Food increases the bioavailability of mefloquine

Objectives: To assess the effect of food on the pharmacokinetics of the antimalarial mefloquine and its major plasma metabolite in healthy volunteers. Methods: In an open, two-way cross-over study, 20 healthy male volunteers who had fasted overnight were randomised to receive a single oral dose of 750 mg mefloquine in the absence or presence of a standardised, high-fat breakfast, administered 30 min before drug administration. Blood samples were taken at specific times over an 8-week period. Plasma concentrations of mefloquine and its carboxylic acid metabolite were determined by high-performance liquid chromatography for pharmacokinetic evaluation. Results: The parameters C_max and AUC of both mefloquine and its metabolite were significantly (P < 0.05) higher under post-prandial conditions than under fasting conditions (mefloquine: mean C_max 1500 vs 868 μg · l⁻¹, mean AUC 645 vs 461 mg l⁻¹ · h; metabolite: C_max 1662 vs 1231 μg · l⁻¹, AUC 1740 vs 1310 mg l⁻¹ · h). The intersubject variability in C_max and AUC of mefloquine was less than 30% (coefficient of variation). The time to peak plasma concentration of mefloquine was significantly shorter after food intake (17 vs 36 h). Compared with absorption in volunteers who had fasted, food did not alter t_1/2 (mefloquine and its metabolite) and t_max (metabolite). Conclusion: Under the conditions of this study, food increases the rate and the extent of mefloquine absorption. It is reasonable to recommend that mefloquine be administered with food in travellers receiving chemoprophylaxis and in patients on recovery receiving curative treatment. In acutely ill patients, mefloquine should be taken as soon as possible and administration with or shortly after meals should be attempted as soon as feasible. Received: 10 February 1997 / Accepted in revised form: 16 June 1997     

Pharmacokinetics and bioequivalence evaluation of three commercial tablet formulations of mefloquine when given in combination with dihydroartemisinin in patients with acute uncomplicated falciparum malaria

Objective: To assess the pharmacokinetics and relative bioavailability/bioequivalence of three commercial tablet formulations of mefloquine, i.e. Lariam (reference formulation), Mephaquin 100 Lactab and Eloquin-250, when given sequentially after dihydroartemisinin in Thai patients with acute uncomplicated falciparum malaria. Methods: Twenty-nine Thai patients with acute uncomplicated falciparum malaria were randomised to receive an initial dose of 300 mg dihydroartemisinin, followed by 1250 mg mefloquine (at 24 h and 30 h after dihydroartemisinin) given as either Lariam (n=10 cases), Mephaquin (n=9 cases) or Eloquin-250 (n=10 cases). Serial blood samples were obtained up to day 42 after treatment with mefloquine. Mefloquine concentrations were determined in whole blood by means of ultraviolet high-performance liquid chromatography. The pharmacokinetic parameters of mefloquine were estimated using non-compartmental and compartmental analysis. Results: The three combination regimens were well tolerated. Patients in all treatment groups had a rapid initial response. However, nine patients (four and five cases in regimen containing Mephaquin 100 Lactab and Eloquin-250, respectively) had reappearance of parasitaemia during the follow-up period. Mefloquine from the three formulations showed significantly different pharmacokinetic and bioavailability metrics. Significantly lower peak plasma concentrations (C_max) and areas under the plasma concentration–time curve (AUC; AUC_0–48h, AUC_0–7days, and total AUC) were observed with Mephaquin 100 Lactab than with the other two formulations. Mean values for relative bioavailability of the test to standard products were 49.1% (Mephaquin 100 Lactab) and 72.4% (Eloquine-250). Based on the criteria set, the bioavailability of the two test products (Mephaquin 100 Lactab and Eloquine-250) was considered non-equivalent to the reference product with respect to the rate (t_max, C_max) and extent (AUC_0–48h, AUC_0–7days, total AUC) of mefloquine absorption. Received: 15 June 1999 / Accepted in revised form: 7 October 1999     

A rapid spectrophotometric method for the determination of mefloquine hydrochloride

A simple ultraviolet spectrophotometric method for the estimation of mefloquine hydrochloride in methanol (ME₂) has been developed and has been compared with the reported ultraviolet spectrophotometric method in 0.1 N hydrochloric acid (ME₁). Analytical parameters such as stability, selectivity, accuracy and precision have been established for both the methods and evaluated statistically to assess the application of the individual methods. Both the methods were compared with the existing pharmacopoeial method for estimation of the drug. Both the methods were found to have the advantages for simplicity, stability, sensitivity, reproducibility and accuracy for using as an alternate to the existing non-spectrophotometric methods for the routine analysis of the drug in pharmaceutical formulations and also in pharmaceutical investigations involving mefloquine hydrochloride.     

Pharmacokinetics and bioequivalence study of a generic desloratadine tablet formulation in healthy male volunteers

The pharmacokinetic profiles and relative bioavailability of desloratadine (CAS 100643-71-8, Denosin as test and another commercially available preparation as reference) tablets from two different pharmaceutical manufacturers were carried out. A single oral dose (10 mg/2 tablets) of desloratadine was administered to 8 healthy young Chinese males in a completely double-blind cross-over design with a two-week washout period between each dose. Plasma samples were obtained before and at various appropriate intervals after dosing up to 120 h. The plasma concentrations were then analyzed by a liquid chromatography/tandem mass spectrometric (LC/MS/MS) method. The limit of quantitation of this LC/MS/MS method was 0.05 ng/mL. The coefficients of variation of the within-day and between-day calibration curves (n = 6) range from 0.05 ng/mL to 10 ng/mL and were less than 10%. The accuracy of this method was verified. Values for the area under the plasma concentration-time curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), elimination rate constant, half-life, oral clearance were estimated and compared for each preparation. By ANOVA, 90% confidence interval, Mann-Whitney test, and paired t-test, the two desloratadine products can be considered bioequivalent for both the extent and the rate of absorption.     

Pharmacokinetics and bioequivalence study of a generic amlodipine tablet formulation in healthy male volunteers

Two different tablets containing amlodipine besylate (CAS 111470-99-6) (Vazkor 10 mg tablet as test preparation and 10 mg tablet of the originator product as reference preparation) were investigated in 18 healthy male volunteers in order to compare the bioavailability and prove the bioequivalence between both treatments after oral single dose administration. The study was performed according to an open-label, randomized, two-period cross-over design with a wash-out phase of 21 days. Blood samples for pharmacokinetic profiling were taken up to 144 h post-dose, and amlodipine plasma concentrations were determined with a validated LC-MS/MS method. Maximum plasma concentrations (Cmax) of 6,183.7 pg/ml (test) and 5,366.7 pg/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 267,231.0 pg x h/ml (test) and 266,061.7 ng x h/ml (reference) were calculated. The median tmax was 5.6 h (test) and 6.1 h (reference). Plasma elimination half-lives (t 1/2) were 46.46 h (test) and 45.34 h (reference). Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA); 90% confidence intervals were between 93.20%-107.16% (AUC(0-infinity) and 103.36%-123.13% (Cmax). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%-125%.     

Comparative efficacy and bioequivalence of a brand-name and a generic triamterene-hydrochlorothiazide combination product

The clinical efficacy, safety, and bioavailability of a generic triamterene-hydrochlorothiazide product were compared with those of Dyazide. Thirty patients who had a diagnosis of nonlabile essential hypertension and who were receiving Dyazide (triamterene 50 mg and hydrochlorothiazide 25 mg) were continued on Dyazide maintenance for 16 days to determine the stability of blood pressure control and serum chemistry values. After this baseline period, the subjects were randomized to receive either Dyazide or a generic version for 21 days. They were then crossed over to receive the opposite product for another 21 days. Blood pressures were monitored throughout the study period, and blood samples were taken for measurement of serum electrolytes and of serum triamterene and its major metabolite, hydroxytriamterene sulfate. Hydrochlorothiazide was assayed in 24-hour urine samples. There were no statistically significant differences between regimens in recumbent and standing mean diastolic blood pressures or in mean concentrations of serum potassium, chloride, glucose, creatinine, and uric acid. Area under the concentration-time curve from 0 to 24 hours after drug administration, maximum concentration in serum, and time to achieve maximum concentration in serum did not differ significantly between regimens for triamterene and hydroxytriamterene sulfate. Similarly, there were no significant differences in excretion, maximum rate of excretion, and time to achieve maximum rate of excretion for urinary hydrochlorothiazide. Patients treated with a brand-name fixed-combination product containing triamterene 50 mg and hydrochlorothiazide 25 mg were given a generic formulation without loss of therapeutic efficacy or development of toxicity.     

Stereoselective pharmacokinetics of mefloquine in young children

Objective: the stereospecificity of mefloquine pharmacokinetics in children has been investigated. Patients: Twelve children aged 6 to 24 months were treated for uncomplicated falciparum malaria with a single oral dose of 25 mg⋅kg⁻¹ racemic mefloquine in combination with sulfadoxine and pyrimethamine. Methods: concentrations of mefloquine enantiomers were determined using a coupled achiral-chiral chromatographic system. Pharmacokinetic parameters were calculated using model-independent analysis. Results: Maximum plasma concentrations, areas under the curve and apparent plasma elimination half-lives were higher for the (−) enantiomer than its antipode. In contrast, the apparent volume of distribution (V/f) and total clearance (Cl/f) values were higher for the (+) enantiomer. Conclusion: the stereoselectivity of mefloquine pharmacokinetics is similar to that observed in adults. Received: 23 March 1995/Accepted in revised form: 26 October 1995     

Adverse effects and compliance with mefloquine or proguanil antimalarial chemoprophylaxis

Objective: We had the impression that adverse reactions to standard antimalarial prophylaxis were reported much more often than stated by the package insert and medical drug references; and that side effects adversely affected compliance. Therefore, we evaluated adverse effects and compliance of the two standard malaria prophylactic regimens (mefloquine 250 mg per week and proguanil 100 mg twice per day) among short-term travellers. We expected that travellers who had experienced possible adverse effects on previous journeys might avoid antimalarial drugs on subsequent journeys (self-selection) and we therefore looked at adverse effects dependent on prior use. Methods: The presence of neuropsychological and gastrointestinal symptoms were assessed by telephone interviewing of 300 travellers who had visited the travel vaccination service of our regional public health institute. Symptoms, prior use and non-compliance of 104 mefloquine users and 103 proguanil users were compared with 93 non-users in order to control for travel-related symptoms. Results: Mefloquine showed the following adverse effects: depression [excess risk (ER) 7.2 per 100 users], dizziness (ER 9.3) and itching (ER 12.3). Adverse effects of proguanil were dizziness (ER 7.5) and nausea (ER 12.7). Adverse effects were mostly mild to moderate and occurred mainly during the time abroad. These results did not change when adjusting for age, sex, or destination. For almost every symptom, we found a remarkable difference between the relationship of symptoms and antimalarial drugs in first-time users and that in prior users: in the first-time users the relationship was positive, while in prior users it was absent or negative. This could be due to self-selection or adaptation to adverse effects. 22% of mefloquine users were non-compliant, whereas 35% of proguanil users were non-compliant. Adverse effects (experienced or expected) were the most often reported reason for mefloquine users to stop or even not to start taking the drug (42%). For proguanil, most of the non-compliant participants saw no point in starting or continuing its use (perceived uselessness 54%). Conclusion: We can confirm the reports by users that adverse effects of mefloquine and proguanil are common and, although mostly mild, adversely affect compliance. We suggest that a longer run-in period for mefloquine as well as counselling travellers about possible adverse effects might improve compliance. Received: 24 May 1996 / Accepted in revised form: 30 January 1997     

氢溴酸西酞普兰咀嚼片人体生物利用度和生物等效性研究

目的比较国产氢溴酸西酞普兰咀嚼片与进口氢溴酸西酞普兰片的人体药动学参数及生物利用度,评价二者的生物等效性。方法 24名健康男性受试者随机交叉单剂量服用20 mg受试制剂和参比制剂,受试制剂空腹咀嚼30～60 s后直接吞咽,参比制剂空腹用200 mL温开水送服。血浆样品采用高效液相色谱-串联质谱法检测。结果受试制剂及参比制剂的主要药代动力学参数:Cmax分别为(16.56±4.12)、(18.30±4.72)μg/L;Tmax分别为(4.42±2.41)、(5.00±2.87)h;t1/2分别为(47.44±7.74)、(48.43±14.56)h;AUC0-tn分别为(819.74±261.18)、(885.38±216.22)μg.h/L;AUC0-∞分别为(939.00±336.16)、(1 016.04±315.32)μg.h/L;受试制剂的相对生物利用度F0-tn、F0-∞分别为91.92%±15.10%、92.09%±15.52%。结论受试制剂和参比制剂具有生物等效性。     

Bioinequivalence of a generic brand of diazepam

Twenty-six healthy male volunteers received a single 10 mg dose of diazepam on two occasions in a crossover bioequivalence study comparing the reference product (Valium) and a generic formulation (NeoCalme). Concentrations of diazepam and its metabolite, desmethyldiazepam, were determined during 264h after each dose. Peak plasma diazepam concentrations were significantly lower for NeoCalme vs Valium (247 vs 394 ng ml-1, p less than 0.001) and reached significantly later after the dose (1.62 vs 0.98 h, p less than 0.001). Total area under the plasma concentration curve (AUC) was also significantly lower for NeoCalme (6614 vs 7552 ng ml-1 x h, p less than 0.001), although AUC ratios for NeoCalme divided by Valium satisfied the '75-75' guidelines. Findings for desmethyldiazepam were similar. Thus, diazepam absorption from the generic brand of diazepam is significantly slower than from Valium, which in turn could lead to therapeutic inequivalence.     

Lack of bioequivalence between generic risperidone oral solution and originator risperidone tablets

Risperidone is an atypical anti-psychotic, available in various formulations. OBJECTIVE: The objective of the study was to compare the bioavailability of a generic oral solution of risperidone (Test formulation) and Risperdal tablets (Reference formulation). Both formulations contained 1 mg risperidone per dosing unit. METHODS: The study was carried out in 32 healthy volunteers under fasting conditions. Risperidone and 9-hydroxyrisperidone concentrations in plasma were determined using HPLC/MS/MS. RESULTS: The results show that the 90% confidence intervals for the geometric mean ratios of the solution and the tablet formulations were not within the acceptance range of 80 125% for risperidone, whereas the confidence intervals for 9-hydroxyrisperidone were within the acceptance range of 80 - 125%. CONCLUSION: Bioequivalence between the generic 1 mg/ml risperidone solution and the originator tablet formulation was not proven in this study.     

Effects of mefloquine alone and with alcohol on psychomotor and driving performance

Objective: To determine whether mefloquine, a quinoline antimalarial drug, affects psychomotor and actual driving performance when given in a prophylactic regimen, alone or in combination with alcohol. Methods: Forty male and female volunteers were randomly assigned in equal numbers to two groups, and were treated double-blind for one month with mefloquine and placebo. The medication was taken in a 250 mg dose on the evenings of Days 1, 2, 3, 8, 15, 22 and 29. Testing was done on Days 4, 23 and 30, the latter after repeated doses of alcohol sufficient to sustain a blood concentration of about 0.35 mg ⋅ml⁻¹. Two real driving tests were used to measure prolonged (1 h) road tracking and car following performance. Critical Flicker/Fusion Frequency (CFF), critical instability tracking and body sway were also measured in the laboratory. Results: Mefloquine caused no significant impairment in any test at any time relative to placebo. It significantly improved road tracking performance on Day 4. A significant interaction between prior treatment and alcohol was found in the body sway test, as the alcohol-induced change was less after mefloquine than placebo. The sensitivity of the driving test and the CFF test were shown by the significant overall effect of alcohol which did not discriminate between the two prior treatments. Conclusion: Mefloquine did not impair driving performance but rather improved it in the longer test, suggesting that the drug may possess psychostimulating properties. Received: 7 December 1995/Accepted in revised form: 27 February 1996     

Whole blood concentrations of mefloquine enantiomers in healthy Thai volunteers

We studied the pharmacokinetics of the enantiomers of mefloquine in whole blood in healthy Thai volunteers after administration of a single oral dose of 750 mg of the racemic mixture.Mefloquine pharmacokinetics were stereoselective. The peak concentrations and areas under the curve of the (–) enantiomer were significantly higher than those of its antipode (0.79 versus 0.46 g · ml^-1 and 402 versus 94 g · h · ml^-1). The half-lives of (–)MQ were significantly longer than those of (+)MQ (531 versus 206 h). No stereoselectivity was observed for t_max values.     

Bioequivalence evaluation of a triamterene-hydrochlorothiazide generic product: a new bioequivalence index for fixed-dose combinations

In this study, an open, double-blind, randomized, two-period, two-group crossover design was conducted in 14 healthy volunteers to study the bioequivalence of a fixed-dose generic product. After administration of test or reference products to each volunteer, both active ingredients were determined simultaneously in plasma samples using a developed and validated HPLC-UV method, and pharmacokinetic parameters, including C(max), T(max), AUC(0-t) , AUC(0∞), terminal elimination rate constant (λz), volume of distribution in steady state (Vd(ss)), mean residence time (MRT), clearance (Cl), terminal elimination rate constant (Kel) were determined in each subject using the standard non-compartmental approach. Statistical comparison showed that the test and reference products were bioequivalent in terms of both the rate and extent of bioavailability of both active ingredients. Finally, a new parameter named range overlap index (ROI) was introduced for the first time in this study in order to judge about the overall bioequivalence of the combination products. This parameter indicates the extent in which the two CI90% ranges of each parameter for two active ingredients overlap with each other. The ROI is suggested to be equal or more than 50% for two combination products in order to be known as bioequivalent. The ROI values of the bioequivalence-indicating parameters were 61.90%, 84.6%, and 76.0% for C(max), AUC(0--->12), and AUC(0--->∞), respectively, which are indicative for bioequivalence in all the cases.     

Liquid-phase microextraction combined with high-performance liquid chromatography for the enantioselective analysis of mefloquine in plasma samples

A simple and rapid method, which involves liquid-phase microextraction (LPME) followed by HPLC analysis using Chiralpak AD column and UV detection, was developed for the enantioselective determination of mefloquine in plasma samples. Several factors that influence the efficiency of three-phase LPME were investigated and optimized. Under the optimal extraction conditions, the mean recoveries were 33.2 and 35.0% for (−)-(SR-)-mefloquine and (+)-(RS)-mefloquine, respectively. The method was linear over 50–1500 ng/ml range. Within-day and between-day assay precision and accuracy were below 15% for both enantiomers at concentrations of 150, 600 and 1200 ng/ml. Furthermore, no racemization or degradation were seen with the method described.     

Primaquine disposition in the isolated perfused rat liver: effect of mefloquine induced bile flow reduction

The disposition of primaquine (0.75 mg, 5 microCi) has been investigated in the isolated perfused rat liver (IPRL) preparation alone and concurrently with mefloquine. In both groups, primaquine concentrations declined exponentially. There were no significant differences between the respective groups in the half-lives (2.5 +/- 1.5, 2.2 +/- 1.1 h), AUCs (0.43 +/- 0.14, 0.372 +/- 0.096 microgram.h ml-1), clearances (19.0 +/- 5.4, 21.1 +/- 4.2 ml h-1), and apparent volume of distribution (78.9 +/- 28.1, 76.2 +/- 31.7 ml). In the presence of mefloquine, total bile production was significantly reduced (1244.5 +/- 317.1 microliters) compared with primaquine alone (1621.5 +/- 174.2 microliters). Hence, although significantly less radioactivity ([3H]) was eliminated in bile in the presence of mefloquine (30.0 +/- 7.9 per cent versus 39.9 +/- 3.6 per cent) there was no significant difference between the groups in [3H]/microliters bile eliminated. Significantly more [3H] was recovered from the livers of the mefloquine/primaquine group. This was underlined by the significantly greater proportions of [3H] recovered from the 10,000 g pellet, 10,000 g supernatant and 105,000 g supernatant in the presence of mefloquine compared with primaquine alone. Hence, it appears mefloquine had little or no direct action or primaquine metabolism, but significantly reduced bile production.     

Sodium ferric gluconate (SFG) in complex with sucrose for IV infusion: bioequivalence of a new generic product with the branded product in healthy volunteers

Abstract

Objective:

Parenteral sodium ferric gluconate in complex (Ferrlecit [branded SFG]) is used to treat patients with iron deficiency anemia undergoing chronic hemodialysis and receiving supplemental epoetin. This comparative pharmacokinetic study (GeneraMedix, Inc., Study 17909) evaluates whether the recently approved generic product Nulecit (generic SFG) and the branded product Ferrlecit (branded SFG) are bioequivalent.