Gabriel Marcelín-Jiménez

A Single-Dose, Three-Period, Six-Sequence Crossover Study Comparing the Bioavailability of Solution, Suspension, and Enteric-Coated Tablets of Magnesium Valproate in Healthy Mexican Volunteers Under Fasting Conditions

BACKGROUND Valproic acid has been associated with a highly variable intersubject absorptive phase; therefore, magnesium salt (magnesium valproate [MgV]) was developed to diminish variation during enteric absorption. OBJECTIVES The aims of this study were to assess the pharmacokinetics of single oral doses of MgV 500-mg solution, suspension, and enteric-coated tablets in a healthy Mexican population, and to compare formulation-related differences. METHODS This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy Mexican volunteers aged 18 to 45 years. In each period, subjects received single oral doses of 500-mg MgV solution, suspension, and enteric-coated tablet formulations, with a 7-day washout period between each dosing period. Serial blood samples were collected at 0 hour (prior to MgV administration) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 24, 48, and 72 hours after dosing. Valproate was measured by a new method of ultraperformance liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters of interest were C(max), T(max), AUC(0-72), AUC(0-infinity), t(1/2), V(d)/F, CL/F, and mean residence time (MRT). Formulation-related differences were assayed in accordance with the Mexican regulatory bioequivalence criteria. Log-transformed values of C(max) and AUC were used to construct a classic 90% CI. Bioequivalence was established if the 90% CI for the mean test:reference ratio of log-transformed C(max) and AUC were within the range of 0.80 to 1.25. Tolerability was assessed based on subject interview, vital sign monitoring, and clinical assessment. RESULTS A total of 24 healthy volunteers (12 women and 12 men; mean [SD] age, 28.79 [6.5] years; height, 164 [9.8] cm; weight, 65.42 [8.95] kg; and body mass index, 24.28 [2.11] kg/m(2)) were included. For the MgV solution, the mean (SD) pharmacokinetic parameters of C(max), T(max), AUC(0-72), AUC(0-infinity), t(1/2), V(d)/F, CL/F, and MRT were 59.75 (8.24) microg/mL, 0.542 (0.14) hours, 1099.67 (241.70) microg h/mL, 1156.30 (264.01) microg h/mL, 16.19 (2.36) hours, 9633.68 (1892.70) mL, 418.35 (92.01) mL/h, and 18.36 (1.44) hours, respectively. For the MgV suspension, the mean (SD) pharmacokinetic parameters of C(max), T(max), AUC(0-72), AUC(0-infinity), t(1/2), V(d)/F, CL/F, and MRT were 55.04 (7.72) microg/mL, 0.773 (0.51) hour, 1057.76 (223.37) microg h/mL, 1111.09 (245.07) microg h/mL, 16.32 (2.20) hours, 1069.05 (1775.64) mL, 435.43 (99.59) mL/h, and 18.41 (1.43) hours, respectively. For the MgV enteric-coated tablets, the mean (SD) pharmacokinetic parameters of C(max), T(max), AUC(0-72), AUC(0-infinity), t(1/2), V(d)/F, CL/F, and MRT were 54.88 (6.73) microg/mL, 2.79 (0.89) hours, 1100.79 (216.70) microg h/mL, 1163.61 (238.36) microg h/mL, 16.48 (2.10) hours, 9675.15 (1659.36) mL, 412.36 (85.24) mL/h, and 19.95 (1.53) hours, respectively. The 90% CIs for the tablets:solution ratio were 82.15 to 95.44, 94.60 to 105.39, and 95.43 to 105.95 for C(max), AUC(0-72), and AUC(0-infinity), respectively. The 90% CIs for the suspension:solution ratio were 84.79 to 98.50, 88.89 to 99.02, and 89.15 to 98.97, respectively. The 90% CIs for the tablets:suspension ratio were 89.90 to 104.43, 100.84 to 112.34, and 101.60 to 112.80, respectively. CONCLUSION This single-dose study found that the 3 formulations (solution, suspension, and enteric-coated tablets) of MgV met the regulatory criteria for bioequivalence in these healthy, fasting, Mexican volunteers.

Ciprofloxacin bioavailability is enhanced by oral co-administration with phenazopyridine: a pharmacokinetic study in a Mexican population.

AbstractBackground and objective: In Mexico, urinary tract infections (UTIs) constitute the second most frequent type of infections treated at primary-care clinics. Ciprofloxacin has played a major role in the treatment of UTIs because it has a broad spectrum of antibacterial activity. In addition to antimicrobial agents, phenazopyridine has been used to alleviate symptoms that occur during episodes of UTI. Thus, the present study was designed to compare the pharmacokinetic behaviour of ciprofloxacin administered alone versus ciprofloxacin combined with phenazopyridine. Patients and methods: Twenty-four healthy male Mexican volunteers participated in this project. The study was carried out with a single oral dose of ciprofloxacin 500mg. The double-blind, crossover, randomised, balanced trial design comprised two treatments, two periods and two sequences. After administration of the study medication, serial blood samples were collected for a period of 12 hours. The harvested plasma was analysed for ciprofloxacin by high-performance liquid chromatography. The area under the concentration-time curve to last measurable concentration (AUCt), area under the concentration-time curve extrapolated to infinity (AUC∞), peak plasma concentration (Cmax), time to reach Cmax (tmax), mean residence time (MRT), elimination constant (ke) and elimination half-life (t½) were determined from plasma concentrations of both treatments and considered as primary variables for statistical analysis. Results: While there were no differences between the two treatments in terms of Cmax and ke, AUCt and AUC∞ were 35% and 29% higher, respectively, in the combined treatment arm. Moreover, a significant delay in tmax (from 1 to 1.5 hours) and a statistical increase of 29% in MRT were also observed with phenazopyridine co-administration. Conclusion: Oral co-administration of phenazopyridine increases ciprofloxacin bioavailability with regard to the amount absorbed (AUC) and permanence in the body (MRT), which could be useful during treatment.

Development of an ultra-performance liquid chromatography–tandem mass spectrometry micromethod for quantification of lamotrigine in human plasma and its use in a bioequivalence trial

BACKGROUND The aim of the present work was to develop a chromatographic technique coupled with mass spectrometry for the measurement of lamotrigine in plasma. Lamotrigine and guanabenz (internal standard) were measured by selected reaction monitoring. The method was validated and applied in a bioequivalence trial on 26 female volunteers. Lamotrigine chewable tablets (100 mg) were administered and monitored for up to 96 h. RESULTS The method was linear between 0.05 and 5.0 µg/ml, with acceptable stability, accuracy and precision. Mean maximum plasma concentration was 1.37 µg/ml and was reached at 1.6 h postdose. Elimination half-life was 32.7 h. CONCLUSION Lamotrigine tablets were bioequivalent. Ultra-performance liquid chromatography with tandem mass spectrometry represents a powerful tool in terms of sensitivity, specificity and high-throughput analysis.

Development of a method by UPLC–MS/MS for the quantification of tizoxanide in human plasma and its pharmacokinetic application

BACKGROUND Nitazoxanide (NTZ) is used for the treatment of gastrointestinal tract colonization by anaerobic bacteria, viruses and other pathogens that represent a major cause of morbidity in Latin America. The aim of the present work was to develop and validate a UPLC-MS/MS method for the selective quantification of tizoxanide (TZN, the major metabolite of NTZ) in human plasma using niclosamide as internal standard; and examine its pharmacokinetic application in healthy volunteers. Nine male subjects received a single oral dose of a NTZ 500-mg tablet under fasting conditions. RESULTS The method was linear between 0.1 and 10 µg/ml and capable of separating signals from free-TZN and those delivered by in-source collision-induced dissociation of TZN-glucuronide, quantifying it with accuracy and precision. Mean maximum plasma concentration was 6.79 µg/ml and was reached at 2.4 h post-dose. CONCLUSION The method was validated, fulfilling regulatory guidelines. Results suggest low pharmacokinetic variability in the assayed population.

Ultra-fast chromatographic micro-assay for quantification of diphenidol in plasma: application in an oral multi-dose switchability trial

Pharmacokinetics of diphenidol (DPN) is limited due to the lack of analytical methodology. Here, a micro-assay for DPN quantification was developed, by coupling ultra-performance liquid chromatography with tandem mass spectrometry. The procedure involved plasma precipitation and injection of supernatant into UPLC with an Acquitytrade mark C18 column. Detection was in positive electrospray, following transitions of m/z 310.3 --> 292.3 and m/z 275.3 --> 230.2 for DPN and chlorphenamine (internal standard), respectively. The method was linear with a range of 4-400 ng/mL, and a 2 min run time. This method was applied in a switchability trial, where both formulations of DPN were bioequivalent.

Comparison of Fasting Bioavailability Among 100-mg Commercial, 100-mg Generic, and 50-mg Chewable Generic Sildenafil Tablets in Healthy Male Mexican Volunteers: A Single-Dose, 3-Period, Crossover Study

BACKGROUND Sildenafil citrate (SIL) was the first oral drug registered in Mexico for the treatment of erectile dysfunction. However, succinct pharmacokinetic data are available in the Mexican population. OBJECTIVE The goals of the present work were: (1) to design a specific method to quantify SIL plasma levels by using UPLC-MS/MS; (2) to compare oral SIL bioavailability in Mexican men with pharmacokinetic data in other populations; (3) to fulfill local regulatory requests; and (4) to describe the relative tolerability of a new 50-mg chewable tablet. METHODS This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy male volunteers. In each period, subjects received single oral doses of 100 mg of sildenafil (1 commercial [reference(⁎)], 1 generic [test 1(†)], or 2 chewable generic tablets [test 2(‡)]), with a 4-day washout period between each dose. Serial blood samples were collected for up to 24 hours. SIL was measured in heparinized plasma by using a validated UPLC-MS/MS method. Pharmacokinetic parameters included C(max), T(max), AUC(0-24), and AUC(0-∞). Bioequivalence was established if 90% CIs for mean test:reference ratios of log-transformed C(max) and AUC fell within the range of 0.80 to 1.25. Tolerability was assessed on the basis of a clinical interview with the subject and monitoring of vital signs. RESULTS Demographic data showed a homogeneous population. Validation of analytical method proved to be linear within the range of 1 to 1000 ng/mL, with selectivity, accuracy, and precision. 90% CIs for test 1:reference ratios were 86.52 to 113.56, 94.75 to 108.84, and 94.97 to 108.82 for the logarithm parameters C(max), AUC(0-24), and AUC(0-∞), respectively. The 90% CIs for the test 2:reference ratios were 82.14 to 107.24, 98.26 to 112.56, and 99.19 to 113.34 for C(max), AUC(0-24), and AUC(0-∞). Regarding relative tolerability, slight cephalea was the most common adverse effect. CONCLUSIONS The developed analytical method was validated in compliance with local requirements and was useful for sildenafil measurement. This single-dose study under fasting conditions suggests that both test products met the Mexican regulatory criteria for assuming bioequivalence in these healthy, male Mexican volunteers. The clinical data suggest that the chewable tablets were well tolerated by volunteers.

Development of an UPLC–MS/MS micromethod for quantitation of cinitapride in plasma and its application in a pharmacokinetic interaction trial

AIM Cinitapride (CIN) is a benzamide-derived molecule used for the treatment of gastroesophageal reflux and dyspepsia. Its pharmacokinetics are controversial due to the use of supratherapeutic doses and the lack of sensitive methodology. Therefore, a sensitive and accurate micromethod was developed for its quantitation in human plasma. RESULTS CIN was extracted from 300 µl of heparinized plasma by liquid-liquid extraction using cisapride as internal standard, and analyzed with an ultra performance liquid chromatograph employing positive multiple-reaction monitoring-MS. CONCLUSION The method proved to be rapid, accurate and stable within a range between 50 and 2000 pg/ml and was successfully validated and applied in a pharmacokinetic interaction trial, where it was demonstrated that oral co-administration of simethicone does not modify the bioavailability of CIN.