Highly Variable Absorption of Clavulanic Acid During the Day: A Population Pharmacokinetic Analysis

Methods: Two groups of healthy male volunteers received amoxicillin/clavulanic acid tablets at the start of a standard meal on two separate days 1 week apart. One group (n = 14) received 875/125 mg q12h and 500/125 mg q8h and the other group (n = 15) received 500/125 mg q12h and 250/125 mg q8h. In total, 1479 blood samples were collected until 8–12 h after administration. Concentrations were analysed using non-compartmental (WinNonLin) and population pharmacokinetic (NONMEM) methods.

Results: Median C_max and AUC_0–8 were 2.21 mg/L (0.21–4.35) and 4.99 mg·h/L (0.44–8.31), respectively. In 40/58 daily concentration–time profiles, C_max and AUC_0–8 of the morning dose were higher than with later doses. The final population model included a lag time (0.447 h), first-order absorption (3.99 h⁻¹ at 8:00 h, between-subject variability 52.8%, between-occasion variability 48.5%), one distribution compartment (33.0 L, between-subject variability 23.9%) and first-order elimination (24.6 L/h, between-subject variability 26.7%). Bioavailability (fixed at 1 at 8:00 h, between-occasion variability 28.2%) and absorption rate decreased over the day. For 97.5% of the simulated population after 125 mg q12h or q8h, %fT > Ct at 0.5 mg/L was 8.33% (q12h) and 15.2% (q8h), %fT > Ct at 1 mg/L was 0% (q12h + q8h), and fAUC_0–24 was 3.61 (q12h) and 5.56 (q8h)  mg·h/L.

Conclusions: Clavulanic acid absorption in healthy volunteers is highly variable. Bioavailability and absorption rate decrease over the day. The model developed here may serve to suggest clavulanic acid dosing regimens to optimize efficacy and prevent underdosing.