{"id":33633,"date":"2018-03-14T11:25:56","date_gmt":"2018-03-14T11:25:56","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=33633"},"modified":"2018-03-15T12:16:19","modified_gmt":"2018-03-15T12:16:19","slug":"once-daily-tenofovir-alafenamide-appears-sufficient-when-dosed-with-rifampicin","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/33633","title":{"rendered":"Once-daily tenofovir alafenamide appears sufficient when dosed with rifampicin"},"content":{"rendered":"

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

Plasma concentrations of tenofovir alafenamide AUC were decreased by 55% and intracellular tenofovir-diphosphate concentrations by 36% when given with rifampicin. But intracellular concentrations were still 76% higher than those with standard dose tenofovir disoproxil fumarate. [1]<\/strong><\/p>\n

These data from RIFT, a pharmacokinetic (PK) study of once-daily tenofovir alafenamide (TAF) with rifampicin (RIF) conducted by Maddalena Cerrone and colleagues from Chelsea and Westminster Hospital, London, UK, The Johns Hopkins University, Baltimore, MD, USA, University of Liverpool, Liverpool, UK, University of Cape Town, Cape Town, South Africa, were presented at CROI 2018.\u2028 The study is the first to measure PK of once-daily TAF with RIF and compare it directly to tenofovir disoproxil fumarate (TDF).<\/p>\n

TAF achieves lower plasma and higher intracellular tenofovir (TFV) concentrations than TDF, but it is a substrate of drug transporters so has potential for drug interactions, especially with inducers like RIF.<\/p>\n

A recent parallel design PK study showed when twice-daily TAF was given with RIF intracellular TFV-diphosphate (DP) decreased by 24% and plasma TAF by 15% compared with once-daily TAF alone. [3, 4]<\/p>\n

RIFT is a phase 1, open label, single arm, single centre evaluation in 23 HIV negative participants (21 completed). Participants received TAF\/ FTC 25\/200mg once daily (28 days) with food, followed by TAF\/FTC + RIF 600mg once daily (28 days, RIF on empty stomach followed by TAF\/\u2028FTC with meal after 30 mins), followed by TDF 300mg once daily (28 days) with food.<\/p>\n

The investigators performed intensive PK sampling on days 28 (TAF\/FTC), 56 (TAF\/FTC+RIF) and\u2028 84 (TDF). Plasma TAF, TFV, FTC and intracellular TFV-DP and FTC-triphosphate (FTC-TP) concentrations were measured by validated LC-MS methods.<\/p>\n

Participants were genotyped for polymorphisms.<\/p>\n

Twenty-one participants completed all PK phases. Geometric mean ratios (GMR) for the main PK parameters are shown in Table 1.<\/p>\n

Table 1: PK once-daily TAF + RIF vs TAF vs TDF<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
PK parameter<\/td>\nTAF + RIF vs TAF
\nGMR (90% CI)<\/td>\n		TAF + RIF vs TDF
\nGMR (90% CI)<\/td>\n<\/tr>\n
Plasma TAF<\/td>\n<\/tr>\n
Cmax ng\/mL CV<\/td>\n0.50 (0.42\u20130.61)<\/td>\n<\/td>\n<\/tr>\n
AUC0\u201324 ng*h\/mL CV<\/td>\n0.45 (0.33\u20130.60)<\/td>\n<\/td>\n<\/tr>\n
Plasma TFV<\/td>\n<\/tr>\n
Cmax ng\/mL CV<\/td>\n0.35 (0.30\u20130.42)<\/td>\n<\/td>\n<\/tr>\n
AUC0\u201324 ng*h\/mL CV<\/td>\n0.46 (0.40\u20130.52)<\/td>\n<\/td>\n<\/tr>\n
C24h fmol*h\/106 <\/sup>CV<\/td>\n0.45 (0.42\u20130.50)<\/td>\n<\/td>\n<\/tr>\n
Intracellular TFV-DP<\/td>\n<\/tr>\n
Cmax ng\/mL CV<\/td>\n0.62 (0.52\u20130.74)<\/td>\n0.23 (0.17\u20130.30)<\/td>\n<\/tr>\n
AUC0\u201324 ng*h\/mL CV<\/td>\n0.64 (0.54\u20130.75)<\/td>\n0.24 (0.18\u20130.32)<\/td>\n<\/tr>\n
C24h fmol*h\/106 <\/sup>CV<\/td>\n0.57 (0.47\u20130.71)<\/td>\n0.24 (0.18\u20130.32)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

FTC-TP PK parameters were not affected by RIF. \u2028There were no significant associations with any polymorphisms.<\/p>\n

There were two grade 3 adverse events and 2\/23 participants discontinued: one case of transient hyper transaminitis during administration of TAF\/FTC only (the investigators judged this to be unlikely drug related); one gastrointestinal symptoms (judged likely RIF-related).<\/p>\n

The investigators concluded that although RIF co-administration decreased the plasma TAF by 55% and intracellular TFV-DP AUC by 36%, intracellular TFV-DP AUC were 76% higher with TAF + RIF than with TDF (300 mg once daily) alone.<\/p>\n

comment<\/h3>\n

These data support further evaluation of TAF + RIF in people with HIV and TB.<\/strong><\/p>\n

Unlike the previous TAF + RIF PK study, because of the comparison of intracellular TFV-DP concentrations with TAF + RIF to those with TDF alone, this evaluation suggests that doubling dose of TAF when coadministered with RIF is unnecessary.<\/strong><\/p>\n

References<\/p>\n

    \n
  1. Cerrone M et al. Rifampin effect on tenofovir alafenamide (TAF) plasma\/ intracellular pharmacokinetics. 25th CROI. Boston. 4\u20137 March 2018.\u2028 Oral abstract 28LB.<\/li>\n
  2. Custodio JM et al. Twice daily administration of tenofovir alafenamide in combination with rifampin: potential for tenofovir alafenamide use in HIV-TB coinfection. 16th European AIDS Conference (EACS). October 25\u201327 2017. Milan. \u00a0Oral abstract PS13\/4.<\/li>\n
  3. Clayden P. Twice-daily tenofovir alafenamide dose might overcome interaction with rifampicin. HTB. 28 November 2017.
    \nhttps:\/\/i-base.info\/htb\/32909<\/li>\n<\/ol>\n\n","protected":false},"excerpt":{"rendered":"

    Polly Clayden, HIV i-Base Plasma concentrations of tenofovir alafenamide AUC were decreased by 55% and intracellular tenofovir-diphosphate concentrations by 36% when given with rifampicin. But intracellular concentrations were still 76% higher than those with standard dose tenofovir disoproxil fumarate. [1] …<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,37],"tags":[251],"class_list":["post-33633","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-tb-coinfection","tag-croi-2018"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/33633","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=33633"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/33633\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=33633"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=33633"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=33633"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}