TANG Xingyu, ZHAN Huizhong, ZHANG Jing, YU Jicheng, WU Xiaojie, FAN Yaxin, WANG Yu, WU Hailan, GUO Beining, YANG Yang, GUO Yan, HU Fupin, HUANG Quanhua, CHEN Ning, CHEN Yuancheng, CAO Guoying
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Objective To investigate the pharmacokinetic (PK) characteristics of amoxicillin-clavulanic acid (10∶; 1) (AMX-CLA) after single or multiple doses via intravenous injection (IV) in healthy subjects, and conduct pharmacokinetic/pharmacodynamic (PK/PD) analysis to evaluate the utility of different dosing regimens. Methods A single-center, randomized, open-label, phase I clinical trial was conducted in healthy Chinese subjects. A single dose (0.55 g, 1.1 g, and 2.2 g, self-cross over, three-cycle) or multiple doses (2.2 g q12h) of AMX-CLA were administered by IV infusion. Blood and urine samples were collected to measure the concentrations of AMX and CLA. The PK parameters were calculated and PK/PD analysis was conducted using Monte Carlo simulation. Results After a single dose of 0.55 g, 1.1 g or 2.2 g AMX-CLA, the peak plasma concentration of AMX (Cmax) was (27.9 ±; 3.97),(50.8 ±; 6.50) and (101 ±; 14.1) mg/L, respectively in the 12 healthy subjects. The Cmax of CLA was (3.19 ±; 0.477), (5.78 ±; 0.594) and (9.82 ±; 1.52) mg/L, respectively. A total of 12 subjects received multiple doses of AMX-CLA 2.2 g q12h IV for 8 consecutive days to reach steady state. The accumulation factors RCmax and RAUC were 1.00 ±; 0.09 and 0.93 ±; 0.10 for AMX, 1.06 ±; 0.20 and 1.00 ±; 0.17 for CLA, respectively. Monte Carlo simulation revealed that when PK/PD (%T > MIC) target of AMX-CLA was 40%, AMX-CLA 2.2 g q12h, 0.5 h infusion provided ≥; 90% probability of target attainment (PTA) for the target pathogens for which the minimum inhibitory concentration (MIC) of AMX was ≤; 1 mg/L. AMX-CLA 1.1 g q8h, 0.5 h infusion achieved the cumulative fraction of response (CFR) of 85.40%, 98.65%, 97.85%-99.85%, and 99.35% respectively for penicillin-sensitive Streptococcus pneumoniae (PSSP), methicillin-sensitive Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis. AMX-CLA 2.2 g q12h, 0.5 h infusion provided CFR of 77.40%, 26.85%, 32.15%, and 17.30% for PSSP, penicillin-intermediate S. pneumoniae (PISP), extension-spectrum β-lactamase-negative Klebsiella pneumoniae and Escherichia coli, respectively. AMX-CLA 2.2 g q8h, 0.5 h infusion could increase CFR to 96.55%, 83.30%, 75.20% and 46.25%, respectively. All of the above dosing regimens could achieve CRF up to 100% against Streptococcus pyogenes. Conclusions Single and multiple doses of AMX-CLA have good safety and tolerability within the dose range of 0.55-2.2 g IV in healthy Chinese subjects. AMX-CLA 2.2 g q12h or 1.1 g q8h dosing regimen is recommended for respiratory tract infections such as community-acquired pneumonia (CAP) caused by PSSP, methicillin-sensitive S. aureus, H. influenzae and M. catarrhalis. AMX-CLA 2.2 g q8h regimen is suitable for CAP caused by PISP, extended-spectrum β-lactamase-negative K. pneumoniae and E. coli. AMX-CLA 1.1 g q12h is adequate for CAP caused by S. pyogenes.;
