The role of Gilbert's syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine

Abstract

Retigabine (RGB) is an investigational antiepileptic drug, which undergoes extensive UGT1A1, 1A9 and 1A4-mediated N-glucuronidation and Nacetylation. The mono-acetylated metabolite of RGB has some pharmacological activity and is denoted AWD21-360. We investigated whether the pharmacokinetics (PK) of RGB and AWD21-360 are altered in subjects with Gilbert's syndrome (GS) and/or with frequent N-acetyltransferase 2 (NAT2) slow acetylator (SA) polymorphisms. Based on consistent genotyping and phenotyping screening results, 37 Caucasian subjects (21-46 years; 31 men, six women) were assigned to one of the following groups:. Subjects received single and multiple (b.i.d.) 200-mg oral RGB doses over 5 days. Blood samples were collected up to 60 h after dosing for plasma PK of RGB and AWD21-360. Group comparisons were performed by ANOVA. Single-dose PK of RGB and AWD21-360 and multipledose PK of RGB did not differ significantly between groups. After multiple dose treatment, RA subjects showed a significantly higher total exposure to AWD21-360 of about 32% (95% CI 101.9-172.5) relative to SA subjects (P ¼ 0.0362). The UGT1A1 metabolic capacity (i.e. presence or absence of GS), however, did not significantly affect the overall exposure to AWD21-360. The results indicate that the PK of RGB is unaltered in individuals with GS, in subjects with NAT2 SA status, and in carriers of both variants, whereas the total exposure to AWD21-360 is significantly related to the RA or SA status of subjects. Results further suggest that metabolic switching to the mono-acetylated metabolite AWD21-360 may partially compensate for the impaired glucuronidation capacity in GS subjects. RGB treatment showed no significant differences in tolerability and safety between groups.

Pharmacogenomics in epilepsy

“…Retigabine is metabolized by extensive N-glucuronidation and N-acetylation. However, its clearance seems not to be affected in Gilbert’s syndrome nor by common N-acetyl-transferase type 2 (NAT-2) polymorphisms [35] . A study in Han Chinese people with epilepsy found an association between the effects of SCN1A , ABCC2 and UGT2B7 genetic polymorphisms and oxcarbazepine maintenance doses [36] .…”

Neuronal potassium channel openers in the management of epilepsy: role and potential of retigabine

“…These differences have been attributed to the decline of renal function with age 68. No significant alterations in tolerability and safety were found in subjects with polymorphisms in the UGT1A1 (ie, Gilbert’s syndrome) and/or in N-acetyltransferase, NAT2 (ie, fast or slow acetylator) after a single and multiple (twice daily) 200 mg dose of oral retigabine administered over five days, although the total exposure to the monoacetylated metabolite, AWD21-360, was significantly related to the fast or slow acetylator status of subjects 69. In vitro assays in human liver microsomal preparations showed that 6 μM retigabine (a concentration similar to the peak concentration in subjects receiving a therapeutic dose of the drug) has a moderate capacity to inhibit cytochrome (CYP)2A6 and low or no potential to inhibit CYP1A2, CYP2C8/9/19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11.…”

Retigabine (Ezogabine)

“…In a combined pharmacokinetic/pharmacogenomic study in which 36 healthy subjects received oral retigabine 200 mg twice daily for several days, [37] no significant difference in steady-state retigabine exposure was observed between individuals with or without Gilbert's syndrome (i.e. reduced expression of UGT1A1) or between those with slow or rapid N-acetyltransferase 2 acetylator status.…”