Investigation of mutual pharmacokinetic interactions between macitentan,a novel endothelin receptor antagonist,and sildenafil in healthy subjects

AimTo study the mutual pharmacokinetic interactions between macitentan, an endothelin receptor antagonist, and sildenafil in healthy male subjects.MethodsIn this open-label, randomized, three way crossover study, 12 healthy male subjects received the following oral treatments: A) a loading dose of 30 mg macitentan on day 1 followed by 10 mg once daily for 3 days, B) sildenafil 20 mg three times a day for 3 days and a single 20 mg dose on day 4 and C) both treatments A and B concomitantly. Plasma concentration−time profiles of macitentan and its active metabolite ACT-132577 (treatments A and C) and sildenafil and its N-desmethyl metabolite (treatments B and C) were determined on day 4 and analyzed non-compartmentally.ResultsThe pharmacokinetics of macitentan were not affected by sildenafil. In the presence of sildenafil C_max and AUC_τ of the metabolite ACT-132577 decreased with geometric mean ratios (90% confidence interval (CI)) of 0.82 (0.76, 0.89) and 0.85 (90% CI 0.80, 0.91), respectively. In the presence of macitentan, plasma concentrations of sildenafil were higher than during treatment with sildenafil alone, resulting in increased C_max and AUC_τ values. The respective geometric mean ratios were 1.26 (90% CI 1.07, 1.48) and 1.15 (90% CI 0.94, 1.41). The pharmacokinetics of N-desmethylsildenafil were not affected by macitentan. All treatments were well tolerated.ConclusionA minor, not clinically relevant, pharmacokinetic interaction was observed between macitentan and sildenafil. Based on these results, no dose adjustment of either compound appears necessary during concomitant treatment with macitentan and sildenafil.     

Effect of quercetin on the pharmacokinetics of selexipag and its active metabolite in beagles

ContextAs an inhibitor cytochrome P450 family 2 subfamily C polypeptide 8 (CYP2C8), quercetin is a naturally occurring flavonoid with its glycosides consumed at least 100 mg per day in food. However, it is still unknown whether quercetin and selexipag interact.ObjectiveThe study investigated the effect of quercetin on the pharmacokinetics of selexipag and ACT-333679 in beagles.Materials and methodsThe ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate the pharmacokinetics of orally administered selexipag (2 mg/kg) with and without quercetin (2 mg/kg/day for 7 days) pre-treatment in beagles. The effect of quercetin on the pharmacokinetics of selexipag and its potential mechanism was studied through the pharmacokinetic parameters.ResultsThe assay method was validated for selexipag and ACT-333679, and the lower limit of quantification for both was 1 ng/mL. The recovery and the matrix effect of selexipag were 84.5–91.58% and 94.98–99.67%, while for ACT-333679 were 81.21–93.90% and 93.17–99.23%. The UPLC-MS/MS method was sensitive, accurate and precise, and had been applied to the herb-drug interaction study of quercetin with selexipag and ACT-333679. Treatment with quercetin led to an increased in C_max and AUC_0–t of selexipag by about 43.08% and 26.92%, respectively. While the ACT-333679 was about 11.11% and 18.87%, respectively.Discussion and conclusionThe study indicated that quercetin could inhibit the metabolism of selexipag and ACT-333679 when co-administration. Therefore, the clinical dose of selexipag should be used with caution when co-administered with foods high in quercetin.     

Human Bioequivalence Evaluation of Two Losartan Potassium Tablets Under Fasting Conditions

The bioequivalence of two different tablet formulations containing losartan potassium 100 mg was determined in healthy volunteers after a single oral dose in a randomized crossover study. Test and reference products were administered to 60 volunteers with 240 ml water after overnight fasting. Plasma concentrations of losartan and its active carboxylic acid metabolite were monitored over a period of 36 h after drug administration by validated LC/MS/MS analytical method. The pharmacokinetic parameters C_max, AUC_0-t, AUC_0-∞, AUC_0-t/AUC_0-∞, t_max, K_el and t_½ were determined from plasma concentration time profile of both formulations for losartan and its active metabolite losartan carboxylic acid and were found to be in good agreement. The carboxylic acid metabolite was considered for profiling purpose only. The analysis of variance did not show any significant difference between the two formulations and 90% confidence intervals for the ratio of C_max (84.89-104.09%), AUC_0-t (95.84-102.84%) and AUC_0-∞ (96.43-103.25%) values for losartan between the test and reference products were within the 80-125% interval, satisfying the bioequivalence criteria of the US FDA guidelines. These results indicate that the test and the reference products of losartan potassium are bioequivalent and, thus, may be prescribed interchangeably.     

Bioequivalence studies of a new valproic acid delayed-release capsule and divalproex sodium delayed-release tablet

ABSTRACT

Objective: The study examined relative bioavailability of a novel valproic acid (VPA) delayed-release (DR) soft gelatin capsule formulation to divalproex sodium DR tablet under fasting conditions and the effect of food on the bioavailability of the VPA DR soft gelatin capsule.

Method: This open-label, randomized three-way crossover study enrolled 36 healthy non-smoking adult volunteers. Treatments included a single 500 mg divalproex sodium DR tablet, fasting; a single 500 mg VPA DR soft gelatin capsule, fasting; and, a single 500 mg VPA DR soft gelatin capsule 500 mg, non-fasting. Analysis of variance was performed on the pharmacokinetic parameters. The ratio of geometric means and corresponding 90% confidence intervals (CI) were calculated on ln-transformed data for the area under the serum concentration-time curve (µg-hr/mL) from time zero to the time of the last quantifiable concentration (t) (AUC_0–t), AUC_0–∞ and maximum plasma concentration (C_max). Bioequivalence was shown when 90% CIs were within the 80–125% range.

Results: All subjects completed the study. The 90% CIs of VPA DR soft gelatin capsules compared to divalproex sodium DR tablets were within the 80–125% limits for AUC_0–t, AUC_0–∞, and C_max. The time of maximum or peak concentration (T_max) of VPA DR soft gelatin capsules was 2.3 hours versus 3.7 hours with divalproex sodium DR tablets. AUC_0–t and AUC_0–∞ of VPA soft gelatin capsules were not affected in the non-fasting condition, but T_max occurred at 6.1 hours compared to 2.3 hours fasting. Eight subjects experienced a total of 10 adverse events; none were serious.

Conclusion: The VPA DR soft gelatin capsule formulation was shown to be bioequivalent to divalproex sodium DR tablet and no serious adverse events occurred. Because this was not a multiple-dose study, however, direct comparisons in chronic dosing were not possible. Administration with food affected rate but not extent of absorption of the VPA DR soft gelatin capsules, but comparisons with the reference product were not conducted under non-fasting conditions.     

Pharmacokinetic evaluation of novel oral fluorouracil antitumor drug S-1 in Chinese cancer patients

Aim:

S-1 is an oral anticancer fluoropyrimidine formulation consisting of tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate. The aim of this study was to evaluate the pharmacokinetics and bioequivalence of a newly developed generic formulation of S-1 in Chinese cancer patients in comparison with the branded reference formulation of S-1.

Methods:

A single-dose, randomized-sequence, open-label, two-way self-crossover study was conducted in 30 Chinese cancer patients. The subjects alternatively received the two formulations (40 mg/m², po) with a 7-d interval. Plasma concentrations of FT, CDHP, Oxo, and 5-Fu were determined using LC-MS/MS. Pharmacokinetic parameters, including C_max, T_max, t_1/2, AUC_0–t, and AUC_0–∞ were determined using non-compartmental models with DAS2.0 software. Bioequivalence of the two formulations were to be evaluated according to 90% CIs for the log-transformed ratios of AUC and C_max of S-1. Adverse events were evaluated through monitoring the symptom, physical and laboratory examinations, ECGs and subject interviews.

Results:

The mean values of C_max, AUC_0–t, and AUC_0–∞ of FT, 5-Fu, CDHP, and Oxo for the two formulations had no significant differences. The 90% CIs for natural log-transformed ratios of C_max, AUC_0–t, and AUC_0–∞ were within the predetermined bioequivalence acceptance limits. A total of 11 mild adverse events, including fatigue, nausea and vomiting, anorexia, diarrhea and myelosuppression, were observed, and no serious and special adverse events were found.

Conclusion:

The newly developed generic formulation and reference formulation of S-1 have similar pharmacokinetics with one dose (40 mg/m²) in Chinese cancer patients. Both the formulations of S-1 are well tolerated.     

Pharmacokinetic–Pharmacodynamic Relationships of Macitentan,a New Endothelin Receptor Antagonist,After Multiple Dosing in Healthy Korean Subjects

Background and objectives

Macitentan is a novel dual endothelin (ET)-1 receptor antagonist to be used in patients with pulmonary arterial hypertension. This study aimed to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of macitentan after administration of multiple doses to healthy Korean male subjects.

Methods

A randomized, double-blind, placebo-controlled, multiple-ascending dose study was performed in 30 healthy male subjects receiving oral macitentan (3, 10, or 30 mg) or placebo once daily for 10 days. Plasma concentrations of macitentan, its active metabolite ACT-13277, and ET-1 were evaluated. Safety and tolerability measurements were conducted throughout the study.

Results

The concentration–time profile of macitentan was characterized by slow absorption (median time to maximum plasma concentration [t _max] 9–10 h) and slow elimination (mean elimination half-life [t _½] 11–15 h). After repeated doses of 3, 10, and 30 mg of macitentan over the course of 10 days, the peak concentration (C _max) increased as the dose increased and the area under the plasma concentration–time curve during the dosing interval (AUC _τ ) increased in a dose-proportional manner. Plasma concentrations showed approximately 1.5- to 1.9-fold accumulation on day 10 compared with day 1. ACT-132577 showed higher levels of exposure than macitentan, its mean half-life was 46–48 h, and it accumulated 7- to 12-fold. Macitentan increased plasma ET-1 concentrations at all doses tested and was well tolerated and elicited no serious adverse events.

Conclusion

Multiple oral doses of 3, 10, and 30 mg of macitentan were well tolerated in healthy Korean subjects, and its pharmacokinetics correlated positively with ET-1 concentrations.     

Biocomparison of Three Formulations of the S1P1 Receptor Modulator Ponesimod in Healthy Subjects

Background

Ponesimod is a potent selective sphingosine-1-phosphate receptor 1 (S1P₁) modulator, which leads to a reduction in circulating lymphocytes, reflecting their sequestration within lymphoid organs. Modulation of the S1P₁ receptor has been previously described to be an effective treatment of autoimmune diseases (e.g., multiple sclerosis).

Objectives

The aim of this study was to compare the relative bioavailability of two polymorphic forms of ponesimod in capsules (Form A versus Form C; Study 1) and the relative bioavailability of a capsule formulation and a tablet formulation (both polymorphic Form C; Study 2).

Methods

Two open-label, randomized, two-way crossover studies in healthy subjects were performed. In Study 1, 12 male subjects received a single dose of 20 mg of polymorphic Form A or Form C of ponesimod in a capsule. In Study 2, 14 male and female subjects (ratio 1:1) received a single dose of 40 mg of polymorphic Form C of ponesimod in either a capsule or a tablet formulation. Pharmacokinetic and safety variables (clinical laboratory test results, vital signs, and an electrocardiogram) were assessed.

Results

Comparison of the exposure to ponesimod following administration of the formulations in Study 1 showed that the 90 % confidence intervals of the geometric mean ratios for the area under the curve from time zero to infinity (AUC_0–inf), the area under the curve from time zero to the time of the last measurable concentration (AUC_0–t), the terminal half-life (t_½), and the maximum plasma concentration (C_max) were all within the 0.80–1.25 bioequivalence interval. In Study 2, more rapid absorption of ponesimod was observed from the tablet formulation than from the capsule formulation. There were no relevant differences in the safety and tolerability profiles between the different formulations.

Conclusion

The two polymorphic forms of ponesimod and tablet versus capsule formulations were similar in terms of pharmacokinetics, safety, and tolerability.     

伏立康唑胶囊人体药动学及相对生物利用度研究

目的 研究健康受试者口服伏立康唑胶囊的药动学和相对生物利用度。方法 20名健康受试者随机服用伏立康唑受试胶囊剂和参比片剂各100 mg,用HPLC-MS/MS测定血浆中伏立康唑的浓度。结果 主要药动学参数,伏立康唑受试制剂与参比制剂的T_max分别为(0.75±0.15)和(0.84±0.25)h,C_max分别为(605.4±136.6)和(595.2±134.7)ng·mL^-1;t_1/2分别为(4.91±1.44)和(5.06±2.06)h,AUC_0-15分别为(1737.6±325.1)和(1750.6±352.8)ng·h·mL^-1。受试制剂与参比制剂的AUC_0-15和C_max经双单侧t检验,T_max经非参数检验,差异均无统计学意义。结论 统计学结果表明,2种制剂生物等效。     

Lack of bioequivalence of a generic mefloquine tablet with the standard product

Objective: To assess the bioequivalence between a generic tablet of mefloquine (Mephaquin^®?= M1) with the reference tablet (Lariam^®?=?M2) in healthy volunteers. Methods: This open label, randomized two-way cross-over study was performed in a single centre. Following an overnight fast, eighteen healthy volunteers received a single oral dose of 750?mg mefloquine either in the form of three M1 lactabs or three M2 tablets. Serial blood samples were collected up to 8 weeks after drug administration. Plasma samples were analysed for mefloquine and its carboxylic acid metabolite using liquid chromatography and subsequent tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of mefloquine and its metabolite were estimated by non-compartmental methods. Results: The pharmacokinetics of mefloquine after administration of M1 and M2 tablets were significantly different as reflected by the respective mean values of maximum plasma concentration (C_max 656 vs 1018?ng?·?ml^?1), time to reach maximum concentration (t_max 46 vs 13?h) and area under the plasma concentration-time curve (AUC_0→∞ 338 vs 432?μg?·?h?·?ml^?1). No significant differences existed between the elimination half-lives of the two formulations (394 vs 396?h). The relative bioavailability (M1 vs M2) was 0.78 and ranged from 0.38 to 1.37. Bioequivalence could not be demonstrated for log-transformed data of AUC_0→∞ or AUC_0→last within a predefined range of 80–125% and for C_max within a range of 70–143%. Conclusions: The observed differences in C_max, t_max and AUC are consistent with a slower rate and lower extent of mefloquine absorption after administration of M1. Statistical evaluation of these kinetic data showed that the M1 tablet is not bioequivalent to the M2 tablet. Clinical consequences of this finding cannot be excluded.     

The effect of grapefruit juice on the pharmacokinetics of orally administered verapamil

Objective: To investigate the effect of grapefruit juice (GJ) on the pharmacokinetics of orally administered verapamil in hypertensive patients. Methods: Ten hypertensive patients on chronic verapamil treatment participated in a two-day study. On day 1 200 ml of water was given 1 hour before, and together with the morning verapamil dose; on the day 2, water was replaced by GJ in the same order. Serial blood samples were collected and the concentrations of verapamil and its main dealkylated metabolite (D-617) were determined by high-performance liquid chromatography (HPLC). The area under the concentration versus time curve of verapamil (AUC_v) and its metabolite D-617 (AUC_M) were calculated before and after GJ ingestion. The peak serum concentration (C_max) and the time until its appearance (t_max) were also determined. Results: GJ did not affect C_max, t_max, AUC_v or AUV_m. The AUC_v/AUC_m ratio (AUC_R) was slightly, but significantly, increased after GJ (1.67 vs 1.92). Conclusions: A single administration of GJ with short-acting verapamil has no significant effect on the pharmacokinetics, of verapamil. Received: 2 October 1997 / Accepted in revised form: 2 March 1998     

Comparative bioavailability of josamycin,a macrolide antibiotic,from a tablet and solution and the influence of dissolution on in vivo release

The bioavailability of josamycin from a tablet formulation (2 × Josacine® 500 mg tablets) was investigated and compared with the bioavailability of a solution (containing 1 g drug and buffered at pH 4.0) following administration to six healthy human volunteers. Bioavailability profiles for the solution indicated that the drug was inherently rapidly absorbed with a mean C_max of 1.64±0.67 mg L⁻¹ attained at a mean t_max of 0.39±0.08 h. The AUC_0–last was 1.510±0.687 mg h L⁻¹. Bioavailability was significantly lower from the tablets than from the solution. Highly variable serum concentration–time profiles were obtained from the tablets and C_max values ranged from 0.05 to 0.71 mg L⁻¹ with a t_max range of 0.33–2.0 h. AUC_0–last values ranged from 0.03 to 0.95 mg h L⁻¹. Dissolution of josamycin from the tablets was generally unaffected at low pH (pH 1.2–5.0), but, rather, limited predominantly by tablet disintegration. However, dissolution was increasingly limited as the pH increased from 5.0 to 9.0. Besides poor disintegration, the particularly low intrinsic dissolution rate and solubility of josamycin at these pH values is likely to further reduce the dissolution rate. Comparison of the solution and tablet serum concentration–time profiles suggests that the absorption of josamycin from the tablets was dissolution rate limited. This is supported by the in vitro dissolution–pH topogram, which suggests that dissolution will be particularly rate limiting if dissolution of whole or parts of tablets occurs in gastro-intestinal fluid above pH 5.0. © 1998 John Wiley & Sons, Ltd.     

Dose proportionality of stavudine in hiv seropositive asymptomatic subjects: Application to bioequivalence assessment of various capsule formulations

The dose proportionality and bioequivalence of the capsule formulations used in clinical trials and the proposed commercial formulations of stavudine were assessed in an openlabel, single-dose, randomized four-way crossover study in 16 asymptomatic HIV-infected males. One capsule of stavudine (5, 10, 20, or 40 mg) was administered orally to each subject in each of the four treatment periods. Serial blood samples were collected for 10 h after each dose and the plasma was assayed for intact stavudine by a validated radioimmunoassay method. The plasma concentration-time data were subjected to noncompartmental pharmacokinetic analysis. For doses ranging from 5 to 40 mg, mean C_max and AUC_0-∞ values were in the range of 110.36–889.34 ng mL^?1 and 246.46–1945.97 h ng mL^?1 respectively. The mean C_max and AUC_0-∞ of stavudine increased in a dose-proportional manner. Irrespective of the dose, mean C_max values were observed at a median t_max of 0.75 h or less. Mean t_1/2 values were 1.97, 1.77, 1.67 and 1.66 h for the 5, 10, 20, and 40 mg capsules, respectively. For bioequivalence assessment, C_max and AUC_0-∞ values were normalized to the 10 mg dose since these parameters were dose proportional. The 10 mg capsule formulation used in phase-3 clinical trials was chosen as the reference. The relative bioavailability estimates and 90% confidence limits for the dose-normalized C_max values with the 10 mg capsule as the reference were 86% (76%, 96%), 99% (88%, 110%), and 90% (80%, 100%) for the 5, 20, and 40 mg capsules, respectively. The differences in the point estimates of the dose-normalized AUC_0-∞ values for the 5, 20, and 40 mg capsules relative to the 10 mg phase-3 capsule were 1% or less, and the 90% confidence limits were all within 95–106%. These results indicate that stavudine exhibits linear pharmacokinetics and that the 5, 10, 20, and 40 mg capsules of stavudine are bioequivalent.     

Effect of menthol on the pharmacokinetics and pharmacodynamics of felodipine in healthy subjects

Objectives The present study was undertaken to determine whether menthol affects the metabolism of and pharmacological responses to the calcium channel antagonist felodipine in people.Methods Eleven healthy subjects (ten female, one male) participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of felodipine ER tablet (Plendil, 10 mg) with menthol (test) or placebo (reference) capsules. Ten subjects completed the study. At the beginning of the study, a 10-mg felodipine ER tablet and a 100-mg menthol or placebo capsule were given. During the 2^nd, 5^th and 7^th hours of the study, 50, 25 and 25 mg menthol or placebo capsules were given, respectively. Blood samples and cardiovascular measurements were obtained at frequent intervals. Serum felodipine and dehydrofelodipine concentrations were determined by means of gas chromatography/mass spectrometry.Results Pharmacokinetic parameters of felodipine and dehydrofelodipine (AUC_0–24, C _max, t _max, dehydrofelodipine/felodipine AUC_0–24 ratio) were not markedly changed with menthol coadministration. Only eight female subjects cardiovascular data were included in the analysis because of technical problems during the measurements. There were no statistically significant differences in blood pressures and heart rates between the two treatments.Conclusions We conclude that the pharmacokinetics and pharmacodynamics of felodipine were essentially unaltered by menthol.     

Comparative analysis of the experimental and clinical pharmacokinetics of Amiodarone

The pharmacokinetics of two tablet formulations of amiodarone – Amiodarone and Amiodaron-Akri – were studied in 12 rabbits and 18 healthy human volunteers after single p.o. doses of 200 mg. A highly statistically significant correlation was found between plasma amiodarone concentrations in rabbits and volunteers (r = 0.8263, p < 0.001). Normalized C _max and AUC _0−∞ values were significantly greater in volunteers than rabbits, while specific V _Z and Cl _t values were lower and MRT was significantly higher; rate coefficients of absorption and measures of relative bioavailability showed no statistically significant differences between rabbits and healthy humans.     

An in situ crosslinked compression coat comprised of pectin and calcium chloride for colon-specific delivery of indomethacin

Abstract

The use of pectin for colon-specific drug delivery has been extensively investigated; however, when used alone, pectin is often compromised due to its high solubility. This study explored the feasibility of using an in situ compression-coated crosslinking system, composed of pectin and calcium chloride, for colon-specific drug delivery. A pectin/calcium chloride (P/Ca) coating was compressed onto a core tablet. The colon specificity of the compression-coated tablet was verified by dissolution, pharmacokinetics and scintigraphy with ^99mTc labeling. The in situ pectin and calcium chloride gel slowed the release of indomethacin. The lag time varied between 3?h and 7?h depending on the amount of calcium chloride and the coating weight. Pectinase triggered the release of indomethacin from the compression-coated tablet, which was then accelerated by the calcium chloride in the coating layer. The compression-coated tablet had a prolonged t_max and apparent t_1/2, as well as a decreased C_max and AUC_0–t, compared with the core tablet counterpart. Evaluation with γ-scintigraphy verified colon-specific delivery of the compression-coated tablet. In conclusion, the P/Ca in situ crosslinking system worked well for colon-specific drug delivery.     

Bioequivalence of Samchundang Berastolin tablet to Jeil Berasil tablet (beraprost sodium 20 μg)

Beraprost sodium, sodium (±)-(1R^*,2R^*,3aS^*,8bS^*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S^*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butyrate), an orally absorbable prostacyclin derivative (PGI₂), has marked ischemic symptom treatments like ulcer and pain with chronic arterial occlusion. The purpose of the present study was to evaluate the bioequivalence of two beraprost sodium tablets, Samchundang Berastolin tablet (Samchundang Pharm. Co., Ltd.) and Jeil Berasil tablet (Jeil Pharm. Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The in vitro release of beraprost from the two beraprost sodium formulations was tested using KP IX Apparatus II method with various dissolution media. Thirty-two healthy Korean male volunteers, 23.44 ± 1.48 years in age and 65.95 ± 8.94 kg in body weight, were divided into two groups and a randomized 2 × 2 crossover study was employed. After single administration, three tablets containing 20 μg as beraprost sodium, blood samples were taken at predetermined time intervals and the concentrations of beraprost in serum were determined using a LC/MS/MS method with multiple reaction-monitoring. The dissolution profiles of two formulations were similar in all tested dissolution media. The pharmacokinetic parameters such as AUC_t, C_max and T_max were calculated, and computer programs (Equiv Test and K-BE Test 2002) were utilized for the statistical analysis of the parameters using logarithmically transformed AUC_t, C_max and un-transformed T_max. The results showed that the differences between two formulations based on the reference drug, Jeil Berasil tablet, were 2.12, 0.15 and 4 % for AUC_t, C_max, and T_max, respectively. There were no sequence effects between two formulations in these parameters. The 90 % confidence intervals using logarithmically transformed data were within the acceptance range of log 0.8–log 1.25 (e.g., log 0.9114–log 1.0912 and log 0.8471–log 1.1253 for AUC_t and C_max, respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Samchundang Berastolin tablet was bioequivalent to Jeil Berasil tablet.     

Comparison of pharmacokinetics of citalopram in healthy Asian Indian and Mexican volunteers

Randomized, two-way crossover, bioequivalence studies were conducted separately in healthy Mexican and Asian Indian volunteers. One tablet either of test or of reference product was administered after 10?h of overnight fasting. After dosing, serial blood samples were collected for a period of 72?h and 168?h, respectively, for both the studies. Plasma samples were analyzed for citalopram by a validated liquid chromatographic and mass spectrometric method (LC-MS/MS). The pharmacokinetic parameters AUC_0–t, AUC_0–72, AUC_0–∞, C_max, and T_max were determined from plasma concentration-time profiles for both the test and reference formulation of citalopram 20?mg tablets, and were compared statistically to evaluate bioequivalence between the two brands of citalopram. In both the studies, the analysis of variance (ANOVA) did not show any significant difference between the test and reference formulations and 90% confidence intervals (CI) were lying within the acceptable range for bioequivalence. The test and reference formulations exhibited comparable pharmacokinetics profiles and were bioequivalent, but high values of both C_max (~ 23%) and AUC (~ 34%) were observed in Asian Indian healthy volunteers as compared to the Mexican volunteers. This may be due to the poor metabolism of Citalopram in the Asian population. This difference in the results of pharmacokinetic parameters of Asian Indian and Mexican volunteers may be attributed to ethnic factors.     

The Preparation and Evaluation of a Tablet Dosage Form of Cyclosporine in Dogs

Cyclosporine (CsA) is commercially available for oral administration as a solution in olive oil with alcohol and an emulsifier. To improve its variable absorption and low patient acceptability, several oral formulations were prepared and tested in vitro and in vivo in dogs. A tablet formulation prepared by direct compression was then selected for comparison with the commercial oil solution placed into soft gelatin capsules. The study involved a randomized crossover design in six dogs. In order to determine absolute bioavailability and to compensate for any time-dependent changes in clearance, an intravenous tracer dose of ³H-CsA was administered along with each oral test product on each of two occasions. Absolute bioavailability (mean ± SD) was 46.0 ± 11.1 and 45.4 ± 9.9% for the capsules and tablets, respectively. C _max, t _max, and mean absorption time were not significantly different between the two products. No differences were observed in the pharmacokinetics of the intravenously administered CsA in the two experiments, which were separated by 8–13 days. We conclude that the proposed tablet formulation for CsA is equivalent in dogs to the commercial dosage form placed into soft gelatin capsules.     

Comparative bioavailability of two capsule formulations of ofloxacin in healthy volunteers after a single dose administration

Abstract

The bioavailability of two ofloxacin (OFX) tablet formulations (OTT, test formulation from Laboratorio Atral SA - Portugal, and Tarivid, reference formulation from Hoechst AG - Germany) were compared in 24 (12M, 12F) healthy volunteers who received a single oral dose of 200 mg of each formulation in an open, randomized, two-period crossover fashion with a 14 day washout interval between doses. Plasma samples were obtained over a 24 h interval and OFX concentrations were determined by HPLC with UV detection. From the OFX plasma concentration vs time curves, the AUC_[0-24] (area under the concentration vs time curves from 0 to 24 h), AUC_[0-α] (area under the concentration vs time curves extrapolated to infinity), C_max (maximum concentration achieved), t_max (time to achieve C_max), t_1/2 (terminal first order elimination half-life), and elimination constant (K_e) were obtained. All these variables were analyzed using both parametric and non-parametric statistics. The two OFX tablet brands did not show statistically significant differences in bioavailability as assessed by the statistical analysis of AUC_[0-24] (14.8 and 14.7μg h ml^?1, respectively for OTT and Tarivid), AUC_[0-α] (16.0 and 15.6 μg h ml^?1), C_max (2.9 and 3.1 μg/ml), t_max (0.8 and 1.5 h), t_1/2 (5.9 and 5.6 h), and K_e (0.12 and 0.13 h^?1) values. Based on these results and on the United States Food and Drug Administration (FDA) requirements [1993], both formulations were considered to be bioequivalent.