{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T08:10:59Z","timestamp":1778141459848,"version":"3.51.4"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Givosiran, an RNA interference\u2010based therapeutic, is a recent addition to the limited treatment armamentarium for acute hepatic porphyria (AHP). As a small interfering RNA that is selectively taken up in the liver, both the mechanism and targeted delivery create a complex relationship between givosiran pharmacokinetics (PK) and the pharmacodynamic (PD) response. Using pooled data from phase I\u2013III clinical trials of givosiran, we developed a semimechanistic PK\/PD model to describe the relationship between predicted liver and RNA\u2010induced silencing complex concentrations of givosiran and the associated reduction in synthesis of \u03b4\u2010aminolevulinic acid (ALA), a toxic heme intermediate that accumulates in patients with AHP, contributing to disease pathogenesis. Model development included quantification of variability and evaluation of covariate effects. The final model was used to assess the adequacy of the recommended givosiran dosing regimen across demographic and clinical subgroups. The population PK\/PD model adequately described the time course of urinary ALA reduction with various dosing regimens of givosiran, the interindividual variability across a wide range of givosiran doses (0.035\u20135\u00a0mg\/kg), and the influence of patient characteristics. None of the covariates tested had a clinically relevant effect on PD response that would necessitate dose adjustment. For patients with AHP, including adults, adolescents, and patients with mild to moderate renal impairment or mild hepatic impairment, the 2.5\u2010mg\/kg once monthly dosing regimen of givosiran results in clinically meaningful ALA lowering, reducing the risk for AHP attacks.<\/jats:p>","DOI":"10.1002\/psp4.12957","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T12:24:51Z","timestamp":1678278291000},"page":"842-852","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pharmacokinetic\u2010pharmacodynamic model of urinary \u03b4\u2010aminolevulinic acid reduction after givosiran treatment in patients with acute hepatic porphyria"],"prefix":"10.1002","volume":"12","author":[{"given":"Jongtae","family":"Lee","sequence":"first","affiliation":[{"name":"Alnylam Pharmaceuticals  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Melch","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel J.","family":"Robbie","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals  Cambridge Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03121"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio839"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/1758-907X-1-14"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2015.36"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1807838"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30936"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmd2.12173"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29313"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2014.10.026"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.14218\/JCTH.2014.00039"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2015.97"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.715523"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.121.000381"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja505986a"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1802"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1913147"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15090"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2019.0841"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2021.08.015"},{"key":"e_1_2_10_21_1","unstructured":"KuterDJ BonkovskyHL MonroyS et al.Efficacy and safety of givosiran in patients with acute hepatic porphyria: 36\u2010month results of the phase 3 ENVISION randomized clinical trial. American Society of Hematology 2021 Annual Meeting; December 11\u201014 2021; Atlanta GA & Virtual."},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4165(86)90102-9"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.121.000428"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(89)92688-3"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.md.0000152454.56435.f3"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1986.tb02895.x"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2005.058198"},{"key":"e_1_2_10_28_1","unstructured":"GIVLAARI (givosiran) injection for subcutaneous use [prescribing information].2021."},{"key":"e_1_2_10_29_1","unstructured":"GIVLAARI \u2013 Summary of Product Characteristics.2021."},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx818"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12957","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.12957","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12957","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,16]],"date-time":"2023-09-16T19:06:32Z","timestamp":1694891192000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.12957"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,23]]},"references-count":29,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,6]]}},"alternative-id":["10.1002\/psp4.12957"],"URL":"https:\/\/doi.org\/10.1002\/psp4.12957","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,23]]},"assertion":[{"value":"2022-11-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}