(M1130-05-25) Preclinical Evaluation of Soluplus-Based Amorphous Solid Dispersion of Alectinib: Bioavailability Enhancement and IVIVC Model Establishment

Purpose: Poorly soluble drugs present a big challenge to formulators owing to their limited solubility and bioavailability. Alectinib HCl (ALB) is a BCS class IV molecule with low solubility and moderate in-vitro permeability [1, 2], and indicated for the treatment of patients with Anaplastic Lymphoma kinase-positive non-small-cell lung cancer [3]. To meet clinical efficacy, the recommended dose of ALB is high (4 capsules of 150 mg twice a day) primarily due to low oral bioavailability (37%) when taken with food [4, 5]. The bioavailability under fasting conditions is further lowered to one-third of that under fed conditions [6]. Thus, there is a need for a delivery system to overcome the bioavailability concerns associated with ALB. Further, the development of an In-vitro and In-vivo correlation (IVIVC) model can act as a surrogate to predict in-vivo performance.

Methods: Amorphous solid dispersion (ASD) technology was considered to tackle the challenges posed by ALB. ASD formulation A was prepared with ALB and Solpulus in a 1:5 ratio and ASD formulation B was prepared by including 5% Poloxamer P407 (surfactant) in the former composition. These formulations were examined for in-vitro dissolution across the physiological pH range, and biorelevant media compared to the API alone. In-vivo pharmacokinetics studies were performed with the oral administration of ALB equivalent to 10 mg/kg in healthy Wistar rats, comparing the formulations against the unprocessed API. The plasma concentration of ALB was assayed using a validated LC-MS/MS method to estimate T_max, C_max, and AUC_0-last. An IVIVC model was built using Phoenix Winnonlin software to establish a relationship between in-vitro dissolution data and in-vivo pharmacokinetics data. Intravenous data from the literature [7] was used to generate Unit impulse response (UIR) for model fitting, followed by numerical deconvolution. Data from API standalone and Formulation A were used for internal predictability and Formulation B was kept for external predictability. The software was used to establish a relationship between the mean in-vitro fractions dissolved (Fdisso) and in-vivo fraction absorbed (Fabs), as described by the equation: Fabs = Abs Scale*Diss (Tscale*Tvivo).

Results: Both formulations showed improved dissolution as compared to the drug alone in all evaluated media (Figure 1). Dissolution in pH 4.5 acetate buffer containing 0.25% SLS and pH 6.8 phosphate buffer, showed the following rank order: Formulation B > Formulation A > > API alone. However, the two formulations exhibited similar dissolution profiles in pH 1.2 simulated gastric fluid containing 0.25% SLS, and Fasted state simulated intestinal fluid (FaSSIF) media while were approximately two times superior to the drug alone. In-vivo evaluation in Wistar rats presented a two times higher pharmacokinetics profile from both formulations compared to the drug alone (Figure 2), signifying the potential of ASD formulations to improve bioavailability. Both formulations showed similar C_max with shorter T_max for Formulation B. Also, a higher AUC_0-last was observed for Formulation B, indicating the advantage of the presence of surfactant in the formulation. Level A IVIVC was developed with in-vivo pharmacokinetics data and in-vitro dissolution in pH 4.5 containing 0.25% SLS. The observed % prediction error (% PE) for the IVIVC model is depicted in Table 1. API and Formulation A, used as internal predictability, exhibited % PE of 6.19% & -9.36% for C_max and 13.80% and - 5.42% for AUC_0-last respectively. The average % PE for internal predictability was 7.77% for C_max and 9.61% for AUC_0-last. The developed IVIVC model is predictive as the observed % PE for each tested component and the average % PE was within 15% and 10%, respectively. The additional evaluation of the developed IVIVC model using external predictability showed that the observed % PE for C_max was less than 10%, thus, the external predictability of the IVIVC model for C_max was also established. However, % PE for AUC_0-last was between 10 to 20%, thus, indicating inconclusive predictability for AUC_0-last, and more studies are required using additional data sets.

Conclusion: ASD formulation containing ALB was successfully developed with enhanced dissolution. Proof of concept for bioavailability enhancement under fasting conditions in the animal model is available. The developed IVIVC correlation model would assist in effectively predicting in-vivo input functions, and consequently, plasma concentrations based on in-vitro dissolution data of formulations. Further, these lab-scale formulations of ALB represent a key step in advancing toward clinical evaluation. From future perspectives, these ASD formulations of ALB can be scaled up using spray drying or freeze-drying techniques and can be transformed into oral dosage formulations in combination with other excipients.

References: 1. Parrott NJ, Yu LJ, Takano R, et al (2016) Physiologically Based Absorption Modeling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Alectinib. AAPS J 18:1464–1474.
2. Zhao D, Chen J, Chu M, et al (2020) Pharmacokinetic-based drug–drug interactions with anaplastic lymphoma kinase inhibitors: A review. Drug Des Devel Ther 14:1663–1681.
3. Larkins E, Blumenthal GM, Chen H, et al (2016) FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non–Small Cell Lung Cancer Following Crizotinib. Clinical Cancer Research 22:5171–5176.
4. FDA (2021) ALECENSA, Highlights of Prescribing Information (FDA). https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208434s010lbl.pdf
5. Morcos PN, Yu L, Bogman K, et al (2017) Absorption, distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects. Xenobiotica 47:217–229.
6. Morcos PN, Guerini E, Parrott N, et al (2017) Effect of Food and Esomeprazole on the Pharmacokinetics of Alectinib, a Highly Selective ALK Inhibitor, in Healthy Subjects. Clin Pharmacol Drug Dev 6:388–397.
7. FDA (2015) Pharmacology Review(s); Alecensa (alectinib)

Acknowledgements: All animal experiments adhered to the guidelines of the Institutional Animal Ethics Committee (IAEC) under Protocol No. 1867 at Jamia Hamdard, New Delhi, India.


Figure 1 Dissolution of API and ASD formulations in 900 mL, 100 rpm, USP-II (paddle) [A] SGF, pH 1.2 containing 0.25% SLS [B] pH 4.5 Acetate buffer containing 0.25% SLS [C] pH 6.8 phosphate buffer containing 0.25% SLS [D] FaSSIF


Figure 2 Mean plasma concentration versus time plots after a single oral dose of API alone and ASD formulations of ALB in Wistar rats


Table 1 IVIVC validation output with Prediction error