{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T11:27:59Z","timestamp":1775215679358,"version":"3.50.1"},"reference-count":30,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T00:00:00Z","timestamp":1675900800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Population pharmacokinetic (PK) and pharmacokinetic\u2013pharmacodynamic (PK\u2010PD) models were used to describe the exposure\u2013response (E\u2010R) relationship between nalbuphine exposure and two widely used rating scales for itch: the Numerical Rating Scale for the subject's \u2018average\u2019; itch experience (NRS\u2010AV) and the Worst Itch (WI\u2010NRS), with 24\u2010h recall. Simulations based on the model E\u2010R relationship were used to support dose selection for Phase 3 clinical trials and were evaluated with a target of reducing the 7\u2010day average of the 24\u2010h WI\u2010NRS by at least 30% from baseline in most of the analysis population.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data from two clinical trials (NCT02373215: 9 healthy subjects; NCT02174419: 62 subjects with PN), in patients with prurigo nodularis (PN) with moderate to severe itch who received treatment with either of two doses of nalbuphine extended release (ER) or placebo, were used for the analysis. A two\u2010compartment PK model with serial zero and first\u2010order oral absorption was used to describe drug exposure. A maximum effect (\n) model with a placebo effect was used to model the itch response endpoints (NRS\u2010AV, WI\u2010NRS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The PK\u2010PD model predicted the exposure\u2010related reduction in both NRS\u2010AV and WI\u2010NRS over time with approximately 63% and 27% of \n, respectively. Exposures associated with 80% of \n were achieved in about 78% of the patients at 162 mg, twice daily (BID), compared to 35% at 81 mg BID.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Simulated dose response indicated that 108 and 162 mg BID doses result in the highest proportion of patients achieving at least a 30% reduction in NRS\u2010AV and WI\u2010NRS, respectively.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15663","type":"journal-article","created":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T08:03:06Z","timestamp":1674288186000},"page":"2088-2101","source":"Crossref","is-referenced-by-count":2,"title":["A population pharmacokinetic\u2013pharmacodynamic model evaluating efficacy of nalbuphine extended\u2010release in patients with prurigo nodularis"],"prefix":"10.1111","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2067-6441","authenticated-orcid":false,"given":"Rena","family":"Eudy\u2010Byrne","sequence":"first","affiliation":[{"name":"Metrum Research Group  Tariffville CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5542-6058","authenticated-orcid":false,"given":"Matthew","family":"Riggs","sequence":"additional","affiliation":[{"name":"Metrum Research Group  Tariffville CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amale","family":"Hawi","sequence":"additional","affiliation":[{"name":"A. Hawi Consulting  Ridgefield CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Sciascia","sequence":"additional","affiliation":[{"name":"Trevi Therapeutics  New Haven CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shashank","family":"Rohatagi","sequence":"additional","affiliation":[{"name":"Trevi Therapeutics  New Haven CT USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,2,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.14570"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.2340\/00015555\u20102774"},{"key":"e_1_2_11_4_1","unstructured":"HoganD BowerS.M.S.P.Prurigo Nodularis: background pathophysiology etiology. Published September 19 2018. Accessed January 14 2019.http:\/\/emedicine.medscape.com\/article\/1088032-treatmentJune (2012)."},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/ced.12365"},{"key":"e_1_2_11_6_1","first-page":"140","article-title":"Prurigo nodularis","volume":"4","author":"Eigelshoven S","year":"2009","journal-title":"CME Dermatol"},{"issue":"1","key":"e_1_2_11_7_1","first-page":"38","article-title":"Prurigo nodularis: a benign dermatosis derived from a persistent pruritus","volume":"16","author":"Vaidya DC","year":"2008","journal-title":"Acta Dermatovenerol Croat"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00005.2009"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1159\/000484573"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12882\u2010015\u20100043\u20103"},{"key":"e_1_2_11_11_1","article-title":"Nalbuphine attenuates itch in the substance\u2010P induced mouse model","volume":"93","author":"Hawi A","year":"2013","journal-title":"Acta Derm Venereol"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.2340\/00015555\u20101620"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.2340\/00015555\u20101246"},{"key":"e_1_2_11_14_1","volume-title":"NONMEM Users Guide: Part I\u2010VII","author":"Beal SL"},{"key":"e_1_2_11_15_1","volume-title":"Model Selection and Multimodel Inference: A Practical Information\u2010Theoretic Approach","author":"Burnham KP","year":"2002"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20104757\u20103462\u20101"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1016215116835"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aer001"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.837492"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.276.5309.122"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.2165\/11590590\u2010000000000\u201000000"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2014.15"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010009\u20109110\u20103"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248\u2010014\u20109655\u2010y"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1011555016423"},{"key":"e_1_2_11_26_1","unstructured":"Home|IUPHAR\/BPS Guide to PHARMACOLOGY. Accessed January 25 2019.http:\/\/www.guidetopharmacology.org\/"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13882"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp358"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1989.130"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2018.00310"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.1997.v113.pm9322521"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.15663","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bcp.15663","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.15663","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T03:54:00Z","timestamp":1714449240000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.15663"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,9]]},"references-count":30,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2023,7]]}},"alternative-id":["10.1111\/bcp.15663"],"URL":"https:\/\/doi.org\/10.1111\/bcp.15663","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,9]]}}}