Dong-Hwan Lee1,2, Jong-Lyul Ghim1,2, Jae-Gook Shin1,2, Sung-min Kim3
1Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Korea 2Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, 3Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea
Objectives: The aim of this study is to investigate the population pharmacokinetic (PK) profiles of Doripenem in Korean patients with acute infections.
Methods: Four consecutive 250-mg or 500-mg doses of doripenem were intravenously infused over 1 hour every 8 hour for patients with creatinine clearance of ≤ 50 ml/min or > 50 ml/min, respectively. Blood samples from 38 patients at steady-state were taken pre-dose and at 0 min, 30 min and 4-6 hours after the 4th infusion. The population PK analysis was conducted using a nonlinear mixed effect modeling software, NONMEM. Covariate screening was conducted applying general additive models for PK parameters. Likelihood ratio test was used to select significant covariates, with the significance levels of p < 0.05 for selection and p < 0.01 for elimination. The final model was evaluated by the visual predictive check. The probability of patients with %T>MIC (the percentage of a dosing interval during which the concentration of drug exceeds the minimal inhibitory concentration) of ≥40% (1, 2) for MIC of 1, 2, 3, 4, 6 and 8 μg/mL was calculated in each dataset with 38 patients for 100 simulation datasets.
Results: The doripenem PK was well described by a one-compartment model. The typical values (relative standard error) were 6.921 L/h (7.940%) and 16.71 L (8.320%) for clearance and volume of distribution, respectively. The coefficient of variations of the inter-individual variability (relative standard error) for these parameters were 45.64% (10.45%) and 37.89% (15.72%), respectively. The correlation coefficient between clearance and volume of distribution was 0.2819. Residual variability was best explained by a combined error model with 23.62% proportional and 0.1767 μg/mL additive error. Doripenem clearance increased by 1.102% with creatinine clearance increasing by 1 ml/min and the inter-individual variability for clearance decreased from 60% to 45% with the covariate. (Table 1) Some lack of fits by under-predictions were observed at higher concentrations. (Figure 1&2) Most of the observed data were within the 90% prediction interval in the visual predictive check. (Figure 3) The simulated probability of patients with %T>MIC of ≥40% were calculated from the final model. (Figure 4) The median (range) probability of patients with T>MIC of 40% were 97% (84-100%), 92% (74-100%), 87% (76-97%), 79% (61-92%), 61% (39-84%) and 42% (18-71%) for MIC of 1, 2, 3, 4, 6 and 8 μg/mL. When 10%, 20%, or 30% of standard deviation (SD) for MICs were assumed, %T>MICs were hardly different from %T>MIC with 0% SD.
Conclusions: The PK profiles of Doripenem at steady-state in Korean patients with acute infections were well described by a one-compartment model. Doripenem clearance was significantly influenced by the creatinine clearance. The dose of Doripenem should be adjusted according to MIC.
References:
[1] Alvarez-Lerma F, Grau S, Ferrandez O. Characteristics of doripenem: a new broad-spectrum antibiotic. Drug design, development and therapy. 2009;3:173-90. PubMed PMID: 19920933. Pubmed Central PMCID: 2769234.
[2] Chahine EB, Ferrill MJ, Poulakos MN. Doripenem: a new carbapenem antibiotic. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2010 Dec 1;67(23):2015-24. PubMed PMID: 21098373
Reference: PAGE 24 (2015) Abstr 3504 [www.page-meeting.org/?abstract=3504]
Poster: Drug/Disease modeling - Infection