{"id":20335,"date":"2012-10-01T12:07:33","date_gmt":"2012-10-01T12:07:33","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=20335"},"modified":"2012-10-05T16:32:04","modified_gmt":"2012-10-05T16:32:04","slug":"efavirenz-interaction-studies-with-tb-compounds-bedaquiline-and-delamanid","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/20335","title":{"rendered":"Efavirenz interaction studies with TB compounds bedaquiline and delamanid"},"content":{"rendered":"

Polly Clayden, HIV i-Base<\/strong><\/p>\n

HIV and TB co-infection is common and treatment is complicated by drug-drug interactions.\u00a0<\/strong><\/p>\n

Two poster presentations at ICAAC described potential reduced exposure of bedaquiline and a lack of interaction with delamanid when co-administered with efavirenz (EFV).<\/p>\n

Bedaquiline, is metabolised to an N-monodesmethyl metabolite (M2) by CYP3A4. For the population pharmacokinetic (PK) study presented, data were obtained from a previously reported drug-drug interaction trial (ACTG A5267) conducted in 33 HIV negative volunteers, who received two doses of 400 mg bedaquiline, the second co-administered with EFV after two weeks of receiving this at 600 mg once daily. Samples were obtained over 14 days after each bedaquiline dose. The investigators used non-linear mixed effects modeling for this analysis.<\/p>\n

They reported oral clearance of bedaquiline (CL\/F) and M2 (CL\/F\/fm) of 3.1 L\/h (relative standard error, RSE, 6.9%) and 13.2 L\/h (RSE 7.1%) respectively. The impact of induction was described as an immediate change in CL\/F one week after starting EFV. The estimated change in CL\/F was the same for bedaquiline and M2, an increase of 104% (RSE 4.3%).<\/p>\n

Both bedaquiline and M2 exposure was decreased by 40-50% under a range of plausible assumptions used in this model-based analysis. This is more than previously concluded from the single-dose data.<\/p>\n

Delamanid does not inhibit or induce CYP enzymes. EFV is metabolised by CYP2B6.<\/p>\n

Data were presented from a phase 1, open-label, randomised, multiple dose trial in 30 (15 per group) healthy volunteers, conducted to investigate the effect on drug exposure and safety of co-administered delaminid 100 mg twice daily and EFV 600 mg once daily.<\/p>\n

In this study, EFV was given alone for 10 days (Group 1); delamanid was given alone for seven days and with EFV for a further 10 days (Group 2). Pre-dose and at trough samples were obtained before full PK sampling. For EFV PK, samples were taken on day 10\/11 (Group 1) and day 17\/18 (Group 2); for delamanid PK on day 7\/8 (Group 1) and day 17\/18 (Group 2).<\/p>\n

The investigators calculated plasma PK parameters including geometric mean ratios for Cmax and AUCt with 90% CI. This revealed that exposure to both drugs does not appear to be affected by co-administration. One participant in each group had elevated EFV exposure associated with CYP2B6 polymorphisms.\u00a0<\/span><\/p>\n

Adverse events were reported in 93% of participants who received both drugs, 73% EFV alone and 60% delamanid alone. All were mild to moderate. One participant discontinued while on two drugs due to abnormal liver function tests.<\/p>\n

The phase 3 trial of delaminid is now enrolling a subgroup of HIV positive people receiving ART.<\/p>\n

References:<\/p>\n

    \n
  1. Svensson E et al. Population pharmacokinetics (PK) of TMC207 and its M2 metabolite with efavirenz (EFV) demonstrate reduced Exposure. 52nd ICAAC, San Francisco, 9-12 September 2012. Poster abstract A-1256.<\/li>\n
  2. Petersen C et al. Delamanid, a new drug for multi-drug resistant tuberculosis (MDR-TB), and efavirenz do not show clinically relevant drug interactions in healthy subjects. 52nd ICAAC, San Francisco, 9-12 September 2012. Poster abstract A-1255.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Polly Clayden, HIV i-Base HIV and TB co-infection is common and treatment is complicated by drug-drug interactions.\u00a0 Two poster presentations at ICAAC described potential reduced exposure of bedaquiline and a lack of interaction with delamanid when co-administered with efavirenz (EFV). …<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,3,34],"tags":[165],"class_list":["post-20335","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-antiretrovirals","category-pk-and-drug-interactions","tag-icaac-52nd-2012"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/20335","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\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=20335"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/20335\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=20335"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=20335"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=20335"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}