Proposals of statistical consideration to evaluation of results for a specific region in multi-regional trials--Asian perspective.

In recent years, global collaboration has become a conventional strategy for new drug development. To accelerate the development process and to shorten approval time, the design of multi-regional trials incorporates subjects from many countries around the world under the same protocol. After showing the overall efficacy of a drug in all global regions, one can also simultaneously evaluate the possibility of applying the overall trial results to all regions and subsequently support drug registration in each of them. Recently, the trend for simultaneous clinical development in Asian countries being undertaken simultaneously with clinical trials conducted in Europe and the United States has been rapidly rising. In this paper, proposals of statistical consideration to multi-regional trials are provided. More specifically, three aspects are addressed: the definition of the 'Asian region,' the consistency criterion between the 'Asian region' and the overall regions, and the sample size determination for the multi-regional trial.

CYP2C9 polymorphism and warfarin sensitivity in Taiwan Chinese.

BACKGROUND: Warfarin prevents thromboembolism in patients with prosthetic heart valvular replacement. Cytochrome P4502C9 (CYP2C9) is polymorphic in human and is principally responsible for the metabolism of warfarin. However, known CYP2C9 polymorphisms cannot entirely account for the low dose requirement of warfarin in Chinese-Taiwanese receiving mitral valve replacement. We screened a new polymorphism of CYP2C9 and investigated its role in warfarin sensitivity. METHODS: We examined warfarin dose requirements in 239 Chinese-Taiwanese patients who had attended a cardiac surgery clinic in National Taiwan University Hospital. DNA samples were obtained from 106 Chinese-Taiwanese (37 patients and 69 unrelated healthy controls), and healthy control subjects of Caucasians (n=28) and African-Americans (n=28). Four out of those 37 patients were poor metabolizers of warfarin, and their DNA were subjected to sequencing analysis. Moreover, CYP2C9 genotyping analyses were performed using PCR-RFLP analysis. The chi2 test and Fisher's exact test were used to compare the differences of the allelic frequency and genotype. The association between warfarin dose requirement and genetic polymorphism of CYP2C9 was also analysed. RESULTS: The mean daily warfarin dose was 3.11+/-1.62 mg for the maintenance of the international normalized ratio of 2 to 3 in 239 patients. A single nucleotide substitution from G to C was found in this study. This SNP, G-65/C, is in intron 3, 65 base pairs upstream of exon 4. The allelic frequencies of C-65 in healthy controls were 0.125, 0.058 and approximately 0 with respect to African-American, Chinese-Taiwanese and Caucasian, implying inter-ethnic variations of the C-65 allele. In addition, patients who were carrier of either the heterozygous or homozygous C-65 variant received half of the usual warfarin dose. CONCLUSION: The novel intronic G-65/C mutation appears to be inter-racially different in allelic frequency, and that the anticoagulation was affected in response to warfarin sensitivity in Chinese-Taiwanese patients receiving mitral valve replacement.

Time-dependent amplified pharmacokinetic and pharmacodynamic responses of rabeprazole in cytochrome P450 2C19 poor metabolizers.

STUDY OBJECTIVES: To determine the pharmacokinetic and pharmacodynamic rationale for the optimum regimen of rabeprazole in the treatment of Helicobacter pylori infection in patients who are cytochrome P450 (CYP) 2C19 poor metabolizers or extensive metabolizers. DESIGN: Prospective, multiple-dose pharmacokinetic and pharmacodynamic study. SETTING: University-affiliated medical center in Taiwan. SUBJECTS: Twelve healthy volunteers (aged 20-30 yrs) who were identified as CYP2C19 poor metabolizers (six subjects) or extensive metabolizers (six). INTERVENTION: Each subject received rabeprazole 20 mg twice/day for 3 consecutive days and once/day on the fourth day. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic and pharmacodynamic parameters were compared between CYP2C19 poor and extensive metabolizers on day 1 and day 4 of dosing. The mean +/- SD values of area under the concentration-time curve of rabeprazole and rabeprazole thioether were significantly higher in poor metabolizers than in extensive metabolizers on day 1 (5357 +/- 883 vs 1131 +/- 512 ng x hr/ml and 1703 +/- 432 vs 561 +/- 358 ng x hr/ml, respectively; p<0.001) and on day 4 (5601 +/- 669 vs 1619 +/- 778 ng x hr/ml and 1914 +/- 378 vs 511 +/- 360 ng x hr/ml, respectively; p<0.001). However, no significant difference was noted between day 1 and day 4 of dosing within the same genotype groups. Only CYP2C19 poor metabolizers had significantly higher plasma gastrin levels on day 4 compared with those levels on day 1 (p<0.05). The pharmacokinetic-pharmacodynamic relationship of rabeprazole appears to be time dependent. CONCLUSION: The pharmacokinetic and pharmacodynamic data suggest that CYP2C19 poor metabolizers might be subject to advantageous conditions, especially after day 4, for treating H. pylori infection with rabeprazole.

Characterizing Good Review Practices: A Survey Report Among Agencies of APEC Member Economies.

As a first step in the implementation of the Asia-Pacific Economic Cooperation (APEC) Best Regulatory Practice Project, the Centre for Innovation in Regulatory Science conducted a gap analysis survey among regulatory agencies of 14 APEC member economies to assess the current use of good review practices (GRevP) to support transparent, consistent, predictable, and good-quality regulatory decision making. Although the majority of responding agencies have established some form of GRevP, most practices are currently evolving and are applied on an informal basis. Most agencies have developed standard operating procedures and guidelines and use a variety of training methods. The use of a common approach to regulatory review across jurisdictions would help build trust and confidence in each agency's processes, setting the stage for the possibility of work sharing across resource-constrained agencies and bringing consistency and transparency to the review process.

Role of omeprazole dosage and cytochrome P450 2C19 genotype in patients receiving omeprazole-amoxicillin dual therapy for Helicobacter pylori eradication.

STUDY OBJECTIVE: To determine the factors that may influence Helicobacter pylori eradication in patients receiving omeprazole-amoxicillin dual therapy. DESIGN: Prospective, randomized study. SETTING: University-affiliated hospital in Taiwan. PATIENTS: A total of 128 adults (age range 20-75 yrs) with H. pylori-positive duodenal ulcer were enrolled; 121 completed the final evaluation. INTERVENTION: Patients were randomly assigned to one of four omeprazole-amoxicillin treatment groups, with each treatment administered for 2 weeks: O2A2 group (33 patients)--omeprazole 20 mg twice/day plus amoxicillin 500 mg 4 times/day; O2A1 group (32 patients)--omeprazole 20 mg twice/day plus amoxicillin 250 mg 4 times/day; O1A2 group (32 patients)--omeprazole 20 mg once/day plus amoxicillin 500 mg 4 times/day; and O1A1 group (31 patients)--omeprazole 20 mg once/day plus amoxicillin 250 mg 4 times/day. MEASUREMENTS AND MAIN RESULTS: Data were collected on H. pylori status, histologic parameters, antibiotic resistance, intragastric pH, cytochrome P450 (CYP) 2C19 genotype, and adverse reactions. The intent-to-treat cure rates (95% confidence interval [CI]) in groups O2A2, O2A1, O1A2, and O1A1 were 76% (95% CI 59-87%), 72% (95% CI 54-84%), 50% (95% CI 34-66%) and 52% (95% CI 35-68%), respectively. Eradication of H. pylori infection was statistically significantly dependent on omeprazole dosage, CYP2C19 genotype, age, gastritis status, and H. pylori density. All CYP2C19 poor metabolizers were cured, whereas the H. pylori cure rate in CYP2C19 extensive metabolizers varied from 44-76% in the different treatment groups. Eradication of H. pylori was favored in the omeprazole higher dose groups versus the lower dose groups (79% vs 53%, p=0.004). No secondary antibiotic resistance was found. Thirty-seven (95%) of 39 patients who failed with the initial treatment were cured by subsequent antibiotic susceptibility-driven proton pump inhibitor-based triple therapy. CONCLUSION: Provided a maintenance dose of amoxicillin is given every 6 hours, eradication of H. pylori infection was significantly dependent on omeprazole dosage, CYP2C19 genotype, age, gastritis status, and H. pylori density.

Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis.

Most cases with antituberculosis drug-induced hepatitis have been attributed to isoniazid. Isoniazid is metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. However, the role of CYP2E1 in this hepatotoxicity has not yet been reported. The aim of this study was to evaluate whether the polymorphism of the CYP2E1 gene is associated with antituberculosis drug-induced hepatitis. A total of 318 tuberculosis patients who received antituberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using a polymerase chain reaction with restriction fragment length polymorphism method. Twenty-one healthy volunteers were recruited for CYP2E1 phenotype study using a chlorzoxazone test. Forty-nine (15.4%) patients were diagnosed to have drug-induced hepatotoxicity. Patients with homozygous wild genotype CYP2E1 c1/c1 had a higher risk of hepatotoxicity (20.0%; odds ratio [OR], 2.52) than those with mutant allele c2 (CYP2E1 c1/c2 or c2/c2, 9.0%, P =.009). If CYP2E1 c1/c2 or c2/c2 genotype combined with rapid acetylator status was regarded as the reference group, the risk of hepatotoxicity increased from 3.94 for CYP2E1 c1/c1 with rapid acetylator status to 7.43 for CYP2E1 c1/c1 with slow acetylator status. After adjustment for acetylator status and age, the CYP2E1 c1/c1 genotype remained an independent risk factor for hepatotoxicity (OR, 2.38; P =.017). Furthermore, under the administration of isoniazid, the volunteers with CYP2E1 c1/c1 genotype had higher CYP2E1 activity than those with other genotypes had and, hence, might produce more hepatotoxins. In conclusion, CYP 2E1 genetic polymorphism may be associated with susceptibility to antituberculosis drug-induced hepatitis.

Polymorphism of the N-acetyltransferase 2 gene, red meat intake, and the susceptibility of hepatocellular carcinoma.

OBJECTIVE: Carcinogenic aromatic amines, derived from cooked meat, are activated or inactivated by hepatic N-acetyltransferase (NAT). The aim of this study was to evaluate the relationship of NAT2 genetic polymorphisms with hepatocellular carcinoma (HCC), with special reference to the interaction of dietary habits. METHODS: Peripheral white blood cell DNA from 185 HCC patients and 185 matched controls were genotyped for NAT2 by a polymerase chain reaction-restriction fragment length polymorphism method. All the subjects studied were chronic viral hepatitis B or C carriers with liver cirrhosis. Dietary habits of the subjects were assessed using a semiquantitative food frequency questionnaire. RESULTS: There was no association between the susceptibility of HCC and the overall NAT2 genotypes. However, in rapid acetylators (with two wild type NAT2*4 alleles), there was a trend of increased HCC risk from low to intermediate and high red meat intake (OR = 1, 2.66, 3.89; p(trend) = 0.016), even when adjusted for family history of HCC and habitual alcohol drinking. The interaction between red meat intake and the NAT2*4 acetylator status for an increased risk of HCC was significant (p = 0.007). CONCLUSIONS: Polymorphisms of the NAT2 gene may confer different susceptibilities to the effect of red meat intake on HCC. In rapid acetylators with chronic viral hepatitis-related cirrhosis, red meat intake may play a role in hepatocarcinogenesis.

Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis.

Antituberculosis drug-induced hepatitis is one of the most prevalent drug-induced liver injuries. Isoniazid is the major drug incriminated in this hepatotoxicity. Isoniazid is mainly metabolized to hepatotoxic intermediates by N-acetyltransferase (NAT). However, the association of polymorphic NAT acetylator status and antituberculosis drug-induced hepatitis is debatable. To determine whether acetylator status is a risk factor for antituberculosis drug-induced hepatitis, we genotyped NAT2 in 224 incident tuberculosis patients who received antituberculosis treatment. Antituberculosis drug-induced hepatitis was diagnosed based on a positive isoniazid rechallenge test and exclusion of viral hepatitis. Acetylator status was determined by genotyping NAT2 in patients using a polymerase chain reaction with restriction fragment length polymorphism. Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. Thirty-three patients (14.7%) were diagnosed with antituberculosis drug-induced hepatitis. Slow acetylators had a higher risk of hepatotoxicity than rapid acetylators (26.4% vs. 11.1%, P =.013). Among patients with hepatotoxicity, slow acetylators had significantly higher serum aminotransferase levels than rapid acetylators. Logistic regression showed that slow-acetylator status (odds ratio [OR], 3.66; 95% CI, 1.58-8.49; P =.003) and age (OR, 1.09; 95% CI, 1.04-1.14; P <.001) were the only 2 independent risk factors for antituberculosis drug-induced hepatitis. In conclusion, slow-acetylator status of NAT2 is a significant susceptibility risk factor for antituberculosis drug-induced hepatitis. Additionally, slow acetylators are prone to develop more severe hepatotoxicity than rapid acetylators. Regular monitoring of serum aminotransferase levels is mandatory in patients receiving antituberculosis treatment, especially in slow acetylators.