Pharmacokinetic modeling and simulation for dose rationale of doripenem in neonates and infants.

The aims of this study were to construct a population pharmacokinetic model of doripenem in neonates and infants and to assess the dosing regimen for patients <3 months of age using Monte-Carlo pharmacokinetic/pharmacodynamic (PKPD) simulations. In the population pharmacokinetic analysis using 187 plasma concentrations from 47 neonates and infants, a two-compartment model well described plasma doripenem concentrations with the most significant covariates of chronological age and gestational age identified for the pharmacokinetics of doripenem. Monte-Carlo simulations suggested that the selected dosages for neonates and infants based on chronological age and gestational age (5 or 10 mg/kg) would provide ≥90% target attainment of 40%fT>MIC against MIC of 2 µg/mL in all age groups. These results would be useful for understanding the PKPD characteristics of doripenem, which could provide essential information on optimal therapeutic treatment for neonates and infants.

In vitro and in vivo assessment of the antibacterial activity of colistin alone and in combination with other antibiotics against Acinetobacter baumannii and Escherichia coli.

OBJECTIVES: Limited therapeutic options exist for treating severe infections caused by multidrug-resistant (MDR) and extensively drug-resistant Gram-negative bacteria (GNB). In this study, the activity of colistin (COL) as monotherapy and in combination with other antibiotics against Acinetobacter baumannii in vitro was investigated. In addition, the efficacy of intravenous colistimethate sodium (CMS) was evaluated in a murine model of urinary tract infection (UTI) induced by MDR Escherichia coli. METHODS: Minimum inhibitory concentration (MIC), Monte Carlo simulation, fractional inhibitory concentration index (FICI), time-kill study and erythrocyte lysis assay were applied to evaluate the effect and cytotoxicity of COL, meropenem, imipenem, doripenem (DOR) and sulbactam alone and in combination. For the in vivo experiment, determination of the bacterial burden and histopathological examination were performed to evaluate the efficacy of CMS against UTI. RESULTS: Of 106 A. baumannii isolates, 104 (98.1%) were susceptible to COL. In the chequerboard assay, COL + DOR showed the highest rate of synergism (60%). No antagonism or cytotoxicity was observed. All COL-based combinations were able to inhibit or slow bacterial re-growth in a time-kill assay. In an in vivo activity study, intravenous CMS reduced not only the bacterial load but also inflammation and maintained structural integrity of infected bladders and kidneys. CONCLUSION: The effectiveness of COL alone in vitro and in vivo suggested that intravenous CMS will be an effective and available therapeutic strategy for UTI due to MDR-GNB. In-depth in vitro tests demonstrated that COL + DOR could be an attractive option, especially when the COL MIC is ≥1 µg/mL.

Effect of pharmacokinetic model misspecification on antibiotic probability of target attainment predicted by Monte Carlo simulation
.

OBJECTIVE: The first aim of this study was to compare the predictability of efficacy by Monte Carlo simulation between a true one-compartment model and a true two-compartment model for doripenem. The second aim was to explore how we can identify the usefulness of a one-compartment model when the pharmacokinetic/pharmacodynamic (PK/PD) indices between three misspecified one-compartment models and a true two-compartment model are compared. MATERIALS AND METHODS: The reported two-compartment model parameters of two doripenem studies and a vancomycin study were used to generate 200 virtual concentration-time profiles for each study. Sparse and dense sampling designs were selected to build the one- and two-compartment models, respectively. The probability of target attainment (PTA) for the PK/PD indices were compared between the one- and two-compartment models of the same drug, applying the clinical breakpoint distribution of minimum inhibitory concentrations (MICs). RESULTS: The simulated concentration-time profiles reproduced the original data well. In addition, PTAs were similar between the one- and two-compartment models when infusion time and MIC were the same in the doripenem studies. For vancomycin simulations, the maximum difference was 65.9% between a misspecified one-compartment model and the true two-compartment model. CONCLUSION: When a misspecified one-compartment model was established with sparse sampling data, the PTA was significantly different from that of the two-compartment model. Thus, a useful PK model must be verified through diagnostic plots and visual predictive checks and the range of sampling time should be sufficient to explain the PK of a drug.

Population Pharmacokinetics of Doripenem in Pediatric Patients and Monte-Carlo Pharmacokinetic-Pharmacodynamic Simulations for Dosing Regimen Assessment.

The aims of this study were to evaluate the pharmacokinetics of doripenem (Finibax®, Doribax®, S-4661), a parenteral carbapenem antibiotic, in pediatric patients based on concentrations of doripenem in plasma after administration of 20 mg/kg 2 or 3 times daily and to evaluate the dosing regimens by using Monte-Carlo pharmacokinetic-pharmacodynamic simulations. Population pharmacokinetic analysis was performed by using 190 plasma concentrations of doripenem from 99 patients (2 months-13 years old). The two-compartment model well described the doripenem plasma concentrations in pediatric patients. Body weight was found to be the most significant influential factor. Gender was also found to be a significant covariate although the effect was relatively small. Monte-Carlo simulations indicated that 20 mg/kg over 1 h infusion would give 90% probability of target attainment for 40% of time above minimum inhibitory concentration against Haemophilus influenzae and Streptococcus pneumoniae, major causative pathogens in pediatric infections, and that 40 mg/kg, the highest approved dose for Japanese pediatric patients, administered over 3 h infusion achieved 98.6% against 8 µg/mL. The developed population pharmacokinetic model of doripenem and Monte-Carlo simulations for pediatric patients should provide useful information for understanding the pharmacokinetic and pharmacokinetic-pharmacodynamic characteristics of doripenem and for optimal treatment of pediatric patients.

Pharmacokinetics of Doripenem in Healthy Koreans and Monte Carlo Simulations to Explore Optimal Dosage Regimens in Patients With Normal and Enhanced Renal Function.

BACKGROUND: Dose adjustment is often required in patients with normal or enhanced renal function. The aim of this study is to investigate the pharmacokinetic (PK) properties of doripenem and explore optimal dosing regimens in patients with normal or enhanced renal function according to various minimum inhibitory concentrations (MICs). METHODS: The authors conducted a clinical trial and analyzed PK samples in 11 healthy Korean subjects applying noncompartmental analysis and a population approach. The population PK parameter estimates were used in Monte Carlo simulations to explore optimal dosing regimens for a probability of target attainment of 90% at 40% fTMIC (free drug concentrations above MIC). RESULTS: The time course of doripenem concentrations was well described by a 2-compartment model. The population typical values of clearance and steady-state volume were 22.9 L/h and 19.1 L, respectively, and were consistent with our noncompartmental analysis results. When the MIC was greater than 1 mcg/mL, at least increasing the dose or prolonging the infusion time was essential in patients with normal or enhanced renal function. CONCLUSIONS: These results suggest that dosage adjustment such as increasing the dose or lengthening the infusion time should be considered in patients with normal or enhanced renal function.

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

Doripenem (DRPM) is a broad-spectrum antibacterial agent often used as empirical therapy for critically ill patients, although there is a lack of studies validating the recommended dosage regimen for patients admitted to intensive care unit (ICU), based on pharmacokinetic (PK)/pharmacodynamic (PD) index. In this study, we estimated the free time above minimum inhibitory concentration (fT>MIC (%)) of DRPM using population PK analysis of 12 patients in ICU, and evaluated the validity of the dosage regimen stratified by creatinine clearance. Using a 2-compartment population PK model reported previously, the mean total clearance or distribution volume of DRPM estimated by Bayesian estimation was significantly lower or higher than that of based on population PK model. The estimated fT>MIC (%) of the recommended standard (normal renal function: 0.5 g every 8 h, moderate: 0.25 g every 8 h, severe renal impairment: 0.25 g every 12 h) and higher doses (normal: 1.0 g every 8 h, moderate: 0.5 g every 8 h, severe: 0.25 g every 8 h) against MICs of 0.5, 1 and 2 µg/mL exceeded 40% in all patients. When stratified by creatinine clearance, the PK/PD breakpoints estimated by Monte Carlo simulation in three grades of renal function tended to be higher than the previously reported PK/PD breakpoints for patients with urinary tract infection, an infection of lesser severity than ICU patients. These results suggest that the dosage regimen stratified by renal function derived from Japanese package insert may be sufficient to achieve effective treatment in ICU patients.

Population Pharmacokinetic Analysis of Doripenem after Intravenous Infusion in Korean Patients with Acute Infections.

We investigated the population pharmacokinetics (PK) of doripenem in Korean patients with acute infections and determined an appropriate dosing regimen using a Monte Carlo simulation for predicting pharmacodynamics (PD). Patients (n = 37) with a creatinine clearance (CLCR) of 20 to 50 ml/min or >50 ml/min who received a 250-mg or 500-mg dose of doripenem over the course of 1 h every 8 h, respectively, were included in this study. Blood samples were taken predosing and 0 h, 0.5 h, and 4 to 6 h after the fourth infusion. A nonlinear mixed-effect modeling tool was used for the PK analysis and pharmacodynamic simulation; doripenem PK were well described by a one-compartment model. The population mean values of the body weight (WT)-normalized clearance (CL/WT) and the body weight-normalized volume of distribution (V/WT) were 0.109 liter/h/kg of body weight (relative standard error, 9.197%) and 0.280 liter/kg (relative standard error, 9.56%), respectively. Doripenem CL was significantly influenced by CLCR The proposed equation to estimate doripenem CL in Korean patients was CL/WT = 0.109 × WT × (CLCR/57)0.688, where CL/WT is in liters per hour per kilogram. CL in Korean patients was expected to be lower than that in Caucasian patients, regardless of renal function. The Monte Carlo simulation showed that 90% attainment of target PK/PD magnitudes could be achieved with the usual dosing regimens when the MIC was ≤1 mg/liter. However, prolonged infusions (4 h) should be considered, especially when patients have augmented renal function and for patients infected with pathogens with a high MIC. Our results provide an individualized doripenem dosing regimen for patients with various renal functions and for patients infected with bacteria with decreased susceptibility.

Population Pharmacokinetics and Pharmacodynamics of Doripenem in Obese, Hospitalized Patients.

BACKGROUND: Doripenem population pharmacokinetics and dosing recommendations are limited in obesity. OBJECTIVE: To evaluate the population pharmacokinetics and pharmacodynamics of doripenem in obese patients. METHODS: Hospitalized adults with a body mass index (BMI) ≥ 40 kg/m2 or total body weight (TBW) ≥45.5 kg over their ideal body weight received doripenem 500 mg every 8 hours, infused over 1 hour. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed for 5 intermittent and prolonged infusion dosing regimens to calculate probability of target attainment (PTA) at 40% and 100% fT>MIC (free drug concentrations above the minimum inhibitory concentration). RESULTS: A total of 20 patients were studied: 10 in an intensive care unit (ICU) and 10 in a non-ICU. A 2-compartment model with first-order elimination best described the serum concentration-time data. Doripenem clearance (CL) was significantly associated with creatinine CL (CRCL), volume of the central compartment with TBW and ICU residence, and volume of the peripheral compartment with TBW ( P < 0.05). Using 40% fT>MIC, PTA was >90% for all simulated dosing regimens at MICs ≤2 mg/L. Using 100% fT>MIC, prolonged infusions of 1 g every 6 hours and 2 g every 8 hours achieved >90% PTA at MICs ≤2 mg/L. CONCLUSIONS: CRCL, ICU residence, and TBW are significantly associated with doripenem pharmacokinetics. Currently approved dosing regimens provide adequate pharmacodynamic exposures at 40% fT>MIC for susceptible bacteria in obese patients. However, prolonged infusions of larger doses are needed if a higher pharmacodynamic target is desired.

Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit.

Doripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CL(CR)), such that a 30-ml/min increase in the estimated CL(CR) would increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CL(CR) of 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CL(CR) of >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.

Evaluation of a pharmacokineticpharmacodynamic approach using software to optimize the carbapenem antibiotic regimen.

OBJECTIVE: Meropenem (MEPM) and doripenem (DRPM), whose antipseudomonal activity is more potent than that of other carbapenem antimicrobials, were used in the study. Monte Carlo simulation of drug concentrations was performed to develop an administration plan for MEPM and DRPM that takes into account the pharmacokinetics (PK)-pharmacodynamics (PD) of MEPM and DRPM and the renal function of each patient. Drug administration plans were proactively applied to patients with pneumonia to determine the usefulness of the method by assessing treatment efficacy and safety. METHODS: Patients with healthcareassociated pneumonia and an indication for MEPM or DRPM chemotherapy underwent drug administration in accordance with the MEPM and DRPM treatment plan developed by the PK-PD software applications. The primary efficacy endpoints were the clinical and bacteriological efficacy of the drugs agains pneumonia. The safety of the antimicrobials was assessed based on abnormal laboratory findings and the seizure disorders in accordance with the criteria for safety evaluation of antimicrobial agents. RESULTS: This study examined 12 and 11 patients in the MEPM and DRPM group, respectively; however, 3 DRPM patients were excluded due to the administration of anti-methicillin-resistant Staphylococcus aureus drugs after the initiation of DRPM treatment. MEPM and DRPM drug administration was determined to be safe and effective in all patients. CONCLUSIONS: The present results suggest that the Monte Carlo simulation-based PK-PD software is an effective tool for planning individualized antimicrobial chemotherapy with carbapenem in accordance with the PK-PD theory of antimicrobials. It is also possible to propose safe and effective drug administration plans for patients with healthcare-associated pneumonia.

Prediction of Pharmacokinetics and Pharmacodynamics of Doripenem in Pediatric Patients.

The aim of this paper was to predict the pharmacokinetics of doripenem in pediatrics from adult pharmacokinetic data and to investigate dosing regimens in pediatrics using Monte-Carlo pharmacokinetics/pharmacodynamics (PK/PD) simulations prior to the initiation of pediatric clinical trials. The pharmacokinetics in pediatrics was predicted by using a previously reported approach for ß-lactam antibiotics. Monte-Carlo simulation was employed to assess dosing regimens in pediatrics based on the predicted pharmacokinetic profiles and the minimum inhibitory concentration (MIC) distributions of Haemophilus influenzae and Streptococcus pneumoniae, which frequently cause infectious pediatric diseases. The probabilities of attaining target time above MIC (40%T>MIC) were calculated for dosing regimens of 1-30 mg/kg with two or three times daily dosing (TID) based on simulations of 5000 pediatric patients and MICs. The results suggested 15 and 5 mg/kg TID would give approximately 90% or more probability of target attainment against Haemophilus influenzae and Streptococcus pneumoniae, respectively. The pediatric phase 3 study confirmed that pharmacokinetics in pediatrics could be well predicted by this method, indicating that the dosing regimen had been appropriately selected. The framework of dose selection for pediatric clinical trials based on predictions of pharmacokinetic profiles and PK/PD indices should be applicable to the development of other ß-lactam antibiotics for pediatric use.

Pharmacokinetics of doripenem during high volume hemodiafiltration in patients with septic shock.

Pharmacokinetics (PK) of doripenem was determined during high volume hemodiafiltration (HVHDF) in patients with septic shock. A single 500 mg dose of doripenem was administered as a 1 hour infusion during HVHDF to 9 patients. Arterial blood samples were collected before and at 30 or 60 minute intervals over 8 hours (12 samples) after study drug administration. Doripenem concentrations were determined by ultrahigh performance liquid chromatography-tandem mass spectrometry. Population PK analysis and Monte Carlo simulation of 1,000 subjects were performed. The median convective volume of HVHDF was 10.3 L/h and urine output during the sampling period was 70 mL. The population mean total doripenem clearance on HVHDF was 6.82 L/h, volume of distribution of central compartment 10.8 L, and of peripheral compartment 12.1 L. Doses of 500 mg every 8 hours resulted in 88.5% probability of attaining the target of 50% time over MIC for bacteria with MIC = 2 µg/mL at 48 hours, when doubling of MIC during that time was assumed. Significant elimination of doripenem occurs during HVHDF. Doses of 500 mg every 8 hours are necessary for treatment of infections caused by susceptible bacteria during extended HVHDF.

Population pharmacokinetics of doripenem in Japanese subjects and Monte-Carlo simulation for patients with renal impairment.

Integrated analysis of all plasma concentration data obtained from phase 1 studies in Japanese subjects, including a high dose study and special population studies, was conducted to thoroughly re-investigate the pharmacokinetics of doripenem by means of a population approach. Dose adjustments for patients with renal impairment were assessed by Monte-Carlo pharmacokinetics/pharmacodynamics simulation. The population pharmacokinetics of doripenem was evaluated using 921 plasma concentration data from 92 subjects from eight phase 1 studies in Japan. The two-compartment model could well describe the plasma concentration profile of doripenem after intravenous infusion. Creatinine clearance and age were found to be covariates of doripenem clearance, and creatinine clearance was the most important factor influencing the pharmacokinetics of doripenem, which is consistent with the fact that doripenem is mainly excreted via the urine. Simulations suggest that exposures (AUC) to 1 g every 8 h for patients with normal renal function would be similar to those expected at 1 g every 12 h, 0.5 g every 8 h and 0.25 g every 8 h for patients with mild, moderate and severe renal impairment, respectively. These dosing regimens also provide sufficient exposure to doripenem from the viewpoint of the percentage of time above the minimum inhibitory concentration.

Comparative pharmacokinetics and pharmacodynamics of doripenem and meropenem in obese patients.

BACKGROUND: Antimicrobial pharmacokinetic and pharmacodynamic data are limited in obesity. OBJECTIVE: To evaluate the steady-state pharmacokinetics and pharmacodynamics of doripenem and meropenem in obese patients hospitalized on a general ward. METHODS: Patients with a body mass index (BMI) ≥40 kg/m² or total body weight (TBW) ≥100 pounds over their ideal body weight randomly received doripenem 500 mg (1-hour infusion) or meropenem 1 g (0.5-hour infusion) every 8 hours. Differences in pharmacokinetic parameters were determined by unpaired t test. Monte Carlo simulations were performed for 500 mg and 1 g every 8 hours, infused over 1 and 4 hours for doripenem and 0.5 and 3 hours for meropenem. Probability of target attainment (PTA) was calculated using a pharmacodynamic target of 40% fT > MIC (free drug concentrations above the minimum inhibitory concentration [MIC]), and cumulative fraction of response (CFR) was calculated using MIC data for 8 Gram-negative pathogens. RESULTS: Twenty patients were studied. Volume of distribution at steady state, corrected for TBW, was significantly larger (0.18 ± 0.04 vs 0.13 ± 0.05 L/kg, P = .048) and systemic clearance was significantly faster for doripenem (11.7 ± 4.1 vs 8.1 ± 2.6 L/h, P = .03). PTA was >90% for all regimens at MICs ≤2 µg/mL. CFR was >90% for all regimens against 6 enteric Gram-negative pathogens and for 3 of 4 regimens for each drug against Pseudomonas aeruginosa. CONCLUSIONS: Doripenem and meropenem pharmacokinetics differ in obesity. However, currently approved dosing regimens provide adequate pharmacodynamic exposures for susceptible bacteria in obese patients.

Assessment of the combination of doripenem plus a fluoroquinolone against non-susceptible Acinetobacter baumannii isolates from nosocomial pneumonia patients.

Carbapenem- and fluoroquinolone-non-susceptible Acinetobacter baumannii were obtained from four nosocomial pneumonia patients who were clinically cured following combination therapy with doripenem/levofloxacin or ciprofloxacin. In vitro synergy of doripenem/levofloxacin or ciprofloxacin was evaluated using time-kill analysis. In vivo synergy was tested using a mouse lethal infection model. In time-kill studies, doripenem and levofloxacin were both bactericidal when tested at Cmax; at ½Cmax, the combination showed synergy up to 8 hours. Ciprofloxacin, alone or combined with doripenem, was not bactericidal. For mouse septicemia, doripenem (100 mg/kg) was ≥90% effective in preventing death in all four isolates. Levofloxacin (200 mg/kg) was 73% effective, and ciprofloxacin (35 mg/kg) was ineffective in preventing death. At lower drug concentrations, increased efficacy was observed for doripenem/levofloxacin, but not for doripenem/ciprofloxacin. Overall, the results suggest that a doripenem/levofloxacin combination may have clinical utility in treating some non-susceptible A. baumannii infections.

When pharmacodynamics trump costs: an antimicrobial stewardship program's approach to selecting optimal antimicrobial agents.

BACKGROUND: Treatment of Pseudomonas aeruginosa infections is increasingly challenging because of escalating resistance. Antimicrobial stewardship programs provide guidance for clinicians regarding use of the most appropriate antimicrobial at the right dose, duration, and route in addition to being cost-effective. Optimizing antimicrobial therapy by using pharmacokinetic/pharmacodynamic principles such as extending time above the MIC is 1 stewardship strategy to reduce antimicrobial resistance. OBJECTIVE: The goal of this study was to evaluate our current dosing strategy for cefepime and the formulary carbapenem (imipenem) compared with meropenem and doripenem to determine the best dosing strategy for achieving maximal pharmacodynamic activity against an institution-specific population of P aeruginosa isolates. METHODS: Consecutive, nonduplicate, blood (n = 39) or bronchial alveolar lavage (n = 25) isolates of P aeruginosa from adult, hospitalized (2009-2010) critically ill patients underwent MIC testing by using broth microdilution. A pharmacokinetic model was developed and used with Monte Carlo simulation to evaluate the ability of imipenem, meropenem, doripenem, and cefepime to achieve optimal bactericidal activity as varying doses infused over standard infusions (SIs; 0.5-1 hour) or prolonged infusions (PIs; 3-4 hours). A regimen was defined as optimal if the cumulative fraction response (CFR) was ≥90%. RESULTS: None of the imipenem regimens modeled as SI or PI achieved a CFR ≥90%. Meropenem at 1 to 2 g q8h PI achieved a CFR ≥90%. Doripenem 0.5, 1, or 2 g q8h PI achieved a CFR ≥90%. The only cefepime regimen that achieved a CFR ≥90% was 2 g q8h PI. Overall susceptibility rates to P aeruginosa were highest with cefepime (91%), followed by meropenem (83%), doripenem (78%), and imipenem (72%). Our antimicrobial stewardship programs recommended switching from imipenem to doripenem 0.5g q8h PI, which was 36% more costly in drug acquisition costs. Cefepime dosing was increased from 2 g q12h SI to 2 g q8h PI, a 52% increase in drug acquisition cost. CONCLUSIONS: Antimicrobial stewardship programs should consider pharmacodynamic modeling to select the optimal dosing strategies to guide therapy in an era of escalating antimicrobial resistance. Using the percent susceptibility alone can be misleading and ultimately the most expensive if the patient fails to respond.

Pharmacokinetics of doripenem in infected patients treated within and outside the intensive care unit.

BACKGROUND: Doripenem often is used in the intensive care unit (ICU) to treat serious infections. However, pharmacokinetics in this population often are altered by various physiologic changes. Current pharmacokinetic data in critically ill patients receiving doripenem are limited. OBJECTIVE: To determine the pharmacokinetics of doripenem in patients treated in the ICU versus outside the ICU. METHODS: A total of 3-4 serum samples were collected from 25 infected patients receiving doripenem. A 2-compartment model was fit to serum pharmacokinetic data with nonparametric adaptive grid with adaptive γ. In the structural pharmacokinetic model, clearance (Cl) was made proportional to creatinine clearance (CrCl) and an intercept term. Bayesian pharmacokinetic parameters were compared between the 2 populations. A 5000-patient Monte Carlo simulation was performed for various CrCl ranges. The probability of pharmacodynamic target attainment was calculated over a range of minimum inhibitory concentrations (MICs), assuming a target of 35% of the dosing interval that unbound drug concentrations remain above the MIC. RESULTS: Mean (range) age, body mass index, and CrCl were 61 (31-90) years, 31.2 (15.1-55.5) kg/m(2), and 86 (15-221) mL/min, respectively. After the Bayesian step, r(2), bias, and precision were 0.97, 0.04, and 1.44 µg/mL, respectively. Mean (SD) parameters for ICU (n = 13) and non-ICU (n = 12) patients were not significantly different (p > 0.05): volume of central compartment (17.3 [11.2] vs 18.5 [11.7] L), Cl (10.1 [10.2] vs 15.5 [16.9] L/h), k12 (4.7 [4.7] vs 4.7 [4.8] h(-1)), and k21 (7.1 [5.5] vs 5.7 [5.3] h(-1)), respectively. Optimal target attainments were obtained for patients with normal renal function up to MICs of 2 µg/mL with a dose of 500 mg every 8 hours as 1-hour and 4-hour infusions. CONCLUSIONS: Doripenem pharmacokinetics were similar between ICU and non-ICU patients in this population. Optimal dosing regimens should be selected based on underlying renal function and suspected MIC of the infecting pathogen.

Pharmacodynamic variability beyond that explained by MICs.

Monte Carlo simulations (MCS) present a powerful tool to evaluate candidate regimens by determining the probability of target attainment. Although these assessments have traditionally incorporated variability in pharmacokinetic (PK) parameters and MICs, consideration of interstrain pharmacodynamic (PD) variability has been neglected. A population PK/PD model was developed for doripenem using murine thigh infection data based on 20 bacterial strains. PK data were fit to a linear two-compartment model with first-order input and elimination processes and an absorption lag time from a separate site (r(2) > 0.96). PK parameters were utilized to simulate free-drug profiles for various regimens in PD studies, from which the percentage of the dosing interval for which free-drug concentrations exceed the MIC of the targeted strain (%fT>MIC) was calculated. Doripenem PD was excellently described with Hill-type models (r(2) > 0.98); significant differences between mean PD estimates determined using a two-stage approach versus population analyses were not observed (P > 0.05); however, the variance in 50% effective concentration (EC50) and maximum effect (Emax) among strains was much greater using the two-stage approach. Even using the population approach, interstrain variability in EC50 (coefficient of variation expressed as a percentage [CV%] = 29.2%) and H (CV% = 46.1%) parameters was substantive, while the variability in Emax (CV% = 19.7%) was modest. This resulted in extensive variability in the range of %fT>MIC targets associated with stasis to those associated with a 2-log10 reduction in bacterial burden (CV% ∼ 50%). It appears that MCS, based on the assumption that PD variability is due to MIC alone, underestimates variability and may consequently underestimate treatment failures.

Optimal doripenem dosing simulations in critically ill nosocomial pneumonia patients with obesity, augmented renal clearance, and decreased bacterial susceptibility.

OBJECTIVE: Doripenem is a valuable broad-spectrum antibiotic for empirical therapy in critically ill patients, although little data exist to guide effective dosing. We sought to describe the population pharmacokinetics of doripenem in critically ill patients with nosocomial pneumonia and then to use Monte Carlo dosing simulations to procure clinically relevant dosing recommendations for that population. DESIGN: Pharmacokinetic analysis of Phase III Trial data. SETTING: Critical care units at multiple centers. PATIENTS: Thirty-one critically ill adult patients with nosocomial pneumonia. INTERVENTIONS: Serial blood samples were taken on day 2 or 3 of treatment and used for population pharmacokinetic analysis with nonlinear mixed effects modelling and Monte Carlo simulation. MEASUREMENTS AND MAIN RESULTS: A two-compartment linear model was most appropriate. The mean values for doripenem clearance (20.4 ± 14.2 L/hr) and volume of distribution (45.9 ± 36.3 L) were larger than that observed in previous studies in noncritically ill patients. Doripenem clearance was correlated with creatinine clearance and peripheral volume of distribution with patient body weight. Administration by extended infusion negated much of the pharmacokinetic variability caused by different patient body weight and renal function and enabled achievement of concentrations associated with maximal bacterial killing. CONCLUSION: : This is the first article describing the pharmacokinetics/pharmacodynamics of doripenem solely in critically ill patients and emphasizes the effect of patient weight and creatinine clearance on pharmacokinetics. Use of extended infusions with this antibiotic should be encouraged as it maximizes the likelihood of achieving target blood concentrations.