Pharmacokinetics of amoxicillin / clavulanate

  • Amoxicillin and clavulanate is well absorbed from the gastrointestinal tract, the maximum plasma concentration observed after 60-90 minutes, and 40-120 minutes, respectively, after oral administration of the separate funds. The combination of both agents does not affect their pharmacokinetics. The average maximum concentration after a single dose of amoxicillin / clavulanate 250/125 mg in a dose of 4.2 mg / l for amoxicillin and 2.6 mg / L of clavulanic acid. The average maximum concentration of amoxicillin after a single dose of 500/125 and 875/125 mg amoxicillin / clavulanate is 7.2 and 11.6 mg / L, respectively. For amoxicillin in the range of 250-2000 mg characteristic nearly linear relationship between dose and effect.
  • Penetration of amoxicillin secret airway greater than, for example, ampicillin, despite the same maximum plasma concentration. This is evidenced by a significantly higher content of amoxicillin in sputum compared with ampicillin in patients both drugs are administered intravenously. Studies amoxicillin / clavulanate indicate that content in sputum clavulanate comparable to that of amoxicillin, given the relative difference between the two doses.

The half-life of amoxicillin and clavulanate is the same:

  • when administered to healthy volunteers, he is 63 minutes for a dose of 500 mg amoxicillin and 60 minutes for a dose of 125 mg clavulanate. Amoxicillin is excreted in the urine almost unchanged: 6 hours after oral administration of 50-85% of the administered dose is detected in urine. Clavulanate, in contrast, well metabolised and the formed substance derived light, and in the feces and urine. After 6 h after oral administration of 20-60% of the dose of clavulanate in unchanged form excreted in the urine.

Pharmacodynamic study for the optimization of doses of amoxicillin / clavulanate:

    • The main purpose of the selection of a particular antimicrobial therapy for infections of the respiratory tract is the maximum eradication of bacteria. Bacteriological eradication is important not only to achieve clinical effect, but also reduce the potential for the formation and propagation resistance [50-52]. Bacteriological efficacy of antimicrobial agents depends on the PK / PD properties. In β-lactam agents bacteriological efficacy is highly dependent on the time during which the free drug concentration in the blood plasma exceeds the MIC for the pathogen (T> MIC).
    • In order to exercise the utmost amoxicillin bacteriological efficacy against major respiratory pathogen in modeling S.pneumoniae infections in animals, it is necessary that T> MIC was 30-40% of the interval between doses of the agents. It is believed that the maximum required eradication H.influenzae same value PK / PD index. When using β-lactams, especially those who have a relationship between dose and effect is linear with increasing BMD pathogens can be overcome by increasing the single dose, dosing frequency and / or improve the pharmacokinetics, which will help to maintain an adequate level of T> MIC.
    • In contrast, macrolides limitations associated with pharmacokinetics and safety, do not allow to modify or increase the dose to such an extent as to cope with the macrolide-resistant or procure S.pneumoniae bacteriological efficacy in vivo against H.influenzae. Bacteriological efficacy depends on the concentration of fluoroquinolones.

Consequently, in order to increase efficiency, it is necessary to increase the total amount of drug.

  • Fluoroquinolones have relatively narrow safety window, which limits those doses which can be administered, however, most tools of this group are not able to maintain an acceptable safety profile / tolerability and overcome resistance in S.rneumoniae quinolone. Thus, modification of the PK / PD needed to overcome the resistance to execute at macrolides and fluoroquinolones practically impossible that requires the development of new, more active molecules.

Figure 1 shows the equilibrium mean T> MIC of various forms of amoxicillin / clavulanate for different pathogens BMD. Based on PK / PD parameters, amoxicillin / clavulanate in a dose of 875/125 mg, taken twice a day, will reach a maximum bacteriological efficacy against strains whose MIC of amoxicillin or amoxicillin / clavulanate will be ≤ 2 mg / l but not ≥ 4 mg / l, although amoxicillin / clavulanic acid 875/125 mg dose, received three times a day and at a dose of 1000/125 mg taken three times a day, would have some efficacy against strains with an MIC of 4 mg / L.