Population Pharmacokinetic Modeling and Probability of Pharmacodynamic Target Attainment for Ceftazidime-Avibactam in Pediatric Patients Aged 3 Months and Older.

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel ß-lactam ß-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2,000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m2 .

Impact of renal impairment and human organic anion transporter inhibition on pharmacokinetics, safety and tolerability of relebactam combined with imipenem and cilastatin.

AIMS: Two phase 1, open-label studies were conducted to investigate the effect of renal impairment (RI) and organic anion transporter (OAT) inhibition on pharmacokinetics (PK) and safety of relebactam (REL) plus imipenem/cilastatin (IMI). METHODS: Study PN005 evaluated the PK of REL (125 mg) plus IMI (250 mg) in participants with RI vs healthy controls. Study PN019 evaluated the PK of REL (250 mg) and imipenem (500 mg; dosed as IMI) with/without probenecid (1 g; OAT inhibitor) in healthy adults. RESULTS: Geometric mean ratios (RI/healthy matched controls) of area under the concentration-time curve from time 0 to infinity (AUC0-∞ ; 90% confidence interval) for REL, imipenem and cilastatin increased as RI increased from mild (1.6 [1.1, 2.4], 1.4 [1.1, 1.8] and 1.6 [1.0, 2.5], respectively) to severe (4.9 [3.4, 7.0], 2.5 [1.9, 3.3] and 5.6 [3.6, 8.6], respectively). For all 3 analytes, plasma and renal clearance decreased and corresponding plasma apparent terminal half-life increased with increasing RI. Geometric mean ratios ([probenecid+IMI/REL]/[IMI/REL]) of plasma exposure for REL and imipenem were 1.24 (1.19, 1.28) and 1.16 (1.13, 1.20), respectively. The dose fraction excreted (fe) in the urine decreased progressively from mild to severe RI. Probenecid reduced renal clearance of REL and imipenem by 25 and 31%, respectively. Compared with IMI/REL, coadministration of IMI/REL with probenecid yielded lower fe for REL and imipenem. In both studies, treatment was well tolerated; there were no serious adverse events or discontinuations due to adverse events. CONCLUSION: RI increased plasma exposure and similarly decreased clearance of REL, imipenem and cilastatin; IMI/REL dose adjustment (fixed-ratio) will be required for patients with RI. Probenecid had no clinically meaningful impact on the PK of REL or imipenem.

Role of transporters in the disposition of a novel ß-lactamase inhibitor: relebactam (MK-7655).

OBJECTIVES: To identify the transporters involved in renal elimination of relebactam, and to assess the potential of relebactam as a perpetrator or victim of drug-drug interactions (DDIs) for major drug transporters. METHODS: A series of bidirectional transport, uptake and inhibition studies were conducted in vitro using transfected cell lines and membrane vesicles. The inhibitory effects of relebactam on major drug transporters, as well as the inhibitory effects of commonly used antibiotics/antifungals on organic anion transporter (OAT) 3-mediated uptake of relebactam, were assessed. RESULTS: Relebactam was shown to be a substrate of OAT3, OAT4, and multidrug and toxin extrusion (MATE) proteins MATE1 and MATE2K. Relebactam did not show profound inhibition across a panel of transporters, including organic anion-transporting polypeptides 1B1 and 1B3, OAT1, OAT3, organic cation transporter 2, MATE1, MATE2K, breast cancer resistance protein, multidrug resistance protein 1 and the bile salt export pump. Among the antibiotics/antifungals assessed for potential DDIs, probenecid demonstrated the most potent in vitro inhibition of relebactam uptake; however, such in vitro data did not translate into clinically relevant DDIs, suggesting that relebactam can be co-administered with OAT inhibitors, such as probenecid. CONCLUSIONS: Overall, relebactam has low potential to be a victim or perpetrator of DDIs with major drug transporters.

Individualizing piperacillin/tazobactam dosing in adult patients with cystic fibrosis: can tobramycin measurements help?

Background: Empirical models to predict ß-lactam pharmacokinetics (PK) using information from routine aminoglycoside therapeutic drug monitoring (TDM) have been proposed for critically ill patients; however, no such models exist for patients with cystic fibrosis (CF). Objectives: To investigate whether PK parameters of tobramycin could be used to predict those of piperacillin. Methods: A non-interventional, open-label PK study was conducted in hospitalized adults treated with piperacillin/tazobactam and tobramycin for acute pulmonary exacerbations of CF. Six serum samples per patient were collected and analysed. One- and two-compartment population PK models with linear, Michaelis-Menten or mixed elimination were evaluated for both drugs within the PmetricsTM package for R. Models were developed and compared iteratively using the log-likelihood and Akaike information criterion (AIC) objective functions. Results: Nine primarily female (n = 8) and Caucasian (100%) adult CF patients were enrolled. The median (IQR) age, height, weight and serum creatinine of included patients was 31 (27-32) years, 51.4 (49.9-55.8) kg, 162.6 (160.0-165.1) cm and 0.6 (0.5-0.6) mg/dL, respectively. The final model with the lowest objective function values consisted of one compartment with first-order elimination for tobramycin and two compartments with mixed-order elimination for piperacillin with the elimination rate constant of piperacillin modelled as a linear function of the elimination rate constant of tobramycin. Conclusions: A relationship was identified between the elimination rate constants of tobramycin and piperacillin. Validation of this relationship in larger studies of adult patients with CF is needed before application to the precision dosing of piperacillin/tazobactam in this patient population.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis.

Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several beta-lactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (fT>MIC) was evaluated for ceftazidime (CAZ), and an exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds a 1-mg/liter threshold concentration (fT>1 mg/liter) was evaluated for avibactam (AVI). Published CAZ and CZA MIC distributions were incorporated to evaluate cumulative response probabilities. CAZ and AVI were best described by one-compartment models. The values of total body clearance (CL; CAZ CL, 7.53 ± 1.28 liters/h; AVI CL, 12.30 ± 1.96 liters/h) and volume of distribution (V; CAZ V, 18.80 ± 6.54 liters; AVI V, 25.30 ± 4.43 liters) were broadly similar to published values for healthy adults. CZA achieved a PTA (fT>MIC, 50%) of >0.9 for MICs of ≤16 mg/liter. The overall likelihood of a treatment response was 0.82 for CZA, whereas it was 0.42 for CAZ. These data demonstrate improved pharmacodynamics of CZA in comparison with those of CAZ and provide guidance on the optimal dosing of CZA for future studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT02504827.).

Pharmacokinetics of piperacillin-tazobactam in plasma, peritoneal fluid and peritoneum of surgery patients, and dosing considerations based on site-specific pharmacodynamic target attainment.

Piperacillin-tazobactam (PIP-TAZ) is commonly used to treat intraabdominal infections; however, its penetration into abdominal sites is unclear. A pharmacokinetic analysis of plasma, peritoneal fluid, and peritoneum drug concentrations was conducted to simulate dosing regimens needed to attain the pharmacodynamic target in abdominal sites. PIP-TAZ (4 g-0.5 g) was intravenously administered to 10 patients before abdominal surgery for inflammatory bowel disease. Blood, peritoneal fluid, and peritoneum samples were obtained at the end of infusion (0.5 h) and up to 4 h thereafter. PIP and TAZ concentrations were measured, both noncompartmental and compartmental pharmacokinetic parameters were estimated, and a simulation was conducted to evaluate site-specific pharmacodynamic target attainment. The mean peritoneal fluid:plasma ratios in the area under the drug concentration-time curve (AUC) were 0.75 for PIP and 0.79 for TAZ, and the mean peritoneal fluid:plasma ratios in the AUC were 0.49 for PIP and 0.53 for TAZ. The mean PIP:TAZ ratio was 8.1 at both peritoneal sites. The regimens that achieved a bactericidal effect with PIP (time above minimum inhibitory concentration [MIC] >50%) at both peritoneal sites were PIP-TAZ 4.5 g twice daily for an MIC of 8 mg/L, as well as 4.5 g three times daily, and 3.375 g four times daily for an MIC of 16 mg/L. These findings clarify the peritoneal pharmacokinetics of PIP-TAZ, and help consider the dosing regimens for intraabdominal infections based on site-specific pharmacodynamic target attainment.

Phase I study assessing the safety, tolerability, and pharmacokinetics of avibactam and ceftazidime-avibactam in healthy Japanese volunteers.

Avibactam is a novel non-ß-lactam ß-lactamase inhibitor that has been shown to restore the in vitro activity of ceftazidime against pathogens producing Ambler class A, C, and some class D ß-lactamases. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of avibactam alone or with ceftazidime in healthy Japanese subjects. In this Phase I, double-blind study (NCT01291602), 16 healthy Japanese males, mean age 28.8 years, were randomized in a 2:2:1 ratio to receive avibactam 500 mg (n = 6), ceftazidime 2000 mg plus avibactam 500 mg (n = 7), or placebo (n = 3), each administered as a 100 ml intravenous infusion over 2 h, once on Day 1, every 8 h on Days 3-6, and once on Day 7. There were no deaths or serious adverse events. Nine treatment-emergent adverse events were reported in three subjects in the avibactam group - including one elevation in transaminase levels, and three vital signs events (tachycardia, palpitations, and orthostatic hypotension) - and one in the ceftazidime-avibactam group. All events were considered mild. After single or multiple dosing, plasma concentrations of avibactam and ceftazidime declined in a multi-exponential manner. No plasma concentration accumulation was observed, and the majority of avibactam was excreted unchanged in urine within 24 h. No clinically relevant changes in intestinal bacterial flora were observed. In conclusion, avibactam alone and ceftazidime-avibactam were generally well tolerated in healthy male Japanese subjects, and avibactam pharmacokinetics were comparable whether administered alone or in combination with ceftazidime.