{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T02:28:26Z","timestamp":1784341706606,"version":"3.55.0"},"reference-count":50,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T00:00:00Z","timestamp":1704240000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Antimicrobial resistance increasingly complicates neonatal sepsis in a global context. Fosfomycin and amikacin are two agents being tested in an ongoing multicenter neonatal sepsis trial. Although neonatal pharmacokinetics (PKs) have been described for these drugs, the physiological variability within neonatal populations makes population PKs in this group uncertain. Physiologically\u2010based pharmacokinetic (PBPK) models were developed in Simcyp for fosfomycin and amikacin sequentially for adult, pediatric, and neonatal populations, with visual and quantitative validation compared to observed data at each stage. Simulations were performed using the final validated neonatal models to determine drug exposures for each drug across a demographic range, with probability of target attainment (PTA) assessments. Successfully validated neonatal PBPK models were developed for both fosfomycin and amikacin. PTA analysis demonstrated high probability of target attainment for amikacin 15\u2009mg\/kg i.v. q24h and fosfomycin 100\u2009mg\/kg (in neonates aged 0\u20137\u2009days) or 150\u2009mg\/kg (in neonates aged 7\u201328\u2009days) i.v. q12h for Enterobacterales with fosfomycin and amikacin minimum inhibitory concentrations at the adult breakpoints. Repeat analysis in premature populations demonstrated the same result. PTA analysis for a proposed combination fosfomycin\u2010amikacin target was also performed. The simulated regimens, tested in a neonatal sepsis trial, are likely to be adequate for neonates across different postnatal ages and gestational age. This work demonstrates a template for determining target attainment for antimicrobials (alone or in combination) in special populations without sufficient available PK data to otherwise assess with traditional pharmacometric methods.<\/jats:p>","DOI":"10.1002\/psp4.13097","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T14:40:55Z","timestamp":1702910455000},"page":"464-475","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Development and application of neonatal physiology\u2010based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5400-3413","authenticated-orcid":false,"given":"Christopher A.","family":"Darlow","sequence":"first","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6821-7714","authenticated-orcid":false,"given":"Neil","family":"Parrott","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Centre Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1018-9655","authenticated-orcid":false,"given":"Richard W.","family":"Peck","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology University of Liverpool  Liverpool UK"},{"name":"Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Centre Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6187-878X","authenticated-orcid":false,"given":"William","family":"Hope","sequence":"additional","affiliation":[{"name":"Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,3]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31002-4"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(14)70804-7"},{"key":"e_1_2_9_4_1","volume-title":"Pocket Book of Hospital Care for Children","author":"World Health Organization","year":"2013"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1004179"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(17)30362-5"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00293-21"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40272-021-00465-z"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkab083"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/pan.12176"},{"key":"e_1_2_9_11_1","volume-title":"Joint formulary committee British National Formulary (online)"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00476-17"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.7.1842"},{"key":"e_1_2_9_14_1","unstructured":"USCAST the National Antimicrobial Susceptibility Testing Committee for the United States.Aminoglycoside in\u00a0vitro susceptibility test interpretive criteria evaluations version 1.3.2019.http:\/\/www.uscast.org\/"},{"key":"e_1_2_9_15_1","unstructured":"GaohuaL TurnerD FisherC et\u00a0al.A novel mechanistic approach to predict the steady state volume of distribution (Vss) using the Fick\u2010Nernst\u2010Planck equation \u2010 abstract 5709. 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