{"id":34256,"date":"2018-06-08T10:43:01","date_gmt":"2018-06-08T10:43:01","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=34256"},"modified":"2018-06-08T12:05:25","modified_gmt":"2018-06-08T12:05:25","slug":"dolutegravir-50-mg-twice-daily-sufficient-with-rifampicin-but-levels-reduced-significantly-with-100-mg-once-daily","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/34256","title":{"rendered":"Dolutegravir 50 mg twice daily sufficient with rifampicin but levels reduced significantly with 100 mg once daily\u00a0"},"content":{"rendered":"

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

Dolutegravir 50 mg twice daily achieved sufficient concentrations in the presence of rifampicin in HIV\/TB coinfected participants in the NAMSAL trial. But dolutegravir 100 mg once daily dosing with rifampicin reduces C24h by 76% in healthy volunteers. [1, 2]<\/span><\/b><\/p>\n

These findings were presented at the <\/span>19th International Workshop on Clinical Pharmacology.<\/p>\n

ANRS-12313 NAMSAL is a 48 week non-inferior multicentre study looking at a dolutegravir (DTG) 50mg once daily vs EFV 400mg once daily containing regimen as first-line treatment in HIV positive adults. The study is ongoing in Cameroon.<\/span><\/p>\n

DTG is a substrate of UGT1A1 and CYP3A4 and rifampicin (RIF) is a strong inducer of these enzymes. Previous data suggest that giving 50 mg DTG twice daily will overcome DTG\/RIF drug-drug interactions.<\/span><\/p>\n

NAMSAL includes a sub study to assess the steady state pharmacokinetics (PK) and efficacy of twice-daily DTG 50 mg based ART with once-daily RIF 600 mg based TB treatment in HIV\/TB coinfected participants.<\/span><\/p>\n

The investigators collected dried blood spots (DBS) at least 4 weeks after starting ART (steady-state). Antiretroviral DBS concentrations and TB DBS drugs were determined using UPLC-MS\/MS (LOQ <10ng\/mL and <50 ng\/mL, respectively). <\/span><\/p>\n

DTG C12h was interpreted using a 10-fold protein adjusted IC90 (approx 640 ng\/mL) and the inhibitory quotient (C12h\/IC90).<\/span><\/p>\n

Data were presented for eight participants: 23 DBS, weeks 12, 24 and 36.<\/span><\/p>\n

DTG C12h were: 1,123 ng\/mL (IQR 820\u20131,746); between participant variability 63% and within participant variability 72%.<\/span><\/p>\n

TB drug concentrations suggested good adherence to TB treatment. At week 48, all participants had viral load <200 copies\/mL. Among them, two had viral load >50 copies\/mL with DTG C12h <640 ng\/mL, corresponding to an inhibitory quotient of 0.1 and 5.<\/span><\/p>\n

The investigators noted that these results support 24 week interim results from the INSPIRING study which showed DTG twice daily with RIF produced similar concentrations to those for DTG 50 mg once daily in the phase 2\/3 trials. <\/span><\/p>\n

A related presentation showed results from a PK evaluation that <\/span>investigated the effect of RIF on the PK of DTG 100mg once daily. The study was conducted to look at whether doubling the DTG dose over 24 hours could offer an easier option than 50mg twice daily to manage the drug interaction. <\/span><\/p>\n

The study is open label in healthy volunteers receiving DTG 50mg or DTG 100 mg once daily in the presence or absence of RIF 600 mg. Participants were sequentially given: DTG 50 mg for 7 days, DTG 100 mg for 7 days, RIF 600 mg for 14 days, DTG 50 mg + RIF for 7 days, and DTG 100 mg + RIF for 7 days. Four steady-state full PK profiles were evaluated. Fourteen participants completed the study. <\/span><\/p>\n

Geometric mean ratios (GMR) 50 mg DTG + RIF vs 50 mg DTG, C24h and AUC24h respectively: 0.65 (90% CI 0.55 to 0.75), 0.15 (90% CI 0.13 to 0.17) and 0.44 (90% CI 0.37 to 0.52)\u00a0 <\/span><\/p>\n

GMR 100mg DTG + RIF vs 100mg DTG, Cmax, C24h and AUC24h respectively: 0.64 (90% CI 0.55 to 0.74), 0.12 (90% CI 0.10 to 0.15) and 0.42 (0.35 to 0.50) <\/span><\/p>\n

GMR 100mg DTG + RIF vs DTG 50mg, Cmax, C24h and AUC24h respectively: 1.09 (90% CI 0.97 to 1.21), 0.24 (90% CI 0.20 to 0.28) and 0.74 (90% CI 0.64 to 0.86). <\/span><\/p>\n

The investigators noted that RIF reduced DTG 100 mg once daily C24h by 76% and 50 mg once daily by 85% compared with DTG 50 mg alone. <\/span><\/p>\n

They also observed that the maximum induction of RIF was reached at three weeks and drug absorption reached saturation limit in the range of 50\u2013100 mg DTG (RIF has no additional effect on the saturation limit of DTG absorption).\u00a0<\/span><\/p>\n

DTG C24h remained 2\u201314 fold above the in vitro protein adjusted IC90 of 64 ng\/mL in all participants (but <300 ng\/mL in the majority).\u00a0 <\/span><\/p>\n

comment<\/span><\/h3>\n

Whether DTG 100 mg once daily + RIF will be safe and effective in people with HIV\/TB coinfection remains unclear from the PK results above. <\/span><\/b><\/p>\n

The investigators (from Imperial College London, St Stephen\u2019s Centre, Chelsea and Westminster Hospital and University of Cape Town) are planning follow up in patients. These evaluations will be highly monitored for safety.\u00a0\u00a0 <\/span><\/b>\u00a0<\/span><\/p>\n

References<\/span><\/p>\n

    \n
  1. Le M et al. Pharmacokinetic and\u2028efficacy of dolutegravir (50 mg BID) containing regimen in association with rifampin in HIV-infected patients using Dried Blood Spot: ANRS-12313 NAMSAL sub-study in Cameroon. 19th International Workshop on Clinical Pharmacology. Baltimore. 22\u201324 May 2018. Oral abstract 7.
    \n<\/span>http:\/\/regist2.virology-education.com\/presentations\/2018\/Antiviralpk\/23_le.pdf\u00a0<\/span><\/a>(PDF)<\/span><\/li>\n
  2. Wang X et al. Pharmacokinetics of dolutegravir 100 mg once-daily with rifampicin. 19th International Workshop on Clinical Pharmacology. Baltimore. 22\u201324 May 2018.\u00a0 Oral abstract 11.
    \n<\/span>    http:\/\/regist2.virology-education.com\/presentations\/2018\/Antiviralpk\/22_boffito.pdf<\/a>\u00a0<\/span>(PDF)<\/span><\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Polly Clayden, HIV i-Base Dolutegravir 50 mg twice daily achieved sufficient concentrations in the presence of rifampicin in HIV\/TB coinfected participants in the NAMSAL trial. But dolutegravir 100 mg once daily dosing with rifampicin reduces C24h by 76% in healthy …<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,34,37],"tags":[254],"class_list":["post-34256","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-pk-and-drug-interactions","category-tb-coinfection","tag-pk-workshop-2018"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/34256","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\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=34256"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/34256\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=34256"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=34256"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=34256"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}