Identical pattern of highly variable absorption of Clavulanic acid from four different oral formulations of Coamoxiclav in healthy subjects.


×
Rating : Rate It:
 
Embed :   
Post a comment
    Post Comment on Twitter
Comments:  



  Notes
 
 
Slide 1 : Identical pattern of highly variable absorption of Clavulanic acid from four different oral formulations of Co-amoxiclav in healthy subjects. Tom B.Vree 1*, Erik Dammers 2, and Peter S. Exler 3 1 Institute for Anaesthesiology, University Medical Centre Sint Radboud, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands DADA Consultancy, Dennenstraat 109, 6543 JR Nijmegen, The Netherlands, Disphar International, Winkelskamp 6, 7522 PZ Hengelo (Gld), The Netherlands
Slide 2 : Abstract The aims of this investigation were to calculate the pharmacokinetic parameters of amoxicillin and clavulanic acid, and to identify parameters that may affect the observed differences in absorption of both drugs. This was based on data obtained from plasma concentration-time curves from four different open, randomised, two-treatment, two period, two-sequence, crossover phase-I bioequivalence studies, with the following co-amoxiclav formulations: tablets 250/125 mg, 500/125 mg and 875/125 mg, or 10 mL of an oral suspension 250/62.5 mg per 5 mL. Data from 144 subjects and 288 drug administrations were available for evaluation. After a 125 mg clavulanic acid dose (administered as potassium clavulanate) for all four different formulations, the clavulanic acid AUCt data ranged from 1.5 to 8 mg.h/L, varying by a factor of 5. The absorption of clavulanic acid was not related to the absorption of amoxicillin, or demographic factors, and we were unable to identify the reasons for the large variability seen in the absorption of clavulanic acid. We conclude that the absorption of clavulanic acid, after oral administration, is highly variable and may vary over a five fold range between patients.
Slide 3 : Variation in absorption of co-amoxiclav The standard dose of co-amoxiclav (amoxicillin/clavulanic acid) for adults with lower respiratory tract infection has, for many years, been 500/125 mg orally t.i.d. However, it is generally recognised that patient compliance improves with a reduced dosing frequency and co-amoxiclav has now been licensed for use at a dose of 875/125 mg orally b.i.d. The efficacy of this twice daily dosage regimen being supported by pharmacokinetic, microbiological and clinical data. The dosage ratio of amoxicillin/clavulanic acid in oral co-amoxiclav formulations has changed over the period the combination has been in use from initially 2:1, to 4:1, and more recently to 7:1. This reduction in the amoxicillin-clavulanic acid ratio was aimed to reduce the side effects of clavulanic acid in 2:1 ratio. As the efficacy of these combinations appear similar, this would suggest that the amount of clavulanic acid necessary to inhibit bacterial ?-lactamases may vary substantially. The aims of this investigation were to calculate the pharmacokinetic parameters, and to identify parameters that may influence the observed differences in absorption of clavulanic acid and amoxicillin following administration of four different dosage formulations.
Slide 4 : Variation in absorption of co-amoxiclav Materials and methods Experimental Design The evaluation was based on the data from plasma concentration-time curves obtained from four different open, randomised, two-treatment, two period, two-sequence, crossover phase-I bioequivalence studies each involving 36 male subjects treated with any of the following co-amoxiclav formulations given as single dose: tablets 250/125 mg, 500/125 mg and 875/125 mg, or 10 mL of an oral suspension 250/62.5 mg per 5 mL. Thus data from 144 subjects and 288 drug administrations could be evaluated. Treatments were separated by a 1-week washout period. Each subject participated in one study only.
Slide 5 : Variation in absorption of co-amoxiclav Plasma amoxicillin and clavulanic acid concentrations were determined using validated methods using LC/MS/MS analysis (Gesellschaft für Therapeutische Forschung (GTF, Nürnberg-Heroldsberg, Germany). Lower limit of quantification (LOQ) values were respectively 20.0 ng/mL and 50.0 ng/mL . Mass spectrometric positive ion detection (selected Reaction Monitoring SRM) was achieved by precursor [M+H]+?product ion for amoxicillin m/z 366 ? m/z 208 and for the internal standard m/z 350 ? m/z 160. For clavulanic acid the precursor [M+H]+?product ions were m/z 198 ? m/z 108 and for the internal standard m/z 232 ? m/z 140.
Slide 6 : Figure 1Mean (±s.d.) plasma concentration-time curves of amoxicillin (Amoxi) and clavulanic acid (Clav) after an oral dose of 500/125 mg co-amoxiclav tablet to 36 healthy volunteers (formulation A2).
Slide 7 : Figure 2Individual AUCt 's of amoxicillin plotted versus the corresponding AUCt 's of clavulanic acid for both the A2 formulation (open dots) and the B2 formulation (solid dots). It can be noticed that there is a 5 fold variation in the AUCt 's of Clavulanic acid, while that for the amoxicillin is less. Dotted lines represent the 95% confidence interval.
Slide 8 : Figure 3Mean AUCt 's of amoxicillin plotted versus the AUCt 's of clavulanic acid for the oral administration (A/B formulations) of Amoxi-Clav suspension (solid dots) and Amox-Clav oral tablets 500/125 mg (open dots), oral tablets 875/125 mg (open triangles) and oral tablets 250/125 mg (solid triangles). There is a 5 fold variation in the AUCt 's of Clavulanic acid, while that for amoxicillin is nearly constant and nearly dose proportional. Dotted lines represent the 95% confidence interval.)
Slide 9 : Pharmacokinetic parameters of amoxicillin (mean ±SD). Table I Formulation Dose t 1/2 tmax Cmax AUC AUC range mg h h mg/L mg.h/L A1 250 1.43±0.18 1.14±0.41 4.33±1.07 10.1±1.59 (7.26-14.3) A2 500 1.46±0.16 1.46±0.46 6.81±1.94 18.3±3.55 (8.63-24.1) A3 500 1.54±0.17 1.14±0.37 7.59±1.45 19.2±3.29 (10.9-25.4) A4 875 1.76±0.36 2.02±0.96 9.93±3.14 32.8±7.05 (19.4-48.7) B1 250 1.40±0.18 1.39±0.60 3.88±1.15 9.87±1.68 (6.31-13.7) B2 500 1.48±0.23 1.70±0.70 6.34±1.63 18.3±3.43 (5.15-22.9) B3 500 1.51±0.17 1.14±0.31 7.19±1.29 18.9±2.83 (10.9-24.1) B4 875 1.71±0.34 2.04±1.01 9.77±3.17 32.9±8.15 (14.3-47.8) A = test formulation B = reference formulation
Slide 10 : Pharmacokinetic parameters of clavulanic acid (mean±SD). Table II Formulation Dose t 1/2 tmax Cmax AUC AUC range mg h h mg/L mg.h/L A1 125 1.00±0.16 1.24±0.48 2.63±0.90 5.49±1.48 (2.32-8.25) A2 125 1.08±0.16 1.17±0.22 2.32±0.83 5.13±1.80 (1.24-8.32) A3 125 1.19±0.29 1.10±0.40 2.99±0.74 6.74±1.43 (3.68-9.74) A4 125 0.98±0.11 1.18±0.30 2.68±0.96 5.85±2.15 (1.88-9.93) B1 125 1.01±0.14 1.29±0.59 2.31±1.09 4.79±1.83 (1.62-8.79) B2 125 1.09±0.17 1.24±0.31 2.03±0.88 4.28±1.76 (1.32-7.90) B3 125 1.15±0.18 1.09±0.37 2.80±0.67 6.28±1.26 (2.79±8.69) B4 125 0.97±0.08 1.20±0.44 2.67±1.12 5.81±2.25 (0.84-9.16) A = test formulation B = reference formulation
Slide 11 : Conclusion In this study we have been able to show that four different co-amoxiclav formulations each gave a 5-fold variation in the absorption, or in the AUCt value, of clavulanic acid. This would suggest that some patients may only achieve a 20:1 amoxicillin-clavulanic acid AUCt ratio after the oral dose of 500/125 mg co-amoxiclav yet they still appear to benefit from the presence of clavulanic acid (or therapy failures with oral co-amoxiclav have not been reported). Even with the 875/125 mg dosage, the individual AUCt ratio may vary up to 35:1. In conclusion, the observed variations in the AUCt ratio of amoxicillin/clavulanic acid (2-10:1) highlight the variable nature of clavulanic acid absorption. However, clinical data would suggest that such variability does not affect the efficacy of co-amoxiclav and that the current dosage ratio of 4:1 may be considered as conservative.
Slide 12 : Reference
Slide 13 : reference For a PDF copy and full details of the study: Contact T.Vree@anes.umcn.nl Erikdammers@dada.nl

 


Related 

 
Free Powerpoint Templates
Add as Friend t.vree@anes.umcn.nl     5 Years ago.
454 Views, 0 favourite
PowerPoint Presentation on Identical pattern of highly variable absorption of Clavulanic acid from    more
More By User

Flag as inappropriate





Browse | Powerpoint Templates | Tags | Contact | About Us | Privacy | FAQ | Blog

© Slideworld