In Vivo Evaluation of Thiamine Hydrochloride with Gastro-Retentive Drug Delivery in Healthy Human Volunteers Using Gamma Scintigraphy Li-Ying Kam, Jia-Woei Wong, Kah-Hay Yuen Pharmaceutics, 2023 A floating tablet system containing thiamine hydrochloride, a model drug with a narrow absorption window, was evaluated. The tablet was found to have a floating lag time of less than 30 s with a sustained drug release over 12 h during in vitro dissolution studies. The gastro-retentive property of the tablet in relation to the bioavailability of thiamine was determined in healthy human volunteers using gamma scintigraphy under fasted and fed conditions. The gastro-retentive time of the floating tablet could be prolonged up to 10 h under the fed state, compared to about 1.8 h in the fasted state. The prolonged gastric retention under the fed state resulted in a 2.8-fold increase in oral bioavailability of thiamine compared to that of the fasted state. There was also a 1.4-fold increase in thiamine absorption compared to that of a conventional immediate release tablet in the fed state. In the fasted state, the extent of thiamine absorption from the floating tablet was only about 70% of that absorbed from the immediate release tablet. Thus, to achieve a better performance, such floating tablet systems should be administered under a fed condition, to prolong the gastric retention time.
A randomized single-dose, two-period crossover bioequivalence study of two fixed-dose Paracetamol/Orphenadrine combination preparations in healthy volunteers under fasted condition Kit Yee Cheah, Kar Yee Mah, Lai Hui Pang, Shi Min Ng, Jia Woei Wong, et al. BMC Pharmacology and Toxicology, 2020 Background Paracetamol/Orphenadrine is a fixed dose combination containing 35 mg orphenadrine and 450 mg paracetamol. It has analgesic and muscle relaxant properties and is widely available as generics. This study is conducted to investigate the relative bioavailability and bioequivalence between one fixed dose paracetamol/orphenadrine combination test preparation and one fixed dose paracetamol/orphenadrine combination reference preparation in healthy volunteers under fasted condition for marketing authorization in Malaysia. Method This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2-period crossover study with a washout period of 7 days. Paracetamol/Orphenadrine tablets were administered after a 10-h fast. Blood samples for pharmacokinetic analysis were collected at scheduled time intervals prior to and up to 72 h after dosing. Blood samples were centrifuged, and separated plasma were kept frozen (− 15 °C to − 25 °C) until analysis. Plasma concentrations of orphenadrine and paracetamol were quantified using liquid-chromatography-tandem mass spectrometer using diphenhydramine as internal standard. The pharmacokinetic parameters AUC0-∞, AUC0-t and Cmax were determined using plasma concentration time profile for both preparations. Bioequivalence was assessed according to the ASEAN guideline acceptance criteria for bioequivalence which is the 90% confidence intervals of AUC0-∞, AUC0-t and Cmax ratio must be within the range of 80.00–125.00%. Results There were 28 healthy subjects enrolled, and 27 subjects completed this trial. There were no significant differences observed between the AUC0-∞, AUC0-t and Cmax of both test and reference preparations in fasted condition. The 90% confidence intervals for the ratio of AUC0-t (100.92–111.27%), AUC0-∞ (96.94–108.08%) and Cmax (100.11–112.50%) for orphenadrine (n = 25); and AUC0-t (94.29–101.83%), AUC0-∞ (94.77–101.68%) and Cmax (87.12–101.20%) for paracetamol (n = 27) for test preparation over reference preparation were all within acceptable bioequivalence range of 80.00–125.00%. Conclusion The test preparation is bioequivalent to the reference preparation and can be used interchangeably. Trial registration NMRR- 17-1266-36,001; registered and approved on 12 September 2017.
Presentation of coefficient of variation for bioequivalence sample-size calculation Yi Lin Lee, Wen Yao Mak, Irene Looi, Jia Woei Wong, Kah Hay Yuen International Journal of Clinical Pharmacology and Therapeutics, 2017 The current study aimed to further contribute information on intrasubject coefficient of variation (CV) from 43 bioequivalence studies conducted by our center. Consistent with Yuen et al. (2001), current work also attempted to evaluate the effect of different parameters (AUC<sub>0-t</sub>, AUC<sub>0-∞</sub>, and C<sub>max</sub>) used in the estimation of the study power. Furthermore, we have estimated the number of subjects required for each study by looking at the values of intrasubject CV of AUC<sub>0-∞</sub> and have also taken into consideration the minimum sample-size requirement set by the US FDA. A total of 37 immediate-release and 6 extended-release formulations from 28 different active pharmaceutical ingredients (APIs) were evaluated. Out of the total number of studies conducted, 10 studies did not achieve satisfactory statistical power on two or more parameters; 4 studies consistently scored poorly across all three parameters. In general, intrasubject CV values calculated from C<sub>max</sub> were more variable compared to either AUC<sub>0-t</sub> and AUC<sub>0-∞</sub>. 20 out of 43 studies did not achieve more than 80% power when the value was calculated from C<sub>max</sub> value, compared to only 11 (AUC<sub>0-∞</sub>) and 8 (AUC<sub>0-t</sub>) studies. This finding is consistent with Steinijans et al. (1995) [<xref-ref>2</xref-ref>] and Yuen et al. (2001) [<xref-ref>3</xref-ref>]. In conclusion, the CV values obtained from AUC<sub>0-t</sub> and AUC<sub>0-∞</sub> were similar, while those derived from C<sub>max</sub> were consistently more variable. Hence, CV derived from AUC instead of C<sub>max</sub> should be used in sample-size calculation to achieve a sufficient, yet practical, test power. .
Clinical investigation of the protective effects of palm vitamin e tocotrienols on brain white matter Yogheswaran Gopalan, Ibrahim Lutfi Shuaib, Enrico Magosso, Mukhtar Alam Ansari, Mohd Rizal Abu Bakar, et al. Stroke, 2014 Background and Purpose— Previous cell-based and animal studies showed mixed tocotrienols are neuroprotective, but the effect is yet to be proven in humans. Thus, the present study aimed to evaluate the protective activity of mixed tocotrienols in humans with white matter lesions (WMLs). WMLs are regarded as manifestations of cerebral small vessel disease, reflecting varying degrees of neurodegeneration and tissue damage with potential as a surrogate end point in clinical trials. Methods— A total of 121 volunteers aged ≥35 years with cardiovascular risk factors and MRI-confirmed WMLs were randomized to receive 200 mg mixed tocotrienols or placebo twice a day for 2 years. The WML volumes were measured from MRI images taken at baseline, 1 year, and 2 years using a validated software and were compared. Fasting blood samples were collected for full blood chemistry investigation. Results— According to per-protocol (88 volunteers) and intention-to-treat (121 volunteers) analyses, the mean WML volume of the placebo group increased after 2 years, whereas that of the tocotrienol-supplemented group remained essentially unchanged. The mean WML volume change between the 2 groups was not significantly different ( P =0.150) at the end of 1 year but was significant at the end of 2 years for both per-protocol and intention-to-treat analyses ( P =0.019 and P =0.018). No significant difference was observed in the blood chemistry parameters between the 2 groups. Conclusions— Mixed tocotrienols were found to attenuate the progression of WMLs. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00753532.
Tocotrienols for normalisation of hepatic echogenic response in nonalcoholic fatty liver: A randomised placebo-controlled clinical trial Enrico Magosso, Mukhtar Alam Ansari, Yogheswaran Gopalan, Ibrahim Lutfi Shuaib, Jia-Woei Wong, et al. Nutrition Journal, 2013 Background Nonalcoholic fatty liver disease (NAFLD) is one of the commonest liver disorders. Obesity, insulin resistance, lipid peroxidation and oxidative stress have been identified amongst the possible hits leading to the onset and progression of this disease. Nutritional evaluation of NAFLD patients showed a lower-than-recommended intake of vitamin E. Vitamin E is a family of 8 isoforms, 4 tocopherols and 4 tocotrienols. Alpha-tocopherol has been widely investigated in liver diseases, whereas no previous clinical trial has investigated tocotrienols for NAFLD. Aim of the study was to determine the effects of mixed tocotrienols, in normalising the hepatic echogenic response in hypercholesterolaemic patients with ultrasound-proven NAFLD. Methods Eighty-seven untreated hypercholesterolaemic adults with ultrasound-proven NAFLD were enrolled and randomised into control group (n = 44) and tocotrienols group (n = 43). The treatment, either mixed tocotrienols 200 mg twice daily or placebo, had a 1-year duration. Normalisation of hepatic echogenic response, being the trial primary aim, was used in sample size calculations. The data were assessed according to intention to treat principle as primary outcome. Per protocol analysis was also carried out as secondary outcome measurement. Results Thirty and 34 participants concluded the study in the tocotrienols and placebo group respectively. Alpha-tocopherol levels were within the normal range for all subjects. As primary outcome, the normalisation of hepatic echogenic response was significantly higher for the tocotrienols treated group compared to the placebo group in the intention to treat analysis (P = 0.039; 95% CI = 0.896-6.488). As secondary objective, the per protocol assessment also showed significant rate of remission (P = 0.014; 95% CI = 1.117-9.456). Worsening of NAFLD grade was recorded in two patients in the placebo group, but none in the group treated with tocotrienols. No adverse events were reported for both groups. Conclusion This is the first clinical trial that showed the hepatoprotective effects of mixed palm tocotrienols in hypercholesterolemic adults with NAFLD. Trial registration Clinicaltrials.gov, NCT00753532.
Bioequivalence evaluation of two different controlled release matrix formulations of ketoprofen tablets in healthy malaysian volunteers Latin American Journal of Pharmacy, 2011
Effect of mixed-tocotrienols in hypercholesterolemic subjects Kah Hay Yuen, Jia Woei Wong, Ai Beoy Lim, Bee Hong Ng, Wai Peng Choy Functional Foods in Health and Disease, 2011 Background: Studies on the cholesterol lowering activity of tocotrienols have yielded mixed results, with some showing cholesterol lowering effect while some showing no activity.Aim: A randomized, double-blind, parallel group study was conducted to investigate the cholesterol lowering activity of tocotrienols. Methods: Thirty-two hypercholesterolemic subjects were randomly assigned to orally receive either 300 mg of mixed tocotrienols capsules daily or placebo capsules containing 300 mg of soya bean oil for a period of 6 months. The subjects were monitored before supplementation and monthly thereafter for their serum cholesterol as well as tocotrienol and tocopherol concentrations.Results: The serum total cholesterol and low density lipoprotein (LDL) cholesterol of the subjects in the tocotrienol supplementation group were decreased significantly by -8.9 ± 0.9% and -12.8 ± 2.6% respectively after 4 months of supplementation and the reduction persisted till the end of the 6-month study, with a reduction of -10.8 ± 1.0% and -17.3 ± 1.8%, respectively from baseline. Moreover, there was a 22-fold increase in the total tocotrienol concentrations from baseline during supplementation compared to the placebo group, while the concentration of α-tocopherol recorded only a modest increase. On the other hand, the serum cholesterol, total tocotrienol and α-tocopherol concentrations of subjects in the placebo group remained essentially unchanged.Conclusions: Supplementation with mixed tocotrienols at dose of 300 mg per day resulted in the lowering of the serum total and LDL cholesterol levels after 5 months of supplementation.Keywords: tocotrienols, cholesterol-lowering, total cholesterol, LDL cholesterol, tocopherols
Preparation and physicochemical characterization of artemisinin-gelucire 44/14 solid dispersions Healthmed, 2010
Prevalence of non-alcoholic fatty liver in a hypercholesterolemic population of northwestern peninsular Malaysia Southeast Asian Journal of Tropical Medicine and Public Health, 2010
