{"id":5976,"date":"2009-10-05T08:25:26","date_gmt":"2009-10-05T07:25:26","guid":{"rendered":"http:\/\/moomango.co.uk\/htb\/?p=5976"},"modified":"2013-08-16T09:47:32","modified_gmt":"2013-08-16T09:47:32","slug":"first-results-of-new-integrase-compound-gsk1349572","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/5976","title":{"rendered":"First results of new integrase compound: GSK1349572"},"content":{"rendered":"

Simon Collins, HIV i-Base<\/strong><\/p>\n

Three posters at the meeting provided insight into a new compound in development from Shionogi and GSK.<\/strong><\/p>\n

Lalezari and colleagues presented first virological efficacy data from a 10-day Phase IIa dose-finding study (2, 10 and 50mg monotherapy or placebo, all once-daily) of GSK1349572 (GSK572) in 35 treatment-naive patients. [1]<\/p>\n

Patients in the 50mg arm showed a mean viral load drop of almost 2.5 logs and 7\/10 patients in this arm had viral load reductions to <50 copies\/mL.<\/p>\n

The 10 mg and 2mg doses reached mean viral load declines of approximately -2.0 and -1.5 logs respectively. No serious side effects were observed and reported events were generally similar to the placebo group.<\/p>\n

Two pharmacology studies showed the advantages of limited interpatient variability and an indication that the 50mg dose left a significant safety buffer before activity dropped, and that higher doses were unlikely to increase activity. Median half-life was 15 hours. Steady state geometric mean (CV%) AUC (0-24) and Cmax ranged from 16.7 (15) ug.h\/mL and 1.5 (24) ug\/mL at 10 mg once daily to 76.8 (19) ug.h\/mL and 6.2 (15) ug\/mL at 50mg once daily. The geometric mean steady-state C24 at 50mg was 1.5 ug\/mL which is ~23-fold higher than the in vitro protein-adjusted IC90. [2, 3]<\/p>\n

In vitro results with a broad panel of resistant isolates, suggested minimal cross-resistance to elvitegravir and raltegravir. with high level resistance only developing after serial passaging for 56 and 84 days respectively. [4]<\/p>\n

A second resistance poster looking at GSK572 susceptibility to a range of common integrase mutation patterns seen in raltegravir and elvitegravir studies (based on limited in vivo data), suggested that cross-resistance with other integrase inhibitors might be sufficiently likely for GSK572 not to be able to rescue people with previous integrase resistance. For example, although G140S\/Q148H resulted in a median fold-change in susceptibility of less than 4-fold (n=7), G140S\/Q148R lead to a range of around 8-19-fold changes (n=2). By comparison both these dual mutations confer high-level phenotypic resistance to raltegravir (>87-fold). [5]<\/p>\n

Of note, in addition to greater virological impact during a short monotherapy than other currently used drugs, this compound is being developed as a once-daily drug, does not require boosting and PK is unaffected by food.<\/p>\n

References<\/p>\n

    \n
  1. Lalezari J et al. Potent antiviral activity of S\/GSK1349572: a next generation integrase inhibitor (INI), in INI-naive HIV-1-infected patients: ING111521 protocol. 5th IAS 2009, Cape Town. Abstract TUAB105.
    \nhttp:\/\/www.ias2009.org\/pag\/Abstracts.aspx?AID=2120<\/a><\/li>\n
  2. Song I et al. Pharmacokinetic (PK) and pharmacodynamic (PD) relationship of S\/GSK1349572, a next generation integrase inhibitor (INI), in HIV-1 infected patients. 5th IAS 2009, Cape Town. Abstract WEPEB250.
    \n    http:\/\/www.ias2009.org\/pag\/Abstracts.aspx?AID=534 <\/a><\/li>\n
  3. Min S et al. Pharmacokinetics (PK) and safety in healthy subjects of S\/GSK1349572, a next generation, once-daily HIV integrase inhibitor (INI). 5th IAS 2009, Cape Town. Abstract WEPEA099.
    \n    http:\/\/www.ias2009.org\/pag\/Abstracts.aspx?AID=2108 <\/a><\/li>\n
  4. Sato A et al. S\/GSK1349572 is a potent next generation HIV integrase inhibitor. 5th IAS 2009, Cape Town. Abstract WEPEA097.
    \n    http:\/\/www.ias2009.org\/pag\/Abstracts.aspx?AID=1181 <\/a><\/li>\n
  5. Underwood M et al. S\/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor-resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy. 5th IAS 2009, Cape Town. Abstract WEPEA098.
    \n     http:\/\/www.ias2009.org\/pag\/Abstracts.aspx?AID=2051<\/a><\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Simon Collins, HIV i-Base Three posters at the meeting provided insight into a new compound in development from Shionogi and GSK. Lalezari and colleagues presented first virological efficacy data from a 10-day Phase IIa dose-finding study (2, 10 and 50mg …<\/p>\n","protected":false},"author":4,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,3],"tags":[93],"class_list":["post-5976","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-antiretrovirals","tag-ias-5th-2009"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/5976","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/4"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=5976"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/5976\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=5976"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=5976"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=5976"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}