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The Role of Gilbert's Syndrome and Frequent NAT2 Slow Acetylation

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The Role of Gilbert's Syndrome and Frequent NAT2 Slow Acetylation The Pharmacogenomics Journal (2006) 6, 211–219 & 2006 Nature Publishing Group All rights reserved 1470-269X/06 $30.00 www.nature.com/tpj ORIGINAL ARTICLE The role of Gilbert’s syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine R Hermann1, J Borlak2, Retigabine (RGB) is an investigational antiepileptic drug, which undergoes 3 4 5 extensive UGT1A1, 1A9 and 1A4-mediated N-glucuronidation and N- U Munzel , G Niebch , U Fuhr , acetylation. The mono-acetylated metabolite of RGB has some pharmaco- 6 7 J Maus and K Erb logical activity and is denoted AWD21-360. We investigated whether the pharmacokinetics (PK) of RGB and AWD21-360 are altered in subjects with 1Department of Clinical Pharmacology, ALTANA Pharma AG, Konstanz, Germany; 2Fraunhofer Gilbert’s syndrome (GS) and/or with frequent N-acetyltransferase 2 (NAT2) Institute of Toxicology and Experimental Medicine slow acetylator (SA) polymorphisms. Based on consistent genotyping and (ITEM), Center for Drug Research and Medical phenotyping screening results, 37 Caucasian subjects (21–46 years; 31 men, Biotechnology, Hannover, Germany; 3Biostatistics six women) were assigned to one of the following groups: (1) absence of GS and Data Management VIATRIS GmbH, Bad Homburg, Germany; 4Early Phase Development (non-GS)/rapid acetylator (RA) (N ¼ 11); (2) GS/RA (N ¼ 8); (3) non-GS/SA VIATRIS GmbH, Bad Homburg, Germany; (N ¼ 11); (4) GS/SA (N ¼ 7). Subjects received single and multiple (b.i.d.) 5Department of Pharmacology, Clinical 200-mg oral RGB doses over 5 days. Blood samples were collected up to 60 h Pharmacology, University of Cologne, Ko¨ln, after dosing for plasma PK of RGB and AWD21-360. Group comparisons were Germany; 6Clinical Research VIATRIS GmbH, Bad Homburg, Germany and 7Clinphase – Clinical performed by ANOVA. Single-dose PK of RGB and AWD21-360 and multiple- Pharmacology Services, Hanau am Main, dose PK of RGB did not differ significantly between groups. After multiple Germany 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 Correspondence: (P ¼ 0.0362). The UGT1A1 metabolic capacity (i.e. presence or absence of Dr R Hermann, Department of Clinical Pharmacology, ALTANA Pharma AG, Konstanz, GS), however, did not significantly affect the overall exposure to AWD21- Byk-Gulden-Strae 2, 78467 Konstanz, 360. The results indicate that the PK of RGB is unaltered in individuals with Germany. GS, in subjects with NAT2 SA status, and in carriers of both variants, whereas E-mail: [email protected] 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. The Pharmacogenomics Journal (2006) 6, 211–219. doi:10.1038/sj.tpj.6500359; published online 10 January 2006 Keywords: retigabine; pharmacokinetics; Gilbert’s syndrome; UGT1A1*28 polymorphism; N-acetyltransferase 2 slow acetylation polymorphisms; genetic polymorphisms Introduction Gilbert’s syndrome (GS) is a mild congenital non-hemolytic unconjugated hyperbilirubinemia, which is as frequent as 10–13% in western European Received 15 August 2005; revised 7 1–3 November 2005; accepted 16 November Caucasian populations. GS is functionally characterized by reduced expression 2005; published online 10 January 2006 of the hepatic bilirubin UDP-glucuronyltransferase 1A1 (UGT1A1) by about 30%. Retigabine PK in Gilbert’s syndrome and NAT2 polymorphisms R Hermann et al 212 Subjects with GS have a normal coding region for the following isoniazid, procainamide, and hydralazine are well UGT1A1 gene, but show homozygousity for two extra bases acknowledged.8,9 The prevalence of functional NAT2 slow (TA) in the TATAA element of the 50 promoter region of the acetylation polymorphisms is approximately 50% in Cau- gene, that is, A(TA)7TAA instead of the normal A(TA)6TAA casians and African Americans and about 10% in subjects of configuration.1–3 The longer TATAA element results in Asian descent.10 reduced transcription of the gene. Although (TA)7 is the Retigabine (RGB) is a first in class investigational anti- only polymorphic allele associated with GS in the Caucasian epileptic drug, which acts as specific neuronal M-current population, additional (TA)5 and (TA)8 variants were found potassium channel opener (KCNQ2/3 and KCNQ3/5 chan- in GS individuals of African origin.4 From a clinical nels).11–19 RGB further enhances gamma amino butyric acid perspective, GS is frequently regarded as a harmless variant (GABA)-evoked currents in a concentration-dependent in the individual genetic make-up of affected individuals. fashion. These effects, however, require much higher However, there is growing awareness that GS may affect concentrations to become effective.20,21 Recently, the anti- drug glucuronidation and could be associated with un- epileptic efficacy of RGB was confirmed in patients with expected adverse drug reactions.5 Impaired drug glucuroni- partial epileptic seizures.22 The drug is predominantly dation capacity in carriers of GS may even result in serious metabolized by N-glucuronidation resulting in the forma- drug toxicity, as evidenced by published case reports for tion of two N-glucuronides and to a considerably smaller irinotecan (CPT-11).6,7 extent by N-acetylation to form a pharmacologically less The clinical significance of N-acetyltransferase 2 (NAT2) active N-acetyl derivative denoted AWD21-360 (Figure slow acetylation polymorphisms is well established for a 1).23,24 AWD21-360 also undergoes glucuronidation similar number of drugs, including isoniazid, hydralazine, dapsone, to RGB (Figure 1). RGB is not subject to any metabolism by procainamide and sulfoniazide. Increased risks for various cytochrome P450 enzymes.24 Based on in vitro studies using types of adverse drug reactions in slow acetylators (SAs) of monoclonal human UGTs the UDP-glucuronosyltransferase NAT2, such as nephrotoxicity and peripheral neuropathy (UGT) isozymes 1A1, 1A9, 1A4 and to a smaller extent 1A3 due to isoniazid therapy, increased hypersensitivity to were found to catalyze the N-glucuronidation of sulfonamines as well as systemic lupus erythematosus RGB. However, some inconsistent findings on the relative Urine: 36 % NH O CH3 O N NH2 Urine: 0.5 % NH O CH3 H F O Glucosidation N NH Retigabine H CH OH Feces: 3 % F O 2 OH M4 OH Hydrolysis/ Decarboxylation OH Glucuronidation Acetylation Urine: 16 % NH O CH3 Urine: 18 % NH CH3 O O N NH N NH H H 2 COOH F O F M2 OH OH M1 OH Glucuronidation Cyclization Urine: 2 % NH O CH3 NH CH Urine: 2 % H Urine: 4 % 3 N O O CH3 N NH 2 N NH N N H COOH H F O OCOOH F F OH OH M7 M3 OH M5 OH OH OH Urine: 2 % NH CH3 O N NH2 COOH F O OH OH M6 OH Figure 1 Metabolic pathways of [14C] RGB in healthy male subjects after a single oral dose of 200 mg RGB. The Pharmacogenomics Journal Retigabine PK in Gilbert’s syndrome and NAT2 polymorphisms R Hermann et al 213 contributions of these UGTs to RGB’s N-glucuronidation statistically significant differences in age and body weight have been reported by two independent working were noted between groups, whereas mean total serum groups.25,26 Furthermore, predictions from in vitro data on bilirubin concentrations were 88 and 45% higher in GS the relative metabolic contributions of single enzymes in subjects than in non-GS subjects with corresponding rapid vivo is generally difficult and often unreliable. acetylator (RA) and SA status, respectively (P ¼ 0.0098 for RGB pharmacokinetics (PK) in healthy young subjects are GS/RA compared with non-GS/RA; P ¼ 0.0187 for GS/SA characterized by rapid absorption (tmax 1.6 h), a clearance of compared with non-GS/SA, and P ¼ 0.0004 for all GS 0.58 l/h/kg, a volume of distribution of 6.2 l/kg, low plasma subjects compared with all non-GS subjects). Both GS groups protein binding (about 80%), and terminal plasma half-life showed mean bilirubin values 420 mmol/l at baseline. 27,28 times of approximately 8.5 h. Absolute bioavailability The mean (7s.d.) total serum bilirubin AUC0–24 values (F) of RGB oral immediate release dosage forms is about 60% obtained during the drug-free 24 h fasting test (400 kcal diet) (95% confidence interval (CI) 49–75%).22,28 RGB shows were 377787 and 3947121 mmol/l h in the non-GS/RA and linear PK in adult healthy subjects up to 350 mg single and non-GS/SA groups, but 7467276 and 7507232 mmol/l h in b.i.d. repeated oral doses.29 In patients with epilepsy, dose the GS/RA and GS/SA groups, respectively, thus confirming linearity of RGB has been demonstrated up to 1200 mg/ the significant group contrasts between GS and non-GS day.22 The mono-acetylated metabolite AWD21-360 is subjects already seen in total fasting morning serum rapidly formed and cleared at the same rate as RGB.29 bilirubin concentrations. Notably in subjects of African descent, the clearance and The single-dose PK of RGB and AWD21-360 were consistent volume of distribution of RGB is 25 and 30% lower, with previous studies in healthy subjects and did not show respectively.22 This finding is consistent with previously any significant group differences for geometric mean peak 30 described ethnic differences in N-glucuronidation. plasma concentrations (Cmax), systemic exposure (AUC) or Based on the currently available knowledge of RBG’s apparent oral clearance (CL/F). Single-dose data are there- metabolic pathways and the principal enzymes involved, fore not presented in further detail.
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