Pharmacokinetics and Safety of Single Intravenous Doses of Ceftolozane/Tazobactam in Children With Proven or Suspected Gram-Negative Infection

Bradley, John S.; Ang, Jocelyn Y.; Arrieta, Antonio; Larson, Kajal; Rizk, Matthew L.; Caro, Luzelena; Yang, Shan; Yu, Brian; Johnson, Matthew G.; Rhee, Elizabeth G.

doi:10.1097/inf.0000000000002170

Cited by 30 publications

(43 citation statements)

References 24 publications

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“…The pharmacokinetics (PK) of ceftolozane and tazobactam have been investigated in healthy adult volunteers, adults with renal impairment, and adult patients with cUTI and cIAI (9)(10)(11)(12). Exposures of both ceftolozane and tazobactam increase in proportion to dose, and their PK are unaffected by each other.…”

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confidence: 99%

Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections

Larson

Patel

Willavize

et al. 2019

Antimicrob Agents Chemother

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Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum ␤-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to Ͻ18 years old) with proven/suspected Gram-negative bacterial infections, along with pharmacokinetic data from 12 adult studies, were integrated into a population pharmacokinetic (popPK) analysis. Two-compartment linear models with first-order elimination described the concentration-time profiles of ceftolozane and tazobactam in pediatric patients well. Renal function and body weight were identified to be significant predictors of ceftolozane-tazobactam pharmacokinetics. Renal function, as measured by the estimated glomerular filtration rate (eGFR), significantly affected the clearance of both ceftolozane and tazobactam. Body weight significantly affected clearance and the distribution volume, also of both ceftolozane and tazobactam. Patients with infections had a 32.3% lower tazobactam clearance than healthy volunteers. Using the final popPK models, simulations of various dosing regimens were conducted to assess each regimen's plasma exposure and the probability of pharmacokinetic/pharmacodynamic target attainment. Based on these simulations, the following doses are recommended for further clinical evaluation in phase 2 pediatric trials for cUTI and cIAI (in patients with an eGFR of Ն50 ml/min/1.73 m 2 only): for children Ն12 years old, 1.5 g ceftolozane-tazobactam (1 g ceftolozane with 0.5 g tazobactam), and for neonates/very young infants, infants, and children Ͻ12 years old, 20/10 mg/kg of body weight ceftolozane-tazobactam, both via a 1-h intravenous infusion every 8 h.

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confidence: 99%

Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections

Larson

Patel

Willavize

et al. 2019

Antimicrob Agents Chemother

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“…After verifying and ensuring that the adult model was robust, 3 virtual pediatric populations were generated using the approach as outlined above: 0 to 3 months, 3 months to 2 years old, and 2 to 7 years old. Maximal concentration, area under the curve, and CL were all within 1.5‐fold of observed data when the simulation was performed in these 3 cohorts, suggesting that the pediatric PBPK model predicted the exposure of tazobactam adequately in neonates, infants, and children (Figure b) . Significantly, allometric scaling approaches resulted in CL estimations that were comparable to those predicted using PBPK.…”

Section: Application Of Ontogeny Of Transporters To Midd In Childrenmentioning

confidence: 53%

“…Three pediatric cohorts were generated: 0‐3 months old (b), 3 months to 2 years old (c), and 2‐7 years old (d). By taking into account the physiological and anatomical changes during development, and the ontogeny of transporters that are pertinent to the disposition of tazobactam, the tazobactam exposure was predicted reasonably well with C max , AUC, and CL were all within 1.5‐fold of observed data . Allometric scaling approach resulted in CL estimation that were comparable to that predicted using PBPK.…”

Section: Application Of Ontogeny Of Transporters To Midd In Childrenmentioning

confidence: 64%

“…By taking into account the physiological and anatomical changes during development, and the ontogeny of transporters that are pertinent to the disposition of tazobactam, the tazobactam exposure was predicted reasonably well with C max , AUC, and CL were all within 1.5-fold of observed data. 64 Allometric scaling approach resulted in CL estimation that were comparable to that predicted using PBPK. However, for the youngest age group, 0-3 months old (b), the PBPK model performed slightly better, as allometry slightly overpredicted the CL (1.2-fold vs 1.8-fold of observed CL).…”

Section: Considerationsmentioning

confidence: 70%

“…Maximal concentration, area under the curve, and CL were all within 1.5-fold of observed data when the simulation was performed in these 3 cohorts, suggesting that the pediatric PBPK model predicted the exposure of tazobactam adequately in neonates, infants, and children (Figure 4b). 64 Significantly, allometric scaling approaches resulted in CL estimations that were comparable to those predicted using PBPK. However, for the youngest age group, 0-3 months old, the PBPK model performed slightly better, as allometry slightly overpredicted the CL (1.2fold versus 1.8-fold of observed CL).…”

Section: Pbpk Modeling With Integrated Transporter Ontogeny Reasonablmentioning

confidence: 74%

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Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters

Cheung

Groen

Burckart

et al. 2019

The Journal of Clinical Pharma

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Developmental changes in the biological processes involved in the disposition of drugs, such as membrane transporter expression and activity, may alter the drug exposure and clearance in pediatric patients. Physiologically based pharmacokinetic (PBPK) models take these age‐dependent changes into account and may be used to predict drug exposure in children. As a result, this mechanistic‐based tool has increasingly been applied to improve pediatric drug development. Under the Prescription Drug User Fee Act VI, the US Food and Drug Administration has committed to facilitate the advancement of PBPK modeling in the drug application review process. Yet, significant knowledge gaps on developmental biology still exist, which must be addressed to increase the confidence of prediction. Recently, more data on ontogeny of transporters have emerged and supplied a missing piece of the puzzle. This article highlights the recent findings on the ontogeny of transporters specifically in the intestine, liver, and kidney. It also provides a case study that illustrates the utility of incorporating this information in predicting drug exposure in children using a PBPK approach. Collaborative work has greatly improved the understanding of the interplay between developmental physiology and drug disposition. Such efforts will continue to be needed to address the remaining knowledge gaps to enhance the application of PBPK modeling in drug development for children.

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Review of novel β‐lactams and β‐lactam/β‐lactamase inhibitor combinations with implications for pediatric use

2023

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Antimicrobial resistance continues to surmount increasing concern globally, and treatment of difficult‐to‐treat (DTR) Pseudomonas aeruginosa, carbapenem‐resistant (CR) Acinetobacter baumannii (CRAB), and CR Enterobacterales (CRE) remains a challenge for clinicians. Although previously rare, the incidence of multidrug‐resistant (MDR) and CR infections in pediatric patients has increased drastically in the last decade and is associated with increased morbidity and mortality. To combat this issue, 14 novel antibiotics, including three β‐lactam/novel β‐lactamase inhibitor combinations (βL‐βLIs) and two novel β‐lactams (βLs), have received approval from the United States Food and Drug Administration since 2010. Improving clinician understanding of the utility of these novel therapies is imperative to improve judicious decision‐making and prevent societal regression to a pre‐penicillin era. In this review, we summarize the pharmacokinetic/pharmacodynamic (PK/PD) properties, clinical efficacy and safety data, dosing considerations, and subsequent role in therapy for ceftazidime‐avibactam (CAZ‐AVI), meropenem‐vaborbactam (MER‐VAB), imipenem‐cilastatin‐relebactam (IMI‐REL), ceftolozane‐tazobactam (TOL‐TAZ), and cefiderocol in pediatric patients.

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Pharmacokinetics and Safety of Single Intravenous Doses of Ceftolozane/Tazobactam in Children With Proven or Suspected Gram-Negative Infection

Cited by 30 publications

References 24 publications

Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections

Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections

Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters

Review of novel β‐lactams and β‐lactam/β‐lactamase inhibitor combinations with implications for pediatric use

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