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ABSTRACTWhile intraperitoneal (i.p.) ceftazidime is commonly used to treat continuous ambulatory peritoneal dialysis (CAPD)-related infections, the ability of i.p. regimens to achieve critical pharmacodynamic targets in both blood and dialysate has not been reported. To understand the pharmacodynamic profile of ceftazidime during CAPD, data were obtained from a single-dose pharmacokinetic (PK) i.p. ceftazidime study that included 10 CAPD patients who received i.p. ceftazidime at 15 mg/kg of body weight. The probability of target attainment (concentrations maintained above the MIC for >60% of the dosing interval [60% T> MIC]) was determined for six simulated regimens. A 3-compartment model with each dialysis dwell modeled as a separate differential equation was fit to ceftazidime concentrations using BigNPAG. Embedded with the final PK model, serum and dialysate concentration-time profiles of ceftazidime at 1, 1.5, and 2 g i.p. every 24 h (q24h) to q48h were simulated using ADAPT 5. The mean population pharmacokinetic parameters were as follows: apparent volume of the central compartment (Vc), 7.57 liter; apparent volume of the peritoneal cavity (Vpd), 2.44 liter; clearance from the central compartment (CL), 0.379 liter/h; intercompartmental transfer rate constants (first order) between the central and peripheral compartments (k12and k21), 4.66 and 4.88 h−1, respectively; and intercompartmental transfer rate constants (first order) between the central and peritoneal compartments (k13and k31), 0.111 and 0.227 h−1, respectively. In serum, the probability of target attainment for MICs of ≤8 mg/liter exceeded 90% for 1.5 to 2 g i.p. q24h to q48h. However, no tested regimen provided adequate dialysate exposure at MICs of ≥8 mg/liter on day 1 without the use of a 3-g loading dose (post hocanalysis). On day 2, 1.5 to 2 g i.p. q24h or 2 g i.p. q48h provided adequate exposure in the peritoneal cavity. These results should be validated in the presence of infection. Ceftazidime i.p. at 1.5 or 2 g q24h to q48h is recommended for nonperitoneal infections. For peritonitis, a 3-g load with maintenance dosing of 1 to 2 g i.p. q24h or 2 g i.p. q48h is recommended.

ABSTRACTWhile the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes that provided efficacy (cumulative and daily area under the concentration-time curve [AUC] values) and toxicity (trough concentrations of ≥24.3 mg/liter) profiles comparable to those from simulations employing the daptomycin PK model derived from the Staphylococcus aureusbacteremia–infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 h). For the 48-h interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72-h interdialytic period, all HD dosing schemes provided noncumulative AUC values from 48 to 72 h (AUC48–72) that were <50% of the SAB-IE AUC48–72values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC48–72values, while maintaining acceptable trough concentration (Cmin) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for Cminreaching ≥24.3 mg/liter were observed in one of the three studies. Given the high probability of Cminbeing ≥24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.

ABSTRACTScant data exist for the pharmacokinetics (PK) of ertapenem in patients on continuous ambulatory peritoneal dialysis (CAPD). The goals of this study were to characterize the PK profile of ertapenem during CAPD, determine the extent of ertapenem penetration into the peritoneal cavity, and quantify the probability of the target attainment (PTA) profile in the serum and peritoneal cavity. A single-dose PK study was conducted in seven patients on CAPD. Population PK modeling and Monte Carlo simulation determined the probability that ertapenem at 500 mg intravenously (i.v.) every 24 h (q24h) would achieve concentrations in excess of the MIC for 40% of the dosing interval (40% T>MIC, where Tis time) in the serum and peritoneal cavity. Monte Carlo simulation was also used to calculate the peritoneal cavity/serum mean and median penetration ratios by estimating the area under the concentration-time curve in the peritoneal cavity and serum (AUCPeritonealand AUCSerum, respectively) from zero to infinity after a single simulated dose. The population mean (± standard deviation [SD]) values for the apparent volume in the central compartment, clearance, and apparent volume in the peritoneal cavity were 2.78 (0.62) liters, 0.24 (0.07) liters/hr, and 5.81 (2.05) liters, respectively. The mean (SD) AUCPeritoneal/AUCSerumratio was 1.039 (0.861), and the median penetration ratio was 0.801 (interquartile range, 0.486 to 1.317). In both the serum and peritoneal cavity, ertapenem at 500 mg i.v. q24h was very likely (>90%) to achieve the pharmacodynamic target for MICs of ≤2 mg/liter. The simulations suggest that 500 mg of ertapenem i.v. q24h is very likely to achieve the exposure target associated with clinical efficacy in both the serum and peritoneal cavity against the range of MIC values deemed susceptible by the Clinical and Laboratory Standards Institute.

Patients with chronic kidney disease (CKD) have complex medication needs to treat chronic conditions, CKD complications, and acute illnesses. However, because CKD significantly alters the pharmacokinetic properties of medications and their pharmacodynamic effects, concerns about compromised efficacy and safety occur. Common complications of CKD include hypertension, hyperkalemia, anemia, mineral and bone disease (MBD), and metabolic acidosis. Screening and management of CKD and related comorbidities allows for early interventions to slow kidney function decline and improve health outcomes.