Acalabrutinib Tablet Formulation Approved in Europe for Chronic Lymphocytic Leukemia

Paolo Ghia, MD

The European Commission has approved the tablet formulation of acalabrutinib (Calquence) for the treatment of adult patients with chronic lymphocytic leukemia (CLL).¹

The regulatory decision is supported by findings from the ELEVATE PLUS trials, in which the capsule and tablet formulations of the drug were found to be bioequivalent, meaning that the same safety and efficacy can be expected from both approaches when prescribed with the same dosing strength and schedule.^2,3

“Many patients with CLL face multiple medical conditions that require daily treatment, including the use of acid-reducing agents for conditions such as gastroesophageal reflux,” Paolo Ghia, MD, director of the Strategic Research Program on CLL at Università Vita-Salute San Raffaele in Milan, Italy, stated in a press release. “The tablet formulation allows for co-administration with these drugs, allowing more patients with CLL to assume [acalabrutinib.]”

ELEVATE PLUS was comprised of three phase 1, open-label, single-dose, crossover studies that were done in 116 healthy patents to understand the pharmacokinetic (PK) similarity of the acalabrutinib tablet formulation administered at 100 mg in comparison with the capsule formulation also given at 100 mg (n = 66).²

Investigators also evaluated proton pump inhibitor (PPI) effect by comparing the PK of the acalabrutinib tablet given at 100 mg in both the presence and absence of the PPI rabeprazole (Aciphex; n = 14). Additionally, food effect was examined by comparing the PK of the tablet formulation given at 100 mg with a high-fat diet vs fasted (n = 16). Lastly, they investigated PK after 100 mg of acalabrutinib maleate suspension was administered via a nasogastric tube, in the presence and absence of rabeprazole (n = 20).

Additional data showed that there was no clinically relevant difference in acalabrutinib/ACP- 5862 exposures after the tablet formulation was given with or without a PPI. The C_max was lower, with up to a ~30% difference, and the AUC was higher, with up to a ~16% difference between the treatment arms; there was similar BTK target occupancy (BTK-TO; ≥95%) across the arms, as well.

Moreover, food had no clinically relevant impact on acalabrutinib/ACP-5862 exposures. The C_max was lower, up to ~54% difference, and there was no impact on AUC, with up to ~3% difference, or BTK-TO (≥95%). Additionally, acalabrutinib/ACP-5862 exposures were determined to be comparable, with up to a 10% difference, between the 100 mg of acalabrutinib maleate NG suspension and 100 mg of the capsules; exposures will also found to be comparable, with up to a 16% difference, after co-administration acalabrutinib maleate NH suspension with or without a PPI.

The tablet formulation was found to be well tolerated. Most of the toxicities that were observed with this formulation were determined to be mild. No serious adverse effects were experienced, and no new safety signals were observed.

The acalabrutinib tablet formulation can be taken with gastric acid-reducing agents, including PPIs, antacids, and H2-receptor antagonists.

In August 2022, the FDA approved the tablet formulation of acalabrutinib for all current indications, including adult patients with CLL, small lymphocytic lymphoma, and for those with relapsed or refractory mantle cell lymphoma based on findings from the ELEVATE PLUS trials.⁴

References

1. Calquence tablet formulation approved in the EU for patients with chronic lymphocytic leukaemia. News release. AstraZeneca. February 22, 2023. Accessed February 22, 2023. https://www.astrazeneca.com/media-centre/press-releases
2. Sharma S, Pepin X, Burri H, et al. New acalabrutinib formulation enables co-administration with proton pump inhibitors and dosing in patients unable to swallow capsules (ELEVATE-PLUS). Blood. 2021;138(suppl 1):4365. doi:10.1182/blood-2021-146610
3. Sharma S, Pepin X, Burri H, et al. Bioequivalence and relative bioavailability studies to assess a new acalabrutinib formulation that enables coadministration with proton-pump inhibitors. Clin Pharmacol Drug Dev. 2022;11(11):1294-1307. doi:10.1002/cpdd.1153
4. Calquence tablet formulation approved in the US across current indications. News release. AstraZeneca. August 5, 2022. Accessed February 22, 2023. https://www.astrazeneca.com/media-centre/press-releases