Effects of UGT1A1 genotype on the pharmacokinetics, pharmacodynamics, and toxicities of belinostat administered by 48-hour continuous infusion in patients with cancer

Abstract

The histone deacetylase inhibitor belinostat is eliminated through glucuronidation by UGT1A1. Polymorphisms that reduce UGT1A1 function could result in increased belinostat exposure and toxicities. We wanted to determine which single-nucleotide polymorphisms alter belinostat exposure and toxicity. In a phase 1 trial (belinostat over 48 hours in combination with cisplatin and etoposide), belinostat (400, 500, 600, or 800 mg/m(2) /24 h, 48-hour continuous infusion) was administered to patients with cancer in combination with cisplatin and etoposide (n = 25). Patients were genotyped for UGT1A1 variants associated with reduced function: UGT1A1*6, UGT1A1*28, and UGT1A1*60. End points were associations between UGT1A1 genotype and belinostat pharmacokinetics (PK), toxicities, and global protein lysine acetylation (AcK). Belinostat AUC was increased (P = .003), and t1/2 increased (P = .0009) in UGT1A1*28 and UGT1A1*60 carriers who received more than 400 mg/m(2) /24 h. The incidence of grades 3-4 thrombocytopenia (P = .0081) was associated with UGT1A1 polymorphisms. The US Food and Drug Administration-approved package insert recommends dose adjustment of belinostat for UGT1A1*28. However, our data suggest dose adjustment is also necessary for UGT1A1*60. UGT1A1 polymorphisms were associated with increased systemic belinostat exposure, increased AcK, and increased incidence of toxicities, particularly at doses > 400 mg/m(2) /24 h.

Keywords: UGT1A1; belinostat; pharmacodynamics; pharmacogenomics; pharmacokinetics.

Figure 1.

Effects of combined variants of uridine diphosphate glucuronosyltransferase I family, polypeptide A I (UGTIAI)*28 and *60 on belinostat pharmacokinetics for all dose levels in the trial of belinostat (400, 500, 600, or 800 mg/m²/24 h, 48-hour continuous infusion) in combination with cisplatin and etoposide. (A) UGT IA I vs dose-normalized area under the plasma concentration-time curve (AUC, n = 23). (B) UGTIAI vs dose­ normalized maximum plasma concentration (C_max, n = 23). (C) UGTIAI versus total body clearance (CL, n = 19). (D) UGTIAI versus elimination half­life (t_1/2, n = 19). P values were obtai ned using the Jonckheere-Terpstra test for trend (α =.0I required for significance). WT, wild type; HT, heterozygous; VAR, homozygous.

Figure 2

Effect of combined variants of uridine diphosphate glucuronosyltransferase I family polypeptide A I (UGTIAI)* 28 and 60* on belinostat pharmacokinetics after exclusion of the 400mg/m²/24h does level in the trial of belinostat (400,500,600, or 800 mg/m²/24h, 48 hour continuous influsion in combination with cisplatin and etoposide. (A) UGTIAI vs does-normalized area under the plasma concentration-time curve (AUC) excluding 400mg/m²/24h (n=15). (B) UGTIAI versus does-normalized maximum plasma concentration (C_max) excluding 400 mg/m²/24h (n=15). (C) UGTIAI versus total body clearance (CL) excluding 400mg/m²/24h(n=13). (D) UGTIAI versus elimination half-life (t_1/2) excluding 400mg/m²/24h (n=13). P values were obtained using the jonckheere-Terpstra test for trend (α=.01 required for significance). WT, wild type; HT, heterozygous; VAR, homozygous.

Figure 3.

Effects of uridine diphosphate glucuronosyltransferase I family, polypeptide A I (UGTIAI) genotype status on the fold change (relative to predose) of global protein lysine acetylation (AcK) i n peripheral blood mononuclear cells (PBMCs) in patients receivi ng belinostat (400, 500, 600, or 800 mg/m²/24 h, 48-hour continuous infusion) in combination with cisplatin and etoposide. (A) Average (± standard deviation) AcK fold change i n PBMCs 1 2, 36, and 60 hours post-start of beli nostat infusion. (B) Effect of UGTIAI *28 on AcK fold change in PBMCs (n = 25). (C) Effect of UGTIAI *60 on AcK fold change i n PBMCs (n = 23). (D) Combined effect of UGTIAI *28 and UGTIAI *60 on AcK fold change i n PBMCs (n = 23). P values were obtained using the Jonckheere-Terpstra test for trend (α =.0 I required for significance). WT, wild type; HT, heterozygous; VAR, homozygous.