Clinical Pharmacokinetics

, Volume 58, Issue 5, pp 659–672 | Cite as

Population Pharmacokinetics of the BTK Inhibitor Acalabrutinib and its Active Metabolite in Healthy Volunteers and Patients with B-Cell Malignancies

  • Helena EdlundEmail author
  • Sun Ku Lee
  • Marilee A. Andrew
  • J. Greg Slatter
  • Sergey Aksenov
  • Nidal Al-Huniti
Original Research Article



Bruton tyrosine kinase (BTK) is a key component of B-cell receptor signalling, critical for cell proliferation. Acalabrutinib, a selective, covalent BTK inhibitor, recently received an accelerated approval in relapsed/refractory mantle cell lymphoma. This analysis characterized the population pharmacokinetics (PK) of acalabrutinib and its metabolite ACP-5862.


Data were obtained from six phase I/II trials in adult patients with B-cell malignancy and seven phase I trials in healthy volunteers. Pooled concentration-time data, at dose levels ranging from 15 to 400 mg, were analysed using non-linear mixed-effects modelling. Base model parameters were scaled with body weight and normalized to 70 kg (fixed exponents: 0.75 and 1 for clearance and volumes, respectively). A full covariate approach was used to evaluate any relevant effects of dose, health group/disease status, hepatic and renal impairment, use of acid-reducing agents, race and sex.


A total of 11,196 acalabrutinib and 1068 ACP-5862 concentration-time samples were available. The PK of both analytes were well described using two-compartment disposition models. Acalabrutinib absorption was characterized using sequential zero- and first-order constants and a lag time. Apparent clearance (CL/F) of acalabrutinib was 169 L/h (95% CI 159–175). Relative to the 100 mg dose group, the 15 and 400 mg dose groups showed a 1.44-fold higher and 0.77-fold lower CL/F, respectively. The clearance for ACP-5862 was 21.9 L/h (95% CI 19.5–24.0). The fraction metabolized was fixed to 0.4. The central and peripheral volumes of distribution were 33.1 L (95% CI 24.4–41.0) and 226 L (95% CI 149–305) for acalabrutinib, and 38.5 L (95% CI 31.6–49.2) and 38.4 L (95% CI 32.3–47.9) for ACP-5862. None of the investigated covariates led to clinically meaningful changes in exposure.


The PK of acalabrutinib and its metabolite ACP-5862 were adequately characterized. Acalabrutinib CL/F decreased with increasing dose, but the trend was small over the 75–250 mg range. No dose adjustment was necessary for intrinsic or extrinsic covariates.



Karthick Vishwanathan (AstraZeneca), Eric Masson (Biogen, previously at AstraZeneca), Feng Jin (Theravance, previously at Acerta Pharma), Jennifer Juntado (Acerta Pharma), Ming Yin (Acerta Pharma).

Author Contributions

H. Edlund designed and performed the research, analysed the PK data (parent) and drafted the manuscript; S.K. Lee designed and performed the research, analysed the PK data (metabolite) and edited the manuscript; and M.A. Andrew, J.G. Slatter, S. Aksenov, and N. Al-Huniti designed the research and edited the manuscript.

Compliance with Ethical Standards


The underlying clinical studies were sponsored by Acerta Pharma (a member of the AstraZeneca group).

Conflict of interest

Helena Edlund, Sun Ku Lee, Marilee A. Andrew, J. Greg Slatter, Sergey Aksenov and Nidal Al-Huniti were all employed by Acerta Pharma or AstraZeneca at the time this work was conducted.

Supplementary material

40262_2018_725_MOESM1_ESM.docx (4 mb)
Supplementary material 1 (DOCX 4050 kb)


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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Quantitative Clinical Pharmacology, Early Clinical Development, IMED Biotech UnitAstraZenecaBostonUSA
  2. 2.Quantitative Clinical PharmacologyAcerta PharmaSouth San FranciscoUSA
  3. 3.DMPK/Clinical PharmacologyAcerta PharmaBellevueUSA

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