Population pharmacokinetics of tazobactam/ceftolozane in Japanese patients with complicated urinary tract infection and complicated intra-abdominal infection

Abstract

Tazobactam/ceftolozane is a combination of a b-lactamase inhibitor and a cephalosporin antibiotic, with recommended dosage for patients with normal renal function of tazobactam 0.5 g/ceftolozane 1 g administered as a 1-h intravenous infusion every 8 h. The doses in patients with moderate and severe renal impairment are recommended to be reduced by half and 1/4th, respectively. The dose in patients undergoing dialysis is a single loading dose of 750 mg followed after 8 h by a 150 mg maintenance dose. In order to evaluate pharmacokinetics (PK) in Japanese patients, individual Bayes PK parameters were derived using the previously developed population PK models. Furthermore, attainment of PK/pharmacodynamic target in Japanese patients was calculated to confirm the recommended dosage.Based on PK data from 200 Japanese patients in the phase 3 studies, including patients with mild and moderate renal impairment, individual tazobactam/ceftolozane PK parameters were derived. No clinically relevant difference was observed in tazobactam/ceftolozane exposures between Japanese and non-Japanese patients. All Japanese patients achieved a target percent of time that free ceftolozane concentrations are above the minimum inhibitory concentration (MIC) of 30% for MICs of up to 8 mg/mL. Also for tazobactam, all Japanese patients achieved a target percent of time that the free tazobactam concentration exceeds a threshold concentration (1 mg/mL) of 20%. The results suggest that the doses will be efficacious in the Japanese population.The results indicate that the recommended dose in patients with normal renal function or renal impairment is appropriate in Japanese patients.

Population Pharmacokinetics of Unbound Ceftolozane and Tazobactam in Critically Ill Patients without Renal Dysfunction

“…aeruginosa (Table 4). These results are concordant with previous assessments of the approved dose considering a 32.2% f T >MIC target (26, 27). Data from animal model studies show that ∼30 to 40% f T >MIC exposure is adequate to achieve a 1- to 2-log kill at 24 h (23, 28), and therefore, a 1.5-g dose is generally appropriate for most patients with susceptible infections.…”

“…In addition, we determined the PTA for a higher exposure of 60% f T >MIC , which is generally considered optimal for cephalosporins (41), and a more aggressive exposure of 100% f T >MIC , which is advocated as a prudent target for severely ill patient populations (10). For tazobactam, we used a 20% f T >1mg/liter (20% of the time above the minimum effective concentration of 1 mg/liter) as a target for assessment of dosing adequacy as previously suggested based on data from preclinical studies (26, 27, 42).…”

A Population Pharmacokinetics and Pharmacodynamic Approach To Optimize Tazobactam Activity in Critically Ill Patients

“…Based on previously reported literature and the reported sampling scheme (a maximum of two pharmacokinetic samples per patient), the concentration-time data from the patients were fitted to a one-compartment PK model (7,8). Due to the availability of one or two concentrations above the limit of quantification per patient, prior information on clearance from published PK studies was used as the initial estimates for the population PK modeling analysis (7)(8)(9)(10)(11)(12)(13). A lack of concentration data at the end of infusion can lead to an incorrect estimation of the volume of distribution (V).…”

Does dose reduction of renally cleared antibiotics in patients with impaired renal function lead to adequate drug exposure? A systematic review

“…Best evidence on dose reduction of antibiotics in patients with impaired renal function was available for meropenem [19][20][21][22]. Other frequently investigated antibiotics were imipenem/cilastatin, cefepime, ceftolozane/tazobactam, ciprofloxacin and teicoplanin however, only one good quality study per antibiotic was identified [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37].…”

“…Two studies investigated ceftolozane/tazobactam, one multiple dose study in patients with infections (administration of ceftolozane/tazobactam every 8 hours for 4 till 14 days) and one single dose study in volunteers without infections [28,29]. Quality of both studies was fair (Appendix Table 1, Table 2).…”