{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T23:57:32Z","timestamp":1771977452621,"version":"3.50.1"},"reference-count":13,"publisher":"Weston Medical Publishing","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Opioid Management"],"abstract":"<jats:p>Introduction: Prevention of oral overdose of opioids is a critical unmet need. PF614-Multi-Pill Abuse Resistance (MPAR\u00ae) was designed to deliver desired opioid-level analgesia at therapeutic dose levels while providing overdose protection if consumed at higher-than-intended doses, through a unique trypsin-activated prodrug approach. PF614, a prodrug of oxycodone, releases oxycodone only after oral ingestion and exposure to trypsin in the small intestine. PF614-MPAR, a combination of PF614 and a potent trypsin inhibitor, nafamostat, will reduce oxycodone release if taken at higher-than-intended doses. The goal of this Phase 1 study was to determine the optimal PF614-nafamostat formulation to optimize the overdose protection that PF614-MPAR should provide.\r\nMethods: Healthy subjects received oral PF614 25 mg alone or in combination with 10 nafamostat formulations (1-10 mg each), which included immediate-release (IR) solutions, slow or fast extended-release (ER) beads, or a combination of IR\/ER nafamostat. Plasma oxycodone concentrations were measured to determine PF614 activation and to identify a nafamostat formulation that would reduce the release of oxycodone only when more than two doses were consumed orally. Once an optimal nafamostat formulation was identified, \u201cPF614-MPAR 25 mg,\u201d overdose protection was evaluated by administering one to eight escalating oral doses to naltrexone-blocked subjects.\r\nResults: The selected PF614\u2011MPAR 25 mg formulation delivered therapeutic oxycodone concentrations equivalent to PF614 alone when administered as one or two doses. However, oxycodone release was suppressed when PF614-MPAR was delivered at 3\u00d7, 5\u00d7, or 8\u00d7 doses simultaneously.\r\nConclusion: PF614-MPAR may be the first opioid with both abuse resistance and oral overdose protection.<\/jats:p>","DOI":"10.5055\/jom.0991","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T23:02:10Z","timestamp":1771974130000},"page":"37-50","source":"Crossref","is-referenced-by-count":0,"title":["Formulation development and a Phase 1 clinical study of PF614-MPAR, an oxycodone prodrug with oral opioid overdose protection"],"prefix":"10.5055","volume":"22","author":[{"given":"D. Lynn","family":"Kirkpatrick","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda A.","family":"Pestano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cari","family":"Evans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Millard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Levy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Zann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katie","family":"Pepper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5841-4810","authenticated-orcid":false,"given":"William K.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"3008","published-online":{"date-parts":[[2026,2,1]]},"reference":[{"key":"99764","doi-asserted-by":"crossref","unstructured":"Spencer MR, Garnett MF, Mini\u00f1o AM: Drug overdose deaths in the United States, 2002-2022. NCHS Data Brief No. 491. Hyattsville, MD: National Center for Health Statistics, 2024. DOI: 10.15620\/CDC:135849.","DOI":"10.15620\/cdc:135849"},{"key":"99765","doi-asserted-by":"crossref","unstructured":"Kirkpatrick DL, Schmidt WK, Morales R, et al.: In vitro and in vivo assessment of the abuse potential of PF614, a novel BIO-MD\u2122 prodrug of oxycodone. J Opioid Manag. 2017; 13: 39-49. DOI: 10.5055\/jom.2017.0366.","DOI":"10.5055\/jom.2017.0366"},{"key":"99766","doi-asserted-by":"crossref","unstructured":"Kirkpatrick DL, Evans C, Pestano LA, et al.: Clinical evaluation of PF614, a novel TAAP prodrug of oxycodone, versus OxyContin in a multi-ascending dose study with a bioequivalence arm in healthy volunteers. Clin Transl Sci. 2024; 17: E13765. DOI: 10.1111\/cts.13765.","DOI":"10.1111\/cts.13765"},{"key":"99767","doi-asserted-by":"crossref","unstructured":"Fujii S, Hitomi Y: New synthetic inhibitors of C1r, C1 esterase, thrombin, plasmin, kallikrein and trypsin. Biochim Biophys Acta. 1981; 661: 342-345. DOI: 10.1016\/0005-2744(81)90023-1.","DOI":"10.1016\/0005-2744(81)90023-1"},{"key":"99768","doi-asserted-by":"crossref","unstructured":"Aoyama T, Ino Y, Ozeki M, et al.: Pharmacological studies of FUT-175, nafamostat mesilate. I. Inhibition of protease activity in in vitro and in vivo experiments. Jpn J Pharmacol. 1984; 35: 203-227. DOI: 10.1254\/jjp.35.203.","DOI":"10.1254\/jjp.35.203"},{"key":"99769","doi-asserted-by":"crossref","unstructured":"Fisher D, Magruder J, Konstantatos A, et al.: First-in-man evaluation of PF329, a abuse-resistant prodrug of hydromorphone. J Pain. 2012; 13(Suppl.): S76.","DOI":"10.1016\/j.jpain.2012.01.315"},{"key":"99770","doi-asserted-by":"crossref","unstructured":"Kaiko RF, Grandy RP, Reder RF, et al.: A bioequivalence study of oral controlled-release morphine using naltrexone blockade. J Clin Pharmacol. 1995; 35(5): 499-504. DOI: 10.1002\/j.1552-4604.1995.tb04094.x.","DOI":"10.1002\/j.1552-4604.1995.tb04094.x"},{"key":"99771","doi-asserted-by":"crossref","unstructured":"Gosai P, Ducharme MP, Godfrey AR, et al.: Bioequivalence of oxycodone hydrochloride extended release tablets to marketed reference products OxyContin\u00ae in Canada and US. Int J Clin Pharmacol Ther. 2013; 51(11): 895-907. DOI: 10.5414\/CP201764.","DOI":"10.5414\/CP201764"},{"key":"99772","doi-asserted-by":"crossref","unstructured":"Brennan MJ, Kopecky EA, Marseilles A, et al.: The comparative pharmacokinetics of physical manipulation by crushing of Xtampza\u00ae ER compared with OxyContin\u00ae. Pain Manag. 2017; 7(6): 461-472. DOI: 10.2217\/pmt-2017-0030.","DOI":"10.2217\/pmt-2017-0030"},{"key":"99773","unstructured":"Mallinckrodt Pharmaceuticals: Naltrexone hydrochloride tablets USP. Webster Groves, MO, USA. FDA approved label, rev. 2022. Available at www.mallinckrodt.com\/products\/generics\/addiction-treatment-products\/naltrexone-50-mg. Accessed May 12, 2024."},{"key":"99774","doi-asserted-by":"crossref","unstructured":"Yap C, Solovyeva O, de Bono J, et al.: Enhancing reporting quality and impact of early phase dose-finding clinical trials: CONSORT dose-finding extension (CONSORT-DEFINE) guidance. BMJ. 2023; 383: E076387. DOI: 10.1136\/bmj-2023-076387.","DOI":"10.1136\/bmj-2023-076387"},{"key":"99775","unstructured":"Food and Drug Administration: OxyContin summary basis of approval, clinical pharmacology and biopharmaceutics reviews. Application No. 22-272. Silver Spring, MD, April 5, 2010. Study # OTR1003, Table 4.2.3.1. Available at www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2010\/022272s000ClinPharmRpdf. Accessed April 21, 2025."},{"key":"99776","unstructured":"Food and Drug Administration: Abuse-deterrent opioid analgesics. Silver Spring, MD, March 8, 2021. 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Accessed March 8, 2021."}],"container-title":["Journal of Opioid Management"],"original-title":[],"link":[{"URL":"https:\/\/wmpllc.org\/ojs\/index.php\/jom\/article\/download\/3977\/4261","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wmpllc.org\/ojs\/index.php\/jom\/article\/download\/3977\/4261","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T23:02:18Z","timestamp":1771974138000},"score":1,"resource":{"primary":{"URL":"https:\/\/wmpllc.org\/ojs\/index.php\/jom\/article\/view\/3977"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,1]]},"references-count":13,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,2,24]]}},"URL":"https:\/\/doi.org\/10.5055\/jom.0991","relation":{},"ISSN":["1551-7489","1551-7489"],"issn-type":[{"value":"1551-7489","type":"electronic"},{"value":"1551-7489","type":"print"}],"subject":[],"published":{"date-parts":[[2026,2,1]]}}}