{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:55:13Z","timestamp":1789188913844,"version":"build-2803163510"},"reference-count":25,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2016,5,23]],"date-time":"2016-05-23T00:00:00Z","timestamp":1463961600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,6,1]],"date-time":"2016-06-01T00:00:00Z","timestamp":1464739200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor approved worldwide for the treatment of HIV in adults and children over 3 years of age or weighing over 10 kg. Only recently EFV was approved in children over 3 months and weighing at least 3.5 kg in the United States and the European Union. The objective of this analysis was to support the selection of an appropriate dose for this younger pediatric population and to explore the impact of CYP2B6 genetic polymorphisms on EFV systemic exposures. A population pharmacokinetic (PPK) model was developed using data from three studies in HIV-1-infected pediatric subjects (\n            <jats:italic>n<\/jats:italic>\n            = 168) and one study in healthy adults (\n            <jats:italic>n<\/jats:italic>\n            = 24). The EFV concentration-time profile was best described by a two-compartment model with first-order absorption and elimination. Body weight was identified as a significant predictor of efavirenz apparent clearance (CL), oral central volume of distribution (\n            <jats:italic>\n              V\n              <jats:sub>C<\/jats:sub>\n            <\/jats:italic>\n            ), and absorption rate constant (\n            <jats:italic>\n              K\n              <jats:sub>a<\/jats:sub>\n            <\/jats:italic>\n            ). The typical values of efavirenz apparent CL,\n            <jats:italic>\n              V\n              <jats:sub>C<\/jats:sub>\n            <\/jats:italic>\n            , oral peripheral volume of distribution (\n            <jats:italic>\n              V\n              <jats:sub>P<\/jats:sub>\n            <\/jats:italic>\n            ), and\n            <jats:italic>\n              K\n              <jats:sub>a<\/jats:sub>\n            <\/jats:italic>\n            for a reference pediatric patient were 4.8 liters\/h (4.5 to 5.1 liters\/h), 84.9 liters (76.8 to 93.0 liters), 287 liters (252.6 to 321.4 liters), and 0.414 h\n            <jats:sup>\u22121<\/jats:sup>\n            (0.375 to 0.453 h\n            <jats:sup>\u22121<\/jats:sup>\n            ), respectively. The final model was used to simulate steady-state efavirenz concentrations in pediatric patients weighing &lt;10 kg to identify EFV doses that produce comparable exposure to adult and pediatric patients weighing \u226510 kg. Results suggest that administration of EFV doses of 100 mg once daily (QD) to children weighing \u22653.5 to &lt;5 kg, 150 mg QD to children weighing \u22655 to &lt;7.5 kg, and 200 mg QD to children weighing \u22657.5 to &lt;10 kg produce exposures within the target range. Further evaluation of the impact of CYP2B6 polymorphisms on EFV PK showed that the identification of CYP2B6 genetic status is not predictive of EFV exposure and thus not informative to guide pediatric dosing regimens.\n          <\/jats:p>","DOI":"10.1128\/aac.02678-15","type":"journal-article","created":{"date-parts":[[2016,4,12]],"date-time":"2016-04-12T03:39:01Z","timestamp":1460432341000},"page":"3676-3686","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["Population Pharmacokinetics Analysis To Inform Efavirenz Dosing Recommendations in Pediatric HIV Patients Aged 3 Months to 3 Years"],"prefix":"10.1128","volume":"60","author":[{"given":"Man","family":"Luo","sequence":"first","affiliation":[{"name":"Bristol-Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunny","family":"Chapel","sequence":"additional","affiliation":[{"name":"Ann Arbor Pharmacometrics Group, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Sevinsky","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ishani","family":"Savant","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Cirincione","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Bertz","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Roy","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Princeton, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"Sustiva (efavirenz) product monograph","author":"Bristol-Myers Squibb Canada","year":"2012","unstructured":"Bristol-Myers Squibb Canada. 2012. Sustiva (efavirenz) product monograph. Bristol-Myers Squibb Canada, Montreal, Canada."},{"key":"e_1_3_3_3_2","volume-title":"Sustiva","author":"European Medicines Agency","year":"2016","unstructured":"European Medicines Agency. 2016. Sustiva. European Medicines Agency, London, United Kingdom. http:\/\/www.ema.europa.eu\/ema\/index.jsp?curl=pages\/medicines\/human\/medicines\/000249\/human_med_001068.jsp&mid=WC0b01ac058001d124."},{"key":"e_1_3_3_4_2","volume-title":"Sustiva (efavirenz) package insert","author":"Bristol-Myers Squibb","year":"2012","unstructured":"Bristol-Myers Squibb. 2012. Sustiva (efavirenz) package insert. Bristol-Myers Squibb, New York, NY. http:\/\/packageinserts.bms.com\/pi\/pi_sustiva.pdf."},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.049601"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.5414\/CPP40507"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkr304"},{"key":"e_1_3_3_8_2","first-page":"2391","article-title":"Pharmacogenetics of efavirenz and central nervous system side effects: an adult AIDS clinical trials group study","volume":"18","author":"Haas DW","year":"2004","unstructured":"Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM, Clifford DB, Hulgan T, Marzolini C, Acosta EP. 2004. Pharmacogenetics of efavirenz and central nervous system side effects: an adult AIDS clinical trials group study. AIDS 18:2391\u20132400.","journal-title":"AIDS"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1293.2009.00718.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.05.116"},{"key":"e_1_3_3_11_2","volume-title":"Sustiva (efavirenz) pediatric patients labeling update","author":"FDA","year":"2013","unstructured":"FDA. 2013. Sustiva (efavirenz) pediatric patients labeling update. FDA, Silver Spring, MD. http:\/\/www.fda.gov\/ForPatients\/Illness\/HIVAIDS\/History\/ucm350744.htm."},{"key":"e_1_3_3_12_2","volume-title":"Assessment report: Sustiva. EMA\/260283\/2015","author":"European Medicines Agency","year":"2015","unstructured":"European Medicines Agency. 2015. Assessment report: Sustiva. EMA\/260283\/2015. European Medicines Agency, London, United Kingdom. http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/EPAR_-_Scientific_Discussion_-_Variation\/human\/000249\/WC500186956."},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2010-3487"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00554-11"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9255-z"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.2146\/ajhp090327"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1011579109640"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1214\/aos\/1176344136"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2009.234"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/pst.394"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00751-08"},{"key":"e_1_3_3_22_2","volume-title":"Guideline on the role of pharmacokinetics in the development of medicinal products in the paediatric population","author":"European Medicines Agency","year":"2006","unstructured":"European Medicines Agency. 2006. Guideline on the role of pharmacokinetics in the development of medicinal products in the paediatric population. European Medicines Agency, London, United Kingdom. http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2009\/09\/WC500003066.pdf."},{"key":"e_1_3_3_23_2","volume-title":"Guidance for industry. E11 clinical investigation of medicinal products in the pediatric population","author":"US Food and Drug Administration","year":"2000","unstructured":"US Food and Drug Administration. 2000. Guidance for industry. E11 clinical investigation of medicinal products in the pediatric population. U.S. Food and Drug Administration, Rockville, MD. http:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/Guidances\/UCM073143.pdf."},{"key":"e_1_3_3_24_2","volume-title":"CYP2B6 allele nomenclature","author":"National Center for Biotechnology Information","year":"2014","unstructured":"National Center for Biotechnology Information. 2014. CYP2B6 allele nomenclature. National Center for Biotechnology Information, Bethesda, MD. http:\/\/www.cypalleles.ki.se\/cyp2b6.htm."},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199912163412502"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2006-0925"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02678-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02678-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:52:18Z","timestamp":1645476738000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.02678-15"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6]]},"references-count":25,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2016,6]]}},"alternative-id":["10.1128\/AAC.02678-15"],"URL":"https:\/\/doi.org\/10.1128\/aac.02678-15","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6]]},"assertion":[{"value":"2015-11-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-03-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-05-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}