{"id":32909,"date":"2017-11-28T12:25:45","date_gmt":"2017-11-28T12:25:45","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=32909"},"modified":"2017-11-28T17:28:47","modified_gmt":"2017-11-28T17:28:47","slug":"twice-daily-tenofovir-alafenamide-dose-might-overcome-interaction-with-rifampicin","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/32909","title":{"rendered":"Twice-daily tenofovir alafenamide dose might overcome interaction with rifampicin"},"content":{"rendered":"

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

\"\"Twice-daily tenofovir alafenamide (TAF) plus rifampicin (RIF) provided similar exposures to once-daily TAF in pharmacokinetic (PK) study. This strategy might be a suitable option for people with HIV\/TB coinfection.<\/strong><\/p>\n

TAF and tenofovir disoproxil fumarate (TDF) are prodrugs of tenofovir (TFV). TAF is more stable in plasma compared with TDF and gives about 90% lower plasma TFV exposures.<\/p>\n

TAF is a substrate of drug transporters and RIF is a potent inducer and associated with drug-drug interactions and in turn lower drug exposures. The interaction between TAF and RIF has not previously been evaluated. Currently TDF is indicated for use with RIF but once-daily TAF is not.<\/p>\n

Gilead Sciences, the originator company of TDF and TAF, conducted a PK study to look at twice-daily TAF co-administered with once-daily RIF. [1] The results were presented at EACS 2017.<\/p>\n

The study aims were to evaluate the steady state PK of TAF, the active intracellular moiety tenofovir-diphosphate (TFV-DP), and the TAF major metabolite TFV, after co-administration of twice-daily TAF with once-daily RIF 600 mg, compared with once-daily TAF. It was a phase 1, open label, parallel design, multiple dose, single centre study in HIV\/TB negative volunteers.<\/p>\n

Participants were enrolled into two cohorts (26 in each cohort). TAF was given in the fixed dose combination (FDC) tablet bictegravir\/emtricitabine\/TAF (B\/F\/TAF 50\/200\/25 mg).<\/p>\n

Cohort 1 received B\/F\/TAF once daily and cohort 2 B\/F\/TAF twice daily plus RIF 600 mg once daily, both two hours after food, for 28 days. Plasma and intracellular peripheral blood mononuclear cell (PBMC) PK was assessed on days 1 and 28.<\/p>\n

Statistical comparisons used geometric least-square mean (GLSM) ratios and 90% confidence intervals (CI).\u00a0 Cohort 2 was the test regimen and cohort 1 was reference.<\/p>\n

The evaluation revealed that with twice-daily administration of TAF plus RIF, exposures over 24 hours of TAF total plasma, overall systemic plasma TFV and intracellular PBMC-associated TFV-DP are expected to be reduced by <15%, about 20%, and about 24%, respectively, compared with once-daily TAF. See results table 1.<\/p>\n\n\n\n\n\n\n
Table 1: TAF twice daily + RIF vs TAF once daily PK<\/caption>\n
Mean (%CV)<\/th>\nTAF once daily<\/th>\nTAF twice daily + RIF<\/th>\nGLSM ratio (90% CI)<\/th>\n<\/tr>\n
Plasma TAF PK
\nAUC 0\u201324 (ng*h\/mL)<\/td>\n		345 (52)<\/td>\n290 (48)<\/td>\n85.8 (69.7 to 106)<\/td>\n<\/tr>\n
Plasma TFV PK
\nAUC 0\u201324 (ng*h\/mL)<\/td>\n		348 (20)<\/td>\n277 (19)<\/td>\n79.9 (73.1 to 87.3)<\/td>\n<\/tr>\n
Intracellular TFV-DP
\nAUC 0\u201324 (fmol*h\/106<\/sup> cells)<\/td>\n		<\/td>\n<\/td>\n76.3 (58.7 to 99.2)<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Notably, after twice-daily administration of TAF plus RIF, the mean (%CV) steady-state trough concentration of TFV-DP was 359 (58) fmol\/106<\/sup> cells, which is above the historical steady state TFV-DP concentrations achieved with TDF 300 mg.<\/p>\n

comment<\/h3>\n

TAF has the potential to replace TDF as part of an optimised generic first-line regimen for low- and middle-income countries (LMICs). <\/strong><\/p>\n

Due to TAF\u2019s low milligram dose (and lower amounts of active product ingredients) compared with TDF, this could reduce the annual cost per person from the recently agreed US $75 (for a fixed dose combination of TDF\/lamivudine [3TC]\/ dolutegravir [DTG]\/ or TLD) further still.<\/strong> [2] Approval of two generic FDCs of TAF\/3TC\/DTG is expected by mid-2019.<\/strong><\/p>\n

TAF is not yet recommended in WHO or any national guidelines in LMICs as there are insufficient data on its use in pregnancy and in people with HIV\/TB coinfection.\u00a0\u00a0<\/strong><\/p>\n

Previous investigations by Gilead showed co-administration with carbamazepine leads to a 55% decrease in TAF in plasma and results from modelling to predict the interaction with RIF suggested this reduction would be 73% in plasma.<\/strong> [3]<\/p>\n

Results from the PK study described above are welcome and provide preliminary evidence for adjusting the TAF dose to twice daily with RIF. But the parallel design is a limitation, and there is no concurrent TDF comparison.<\/strong><\/p>\n

Further evidence will be available early 2018 from the RIFT study that is currently evaluating the effect of RIF on plasma PK of emtricitabine (FTC) and TAF and TFV-DP and FTC-triphosphate (FTC-TP).<\/strong> [4]<\/p>\n

If, as the results above suggest, dosing TAF twice daily is the solution to co-administration with RIF this will potentially make HIV\/TB co-treatment easier in for programmes in LMICs as twice-daily DTG also looks promising. Botswana is already using this strategy and results from INSPIRING<\/strong> [5] – looking at DTG and efavirenz-containing ART regimens in people with HIV\/TB co-infection – will also be available early next year.<\/strong><\/p>\n

The TAF\/3TC\/DTG could be given twice daily – which is not possible with the TDF-containing FDC that requires giving the extra DTG as a single tablet.\u00a0<\/strong><\/p>\n

References:<\/p>\n

    \n
  1. 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
  2. CHAI. ARV market report. Issue 8. 28 September 2017.
    \nhttps:\/\/clintonhealthaccess.org\/content\/uploads\/2017\/09\/2017-ARV-Market-Report_Final.pdf<\/a> (PDF)<\/li>\n
  3. Gilead Sciences personal communication.<\/li>\n
  4. National Institutes of Health. RIFT: Effect of\u00a0rifampicin\u00a0on plasma PK of FTC, TAF and intracellular TFV-DP and FTC-TP.
    \n    https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03186482<\/a><\/li>\n
  5. National Institutes of Health. Open-label study of\u00a0dolutegravir\u00a0(DTG) or efavirenz (EFV) for human immunodeficiency virus (HIV) – tuberculosis (TB) co-infection.
    \n    https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02178592<\/a><\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Polly Clayden, HIV i-Base Twice-daily tenofovir alafenamide (TAF) plus rifampicin (RIF) provided similar exposures to once-daily TAF in pharmacokinetic (PK) study. This strategy might be a suitable option for people with HIV\/TB coinfection. TAF and tenofovir disoproxil fumarate (TDF) are …<\/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":[246],"class_list":["post-32909","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-pk-and-drug-interactions","category-tb-coinfection","tag-eacs-16-milan-2017"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/32909","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=32909"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/32909\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=32909"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=32909"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=32909"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}