Search

Purpose This study was designed to characterize the pharmacokinetic profile and to assess bioequivalence of the sponsor’s test formulation (imatinib mesylate 400 mg tablets) with an innovator product (Gleevec 400 mg tablets, Novartis Pharmaceuticals) under fed conditions, in adult patients of Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) stabilized on imatinib mesylate 400 mg. In addition, the aim of this study was to monitor the safety profile of investigational medicinal products (IMPs). Materials and Methods A multicenter, randomized, open label, two-period, crossover, single dose bioequivalence study was designed for conduct under fed conditions in 42 adult Ph+ CML patients already stabilized on imatinib 400 mg tablets. Pharmacokinetic parameters Tmax, Cmax, and AUC0-24 were calculated using a non-compartmental model on validated WinNonlin software. Validated SAS software was used for statistical evaluation of data. The safety profile of investigational products was monitored during the course of study by applying a clinical process for recording observed untoward effects postadministration of investigational products. Results The 90% confidence intervals for the test/reference mean ratios of the ln-transformed PK variables Cmax (99.0%) and AUC0-24 (99.2%) were within an acceptable range of 80%-125%, as per bioequivalence assumptions. Both formulations were well tolerated after oral administration of IMPs. Conclusion The test product was found to be bioequivalent and safe, and thus can be used interchangeably in clinical practice.

Background. Artemisinins, which are derived from plants, are subject to risk of supply interruption due to climatic changes. Consequently, an effort to identify a new synthetic antimalarial was initiated. A fixed-dose combination of arterolane maleate (AM), a new synthetic trioxolane, with piperaquine phosphate (PQP), a long half-life bisquinoline, was evaluated in patients with uncomplicated Plasmodium falciparum malaria. Methods. In this multicenter, randomized, double-blind, comparative, parallel-group trial, 1072 patients aged 12–65 years with P. falciparum monoinfection received either AM–PQP (714 patients) once daily or artemether–lumefantrine (A–L; 358 patients) twice daily for 3 days. All patients were followed up until day 42. Results. Of the 714 patients in the AM–PQP group, 638 (89.4%) completed the study; of the 358 patients in the A–L group, 301(84.1%) completed the study. In both groups, the polymerase chain reaction corrected adequate clinical and parasitological response (PCR–corrected ACPR) on day 28 in intent-to-treat (ITT) and per-protocol (PP) populations was 92.86% and 92.46% and 99.25% and 99.07%, respectively. The corresponding figures on day 42 in the ITT and PP populations were 90.48% and 91.34%, respectively. After adjusting for survival ITT, the PCR-corrected ACPR on day 42 was >98% in both groups. The overall incidence of adverse events was comparable. Conclusions. AM–PQP showed comparable efficacy and safety to A–L in the treatment of uncomplicated P. falciparum malaria in adolescent and adult patients. AM–PQP demonstrated high clinical and parasitological response rates as well as rapid parasite clearance. Clinical Trials Registration. India. CTRI/2009/091/000101.

This is the first publication on a complete validated bioanalytical method for estimation of olmesartan (OLM) and hydrochlorothiazide (HCTZ) in human K3 EDTA plasma that chromatographically resolves its olmesartan glucuronide. An API 4000 mass spectrometer was employed in this method where olmesartan d4 (OLMD4) and hydrochlorothiazide −13C, d2 (HCTZD2) served as the internal standard. Sample was prepared by solid phase extraction (SPE) technique using a polymer based, MCX cartridges and chromatographic resolution achieved on Synergi MAX RP-18A, (4.6 × 150 mm, 4 μm) column using a mobile phase of 0.2% formic acid solution/acetonitrile (30:70, v/v). Negative mass transitions (m/z) of OLM, HCTZ, OLMD4, and HCTZD2 were detected in multiple reactions monitoring (MRM) mode at 445.5 → 149.3, 296.0 → 269.0, 449.2 → 149.3, and 299.1→270.0, respectively. The linearity was checked over a concentration range of 4.051–2500.912 ng/mL for OLM and 0.506–304.109 ng/mL for HCTZ. Intra- and inter-run precision of OL...

A bioanalytical method for simultaneous estimation of olmesartan (OLM) and hydrochlorothiazide (HCTZ) in human K3 EDTA plasma is described. An API 3000 mass spectrometer was employed in this method where olmesartan d4 (OLMD4) and hydroflumethiazide (HFTZ) served as the internal standard. Sample preparation involved solid phase extraction (SPE), a polymer based, hydrophilic-lipophilic balanced cartridges, and chromatographic resolution achieved on X Terra RP18, (4.6 × 150 mm, 5 µm) column using a mobile phase of 2 mM ammonium formate buffer, (pH 3.50 ± 0.10 with formic acid)/acetonitrile (30:70, v/v). Negative mass transitions (m/z) of OLM, HCTZ, OLMD4, and HFTZ were detected in multiple reactions monitoring (MRM) mode at 445.6 → 148.4, 295.9 → 268.9, 449.4 → 148.4, and 329.9 → 238.3, respectively. The linearity was checked over a concentration range of 0.11 × 101 to 1.06 × 103 ng/mL for OLM and 0.10 × 101 to 0.32 × 103 ng/mL for HCTZ. Intra- and inter-run precision of OLM and HCTZ assay at four concentrat...

INTRODUCTION: The nicotine bolus theory states that the dependence-producing potential of cigarettes relates to a rapid increase in nicotine at brain receptor sites. It has been suggested that ammonia, a compound typically found in tobacco products, further increases the amount of nicotine absorbed and its absorption rate. The aim of this study was to determine whether different ammonia yields in cigarettes affected the rate or amount of nicotine absorption from the lungs to arterial circulation. METHODS: 34 adult smokers received 3 separate puffs from each of 2 test cigarettes with different ammonia yields (ammonia in smoke: 10.1 μg per cigarette vs. 18.9 μg per cigarette), followed by rapid radial arterial blood sampling (maximum one sample per second) with 30 min between puffs. Arterial blood samples were assayed for nicotine by liquid chromatography tandem mass spectrometry. Pharmacokinetic modeling was performed and the two test cigarettes were assessed for bioequivalence. RESULTS: No significant differences were found in area under the curve, C(max), or T((max)) and the 2 test cigarettes were found to be bioequivalent based on 2 one-sided tests at a significance level of 5%. In addition, the zero-order rate constant (k(0)) obtained from the initial slope of the curves and the model-dependent first-order rate constant (k(a)) were not significantly different. CONCLUSIONS: This study provides strong evidence that the different ammonia yields of the test cigarettes had no impact on nicotine pharmacokinetics; thus, the ammonia did not increase the rate or amount of nicotine absorption from a puff of cigarette smoke.

Ceftazidime is a third generation cephalosporin with a broad range of activity. Clavulanic acid is a β-lactamase inhibitor. A fixed dose combination, with the wide spectrum of action of ceftazidime and clavulanic acid’s high stability to β-lactamases has been developed by Ranbaxy Laboratories Limited (India). The present study was planned to predict any interaction between ceftazidime and clavulanic acid which could affect the safety and efficacy of the fixed dose combination. The study was an open label, balanced, randomized two-treatment, two-period, two-sequence, crossover, single-dose comparative pharmacokinetic study under fed conditions. A single intravenous injection of the test product containing a fixed dose combination of ceftazidime 2000 mg and potassium clavulanate 200 mg and the reference product containing ceftazidime 2000 mg only, was administered during each period. Serial blood samples were collected until 12 h post-dose in each period. Ceftazidime and clavulanic acid concentration in pla...

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 AUC0–t, AUC0–72, AUC0–∞, Cmax, and Tmax 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...

The objective of the study was to evaluate the effect of time of administration of food post-dosing on the oral bioavailability of two formulations of itraconazole 100 mg capsule in 24 healthy adult Indian subjects under fasting conditions. Three different paradigms for time of administrations of food post-dose were selected: 4 h, 5 h, and 6 h. A randomized two-treatment, four-period, three-sequence, single dose bioavailability study was conducted. After dosing, serial blood samples were collected for up to 72 h. Plasma samples were analyzed for Itraconazole (ITZ) and its metabolite Hydroxy Itraconazole (OH-ITZ) by a sensitive and validated simultaneous liquid-chromatographic and mass-spectrometric (LC-MS/MS) method. A comparison of effect of post-dose fasting up to 4 h, 5 h, and 6 h on pharmacokinetic parameters of the two formulations was done, and it was found that pharmacokinetic parameters (Cmax, AUC0–t, AUC0–∞, Tmax) were consistent for both formulations in all the paradigms tested. This result sugg...

Introduction We developed an automated sampling system to allow multiple, discrete blood samples from a human participant to be collected rapidly and immediately following cigarette smoke exposure. We reported the details of the sampling system along with the results of a pilot study for evaluation of the system. Methods Components of the system include silastic tubing, solenoid pinch valves, a peristaltic pump, and a fraction collector. This system incorporates a smoking machine that allows precise delivery of cigarette smoke through a mouthpiece and intricate timing to correlate blood samples with smoke inhalation. All components are controlled via integration from a user interface and are fully customizable. We performed several tests to evaluate the equipment, including tubing dead volume, leakage tests, and sample reproducibility. We also performed a pilot study with 6 adult smokers, who received 6 controlled puffs of a research test cigarette. Each inhalation was followed by radial arterial blood collection (1 sample per second tapered to 1 sample every 4 s) for 1 min. Samples were evaluated for nicotine via liquid chromatography-tandem mass spectrometric methods. Results Sampling times and volumes were sufficient for nicotine analysis. No adverse effects were seen in the pilot study, and a 30-min washout period was deemed appropriate between puffs. A significant rise in plasma nicotine levels above baseline after inhalation of smoke was consistently detected in all participants. Discussion The unique advantage of this system is to allow rapid blood sampling after a puff of cigarette smoke, with the benefits of reproducibility, reduction in labor intensity, and high temporal resolution.

Background Chloroquine has been the treatment of choice for acute vivax malaria for more than 60 years. Malaria caused by Plasmodium vivax has recently shown resistance to chloroquine in some places. This study compared the efficacy and safety of fixed dose combination (FDC) of arterolane maleate and piperaquine phosphate (PQP) with chloroquine in the treatment of uncomplicated vivax malaria. Methods Patients aged 13–65 years with confirmed mono-infection of P. vivax along with fever or fever in the previous 48 h were included. The 317 eligible patients were randomly assigned to receive FDC of arterolane maleate and PQP (n = 159) or chloroquine (n = 158) for 3 days. Primaquine was given as an anti-relapse measure on day 3 and continued for 14 consecutive days. Primary efficacy analysis included assessment of the proportion of aparasitaemic and afebrile patients at 72 h. Safety endpoints were analysis of adverse events, vital signs, laboratory data, and abnormalities on electrocardiograph. Patients participated in the study for at least 42 days. Results In per protocol population, the proportion of aparasitaemic and afebrile patients at 72 h was 100 % (140/140) in the FDC of arterolane maleate and PQP group, and 99.3 % (145/146) in the chloroquine group (Fisher, p > 0.9999). In intent to treat population, the corresponding value was reported to be 96.9 % (154/159) in the FDC of arterolane maleate and PQP group and 98.7 % (156/158) in the chloroquine group (Fisher, p = 0.4479). The median parasite clearance time was 24 h in FDC of arterolane maleate and PQP group and 26 h in chloroquine group (Log-rank, p = 0.2264). Similarly, median fever clearance time was 24 h in both the groups (Log-rank, p = 0.7750). In PP population, day 28 cure rates were 100 % in both the groups (95 % CI (96.52, 100.0 for FDC of arterolane maleate and PQP and 96.73, 100.0 in chloroquine group)). Incidence of adverse events was 82.4 % in the FDC of arterolane maleate and PQP group and 85.4 % in the chloroquine group. Most of the adverse events were mild to moderate in intensity. The commonly reported clinical adverse events in the FDC of arterolane maleate and PQP versus chloroquine group were vomiting (5.0 vs 5.1 %), headache (1.3 vs 3.2 %) and prolonged QT (1.9 vs 3.2 %). No deaths were reported. The pharmacokinetic analysis indicates that arterolane maleate is well absorbed and has a relatively short t1/2 of 3.2 h. Piperaquine is also well absorbed after oral administration with a t1/2 of about 228.33 h. Conclusions The study showed that FDC of arterolane maleate and PQP effectively cured vivax malaria and attained acceptable level of cure up to day 28. Both the groups showed similar safety profile. Trial Registration Clinical Trial Registry India: CTRI/2011/11/002129 Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1084-1) contains supplementary material, which is available to authorized users.

The development of a 'biorelevant' approach for accelerating drug release from an implant is described. A miniature, capillary system has been shown previously to be suitable for real-time release tests for a biodegradable, naltrexone implant. Whereas the real-time study under physiological condition was essential for evaluation of the system, the accelerated (short-term) method provides for a faster assessment of in vitro drug release that would be useful in product development and quality control. Increased temperature was employed as the mechanism for accelerating drug release. Release rates were investigated and compared using modifications of two devices: the flow-through cell and the new, potentially more 'biorelevant' capillary device. The data generated for accelerated release using both devices through 45 days indicated approximately two-fold and four-fold increases in release rates at 45 and 55 degrees C, respectively, as compared to the real-time release rate. The similar activation energy values for both devices obtained from Arrhenius plots demonstrated that the release mechanism had been consistent; and that the rates of release could be used for long-term prediction. The rate of release reverted to that observed in real-time data, however, upon a reduction of temperature to 38 degrees C. The results demonstrated that temperature was the sole factor involved in modification of the release rate in vitro. The profiles using both systems followed zero-order kinetics after an initial period of burst release.

A variety of factors have been recognized that influence media optimization for drug release studies of implant dosage forms. Of primary importance is selection of a medium that physiologically mimics the milieu at the site of administration (a condition termed ‘biorelevance’). We describe in this paper, the characterization of Hanks’ balanced salts solution, with necessary modification, for application as a ‘biorelevant’ medium for in vitro release studies of a biodegradable, subcutaneous implant of naltrexone. A detailed investigation of changes in pH, osmolality and ultraviolet (UV) spectrum as a function of time and temperature was conducted. Variation in the parameters evaluated was found to be within acceptable limits. Validation of a simple and selective, high performance liquid chromatography (HPLC) assay method for naltrexone was carried out to evaluate stability. The calibration curves were linear from 0.16 to 20.00 μg ml −1 . Imprecision and inaccuracy were less than 2% and no interference was observed from degradation peaks. Stability studies of naltrexone indicated the media should be replaced every 7–8 days for real-time testing. This was applied to an investigation of in vitro drug release. The method has been proven to be suitable for investigation of naltrexone released from the implant.

The objective of this study was to adopt a molecular modeling approach to understand changes in signal intensity due to adduct formation with short-chain alkylamines for two anticancer agents, paclitaxel and docetaxel, during electrospray mass spectrometric analysis. We describe a simple and intuitive modeling procedure using a comparison of hydropathic interaction (HINT) scores to explain differences in responses of amine adducts formed with the two analytes. The responses of paclitaxel and docetaxel were generally enhanced considerably (up to approximately 500% in some instances) on adding the amines. However, for the docetaxel adduct formed with added decylamine in the mobile phase, the response dropped by 32%. A mechanistic understanding for this behavior is proposed, and binding scores calculated from corresponding molecular models were found to be consistent with the trend obtained from mass spectrometric data.

We report a selective, accurate, and reproducible liquid chromatography-tandem mass spectrometric (LC-MS/MS) method that employs solid phase extraction for quantification of ketorolac enantiomers in human plasma. Resolution of R(+)-ketorolac and S(−)-ketorolac was achieved using a Chiral-AGP column and a mobile phase of ammonium formate buffer (10 mM, pH ):acetonitrile (85 : 15, v/v and 70 : 30, v/v) in a gradient time program. S(+)-etodolac was used as the internal standard (IS). Quantification was achieved using a positive electrospray ionization (ESI+) interface under multiple reaction monitoring (MRM) condition. The method was validated over the concentration range of 9.36–1198.69 ng/ml for R(+)-ketorolac and 6.07–776.74 ng/ml for S(−)-ketorolac. Matrix effect was found negligible and the method showed good performances in terms of accuracy (89.6–102.7%) and precision (1.7–6.7%) for both enantiomers. Extraction recoveries of R(+)-ketorolac, S(−)-ketorolac, and S(+)-etodolac were 82.04, 70.94, and 93.90%, respectively. Results of all stability exercises in human plasma were within acceptable limits. The method was successfully applied to a single dose cross over bioequivalence study in healthy human male volunteers. Incurred Sample Reanalysis (ISR) was performed by randomly selecting 10% of total subject samples of the study using Statistical Analysis Software (SAS). Values of 91.1% for R (+)-ketorolac and 83.5% for S(−)-ketorolac indicated good acceptance for ISR.

Background The World Health Organization (WHO) recommends artemisinin combination therapy (ACT) for the treatment of uncomplicated Plasmodium falciparum malaria. The present study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate 37.5 mg and piperaquine phosphate (PQP) 187.5 mg dispersible tablets in paediatric patients aged 6 months to 12 years. Methods Male and female patients aged 6 months to 12 years who were confirmed cases of P. falciparum mono-infection with fever or documented history of fever in the previous 24 h were included. The patients were administered FDC of arterolane maleate and PQP as single daily doses for three consecutive days based on their age. The primary efficacy outcome was proportion of patients with polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) on day 28. Safety was analysed based on adverse events (AE), laboratory abnormalities and abnormalities on electrocardiograph. Results A total of 141 eligible paediatric patients received FDC of arterolane maleate and PQP in a 42-day follow-up study. All the enrolled patients (141) were included in intention to treat (ITT) and safety analyses, and 126 patients were considered in per protocol (PP) population. The PCR-corrected ACPR on day 28 was achieved in all patients (100 %; 95 % CI 97.11–100) included in PP population. The median parasite clearance time (PCT) and fever clearance time (FCT) were 24 h (95 % CI 18.0–24.0) and 10 h (95 % CI 4.0–18.0), respectively. The most frequently reported clinical AE was vomiting. Majority of the AEs were mild to moderate in severity and resolved without sequelae. No patient was discontinued for any QTc (corrected QT interval) prolongation. No deaths or serious AEs were reported during the study. Conclusion The findings from this study showed that FDC of arterolane maleate and PQP effectively cures P. falciparum malaria and attains acceptable level of cure by day 28 in paediatric patients. The efficacy and safety results observed in children warrants further studies on FDC of arterolane maleate and PQP dispersible tablets. Trial Registration: Clinical Trial Registry India: CTRI/2009/091/000531