Current Issue : July - September Volume : 2012 Issue Number : 3 Articles : 9 Articles
The statistics of bioequivalence testing have received much attention in the literature. However, there is an ignorance of checking the validity of some of the underlying assumptions imposed on some of these tests. In this paper we review the mostly used tests. Moreover, we introduce Shannon bio-equivalence index and the concept of (1-�Ÿ) 100% Shannon equivalent distributions and apply it together with a bootstrap method to test average bioequivalence of two formulations. An illustrative example is considered to compare the results of the suggested test with those that are given in the literature. The results of suggested test agree with those in the literature....
Valacyclovir is a prodrug of acyclovir. In Mexico, it is indicated for the treatment of herpes zoster and herpes\r\nsimplex infections. The aims of these 2 studies were to compare the bioavailability and to determine the bioequivalence\r\nof 2- test formulations containing 500 mg and 1000 mg of oral valacyclovir. Two separate, single-dose, open-label,\r\nrandomized, 2-period, crossover studies were conducted. For each study a different set of 26 subjects of both\r\ngenders was enrolled, with a 7-day washout period. In both studies, the study formulations were administered\r\nafter a 10-hour overnight fast. For pharmacokinetic analysis, blood samples were drawn at baseline, 0.25, 0.50,\r\n0.75, 1, 1.25, 1.50, 1.75, 2, 3, 4, 6, 8, 12 and 24 hours after administration. Plasma concentrations of acyclovir\r\nwere determined using HPLC coupled to a fluorescence detector. The test and reference formulations were to be\r\nconsidered bioequivalent if the 90% CI for the geometric mean test/reference ratios were within a predetermined\r\nrange of 80% to 125%. In the study with valacyclovir 500 mg, the 90% CI were 95.24% - 115.33% for Cmax, 96.20%\r\n- 103.55% for AUC0-t, 97.12% - 104.34% for AUC0-8. In the study with valacyclovir 1000 mg the 90% CI were 86.22%-\r\n100.87% for Cmax, 89.11% - 98.50% for AUC0-t, 89.00% - 98.34% for AUC0-8. In both studies, a single dose of the test\r\nformulation met the regulatory requirements to assume bioequivalence, based on the rate and extent of absorption....
Lamotrigine is a phenyltriazine used in the treatment of epilepsy and bipolar disorder type I. The purpose of this study was to compare the bioavailability in healthy Colombian volunteers of two brands of lamotrigine 100 mg tablets: a new generic formulation (test product) developed by Humax Pharmaceuticals S.A (MedellÃ?Ân, Col) and LAMICTALÃ?® (reference product) from Glaxo Operations UK Ltd (Ware, UK). A single-dose, randomized, two-period, two-sequence crossover study, with six weeks washout period, was performed. Blood samples were obtained from 0 to 144 hours after dosing and plasma lamotrigine levels were determined by a validated high performance liquid chromatographic (HPLC) method. The 90% confidence intervals (CIs) for the ratios of the ln AUC0-8 and ln Cmax means between the reference and test formulations were constructed under 80/125 rule for bioequivalence limit. Fourteen subjects were enrolled in the study, but only twelve completed both treatment periods. The estimated pharmacokinetic parameters of lamotrigine for the reference and test formulations were Cmax 2.314 Ã?± 0.414 Ã?µg/mL, 2.226 Ã?± 0.355 Ã?µg/mL; AUC0-120 70.148 Ã?± 10.824 Ã?µg.h/mL, 69.277 Ã?± 13.432 Ã?µg.h/mL, and for AUC0-8 were 78.524 Ã?± 16.000 Ã?µg.h/mL, 77.532 Ã?± 15.255 Ã?µg.h/mL, respectively. The 90% CIs for the ln-transformed ratio (test/reference) of AUC0-8 and Cmax were 88.97 to 110.65 and 87.77 to 106.37, respectively.\r\n \r\nConclusions: In this single dose study it was found that the test and reference products of lamotrigine 100 mg tablets complied with the regulatory criteria for equivalence with respect to rate and extent of absorption according to the guidances of Instituto Nacional de Vigilancia de Medicamentos y Alimentos (INVIMA) and FDA....
The marked inter-individual and ethnic variabilities in the metabolism of clopidogrel has been investigated.\r\nAlthough the pharmacokinetics (PK) of clopidogrel has been reported previously in Whites and Korean volunteers,\r\nthe PK characteristics may not be fully extrapolated to the Chinese population. Little is known about the PK\r\ncharacteristics and relative bioavailability of clopidogrel in Chinese population. The present study was to assess\r\nthe PK characteristics and relative bioavailability of clopidogrel in healthy Chinese volunteers. A single-dose,\r\nrandomized-sequence, open-label, 2-period crossover study was performed in fasting healthy Chinese male\r\nvolunteers. Eligible subjects were randomly assigned to receive a single 75-mg dose of the test or reference\r\nformulation of clopidogrel, followed by a 1-week washout period and administration of the alternate formulation. The\r\nplasma samples were collected and at 0 min (baseline), as well as at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 11, 14,\r\n24 and 36 hours, respectively, after drug administration. The concentrations of both clopidogrel and SR26334 were\r\ndetected by a validated liquid chromatography-tandem mass spectrometric method (LC-MS/MS). The formulations\r\nwere considered to be bioequivalent if the 90% CIs for the log-transformed values were within the predetermined\r\nequivalence range (80%ââ?¬â??125% for AUC and Cmax). For clopidogrel, the 90% CIs for the log-transformed ratios\r\nof Cmax and AUC0ââ?¬â??t were 90.26%ââ?¬â??113.91% and 91.82%ââ?¬â??103.27%, respectively. For SR26334, the 90% CIs were\r\n85.23%ââ?¬â??112.97% and 93.11%ââ?¬â??103.67%, respectively. In conclusion, the present results show that the formulation\r\nof clopidogrel was of bioequivalence to the reference, which have been tested in fasting, healthy, male Chinese\r\nvolunteers....
The bioequivalence of a single dose of memantine (Clomenac�®) 10 mg tablets manufactured by Cobalt Pharmaceuticals, Canada/Arrow Farmac�ªutica Ltda was compared with a reference memantine 10 mg tablets (Ebix�®, Lundbeck Inc). The single-dose, randomized-sequence, open-label, two period crossover study was conducted on a total of 26 Brazilian healthy volunteers of both genders. Nineteen blood samples were taken during 72 h. Samples were frozen and kept until time of analysis. Plasma concentrations of memantine were determined using a validated UPLC-MS/MS method. Confidence intervals (CI, 90%) for the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC0-t) were determined by calculating log-transformed data. The test and reference formulations were considered bioequivalent if the 90% CIs for the geometric mean test/reference ratios were within a predetermined range of 80% to 125%. The 90% CI for the geometric mean ratios for Cmax was 100.1% (92.9- 107.9%) and for AUC0-t was 98.8% (93.9-103.9%). In conclusion, the tested 10 mg memantine tablets (Clomenac�®, Arrow Farmac�ªutica Ltda.) was bioequivalent to Ebix�® 10 mg tablets, according to the rate and extent of absorption....
Although drug interactions with Acarbose are uncommon, there is a possibility for\r\ninterference with the pharmacokinetic behaviors of concomitantly administered drugs. The\r\npresent study was designed to evaluate the possible drug interactions between Acarbose\r\nand orally administered MTZ. Twelve healthy volunteers and twelve diabetic patients were\r\nenrolled in a randomized controlled crossover study. The effect of Acarbose (single\r\n100mg dose) on the pharmacokinetics of MTZ was evaluated, while the effect of multiple\r\ndoses was evaluated only in diabetic patients. In both groups, 5ml blood samples were\r\ncollected into plane tubes at 0, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0\r\nand 48.0 hrs; serum levels of MTZ were evaluated using HPLC technique. The results\r\nshowed that diabetes mellitus significantly altered the pharmacokinetic parameters of\r\norally administered MTZ compared to healthy subjects. Moreover, both single and multiple\r\ndoses of Acarbose significantly changed the pharmacokinetic parameters of MTZ when\r\nused concomitantly. The pharmacokinetics of orally administered MTZ was significantly\r\naffected by both diabetes mellitus and concomitant use of single or multiple doses of\r\nAcarbose....
The serotonin-norepinephrine reuptake inhibitor desvenlafaxine has linear and dose-proportional pharmacokinetics from 25 to 900 mg. The effect of diet on the pharmacokinetics, safety, and tolerability of desvenlafaxine in healthy volunteers (N=33) was assessed in this single-dose, open-label, randomized, 4-period, 4-sequence, crossover, inpatient study. Desvenlafaxine 200 mg was administered after an overnight fast or after a low-, medium-, or high-fat breakfast. Blood samples were obtained over 72 hours. Pharmacokinetic parameters were compared across dosing conditions using analysis of variance. The median time to peak concentration for desvenlafaxine was approximately 6 hours under fasting conditions and was delayed by approximately 2 to 4 hours when administered with food. Diet did not affect apparent oral-dose clearance and apparent terminal-phase elimination half-life values. Except for peak plasma concentration under high-fat conditions, both peak plasma concentration and area under the plasma concentration-versus-time curve met bioequivalence test criteria under each dietary condition, compared with an overnight fast (90% confidence interval within 80%-125% limits). The minor increase in peak plasma concentration under high-fat conditions was not clinically relevant. Desvenlafaxine was well tolerated under fasting and fed conditions. These results suggest that pharmacokinetics should not be a factor when considering whether to administer desvenlafaxine with or without food....
Sophora flavescens is a Chinese medicinal herb used for the treatment of gastrointestinal hemorrhage, skin diseases, pyretic\r\nstranguria and viral hepatitis. In this study the herb-drug interactions between S. flavescens and indinavir, a protease\r\ninhibitor for HIV treatment, were evaluated in rats. Concomitant oral administration of Sophora extract (0.158 g/kg or\r\n0.63 g/kg, p.o.) and indinavir (40 mg/kg, p.o.) in rats twice a day for 7 days resulted in a dose-dependent decrease of plasma\r\nindinavir concentrations, with 55%ââ?¬â??83% decrease in AUC0-ââ?¬Ë? and 38%ââ?¬â??78% reduction in Cmax. The CL (Clearance)/F (fraction\r\nof dose available in the systemic circulation) increased up to 7.4-fold in Sophora-treated rats. Oxymatrine treatment (45 mg/\r\nkg, p.o.) also decreased indinavir concentrations, while the ethyl acetate fraction of Sophora extract had no effect. Urinary\r\nindinavir (24-h) was reduced, while the fraction of indinavir in faeces was increased after Sophora treatment. Compared to\r\nthe controls, multiple dosing of Sophora extract elevated both mRNA and protein levels of P-gp in the small intestine and\r\nliver. In addition, Sophora treatment increased intestinal and hepatic mRNA expression of CYP3A1, but had less effect on\r\nCYP3A2 expression. Although protein levels of CYP3A1 and CYP3A2 were not altered by Sophora treatment, hepatic CYP3A\r\nactivity increased in the Sophora-treated rats. All available data demonstrated that Sophora flavescens reduced plasma\r\nindinavir concentration after multiple concomitant doses, possibly through hepatic CYP3A activity and induction of\r\nintestinal and hepatic P-gp. The animal study would be useful for predicting potential interactions between natural\r\nproducts and oral pharmaceutics and understanding the mechanisms prior to human studies. Results in the current study\r\nsuggest that patients using indinavir might be cautioned in the use of S. flavescens extract or Sophora-derived products....
Background and Objective: Desvenlafaxine (administered as desvenlafaxine succinate) is approved for the treatment of major depressive disorder (MDD). If eliminated by the kidney, desvenlafaxine may have more favorable pharmacokinetic or drug-drug interaction profiles compared to its parent compound, venlafaxine, which depends primarily on the CYP2D6 enzyme system. Therefore, the pharmacokinetics and bioavailability of desvenlafaxine was assessed in healthy human subjects.\r\nMethods: In a single-dose, open-label, crossover study, subjects were randomly assigned to 100 mg/d of oral desvenlafaxine or intravenous (50 mg/1 hr) desvenlafaxine. Plasma and urine were collected for 72 hours postdosing and assayed to determine pharmacokinetics and bioavailability of (R)-, (S)-, and (R+S)-desvenlafaxine and N,O-didesmethylvenlafaxine.\r\nResults and Discussion: Pharmacokinetic parameters for (R)- and (S)-desvenlafaxine enantiomers were approximately equivalent for the oral and intravenous formulations of desvenlafaxine. Compared with 50 mg\r\nintravenous desvenlafaxine, 100 mg oral desvenlafaxine had a higher area under the plasma concentration-time curve and an absolute bioavailability of 80.5%. Urinary excretion of total desvenlafaxine and N,O-didesmethylvenlafaxine accounted for 69% of the orally administered desvenlafaxine dose, with the majority of a dose being excreted unchanged or as the glucuronide conjugate (66%).\r\nConclusion: Desvenlafaxine has high oral bioavailability and provides an evenly balanced enantiomeric ratio....
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