Global population pharmacokinetics of the investigational Aurora A kinase inhibitor alisertib in cancer patients: rationale for lower dosage in Asia

Abstract

AimsThis population pharmacokinetic analysis was conducted to describe quantitatively the regional differences and sources of interpatient variability on the apparent oral clearance of alisertib.MethodsA population pharmacokinetic analysis was performed on data from 671 cancer patients in Western countries and in Japan/East Asia to whom alisertib 5–150 mg once or twice daily (b.i.d.) was administered in multiple dosing schedules. The final model was used to simulate alisertib pharmacokinetics in patients in the West and East Asian regions in the single‐agent schedule of 7 days of dosing in a 21‐day cycle. Exposure–safety relationships for mechanism‐related antiproliferative toxicities (neutropenia, mucositis and diarrhoea) were estimated by logistic regression.ResultsAlisertib pharmacokinetics were described by a two‐compartment model with four‐transit compartment absorption and linear elimination. The final model included a covariate effect of region on relative bioavailability, with patients in the East Asian region estimated to have a 52% higher bioavailability compared with Western patients. Population simulated exposure at 30 mg b.i.d. in patients in Asia was similar to that at 50 mg b.i.d. in Western patients [geometric mean (coefficient of variation) steady state area under the concentration‐time curve over the dosing interval (AUC(0–τ)): 21.4 μM.h (52.3%) and 24.1 μM.h (53.6%), respectively]. Exposure–AE relationships could be described for neutropenia, stomatitis and diarrhoea, supporting the lower dosage of alisertib in Asia for global clinical development.ConclusionsModel‐based simulations support the achievement of similar alisertib exposures in patients in Asia who are administered a 40% lower dose compared with the Western population, thereby providing a quantitative clinical pharmacology bridging and regional dosing rationale for global drug development.

Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib in Adult Patients With Advanced Solid Tumors or Relapsed/Refractory Lymphoma With Varying Degrees of Hepatic Dysfunction

“…In vitro studies indicated that UDP‐glucuronosyltransferase (UGT) 1A8, 1A3, and 1A1 were the UGT isoforms responsible for the formation of alisertib acyl glucuronide metabolite M1 (Takeda data on file). Although the relative contributions of these individual UGTs to overall alisertib glucuronidation has not been determined, it has been established that UGT1A1 is not a major contributor based on population pharmacokinetic analyses in which patients harboring the UGT1A1*28 allele did not have reduced apparent clearance of alisertib . There was a notable increase in systemic exposures of M1 in patients with moderate or severe hepatic impairment (approximately 6‐ to 10‐fold greater metabolite/parent AUC ratio vs normal hepatic function), possibly explained by a reduction of its biliary excretion because of impaired hepatic function.…”

“…Although the relative contributions of these individual UGTs to overall alisertib glucuronidation has not been determined, it has been established that UGT1A1 is not a major contributor based on population pharmacokinetic analyses in which patients harboring the UGT1A1*28 allele did not have reduced apparent clearance of alisertib. 5,15 There was a notable increase in systemic exposures of M1 in patients with moderate or severe hepatic impairment (approximately 6-to 10-fold greater metabolite/parent AUC ratio vs normal hepatic function), possibly explained by a reduction of its biliary excretion because of impaired hepatic function. The magnitude of relative increase in systemic exposure of the active oxidative metabolite (M2) did not meaningfully differ from that observed for the parent drug.…”

“…The results of a global population PK analysis indicated that the bioavailability of alisertib in patients enrolled in North/East Asian countries (Japanese, Chinese, or Korean) were approximately 52% higher than exposure previously observed in the Western clinical development program . The specific reasons for these observed differences are not clear, and it is not known whether the contributing factors are primarily intrinsic (eg, race/ethnicity related) or extrinsic/environmental.…”

“…5,6 In phase 2 clinical studies in Western patient populations, a dose regimen of 50 mg of alisertib twice daily administered for 7 days in 21-day cycles has shown clinical antitumor activity when administered as a single agent in multiple malignancies, including small-cell lung cancer, breast cancer, head and neck cancer, gastroesophageal adenocarcinoma, ovarian cancer, and various hematologic malignancies. [7][8][9][10] Antitumor activity has also been observed in small-cell lung cancer when alisertib 40 mg twice daily (on days 1-3, 8-10, and [15][16][17] has been administered in combination with weekly paclitaxel in 28-day cycles. 11 Results from a human absorption, distribution, metabolism, and excretion study 12 confirmed that metabolism is the predominant route of elimination for alisertib, with renal excretion of unchanged alisertib representing a negligible (<0.1%) fraction of the administered dose.…”

“…16 The results of a global population PK analysis indicated that the bioavailability of alisertib in patients enrolled in North/East Asian countries (Japanese, Chinese, or Korean) were approximately 52% higher than exposure previously observed in the Western clinical development program. 15,17 The specific reasons for these observed differences are not clear, and it is not known whether the contributing factors are primarily intrinsic (eg, race/ethnicity related) or extrinsic/environmental. However, given that the primary objective of this hepatic impairment study was to evaluate the effect of moderate or severe hepatic impairment on alisertib PK, Chinese, Korean, or Japanese patients were excluded from enrollment to minimize potential additional sources of variability in PK.…”