Population Pharmacokinetics of Doripenem Based on Data from Phase 1 Studies with Healthy Volunteers and Phase 2 and 3 Studies with Critically Ill Patients

Abstract

A population pharmacokinetic model of doripenem was constructed using data pooled from phase 1, 2, and 3 studies utilizing nonlinear mixed effects modeling. A 2-compartment model with zero-order input and first-order elimination best described the log-transformed concentration-versus-time profile of doripenem. The model was parameterized in terms of total clearance (CL), central volume of distribution (V c ), peripheral volume of distribution (V p ), and distribution clearance between the central and peripheral compartments (Q). The final model was described by the following equations (for jth subject): CL j (liters/h) ‫؍‬ 13. interindividual variability (percent coefficient of variation [% CV]) for CL (liters/h), V c (liters), V p (liters), and Q (liters/h) were 13.6 (19%), 11.6 (19%), 6.0 (25%), and 4.7 (42%), respectively. Residual variability, estimated using three separate additive residual error models, was 0.17 standard deviation (SD), 0.55 SD, and 0.92 SD for phase 1, 2, and 3 data, respectively. Creatinine clearance was the most significant predictor of doripenem clearance. Mean Bayesian clearance was approximately 33%, 55%, and 76% lower for individuals with mild, moderate, or severe renal impairment, respectively, than for those with normal renal function. The population pharmacokinetic model based on healthy volunteer data and patient data informs us of doripenem disposition in a more general population as well as of the important measurable intrinsic and extrinsic factors that significantly influence interindividual pharmacokinetic differences.

Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient

“…Thus, the variation in PK/PD breakpoints may be caused by a subtle difference in population. Secondly, the population PK model established by Nandy et al 15) was developed in non-Japanese subjects, which may contribute to the difference between the PK/PD breakpoint observed in this study and the PK/PD breakpoint reported previously. However, the population mean parameters estimated using a previously reported population PK model for Japanese subjects 21) were comparable to those estimated by the population PK model reported by Nandy et al 15) Hence, the difference in ethnicity in the development of two population PK models established by Nandy et al or Ikawa et al may have little influence on our results.…”

“…Furthermore, as DRPM was administered as empirical therapy for conditions without clearly identified pathogens, a few patients were likely to have no infection. Taken the above factors into consideration, we selected the model reported by Nandy et al 15) as the population PK model to implement Bayesian estimate in our study. In addition, in order to make predicted concentration profile more concrete, Bayesian estimate was implemented using five observed concentration.…”

“…In this study, to estimate the fT>MIC (%) for each subject, individual PK parameters were analyzed by Bayesian estimation using a previously reported population PK model, which is a 2-compartment model with zero-order input and firstorder elimination developed by Nandy et al 15) The model was constructed utilizing nonlinear mixed effects models based on pooled data from studies conducted in the United States, including not only phase I studies with healthy volunteers, but also phase II and III studies with severely ill patients. Thus, the model is critically useful as a predictive tool for estimating individual PK parameters of various populations.…”

“…PK Analysis Nandy et al 15) developed a population PK model of DRPM based on a 2-compartment infusion model from data of phase 1, 2 and 3 studies conducted in both healthy volunteers and critically ill patients. We used this model to estimate the PK parameters of DRPM for each subject.…”

Pharmacokinetic (PK) Characteristics in Critically Ill Patients

“…The median blood, dialysate and replacement fluid rates were 200, 1000 and 1000 mL/h, respectively. The mean value for total doripenem clearance was 4.46 L/h (normal range: ½ to 16 L/h, [22]) and volume of distribution was 0.63 L/kg BW (normal range: 0.23 to 0.35 L/kg BW, [22]). Doripenem elimination by CHDF depended on the rate filtration and contributed from 30% to 37% of total clearance.…”