Population pharmacokinetic analysis and dosing regimen optimization of penicillin G in patients with infective endocarditis

Toshiaki Komatsu, Takayuki Inomata, Ichiro Watanabe, Masahiro Kobayashi, Hideya Kokubun, Junya Ako, Koichiro Atsuda

This study was designed to evaluate the population pharmacokinetics (popPK) of penicillin G in patients with infective endocarditis and establish a dosage regimen based on pharmacokinetic data and clinical outcome. Forty-six serum penicillin G samples from 25 individuals were analyzed using a nonlinear mixed-effects model. popPK were estimated using a one-compartment model. We created a receiver operating characteristic (ROC) curve for penicillin G efficacy and the ratio of its minimum concentration (Cmin)/minimum inhibitory concentration (MIC). Simulations were used to optimize the penicillin G dosage regimen using this ratio. Estimated popPK were: CL (L/h) = 0.21 × creatinine clearance (CLcr) (mL/min), Vd (L) = 28.9. The areas under the ROC curves were 0.87 for clinical efficacy. The cut-off value of penicillin G Cmin/MIC was 60. The continuous administration of 1 million IU penicillin G/h was necessary to achieve a positive outcome for patients with normal renal function (CLcr ≥ 60 mL/min). Our findings suggest that population-based parameters are useful for evaluating penicillin G pharmacokinetics and that an individualized dosage should be determined based on a described dosage regimen.