{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:31:01Z","timestamp":1761060661568},"reference-count":31,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2018,9,25]],"date-time":"2018-09-25T00:00:00Z","timestamp":1537833600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1U54HD090259\u201001","4T32HL066992","5UM1 AI068632\u201011","UM1AI068616","UM1AI068632","UM1AI106716"],"award-info":[{"award-number":["1U54HD090259\u201001","4T32HL066992","5UM1 AI068632\u201011","UM1AI068616","UM1AI068632","UM1AI106716"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Lopinavir\/ritonavir (LPV\/r) is recommended by the World Health Organization as first\u2010line treatment for HIV\u2010infected infants and young children. We performed a composite population pharmacokinetic (PK) analysis on LPV plasma concentration data from 6 pediatric and adult studies to determine maturation and formulation effects from infancy to adulthood. Intensive PK data were available for infants, children, adolescents, and adults (297 intensive profiles\/1662 LPV concentrations). LPV PK data included 1 adult, 1 combined pediatric\u2010adult, and 4 pediatric studies (age 6 weeks to 63\u00a0years) with 3 formulations (gel\u2010capsule, liquid, melt\u2010extrusion tablets). LPV concentrations were modeled using nonlinear mixed effects modeling (NONMEM v. 7.3; GloboMax, Hanover, Maryland) with a one compartment semiphysiologic model. LPV clearance was described by hepatic plasma flow (Q<jats:sub>HP<\/jats:sub>) times hepatic extraction (E<jats:sub>H<\/jats:sub>), with E<jats:sub>H<\/jats:sub> estimated from the PK data. Volume was scaled by linear weight (WT\/70)<jats:sup>1.0<\/jats:sup>. Bioavailability was assessed separately as a function of hepatic extraction and the fraction absorbed from the gastrointestinal tract. The absorption component of bioavailability increased with age and tablet formulation. Monte Carlo simulations of the final model using current World Health Organization weight\u2010band dosing recommendations demonstrated that participants younger than 6 months of age had a lower area under the drug concentration\u2013time curve (94.8 vs &gt;107.4\u00a0\u03bcg\u00a0hr\/mL) and minimum observed concentration of drug in blood plasma (5.0\u00a0vs\u00a0&gt; 7.1\u00a0\u03bcg\/mL) values compared to older children and adults. Although World Health Organization dosing recommendations include a larger dosage (mg\/m<jats:sup>2<\/jats:sup>) in infants to account for higher apparent clearance, they still result in low LPV concentrations in many infants younger than 6 months of age receiving the liquid formulation.<\/jats:p>","DOI":"10.1002\/jcph.1293","type":"journal-article","created":{"date-parts":[[2018,9,25]],"date-time":"2018-09-25T15:52:01Z","timestamp":1537890721000},"page":"1604-1617","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Population Pharmacokinetics of Lopinavir\/Ritonavir: Changes Across Formulations and Human Development From Infancy Through Adulthood"],"prefix":"10.1002","volume":"58","author":[{"given":"Jincheng","family":"Yang","sequence":"first","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Science University of California  San Diego CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mina","family":"Nikanjam","sequence":"additional","affiliation":[{"name":"Division of Hematology\u2010Oncology University of California  San Diego CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brookie M.","family":"Best","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Science University of California  San Diego CA USA"},{"name":"Division of Host\u2010Microbe Systems and Therapeutics University of California San Diego School of Medicine  San Diego CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Pinto","sequence":"additional","affiliation":[{"name":"Division of Immunology School of Medicine Federal University of Minas Gerais  Minas Gerais Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen G.","family":"Chadwick","sequence":"additional","affiliation":[{"name":"Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric S.","family":"Daar","sequence":"additional","affiliation":[{"name":"Los Angeles Biomedical Research Institute at Harbor\u2010UCLA Medical Center  Los Angeles CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter L.","family":"Havens","sequence":"additional","affiliation":[{"name":"Division of Pediatric Infectious Diseases Medical College of Wisconsin and Children's Hospital of Wisconsin  Milwaukee WI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natella","family":"Rakhmanina","sequence":"additional","affiliation":[{"name":"Division of Pediatric Infectious Diseases Children's National Medical Center The George Washington University  Washington DC USA"},{"name":"Elizabeth Glaser Pediatric AIDS Foundation  Washington DC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edmund V.","family":"Capparelli","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Science University of California  San Diego CA USA"},{"name":"Division of Host\u2010Microbe Systems and Therapeutics University of California San Diego School of Medicine  San Diego CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,9,25]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"Guidelines for the use of antiretroviral agents in pediatric HIV infection.https:\/\/aidsinfo.nih.gov\/contentfiles\/lvguidelines\/PedARV_TablesOnly.pdf. Accessed January 2 2018."},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00887-10"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200847100-00005"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2005.02455.x"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00943-05"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.218"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/INF.0000000000000014"},{"issue":"5","key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1097\/FTD.0b013e31822d578b","article-title":"Population pharmacokinetics of lopinavir\/ritonavir (Kaletra) in HIV\u2010infected patients","volume":"33","author":"Lopez Aspiroz E","year":"2011","journal-title":"Ther Drug Monit"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01374-08"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.5402\/2012\/436763"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-014-0297-2"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0b013e32834403f6"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/tmi.12656"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0b013e318232b057"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/INF.0b013e31818cc053"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00224-08"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/INF.0000000000001817"},{"key":"e_1_2_9_19_1","unstructured":"IMPAACT P1080:Psychiatric and antiretroviral medication concentrations in HIV\u2010infected and uninfected children and adolescents (IMPAACT P1080).https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01232361. Accessed January 2 2018."},{"key":"e_1_2_9_20_1","unstructured":"A multicenter study to assess the tolerability of once daily lopinavir\/ritonavir (LPV\/r) liquid versus capsules.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00281606. Accessed January 2 2018."},{"key":"e_1_2_9_21_1","unstructured":"RiegG JainS SunS et\u00a0al.Switching to once\u2010daily lopinavir\/ritonavir liquid capsules and tablets: a randomized open\u2010label cross\u2010over study (CCTG 585). Presented at: 5th IAS Conference on HIV Pathogenesis Treatment and Prevention;2009; Cape Town South Africa."},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.transproceed.2005.09.113"},{"key":"e_1_2_9_23_1","unstructured":"Data table of infant weight\u2010for\u2010age charts.https:\/\/www.cdc.gov\/growthcharts\/html_charts\/wtageinf.htm. Accessed January 2 2018."},{"key":"e_1_2_9_24_1","unstructured":"Prescribing information and weight\u2010based dosing of available arv formulations for infants and children.http:\/\/www.who.int\/hiv\/pub\/paediatric\/paediatric_arv_dosing.pdf?ua=1. Accessed January 2 2018."},{"issue":"5","key":"e_1_2_9_25_1","first-page":"1023","article-title":"Lopinavir\/ritonavir in the treatment of HIV\u20101 infection: a review","volume":"4","author":"Chandwani A","year":"2008","journal-title":"Ther Clin Risk Manag"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200363080-00004"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.3851\/IMP3054"},{"key":"e_1_2_9_28_1","unstructured":"Fact sheet on lopinavir and ritonavir (LPV\/r) oral pellets.http:\/\/apps.who.int\/iris\/bitstream\/10665\/193543\/1\/FactsheetIATT_WHO_UNICEF_lopinavir_eng.pdf. Accessed January 2 2018."},{"key":"e_1_2_9_29_1","unstructured":"Safety and effectiveness of lopinavir\/ritonavir in HIV infected infants.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00038480. Accessed January 2 2018."},{"key":"e_1_2_9_30_1","unstructured":"Safety of saquinavir and high doses of lopinavir\/ritonavir in children with HIV.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00084058. Accessed January 2 2018."},{"key":"e_1_2_9_31_1","unstructured":"A phase II\/III trial of lopinavir\/ritonavir dosed according to the WHO pediatric weight band dosing guidelines.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01172535. Accessed January 2 2018."},{"key":"e_1_2_9_32_1","unstructured":"Lopinavir\/ritonavir (Kaletra) PK in children.https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00810108. Accessed January 2 2018."}],"container-title":["The Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcph.1293","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcph.1293","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,16]],"date-time":"2023-09-16T07:21:20Z","timestamp":1694848880000},"score":1,"resource":{"primary":{"URL":"https:\/\/accp1.onlinelibrary.wiley.com\/doi\/10.1002\/jcph.1293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,25]]},"references-count":31,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2018,12]]}},"alternative-id":["10.1002\/jcph.1293"],"URL":"https:\/\/doi.org\/10.1002\/jcph.1293","archive":["Portico"],"relation":{},"ISSN":["0091-2700","1552-4604"],"issn-type":[{"value":"0091-2700","type":"print"},{"value":"1552-4604","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,25]]},"assertion":[{"value":"2018-03-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-07-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}