Table 1. . Clinical effects of polymorphisms on the pharmacokinetics & pharmacodynamics of histone deacetylase inhibitors.

Polymorphism	Number of subjects	Ethnicity	Monotherapy or combination therapy	Key findings	Ref.
Valproic acid
UGT1A6*3: 19T>G (rs6759892) UGT1A6*5: 541A>G (rs2070959)	98 children with epilepsy	Asian (Chinese)	Monotherapy	UGT1A6 double HT associated with higher VPA doses vs WT or single HT UGT1A6 double HT associated with lower VPA plasma concentrations vs single HT UGT2B7*2: no significant effect on VPA PK	[9]
UGT1A6*9: 552A>C (rs1105879) UGT2B7*2: 802C>T (rs7439366)	162 patients with epilepsy	Asian (Chinese)	Monotherapy	Variant UGT1A6 carriers tended to require higher VPA dosages and had lower exposure to VPA (concentration-to-dose ratios) UGT2B7: no significant effect on VPA PK	[10]
UGT1A6*9: 552A>C (rs1105879)	67 patients with epilepsy	Unknown	Monotherapy	Lower VPA serum concentrations in heterozygous or homozygous patients vs WT patients	[11]
UGT1A6*5: 541A>G (rs2070959) UGT1A6*9: 552A>C (rs1105879) UGT2B7*2: 802C>T (rs7439366) UGT1A3*5: 17A>G/31T>C/81G>A/477A>G (rs28898617/rs3821242/rs6706232/rs7574296)	242 patients with epilepsy	Asian (Chinese)	Monotherapy (n = 136) Combination therapy: – Carbamazepine (n = 38) – Topiramate (n = 19) – Phenytoin (n = 3) – Piracetam (n = 6) – Vitamins and cardiovascular agents (n = 23)	No significant effect of UGT1A6 and UGT2B7 SNPs on VPA PK Patients with the UGT1A3*5 variant had lower trough plasma concentration of VPA than WT carriers No effect of UGT SNPs on VPA PK in patients cotreated with carbamazepine	[12]
UGT1A6*5: 541A>G (rs2070959)	147 children with epilepsy	Asian (Chinese)	Monotherapy	No significant effect on VPA PK	[13]
UGT2B7*2: 802C>T (rs7439366)	14 healthy subjects with homozygous for UGT2B15*2	Asian (Korean)	Combination therapy with lorazepam	Insignificant trend of increased AUC of VPA with increasing numbers of UGT2B7*2 alleles	[14]
UGT2B7*2: 802C>T (rs7439366) UGT2B7*3: 211G>T (rs12233719)	102 patients with epilepsy	Asian (Chinese)	Monotherapy	Significantly lower VPA trough plasma concentrations in patients carrying the TT and CT genotype at UGT2B7*2 vs patients with the CC genotype UGT2B7*3: no significant effect on VPA PK	[15]
UGT2B7: 161C>T (rs7668258) UGT2B7*2: 802C>T (rs7439366)	166 patients with epilepsy	Asian (Chinese)	Combination therapy with lamotrigine	Significantly higher VPA concentrations were found in carriers of UGT2B7 (rs7668258) and -802C>T (rs7439366) vs WT	[16]
UGT2B7: 161C>T (rs7668258)	78 children with epilepsy	Asian (Japanese)	Monotherapy (n = 37) Combination therapy: – Clobazam (n = 17) – Zonisamide (n = 11) – Levetiracetam (n = 5) – Triple therapy (n = 8)	Patients with the CC genotype had lower adjusted plasma VPA concentrations than those with CT or TT genotype	[17]
UGT2B7: 268A>G (rs7662029) UGT2B7*3: 211G>T (rs12233719)	248 patients with epilepsy	Asian (Chinese)	Monotherapy	Carriers of the AA genotype had higher VPA serum concentrations than patients carrying the GG genotype UGT2B7*3: no significant effect on VPA PK	[18]
Romidepsin
ABCB1: 2677G>T/A (rs2032582) 1236C>T (rs1128503) 3435C>T (rs1045642)	98 patients with T-cell lymphoma	Caucasian, African–American, Hispanic, Asian	Monotherapy	Nonsignificant trend toward reduced romidepsin clearance in carriers of ABCB1 2677G>T/A variant alleles	[19]
	83 patients with T-cell lymphoma and other cancers	Caucasian, African–American, Hispanic, Asian	Monotherapy	ABCB1 variants associated with less severe QTc prolongation than WTs	[20]
Vorinostat
UGT2B17*2 (rs7439366)	26 patients with breast adenocarcinoma	Asian (Chinese, Malay, Indian)	Monotherapy	UGT2B17*2 homozygotes had significantly lower mean AUC ratio of vorinostat-O-glucuronide/vorinostat, and trended toward having higher vorinostat AUC, more serious adverse events, higher clinical benefit rate and longer median PFS than patients with at least one WT allele	[21]
UGT1A1 UGT2B17*2	Seven patients with advanced cancers	Unknown	Combination therapy with vinorelbine	Both UGT1A1 and UGT2B17*2 polymorphisms had no significant effects on vorinostat PK No interaction between vorinostat and vinorelbine	[22]
Belinostat
UGT1A1*28: A[TA]7TAA (rs8175347) UGT1A1*60: 3279T>G (rs4124874)	25 patients with solid tumors	Caucasian, African–American, Hispanic, Asian	Combination therapy with cisplatin and etoposide	Increased AUC, t1/2 at doses >400 mg/m2 per 24 h Increased incidence grade 3 or 4 thrombocytopenia	[23]
Panobinostat
CYP3A5*3 (rs776746)	14 patients with advanced or metastatic solid tumors	Caucasian	Monotherapy (day 1) Combination with ketoconazole (day 8)	No differences in panobinostat PK between patients heterozygous and homozygous for CYP3A5*3	[24]

CLL: Chronic lymphocytic leukemia; HT: Heterozygosity; PFS: Progression-free survival; PK: Pharmacokinetic; t_1/2: Elimination half-life; VPA: Valproic acid; WT: Wild-type.