UGT1A1 genotype‐dependent dose adjustment of belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation

Abstract

Belinostat is a second-generation zinc-binding histone deacetylase inhibitor that is approved for peripheral T-cell lymphoma and is currently being studied in small cell lung cancer and other advanced carcinomas as a 48-hour continuous intravenous infusion. Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in belinostat clearance based on UGT1A1 genotype. A 2-compartment population pharmacokinetic (PK) model was developed and validated that incorporated the UGT1A1 genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400 mg/m(2) /24 h given to patients considered extensive or impaired metabolizers, respectively, provided equivalent AUCs. This model and subsequent simulations supported additional PK/toxicity and pharmacogenomics/toxicity analyses to suggest a UGT1A1 genotype-based dose adjustment to normalize belinostat exposure and allow for more tolerable therapy. In addition, global protein lysine acetylation was modeled with PK and demonstrated a reversible belinostat exposure/response relationship, consistent with previous reports.

A population pharmacokinetic/toxicity model for the reduction of platelets during a 48-h continuous intravenous infusion of the histone deacetylase inhibitor belinostat

“…Goey et al demonstrated that patients with an IM status for UGT1A1 (i.e., greater belinostat exposure) had greater incidence of grade 3 (platelet count between 25,000–50,000/µL) or grade 4 (<25,000/µL) thrombocytopenia compared to NM when receiving the belinostat, cisplatin, and etoposide combinanation [6]. This was consistent with IMs having a slower belinostat clearance and thus the recommendation of a 33% dose reduction for IMs based on PPK modelling and simulation when giving belinostat as a 48-h IV infusion [5]. …”

“…Patients categorised as IM not only had slower belinostat plasma clearance [5, 6], but also tented to have a lower platelet nadir vs NM [41,800 ( n = 18) vs 70,400 ( n = 5)] count/µL; p = 0.053 (Mann-Whiteney); Supplemental Figure S2] that occurred roughly 6–7 days after cessation of belinostat. Based on this observation that slower belinostat clearance induced greater platelets decrease, coupled with an overall decrease in platelets with increasing belinostat concentration (Supplemental Figure S3), a semi-mechanistic myelosuppression PD model that included a rate constant between the proliferating and first maturation compartment ( k PT ) was added onto the original PPK model [5]. This differed from comparable models that used the same rate constant for this process as well as the inter-maturation compartment transit rate constant [ k TR ; calculated by mean transit time (MTT) = 4/ k TR , with MTT as an estimable parameter], which was assumed equivalent to k DEG and k PROL at steady state [7, 8, 15].…”

“…This trial was approved by the Institutional Review Board of the National Cancer Institute, and informed consent was obtained from all patients enrolled (Table S1). PK Sampling occurred during cycle 1 at several time points during the 48-h continuous intravenous infusion, as well us up to 12-h post-end of infusion; all samples were measuring using a validate uHPLC-MS/MS assay with a calibration range of 5–1500 ng/mL (see [5] for full details). Platelet counts were obtained at several points throughout cycle 1, per protocol-mandated patient monitoring.…”

“…A two compartment PPK model utilizing non-linear mixed-effects (NLME) modeling with a proportional residual error model and accounting for samples below assay quantitation limits with the M3 method was developed and validated using Phoenix ® NLME 1.3 (Certara, Cary, NC, USA) that utilized the Laplacian algorithm for determining the objective function value, as previously described [5]. Significant covariates were albumin, creatinine clearance, and UGT1A1 genotype status (IM vs NM) on the clearance parameter, and body weight on the central volume parameter.…”

“…The steady-state levels during the 48-h IV infusion are evident, but the elimination phase is not as mush due to the limited x -axis space. For a better depiction of belinostat elimination kinetics, refer to [5]. The simulated platelet levels are depicted in the right y -axis and with “o” symbols…”