Comparative bioavailability of a dispersible formulation of diclofenac and finding of double plasma peaks.
Clinical Pharmacology Service, Hospital La Paz, Madrid, Spain.
We carried out a comparative study of the bioavailability of a typical, enteric-coated diclofenac with regard to a new dispersible formulation whose faster dissolution results in an earlier onset of its analgesic effect. This randomized, crossover study was conducted in 12 healthy male volunteers, who received in fasting 100 mg of enteric-coated diclofenac (Dolotrén, FAES) and 100 mg of dispersible diclofenac (Dolotrén Dispersable, FAES), with one-week interval between both. Blood samples were taken at pre-established times during the 24 hours after dosing, and plasma concentrations of diclofenac were determined by HPLC. Possible adverse experiences were monitored with a check-list, and blood and urinalysis were performed for safety assessment. The dispersible formulation showed a relative extent of bioavailability between 78% and 99%(90% CI) for the AUC0-infinity, being the 90% CI for the Cmax 63%-129%. The time to Cmax (Tmax) was significantly shorter with the dispersible than with the enteric-coated formulation (95% CI for the difference = 1.5-4.25 hours) as the T0(lag) or time to measurable plasma concentrations (1.9-4.2 hours, 95% CI). A relevant feature in the study was the finding of a second peak at 2-2.5 hours post-dosing in 7 out of 11 profiles of subjects receiving the dispersible formulation. Both formulations were well tolerated in clinical and laboratory terms. In conclusion, the new dispersible formulation of diclofenac allows absorption to begin more rapidly and plasma peak is reached earlier, a fact that may be relevant to the analgesic treatment of acute pain.
Duke University Medical Center, Durham, North Carolina 27710, USA. firstname.lastname@example.org
Pharmacokinetic comparison of an oral diclofenac potassium liquid-filled soft gelatin capsule with a diclofenac potassium tablet.
AAIPharma, Inc., Wegenerstrasse 13, D-89231, Neu-Ulm, Germany +49 731 98400125 ;+49 731 9840355 ; email@example.com.
Objective: To compare the pharmacokinetic profiles of diclofenac potassium liquid-filled soft gelatin capsules (DPSGC) using patented ProSorb((R)) dispersion technology with an immediate-release, diclofenac potassium 50-mg comparator tablet in two open-label, single-dose, randomized, crossover relative bioavailability studies in healthy volunteers. Methods: In Study 1, volunteers (n = 21) received DPSGC 50 mg or a diclofenac potassium 50-mg comparator tablet in two inpatient study periods. In Study 2 (n = 54), volunteers received DPSGC 25 mg, DPSGC 50 mg, or a diclofenac potassium 50-mg comparator immediate-release tablet in three inpatient study periods. Results: In both studies, DPSGC 50 mg displayed a significantly shorter T(max) and higher C(max) than the 50-mg diclofenac potassium comparator tablet. DPSGC 25 mg (Study 2) produced a shorter T(max)(0.45 h) and an equivalent C(max)(1125 ng/ml) to the 50-mg comparator drug. Plasma diclofenac concentration-time courses for the diclofenac potassium 50-mg comparator tablet showed many low, delayed, or multiple peaks compared with DPSGC treatments. Conclusions: DPSGC 25 mg and 50 mg were more rapidly and consistently absorbed than diclofenac potassium 50-mg comparator tablets. The C(max) of DPSGC 25 mg was equivalent to the 50-mg diclofenac potassium comparator tablet. These characteristics may be beneficial when fast, consistent drug absorption is needed.
Single-dose pharmacokinetic study of rapidly dispersing diclofenac potassium formulations in healthy volunteers.
AAIPharma, Inc., Neu-Ulm, Germany.
OBJECTIVE The clinical utility of diclofenac potassium, a commonly prescribed analgesic that provides mild to moderate pain relief, may be hindered by its delayed, depressed, and/or inconsistent absorption characteristics. A diclofenac potassium formulation using proprietary dispersion technology (ProSorb) was developed to overcome these limitations. The authors evaluated and compared the pharmacokinetics (PK) of 2 investigational diclofenac potassium liquid filled soft gelatin capsule (DPSGC) preparations and one investigational diclofenac liquid formulation, each incorporating the proprietary dispersion technology, to establish bioequivalence and identify a formulation for further clinical study. RESEARCH DESIGN AND METHODS In an open-label, single-dose, three-way crossover, relative bioavailability study, 24 healthy volunteers were randomized to receive each of the 25-mg DPSGC formulations (development processes A and B) and the 1-mL (25-mg) liquid diclofenac formulation (similar to the fill liquid used in the DPSGC products) during three inpatient visits. Each dose was separated by 3 days. Plasma samples were collected at preselected time points through 6 hours post dose. Diclofenac concentrations were determined using a validated HPLC method. Bioequivalence was established within the 80% to 125% acceptance range. Safety and tolerability were monitored throughout. RESULTS Area under the plasma concentration-time curves (AUC(0-)(t)) for the three formulations were between 577 and 585 ng-hr/mL and peak plasma concentrations (C(max)) were between 958 and 1087 ng/mL, with the DPSGC process B group having the highest C(max). The times to C(max)(t(max)) were all below 30 minutes, with the liquid formulation producing the shortest t(max)(15 minutes). Plasma concentration-time course profiles were similar for all three rapidly dispersing diclofenac potassium formulations. One mild adverse event was observed (lingual paresthesia) and one participant discontinued due to an unrelated event (acute tonsillitis). CONCLUSIONS These data show that diclofenac potassium formulations using proprietary dispersion technology are rapidly and consistently absorbed. These characteristics may be beneficial in settings where rapid and consistent drug absorption is desirable. These results may differ in other patient populations such as those experiencing pain or illness.
Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption.
Stefan Willmann, Andrea N Edginton, Marcus Kleine-Besten, Ekarat Jantratid, Kirstin Thelen, Jennifer B Dressman
Bayer Technology Services GmbH, Leverkusen, Germany. firstname.lastname@example.org
OBJECTIVES Inter-individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated. METHODS Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature. Various scenarios incorporating different extents of inter-individual physiological variability were simulated and the simulation results were compared with experimental human study data obtained after oral cimetidine administration of four different tablets with varying release kinetics. KEY FINDINGS The inter-individual variability in effective surface area was the largest contributor to absorption variability. Based on in-vitro dissolution profiles, the mean plasma cimetidine concentration-time profiles as well as the inter-individual variability could be well described for three cimetidine formulations. In the case of the formulation with the slowest dissolution kinetic, model predictions on the basis of the in-vitro dissolution profile underestimated the plasma exposure. CONCLUSIONS The model facilitates predictions of the inter-individual pharmacokinetic variability after oral drug administration for immediate and extended-release formulations of cimetidine, given reasonable in-vitro dissolution kinetics.
Great Ormond Street Hospital for Children, London, UK. Joseph.Standing@farmbio.uu.se
AIMS To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml(-1)) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children. METHODS Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg(-1) dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults. RESULTS A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and V(D)/F were 53.98 l h(-1) 70 kg(-1) and 4.84 l 70 kg(-1) respectively. Allometric size models appeared to predict adequately changes in CL and V(D) with age. Of the simulated doses investigated, 1 mg kg(-1) gave paediatric AUC((0,12 h)) to adult 50 mg AUC((0,12 h)) ratios of 1.00, 1.08 and 1.18 for ages 1-3, 4-6 and 7-12 years respectively. CONCLUSIONS This study has shown 1 mg kg(-1) diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses.
IPAS SA, Via Mastri, Ligornetto, Switzerland. email@example.com
During the last thirteen years, the author has investigated a relevant number of bioequivalence trials, for the approval of generics, which in the Mediterranean area show an increasing business trend. In his activity the author has faced several problems, most of them not considered in operating guidelines, defined "open questions on bioequivalence". They deal with the most appropriate procedures to adopt in case of studies on drugs with long half-lives, of ethics problems, high data dispersion, endogenous substances, presence of active metabolite(s), prevalent metabolites and reversible metabolism, very low plasma concentrations, multiple peak phenomenon, titre differences, polymorphic metabolism, stereogenic atoms. The relevance of a pilot trial, mainly for modified-release formulations, and the problem of frauds are discussed as well. These open questions are discussed in the present review taking into account EU and US FDA guidelines, current literature and personal experience. In most cases suitable approaches are suggested. Appropriate procedures should be planned and defined in the study protocol and extensively discussed in the final report. An appropriate approach to the "open questions" is a requisite to achieve a clearly defined bioequivalence/bioinequi-valence conclusion.
Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses.
Grzegorz Garbacz, Ralph-Steven Wedemeyer, Stefan Nagel, Thomas Giessmann, Hubert Mönnikes, Clive G Wilson, Werner Siegmund, Werner Weitschies
Department of Biopharmaceutics and Pharmaceutical Technology, University of Greifswald, Greifswald, Germany.
The prediction of the in vivo drug release characteristics of modified release oral dosage forms by in vitro dissolution tests is a prerequisite for successful product development. A novel dissolution test apparatus that mimics the physical conditions experienced by an oral formulation during gastrointestinal transit was developed. This included the simulation of pressure forces exerted by gut wall motility, shear forces generated during propagation, and loss of water contact when the dosage form is located in an intestinal air pocket. The new apparatus was evaluated using a diclofenac extended release (ER) tablet. The in vitro dissolution profiles were compared between the novel test apparatus and a conventional dissolution apparatus (USP II). These data were compared with the profiles of plasma concentration versus time that were obtained after the administration of an ER tablet to 24 healthy volunteers under fasting conditions. Multiple peaks were observed in individual plasma concentration-time profiles after the intake of the reference ER tablet. Standard dissolution testing showed typical characteristics of an almost continuous release for this formulation; however, dissolution testing with the novel apparatus suggested that the diclofenac release from the ER tablets would be extremely variable and dependent on the applied stress. The data suggest that the observed multiple peaks of plasma concentration after dosing of the ER diclofenac tablets are most probably caused by sensitivity to physical stress events during gastrointestinal transit.
I.P.A.S. S.A., Clinical Pharmacology Unit, Via Mastri 36, 6853 Ligornetto, Switzerland. firstname.lastname@example.org
Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans.
Julia Kirchheiner, Ingolf Meineke, Nadine Steinbach, Christian Meisel, Ivar Roots, Jürgen Brockmöller
Institute of Clinical Pharmacology, University Medical Centre Charité, Humboldt University, Berlin, Germany. email@example.com
AIMS: The cytochrome P450 enzyme CYP2C9 catalyses the 4'-hydroxylation of the nonsteroidal analgesic drug diclofenac in humans. We studied the influences of the known amino acid variants, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu), on diclofenac pharmacokinetics after a 50-mg oral dose of diclofenac in healthy volunteers. As a surrogate marker of diclofenac activity, the ex vivo formation of prostaglandin E2 and thromboxane B2, which reflects COX-2 and COX-1 activity, was measured. METHODS: Genotyping was performed in 516 healthy volunteers to obtain 20 participants with all allelic combinations of the two CYP2C9 variants Arg144Cys (*2) and Ile359Leu (*3). Diclofenac and 4'-hydroxydiclofenac were quantified in plasma by reversed phase h.p.l.c. after oral intake of 50 mg diclofenac. Concentrations of thromboxane B2 (TxB2) and prostaglandin E2 (PGE2) were measured by immunoassays. RESULTS: There was no evidence of impaired metabolism of oral diclofenac in heterozygous and homozygous carriers of the CYP2C9 alleles *2 and *3 compared with the wild type (mean CL/F (95% CI) 20.5 (11, 30) l h-1 for *1/*1, 29.9 (19, 40) l h-1 for *1/*2, 30.0 (4, 56) l h-1 for *2/*2, 22.6 (12, 33) l h-1 for *1/*3, 23.5 (11, 37) l h-1 for *3/*3 and 37.3 (-15, 89) l h-1 in *2/*3). Furthermore, plasma concentrations of the metabolite 4'-hydroxydiclofenac were not lower in carriers of the CYP2C9 low-activity alleles *2 and *3 compared with carriers of the CYP2C9*1/*1 genotype. Marked diclofenac mediated inhibition of COX-1- and COX-2 activity was detected in all individuals independent of CYP2C9 genotype. CONCLUSIONS: Polymorphisms of the CYP2C9 gene had no discernible effect on the pharmacokinetics and pharmacodynamics of diclofenac. The question of whether enzymes other than CYP2C9 play a major role in diclofenac 4'-hydroxylation in vivo or whether 4'-hydroxylation is not a rate-limiting step in diclofenac elimination in vivo, or whether the effect of the CYP2C9 polymorphisms is substrate-dependent, needs further investigation.
Other papers by authors:
The importance of sample size, log-mean ratios, and intrasubject variability in the acceptance criteria of 108 bioequivalence studies.
Clinical Pharmacology Department, La Paz University Hospital, School of Medicine, Autonomous University of Madrid, Arzobispo Morcillo s/n, Madrid, Spain. firstname.lastname@example.org
PURPOSE Fulfilling bioequivalence criteria with highly variable drugs is difficult. The aim of this study was to compare the importance of sample size, intrasubject variability, and the point estimate of test and reference formulations with regard to meeting bioequivalence (BE) criteria [maximum observed plasma concentration (C(max)) and area under the concentration-time curve (AUC)]. METHODS We compared 137 pairs of data from BE studies with a conventional number of subjects, approximately 31-32 volunteers, developed in the last 10 years. RESULTS The third part of the studies failed to demonstrate BE, in part due to an unacceptable difference between the mean ratios (T/R)(18) but also due to high variability with small differences between formulations (17). Increasing the number of subjects is hard to justify, and expanding the confidence interval (CI) was insufficient for the most highly variable drugs. CONCLUSIONS Therefore, for low-variable drugs, the difference between formulations was the cornerstone of the fulfillment of BE criteria, but for highly variable drugs, the intrasubject coefficient of variability (ICV) was decisive. Our proposal is that for highly variable drugs that fall outside BE 90% CI limits could result in BE in the absence of formulation effect and maximal differences between formulations below 20%.
Centro de Farmacologia Clinica, Departamento de Farmacologia y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
OBJECTIVE Gender is usually considered to be one of the factors influencing disposition of drugs, but the evidence available is sometimes conflicting and information for a large number of frequently used drugs is lacking. An evaluation of sex differences in the disposition ofmetronidazole was carried out during a bioequivalence study. SUBJECTS AND METHODS Twenty-four volunteers (12 males and 12 females) were included in an open, single-dose, two-sequence, crossover randomized trial with a one-week washout interval. All volunteers received in each period, a single 250 mg dose of one of the two study formulations of metronidazole. Venous blood samples were collected immediately before and at 15 time points in an 48-hour interval after drug administration; metronidazole concentrations were determined by HPLC. Non-compartmental pharmacokinetic analysis was performed and log-transformed AUC(0-infinity) and Cmax were tested for bioequivalence. Sex differences were evaluated by means of a 4-factor (sex, sequence, treatment and period) ANOVA. RESULTS The studied formulations were found bioequivalent according to international standards: average 90% confidence interval for AUC(0-infinity) was 98 to 104 and for Cmax 93 to 115. After correction for the administered dose/kg, AUC was about 12% lower in females than in males (p = 0.0388) and, therefore, a higher calculated oral Cl/kg was found in females. Apparent distribution volume, after correction for weight, was significantly higher in males (p = 0.0019). Metronidazole half-life and MRT were shorter in females than in males (p - 0.0014 and p = 0.0002, respectively). CONCLUSIONS Data obtained in this study suggest that metronidazole clearance in females is about 12% higher than in males although these differences are probably of no clinical relevance.
Methodological pitfalls in bioequivalence studies: sample size, between-subject and within-subject variability, single or multiple dose studies and metabolite determination.
Department of Pharmacology and Therapeutics, Faculty of Medicine, Universidad Autónoma de Madrid, Spain.
Hospital Universitario La Paz, Department of Pharmacology and Therapeutics, Faculty of Medicine, Universidad Autonóma de Madrid, Spain.
A bioequivalence study of two oral formulations of 300 mg ranitidine was carried out in 16 healthy volunteers (8 men and 8 women), and the pharmacokinetics in both sexes were compared. There was bioequivalence of both formulations. The terminal half-life of ranitidine was 7% shorter and the oral apparent clearance 10.5% higher in women (1.44 L/h/kg) than in men (1.29 L/h/kg), although this difference did not reach statistical significance. No differences were observed in maximum concentration (Cmax) or the time of its occurrence (tmax). Sex, age, and weight did not correlate significantly with oral clearance. These results suggest that there are no sex differences in the pharmacokinetics of ranitidine, or that any differences would not be of clinical relevance. It also should be emphasized that bioequivalence trials also can be used to study other pharmacokinetic or pharmacodynamic characteristics of drugs without damaging the main endpoint of the study.
A Pharmacovigilance Program From Laboratory Signals for the Detection and Reporting of Serious Adverse Drug Reactions in Hospitalized Patients.
Clinical Pharmacology Service, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
The detection and reporting of serious adverse drug reactions (SADRs) have become important components of monitoring and evaluation activities performed in hospitals. We present the implementation of a prospective pharmacovigilance program based on automatic laboratory signals (ALSs) at a hospital. We also report the general findings after the first year of operation of the program, which involved ALSs that indicate various SADRs: agranulocytosis, aplastic anemia, liver injury, thrombocytopenia, hyponatremia, and rhabdomyolysis. The number of hospitalizations during the year was 54,525, and 1,732 patients experienced at least one ALS. The review of electronic medical records (EMRs) showed that no alternative cause (i.e., no non-SADR explanation) for the ALS was identified in 520 (30%) of the patients. After the individual ALS-patient evaluation, a total of 110 SADRs (6.35% of those identified after reviewing EMRs and 21.15% of those requiring individual patient evaluations) were identified. In other words, in order to identify a single SADR, we had to review the electronic records of approximately 16 patients and personally visit 5 patients.
Clinical Trials Unit, School of Medicine, Universidad Autónoma Madrid, Spain. email@example.com
OBJECTIVE To test for the bioequivalence of two allopurinol 300 mg tablet formulations (generic allopurinol (Normon) and Zyloric tablets). METHOD A single dose study was carried out in 24 healthy volunteers with a two-sequence, crossover block-randomized design. Blood samples were taken prior to each administration and at 19 points within 72 h after the dose. Plasma concentrations of allopurinol and oxypurinol were determined by HPLC. The pharmacokinetic parameters Cmax and Tmax were obtained directly from plasma allopurinol and oxypurinol concentrations. ke was estimated by log-linear regression and AUC was calculated by the linear trapezoidal rule for both allopurinol and oxypurinol. The pharmacokinetic parameters AUC and Cmax were tested for equivalence after log-transformation of data. Differences of Tmax were evaluated by a non-parametric test. The 90% standard confidence intervals of the mean values for the test/reference ratios were for AUC and for Cmax, within the acceptable bioequivalence limits of 0.80-1.25 for both allopurinol and oxypurinol. CONCLUSION The two formulations are bioequivalent and therefore interchangeable.
Servicio de Farmacologi+58a Clínica, Hospital La Paz, Madrid, Spain.
OBJECTIVE: To report nimodipine concentrations in breast milk and cerebrospinal fluid (CSF) of a lactating woman who was given the drug to prevent a vascular spasm secondary to angiographic examination. METHODS: A 36-year-old woman received a total dose of nimodipine 46 mg iv over 24 hours. She extracted milk when she noted mammary tightness, and blood samples were taken simultaneously by venipuncture in the arm contralateral to that of the nimodipine infusion. A CSF sample also was taken in a diagnostic lumbar puncture. RESULTS: Nimodipine concentration in milk was much lower than that in serum, with a milk/serum ratio of 0.06-0.15. The CSF/serum ratio was 0.01. We estimate that the infant would have received between 0.008% and 0.092% of the weight-adjusted dose that was administered to the mother if the baby had been nursed. CONCLUSIONS: Nimodipine is transferred to human milk in a lower proportion than are other calcium-channel blockers. These results suggest that treating the mother with nimodipine would entail no risk to the nursing infant.
Measurement of tobramycin in bronchoalveolar lavage fluid by a modified fluorescence polarization immunoassay.
Department of Clinical Pharmacology, Hospital La Paz, Paseo de la Castellana, Madrid, Spain.
Coumarin anticoagulants must be strictly monitored because of their narrow therapeutic index and their potential interactions with other drugs. The high probability of interactions can be explained by two pharmacokinetic properties of coumarins: high binding to plasma albumin (99%), being displaced by other drugs with greater affinity to this protein, and metabolism by liver microsomal enzymes (cytochrome P450), which can be induced or inhibited by other compounds (Shinn & Shrewsbury 1985). A case is reported of a clinically relevant drug interaction of phenytoin and acenocoumarol, possibly potentiated by concomitant treatment with paroxetine, leading to a retroperitoneal haematoma.
Cefminox: correlation between in-vitro susceptibility and pharmacokinetics and serum bactericidal activity in healthy volunteers.
Medical Department, SmithKline Beecham Pharmaceuticals, Madrid, Spain.
Plasma concentration of cefminox and serum bactericidal activity against four ATCC strains (Escherichia coli 25992, Klebsiella pneumoniae 13833, Serratia marcescens 8100 and Bacteroides fragilis 25285), were determined over a 24 h period after administration of cefminox 1 and 2 g to six healthy volunteers in a randomized, cross-over, single blind study. The increase observed in the area under the bactericidal curve (AUBC) with the 2 g dose was at least 3.5 times that seen with the 1 g dose for all four test strains and was larger than predicted by the corresponding increase (1.84 times) in the area under the serum concentration versus time curve (AUC); a correlation (r = 0.88, P = 0.0001) between the cefminox concentration and the serum bactericidal titres was, however, observed with all four strains tested. The MBC6h showed a better association with the serum bactericidal titre (P < 0.01) than did the MIC or MBC.
Latest similar papers:
Diclofenac potassium 12.5 mg liquid capsules: earlier and higher exposure to diclofenac. A fasted, single-dose, comparative, bioavailability study versus diclofenac potassium 12.5 mg tablets.
Clinical Pharmacology Consultancy, Ornex, France, and Novartis Consumer Health, Parsippany, NJ, USA.
Background: A fast-release liquid capsule formulation of low-dose diclofenac- K is available, which aims to improve patient convenience and compliance. The new formulation is a soft gelatin capsule designed to facilitate faster absorption of diclofenac versus the tablet form with anticipated overall comparable bioavailability. Objectives: To compare the bioavailability of diclofenac-K 2 × 12.5 mg liquid capsules versus diclofenac- K 2 × 12.5 mg tablets. Design: This randomized, open-label crossover, single-dose study was conducted in 42 healthy subjects (mean age 23.5 years) given diclofenac-K 2 × 12.5 mg liquid capsules or tablets over two 1-day treatment periods separated by a 14-day washout period. Results: Diclofenac-K 12.5 mg liquid capsules were equivalent to the tablets in terms of total systemic exposure (mean AUCt ratio = 112%, 2-sided 90% CI =(107%, 116%)). However, the mean Cmax for the liquid capsules (1,090 ng/ml) was almost double that of the tablets (583 ng/ml)(mean Cmax ratio = 196%, 2-sided 90% CI =(169%, 227%)). Median tmax was ~ 10 min faster with the liquid capsules (0.42 h) compared with the tablets (0.58 h) and AUCtmax ref for the liquid capsules (294 ng×h/ml) was almost double the value for the tablets (158 ng×h/ml). This indicated a faster absorption of diclofenac from the liquid capsules compared to the tablet. There were no differences between the two treatments regarding safety, and both drugs were well tolerated. Conclusions: This study demonstrated equivalent overall systemic exposure to diclofenac but a faster absorption and substantially greater early exposure to diclofenac from diclofenac-K liquid capsules compared with the tablets, which may lead to a more rapid analgesic effect in patients.
Pharmazie. 2009 Oct ;64 (10):648-52 19947166
Comparative in vitro and in vivo evaluations of oral sustained-release formulations of diclofenac sodium in beagle dogs.
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brasil.
PURPOSE: Two sustained release formulations (microspheres and Voltaren SR75) were evaluated for their drug release characteristics in dissolution (in vitro study) and after oral administration to beagle dogs (in vivo study) by HPLC. METHODS: The dissolution study was carried out according to the paddle method and the pharmacokinetic study was conducted using HPLC analysis in a crossover design in six female beagle dogs after oral administration of 75 mg diclofenac sodium (DFS). RESULTS: The dissolution profiles showed 45% release for Voltaren SR75 and around 95% for the microspheres. Oral administration of DFS resulted in AUC(0-24) and Cmax values of 20.4 microg h/mL and 3.04 microg/mL for microspheres and 33.5 microg h/mL and 5.59 microg/mL for Voltaren, respectively. The Tmax was 3.0 h for both formulations. A significant difference in AUC(0-24) and Cmax was observed for DFS absorption from microspheres and Voltaren. CONCLUSIONS: The results from the dissolution assay demonstrated the faster release of diclofenac sodium from microspheres. The bioavailability of DFS in microspheres was about 61% that of Voltaren, for the parameters AUC and Cmax, and they are therefore not bioequivalent to Voltaren in relation to the extent of absorption. However, the rate of drug absorption (Tmax) was similar for the two formulations.
Pharmacokinetics and comparative bioavailability study of two clarithromycin suspensions following administration of a single oral dose to healthy volunteers.
Department of Pharmaceutics, Tabriz University of Medical Sciences, Tabriz, Iran.
The aim of the present study was to compare the pharmacokinetics and bioavailability of two commercial brands of clarithromycin (CAS 81103-11-9) suspensions in healthy male Iranian volunteers. In an open label, single-dose, randomized study with a crossover design an equivalent 500-mg clarithromycin suspension was given orally to each of 24 subjects as a single dose on two treatment days. The treatment periods were separated by a one-week washout period. Blood samples were drawn at different time points and the separated plasma was kept frozen at -20 degrees C for subsequent analysis. The plasma concentrations of the drug were analyzed by a rapid and sensitive HPLC method with UV detection. Mean maximum serum concentrations of 2256.5 +/- 590.1 ng/mL and 2840.2 +/- 717.5 ng/mL were obtained for the test and reference formulation, respectively. The AUC(0-infinity) of clarithromycin was on average 45008.7 +/- 10989.9 ng x h/mL for the test and 45221.3 +/- 2155.7 ng x h/mL for the reference formulation. The calculated 90% confidence intervals for the ratio of Cmax (81.98-94.26%), AUC(0)(t)(91.6-109.15%) and AUC(0)(infinity)(93.08-110.85%) values for the test and reference products were all within the 85-120% interval proposed by the FDA and EMEA. Therefore the clarithromycin suspension of the test and reference formulations are bioequivalent in terms of rate and extent of absorption.
Comparative bioavailability of two dexamethasone tablet formulations in Indonesian healthy volunteers.
Department of Pharmacy, Faculty of Mathematic and Science, University of Indonesia, Depok, Indonesia.
AIM To compare the bioavailability of two dexamethasone (CAS 50-02-2) tablet formulations -- 4 mg Dexmethsone tablets as test formulation and 4 mg tablets of the originator product as reference formulation. METHODS The study was conducted according to an open-label, randomized two-way crossover design with a one-week washout period. Twenty-four volunteers received a single dose of two tablets of the two different dexamethasone formulations. Blood samples for pharmacokinetic profiling were taken up to 24 h after drug administration in fasting condition. Plasma concentrations of dexamethasone were determined with a validated HPLC method using an ultraviolet detector. Pharmacokinetic parameters were calculated from observed plasma concentration-time profiles. RESULT The mean AUC0-t, AUC0-infinity, and Cmax were 501.61 ng x h/ml, 518.88 ng x h/ ml and 98.02 ng/ml, respectively for the test formulation and 507.10 ng x h/ml, 525.20 ng x h/ml and 97.82 ng/ml, respectively, for the reference formulation. The median Tmax, for both formulations was 0.75 h. Plasma elimination half-lives (t1/2) were 3.44 h (test) and 3.38 h (reference). The point estimates and 90% confidence intervals (CI) for AUC0-t, AUC0-infinity and Cmax were 98.92%(94.62-103.41%), 98.80%(94.51-103.28%) and 100.20%(91.43-109.81%), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration guidelines. CONCLUSION These results indicate that the two formulations of dexamethasone are bioequivalent and thus may be prescribed interchangeably.
Pharmacokinetics and bioequivalence of 20 mg omeprazole capsule in 24 healthy Korean male volunteers.
Department of Surgery, Hanyang University, Seoul, South Korea.
OBJECTIVE A randomized, two-way, crossover bioequivalence study in 24 healthy Korean male volunteers was conducted to compare bioequivalence of two brands of 20 mg omeprazole capsules, Hutex omeprazole (Hutex Pharm Co. Korea) as a test and Yuhan Losec (Yuhan Co. Ltd., Korea) as a reference drug. VOLUNTEERS AND METHODS Subjects were administered single dosage of 1 capsule of 20 mg of each formulation with 240 ml of water after 10 hs overnight fasting on 2 treatment days separated by one-week washout period. After dosing, serial blood sampling was held during 9 hs. Plasma was analyzed for omeprazole by a validated HPLC method with ultraviolet detection in the range of 10 approximately 1,000 ng/ml with the lowest limit of quantification of 10 ng/ml. RESULTS Several pharmacokinetic (PK) parameters were determined from the plasma samples, and data from reference and test formulations in the plasma were represented such as AUC0-t (1,223.3 vs 1,284.3 ng x h/ml),[formula in text](1,311.1 vs 1,410.0 ng x h/ml), Cmax (598.7 vs 598.1 ng/ml), tmax (1.9 vs 1.9 h), t1/2 (1.3 vs 1.4 h) and Ke (0.67 vs 0.67 h-1), respectively. AUC0-t,[formula in text] and Cmax were tested for bioequivalence after log-transformation of plasma data. PK parameters with 90% confidence interval (CI) of test/reference ratio based on ANOVA analysis were 0.961 approximately 1.135 for AUC0-t, 0.968 approximately 1.144 for [formula in text] and 0.951 approximately 1.117 for Cmax. CONCLUSIONS PK parameters with 90% CI were within the bioequivalence range of 80 - 125% of FDA statistical limit. Therefore, both omeprazole formulations were bioequivalent during fasting state in these healthy Korean male volunteers.
Bioequivalence study of two capsule formulations containing diacerein 50 mg in healthy human subjects.
Uday S Chakrabarty, Uttam Mandal, Uttam Bhaumik, Bappaditya Chatterjee, Animesh Ghosh, Anirban Bose, Tapan K Pal
Bioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
This study presents the results of a two-way, two-period, two-treatment crossover investigation in 12 healthy Indian male subjects to assess the bioequivalence of two oral formulations containing 50 mg of diacerein (CAS 13739-02-1). Both formulations were administered orally as a single dose separated by a one-week washout period. The content of diacerein in plasma was determined by a validated HPLC method with UV detection. The formulations were compared using the parameters area under the plasma concentration-time curve (AUC(0-t)), area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)), peak plasma concentration (Cmax), and time to reach peak plasma concentration (tmax). The results of this study indicated that there were no statistically significant differences between the logarithmically transformed AUC(0-infinity) and Cmax, values of the two preparations. The 90% confidence interval for the ratio of the logarithmically transformed AUC(0-t), AUC(0-infinity) and Cmax were within the bioequivalence limit of 0.8-1.25 and the relative bioavailability of the test formulation was 96.63% of that of the reference formulation. Thus, these findings clearly indicate that the two formulations are bioequivalent in terms of rate and extent of drug absorption.
Uttam Mandal, Ayan Das, Sangita Agarwal, Uday Chakraborty, Utpal Nandi, Tapas Kumar Chattaraj, Tapan Kumar Pal
Bioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
OBJECTIVE This study presents the results of two-period, two-treatment crossover investigations on 24 healthy Indian male subjects to assess the bioequivalence of two oral formulations containing 400 mg of dexibuprofen (CAS 51146-56-6). An attempt was also made to study the pharmacokinetics of dexibuprofen in the local population of Indian origin. METHOD Both of the formulations were administered orally as a single dose separated by a one-week washout period. The concentration of dexibuprofen in plasma was determined by a validated HPLC method with UV detection using carbamazepine as internal standard. The formulations were compared using the parameters area under the plasma concentration-time curve (AUC(0-t)), area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)), peak plasma concentration (C(max)), and time to reach peak plasma concentration (t(max)). RESULTS The results of this investigation indicated that there were no statistically significant differences between the logarithmically transformed AUC(0-infinity), and C(max) values of the two preparations. The 90% confidence interval for the ratio of the logarithmically transformed AUC(0-t), AUC(0-infinity) and C(max) were within the bioequivalence limit of 0.8-1.25 and the relative bioavailability of the test formulation was 99.04% of that of reference formulation. CONCLUSION Thus, these findings clearly indicate that the two formulations are bioequivalent in terms of rate and extent of drug absorption. Both preparations were well tolerated with no adverse reactions observed throughout the study.
Comparative bioavailability study of two cefixime formulations administered orally in healthy male volunteers.
School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. Pzakeri@tbzmed.ac.ir
The bioavailability of a new cefixime ((6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino) acetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo-[4,2,0]-oct-2-ene-2-carboxylic acid, CAS 79350-37-1) tablet preparation (Loprax) was compared with that of a reference preparation of the drug in 24 healthy male volunteers. The trial was designed as an open, randomized, single-blind, two-sequence, two-period crossover study. Under fasting conditions, each subject received a single oral dose of 400 mg cefixime tablet as a test or reference formulation on 2 treatment days. The treatment periods were separated by a one-week washout period. The plasma concentrations of the drug were analyzed by a rapid and sensitive HPLC method with UV detection. The pharmacokinetic parameters included AUC0-24h, AUC0-infinity, Cmax, t1/2, and Ke. The mean AUC0-infinity of cefixime was 45008.7 +/- 10989.9 and 45221.3 +/- 2155.7 n x h/ml for the test and reference formulation, respectively. The maximum plasma concentration (Cmax) of cefixime was on average 4746.9 +/- 1284 ng/ml for the test and 4726.3 +/- 1206.9 ng/ml for the reference product. No statistical differences were observed for Cmax and the area under the plasma concentration-time curve for test and reference tablets. The calculated 90% confidence intervals based on the ANOVA analysis for the mean test/reference ratios of Cmax, AUC0-infinity and AUC0-24h of cefixime were in the bioequivalence range (94%-112%). Therefore, the two formulations were considered to be bioequivalent.
Clinical Pharmacy, College of Pharmacy, Seoul National University, South Korea.
A bioequivalence study of diclofenac injection (test formulation (diclofenac potassium): HANA, reference formulation (diclofenac sodium): Shinpoong) was conducted in 18 healthy male Korean volunteers who received each medicine at a dose of 75 mg in a 2 x 2 crossover study. There was a one-week washout period between the doses. Plasma concentrations of diclofenac were monitored by high-performance liquid chromatography over a period of 24 hours after the i.m. injection. AUC0-24 (the area under the plasma concentration-time curve from time 0-24 hours) was calculated by the linear-log trapezoidal method. Cmax (maximum plasma drug concentration) and tmax (time to reach Cmax) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC0-24 and Cmax, and non-transformed tmax. There were no significant differences between the medications in AUC0-24 and Cmax. The point estimates and 90% confidence intervals for AUC0-24 (parametric) and Cmax (parametric) were 0.973 (0.8971 to 1.0557) and 0.993 (0.9452-1.0451), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value for tmax was 0.75 (0.00 to 1.00). Moreover, the modified Pitman-Morgan's adjusted F-test indicated that the bioavailabilities of diclofenac in the two medications were comparable regarding intra- and interindividual variability. Therefore, these results indicate that the two medications of diclofenac are bioequivalent and, thus, may be prescribed interchangeably.
Comparative bioavailability study of cefixime (equivalent to 100 mg/5 ml) suspension (Winex vs Suprax) in healthy male volunteers.
Y A Asiri, M S Al-Said, K I Al-Khamis, E M Niazy, Y M El-Sayed, K A Al-Rashood, M J Al-Yamani, I A Alsarra, S A Al-Balla
Department of Clinical Pharmacy, College of Pharmacy, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia. firstname.lastname@example.org
This investigation was carried out to evaluate the bioavailability of a new suspension formulation of cefixime (100 mg/5 ml), Winex, relative to the reference product, Suprax (100 mg/5 ml) suspension. The bio-availability study was carried out in 24 healthy male volunteers who received a single oral dose (200 mg) of the test (A) and the reference (B) products on 2 treatment days after an overnight fast of at least 10 hours. The treatment periods were separated by a one-week washout period. A randomized, balanced two-way crossover design was used. After dosing, serial blood samples were collected over a period of 16 hours. Plasma concentrations of cefixime were analyzed using a sensitive high-performance liquid chromatographic assay. The pharmacokinetic parameters for cefixime were determined using standard non-compartmental method. The parameters AUC(0-t), AUC(0-infinity), Cmax, Kel, t1/2 and Cmax/AUC(0-infinity) were analyzed statistically using raw and log-transformed data. The time to maximum concentration (tmax) was analyzed using raw data. The parametric 90% confidence intervals of the mean values of the pnfinity harmacokinetic parameters: AUC(0-t), AUC(0-infinity) Cmax, and Cmax/AUC(0-infinity) were within the range 80 - 125% which is acceptable for bioequivalence (using log-transformed data). The calculated 90% confidence intervals based on the ANOVA analysis for the mean test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax, and Cmax/AUC(0-infinity) were 88.93 - 107.10%, 89.09 - 107.11%, 89.63 - 108.58% and 96.85 - 105.29%, respectively. The test formulation was found bioequivalent to the reference formulation with regard to AUC(0-t), AUC(0-infinity), and Cmax using the Schuirmann's two one-sided t-tests. Therefore, the two formulations were considered to be bioequivalent.