,100 | ||
| AUC0‐∞ (h*nmol/L) | Capsule | 14 | 14,400 | 1.71 (1.40–2.09) |
| Suspension | 14 | 24,600 | ||
| C max (nmol/L) | Capsule | 14 | 703 | 1.71 (1.39–2.11) |
| Suspension | 14 | 1200 | ||
Abbreviations: AUC0‐∞, area under the concentration–time curve extrapolated to infinity; AUC0‐t , area under the concentration–time curve from time 0 to the last measurable concentration; CI, confidence interval; C max, maximum observed concentration; GLSM, geometric least squares mean; GMR, geometric mean ratio; PK, pharmacokinetic.
For the oral suspension, alectinib and M4 exposure was increased in the presence of high‐ or low‐fat food relative to fasted, as exemplified by plasma concentration–time profiles by meal type (Figure 3). Table 3 shows the food effect on relative bioavailability of combined alectinib + M4 when administered as an oral suspension. Following administration of the oral suspension, the single‐dose AUC0‐∞ increased by 1.7‐ and 1.4‐fold under high‐fat and low‐fat conditions, respectively.
FIGURE 3.
Mean (standard deviation) alectinib (a) and M4 (active metabolite) (b) plasma concentration–time profiles by meal type following administration of single‐dose 600 mg alectinib oral suspension (presented as 0–24 h).
TABLE 3.
Food effect on relative bioavailability of combined alectinib + M4 (active metabolite) pharmacokinetic parameters (oral suspension).
| Parameter | Dietary condition | n | GLSM | Fed vs fasted GMR (90% CI) |
|---|---|---|---|---|
| AUC0‐t (h*nmol/L) | Fasted | 14 | 15,600 | |
| High‐fat meal | 7 | 27,000 | 1.73 (1.37–2.18) | |
| Low‐fat meal | 7 | 21,800 | 1.39 (1.11–1.76) | |
| Mixed fed | 14 | 24,200 | 1.55 (1.29–1.87) | |
| AUC0‐∞ (h*nmol/L) | Fasted | 14 | 16,100 | |
| High‐fat meal | 7 | 27,500 | 1.71 (1.35–2.16) | |
| Low‐fat meal | 7 | 22,400 | 1.39 (1.10–1.76) | |
| Mixed fed | 14 | 24,800 | 1.54 (1.27–1.87) | |
| C max (nmol/L) | Fasted | 14 | 887 | |
| High‐fat meal | 7 | 1220 | 1.37 (1.13–1.67) | |
| Low‐fat meal | 7 | 1170 | 1.32 (1.09–1.61) | |
| Mixed fed | 14 | 1190 | 1.35 (1.15–1.58) |
Abbreviations: AUC0‐∞, area under the concentration–time curve extrapolated to infinity; AUC0‐t , area under the concentration–time curve from time 0 to the last measurable concentration; CI, confidence interval; C max, maximum observed concentration; GLSM, geometric least squares mean; GMR, geometric mean ratio; PK, pharmacokinetic.
Concentrations of alectinib and M4 (alectinib: Table S3 and Figure S2A; M4: Table S4 and Figure S2B) in venous and capillary samples were generally similar following alectinib oral suspension and capsule. The exception was a slight increase in concentrations for capillary versus venous at 0.5 h postdose, but this difference diminished with time such that capillary and venous concentrations were generally comparable at 6 h postdose and thereafter. When the two blood collection techniques were compared based on PK parameters (C max, AUC0‐t , and AUC0‐∞) the results were generally similar (Table 4).
TABLE 4.
Comparison of alectinib and M4 (active metabolite) pharmacokinetic parameters following capillary versus venipuncture sampling methods.
| Parameter | Sampling method | n | GLSM | Capillary vs venipuncture GMR (90% CI) |
|---|---|---|---|---|
| Alectinib | ||||
| AUC0‐t (h*nmol/L) | Capillary | 23 | 4080 | 1.01 (0.85–1.21) |
| Venipuncture | 23 | 4040 | ||
| AUC0‐∞ (h*nmol/L) | Capillary | 22 | 4360 | 1.01 (0.85–1.21) |
| Venipuncture | 23 | 4310 | ||
| C max (nmol/L) | Capillary | 23 | 274 | 1.12 (0.91–1.37) |
| Venipuncture | 23 | 246 | ||
| M4 | ||||
| AUC0‐t (h*nmol/L) | Capillary | 23 | 1290 | 1.08 (0.82–1.42) |
| Venipuncture | 23 | 1200 | ||
| AUC0‐∞ (h*nmol/L) | Capillary | 20 | 2050 | 1.08 (0.85–1.36) |
| Venipuncture | 23 | 1900 | ||
| C max (nmol/L) | Capillary | 23 | 49.9 | 1.08 (0.84–1.38) |
| Venipuncture | 23 | 46.3 | ||
Abbreviations: AUC0‐∞, area under the concentration–time curve extrapolated to infinity; AUC0‐t , area under the concentration–time curve from time 0 to the last measurable concentration; CI, confidence interval; C max, maximum observed concentration; GLSM, geometric least squares mean; GMR, geometric mean ratio; PK, pharmacokinetic.
Safety
There were no serious AEs, AEs of special interest, or grade ≥3 AEs, and no subjects discontinued from the study due to an AE. Overall, 11/28 subjects (39.3%) experienced a total of 19 treatment‐emergent AEs (TEAEs), with all but one TEAE (grade 2 back pain) being grade 1 in severity. The most common all‐causality TEAEs following alectinib treatment were headache (six subjects [21.4%]) and somnolence (three subjects [10.7%]); all other TEAEs (abdominal discomfort, abdominal pain, back pain, erythema, hyperesthesia, muscle strain, and skin abrasion) occurred in one subject (3.6%) each. There was no apparent difference in incidence or severity of TEAEs between formulations. Treatment‐related TEAEs were reported in three subjects (10.7%) and included somnolence (two subjects [7.1%]), abdominal pain (one subject [3.6%]), and headache (one subject [3.6%]); all were grade 1 in severity and were resolved at study completion. No clinically significant findings were noted in clinical laboratory evaluations, vital signs, or ECGs.
DISCUSSION
This study is the first to evaluate the PK and safety of an extemporaneous oral suspension of alectinib for children who cannot swallow capsules. In addition, the study also assessed the impact of different meal types and microsampling blood collection techniques on alectinib and M4 PK for pediatric development.
Results of this study demonstrated that the oral suspension of alectinib has different PK for alectinib and M4 compared to the 150 mg capsule. The oral suspension showed significantly higher peak and overall exposure than the intact capsule under both mixed‐fed and fasted conditions. This finding is likely attributed to the poor solubility of alectinib. 9 Generating the oral suspension by vigorous stirring of the alectinib 150 mg capsule contents may have increased the soluble fraction, leading to increased drug absorption and higher exposure compared with administration of the intact capsules. Our study results support the recommendation in the alectinib prescribing information not to open or dissolve the contents of the capsules as an alternative preparation without a proper suspension preparation and dose adjustment. 6
Based on the 1.7‐fold increase in combined alectinib + M4 single‐dose AUC0‐∞ under mixed‐fed conditions for oral suspension versus capsule, suspension‐based doses should be decreased by a factor of 1.7 to yield oral suspension doses intended to produce similar total overall systemic exposure compared with the capsule. Previously, the dose–response relationship of alectinib tested over a dose range of 300–900 mg orally b.i.d. following the capsule demonstrated higher C trough,ss (combined alectinib + M4) was associated with higher reduction in tumor size with a flat relationship to be reached at C trough,ss corresponding to the 600 mg orally b.i.d. alectinib dosing regimen. 11 The exposure–response of combined alectinib + M4 was confirmed in the plateau at the 600 mg orally b.i.d. dosing regimen in subsequent phase III clinical trials. 12 , 13 Given the well‐established exposure–response relationship and approved alectinib dosing regimen of 600 mg b.i.d. orally administered with the capsule, the exposure following the suspension was adjusted to be in line with that of the capsule as a starting point for pediatric investigation. The 1.7‐fold dose reduction for the suspension is based on the assumption that single‐dose AUC0‐∞ from this study is reflective of steady‐state AUCss‐12h with twice‐daily dosing, as supported by dose proportionality evaluation. Dose adjustment from this healthy volunteer study is considered applicable to patients based on previous results demonstrating that alectinib exposure is similar in adults with cancer and in healthy subjects. With respect to translatability to pediatric patients, this is being further explored clinically (NCT04774718), and additional dose adjustments may be required to account for differences in other factors between pediatric and adult patients that could potentially impact PK and/or response. Some of these factors include age, absorption (i.e., gastrointestinal [GI] ontogeny), distribution, or metabolism (i.e., CYP3A ontogeny), and body weight. A full evaluation of the impact of these factors on alectinib PK is outside the scope of this article.
The metabolic ratios of M4 to alectinib (MR_C max and MR_AUC0‐∞) were generally comparable between the two formulations, with a trend toward slightly higher M4 concentrations following suspension compared with the capsule. Our results suggest the metabolic ratio may also be influenced by food conditions, with a higher metabolic ratio under fed conditions compared with fasted across the formulations. A similar finding was found by Morcos et al. for the capsule, although the metabolic ratios were altogether slightly lower in our study compared to that of Morcos et al. 9 Given that administration with food leads to a slower GI transit time and higher drug absorption, greater M4 generation following a meal may be expected due to the high CYP3A4 activity in the gut and liver, coupled with higher concentrations of alectinib available for first‐pass metabolism. However, this interpretation should be taken with caution given interindividual variability in the patients tested across the food groups of our study as well as inherent limitations of cross‐study comparisons. Lastly, the evaluation of the alectinib suspension with other pediatric‐friendly vehicles (i.e., ice cream, apple sauce) was not tested in this study and may result in an altered impact on alectinib PK based on the composition of the alternative vehicle.
Consistent with the findings of Morcos et al., 9 alectinib exposure increased in the presence of food, regardless of formulation. This finding supports the current recommendation to administer alectinib with food. 6 Interestingly, the impact of food on alectinib PK was partially associated with the formulation: combined alectinib + M4 exposure increased to a greater extent in the presence of a standard high‐fat meal following capsule administration compared to oral suspension (combined alectinib + M4 AUC0‐∞: 3.3‐fold for the capsule 9 vs 1.71‐fold for the oral suspension). This is likely related to the higher fraction of drug absorption observed in the fasted state for the suspension as this suggests food may have a lower impact on the fraction absorbed of alectinib when dispersed in suspension compared to the capsule. Following oral suspension administration, alectinib and M4 drug exposure (AUC0‐∞ and C max) largely overlapped in the high‐fat and low‐fat subgroups, suggesting that careful control of the meal type may not be needed to achieve therapeutic alectinib exposures. However, there may be important differences in the composition and frequency of meals that pediatric patients eat compared to the meals tested in this study, or differences in absorption or pharmacology between very young children and adults that still need to be considered. 14
Microsampling collection techniques using capillary sampling demonstrated generally comparable PK of alectinib and M4 compared with venipuncture methods, though increased exposure was observed for both analytes for capillary versus venipuncture sampling at the earliest timepoint (0.5 h postdose) through 4 h postdosing for alectinib. Fingerstick‐based capillary blood samples contain a mixture of arterial, venous, and capillary blood. Higher drug concentrations have previously been reported in arterial blood with capillary versus venipuncture sampling, particularly at early timepoints, with equilibrium reached around the C max of the drug. 15 In our study, these small exposure differences at early timepoints between the two collection techniques did not impact observed PK parameters. Furthermore, a substantial number of fingerstick capillary PK samples had insufficient blood volume for bioanalysis. A proportion of these samples could still be assayed by diluting to yield a sufficient blood volume for analysis, which resulted in an increase in the LLOQ, and required careful attention to handling of BLQ samples in the data analysis. This also led to a slightly higher percentage of BLQ samples for capillary (17%) versus venipuncture (13%) collection, suggesting there might be opportunity to improve procedures for the optimization of fingerstick‐based capillary blood sample collection. Of note, dilution/LLOQ issues are less likely when sampling at steady state for twice‐daily dosing, where trough concentrations are maintained at relatively higher levels. Nonetheless, when venipuncture sampling is unfeasible, capillary microsampling would be expected to perform reasonably well in pediatric development.
Single oral doses of 600 mg alectinib oral suspension and capsule were well tolerated, with no safety concerns and no apparent difference in the incidence or severity of TEAEs when administered to healthy volunteers in the mixed‐fed and fasted states across both formulations.
CONCLUSIONS
An extemporaneous oral suspension of alectinib, prepared from the contents of the 150 mg capsules, was determined suitable for pediatric studies after appropriate dose adjustment compared to capsule. In addition, a low blood volume PK collection technique was deemed feasible/acceptable based on this study in adult volunteers for a potentially more patient‐centric use in children. Consistent with the capsule formation, the oral suspension showed a positive food effect supporting administration with food. Fat content in meal types may impact alectinib PK, although the effect is not considered clinically relevant.
AUTHOR CONTRIBUTIONS
S.N.L., P.A., K.H., A.D., C.S.‐P., A.C., M.A., and D.M. wrote the manuscript. S.N.L., A.D., C.S.‐P., A.C., and M.A. designed the research. S.N.L., K.H., C.S.‐P., and M.A. performed the research. S.N.L., P.A., K.H., A.D., C.S.‐P., M.A., and D.M. analyzed the data. P.A. contributed new reagents/analytical tools.
FUNDING INFORMATION
This study was funded by F. Hoffmann‐La Roche Ltd/Genentech.
CONFLICT OF INTEREST STATEMENT
S.N.L., P.A., K.H., A.D., C.S.‐P., and D.M. are employees of and own stocks/shares in F. Hoffmann‐La Roche Ltd/Genentech. A.C. is an employee of F. Hoffmann‐La Roche Ltd/Genentech. M.A. was an employee of F. Hoffmann‐La Roche Ltd/Genentech at the time of these analyses.
Supporting information
Figure S1
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Table S1
Table S2
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ACKNOWLEDGMENTS
Third‐party medical writing assistance, under the direction of the authors, was provided by Fiona Duthie, Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann‐La Roche Ltd.
Liu SN, Agarwal P, Heinig K, et al. Relative bioavailability and food effect study of an oral suspension of alectinib in healthy volunteers using venipuncture and capillary microsampling. Clin Transl Sci. 2023;16:1085‐1096. doi: 10.1111/cts.13515
DATA AVAILABILITY STATEMENT
Given the small study population, the decision to share the patient‐level data needs to be handled on a case‐by‐case basis to determine if the clinical data can be adequately anonymized to give an acceptably low risk of patient re‐identification. Qualified researchers may submit an enquiry through the data request platform, Vivli, https://vivli.org/ourmember/roche/, however this does not guarantee that the data can be shared. For up‐to‐date details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents see go.roche.com/data_sharing. Anonymized records for individual patients across more than one data source external to Roche can not, and should not, be linked due to a potential increase in risk of patient re‐identification.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1
Figure S2
Table S1
Table S2
Table S3
Table S4
Data Availability Statement
Given the small study population, the decision to share the patient‐level data needs to be handled on a case‐by‐case basis to determine if the clinical data can be adequately anonymized to give an acceptably low risk of patient re‐identification. Qualified researchers may submit an enquiry through the data request platform, Vivli, https://vivli.org/ourmember/roche/, however this does not guarantee that the data can be shared. For up‐to‐date details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents see go.roche.com/data_sharing. Anonymized records for individual patients across more than one data source external to Roche can not, and should not, be linked due to a potential increase in risk of patient re‐identification.