Should tenofovir dose be 200 – 250 mg when used with protease inhibitors?
1 December 2014. Related: Conference reports, Antiretrovirals, HIV 12 Glasgow 2014.
Polly Clayden, HIV i-Base
In drug-drug interaction studies with boosted protease inhibitors and elvitegravir significantly increased concentrations of tenofovir disoproxil fumarate (TDF). A study presented at the 2014 HIV Drug Therapy Glasgow Congress suggested that this interaction might be cancelled out with a lower dose of TDF.
The efficacy of TDF 300 mg once daily was established in trials with efavirenz (EFV), which does not increase TDF drug levels. Lopinavir/ritonavir (LPV/r), darunavir/ritonavir (DRV/r), atazanavir/ritonavir (ATV/r) and elvitegravir/cobicistat (EVG/c) all increase TDF levels. TDF is associated with renal toxicity, particularly in combination with protease inhibitors.
Andrew Hill and colleagues from Liverpool University and St Stephens AIDS Trust, Chelsea and Westminster Hospital, London performed a literature search to determine the effects of these boosted antiretrovirals on TDF plasma concentrations.
The search revealed increases in TDF AUC of +32%, +37%, +22% and +23% with LPV/r, ATV/r, DRV/r and EVG/c, respectively.
Assuming linear dose-proportional pharmacokinetics – seen in TDF dose-ranging studies – the investigators predicted plasma concentrations using paediatric tablets, available at 200 mg and 250 mg strengths would be bioequivalent to TDF 300 mg given with EFV: GMR 1.26 (95% CI 1.14 to1.38).
Using the 250 mg tablet was predicted to achieve:
| TDF AUC (95% CI) | TDF Cmin (95% CI) | |
|---|---|---|
| LPV/r | +10% (+4 to +15) | +26% (+14 to +38) |
| ATV/r | +14% (+8 to +21) | +7% (+1 to +13) |
| DRV/r | +2% (-9 to +12) | +14% (-1 to +31) |
| EVG/c | +2% (-3 to +16) | +4% (-3 to +13) |
Using the 200 mg tablet these predicted values were:
| TDF AUC (95% CI) | TDF Cmin (95% CI) | |
|---|---|---|
| LPV/r | +12% (-16 to -7) | +2% (-8 to +11) |
| ATV/r | -8% (-13 to -3) | -14% (-18 to -9) |
| DRV/r | -18% (-26 to -10) | -8% (-20 to +5) |
| EVG/c | -18% (-22 to -7) | -16% (-22 to -9) |
All were in the bioequivalent range respective to 300 mg TDF given with EFV.
The investigators commented that available lower doses of TDF could compensate for the drug-drug interaction with boosted protease inhibitors and elvitegravir, while maintaining efficacy. They noted that TDF toxicity might be over estimated in clinical trails were it is only combined with these boosted antiretrovirals.
Reference:
Hill A et al. Should the dose of tenofovir be reduced to 200-250 mg/day, when combined with protease inhibitors? HIV Drug Therapy Glasgow Congress, 2-6 November 2014. Poster abstract P-51. Journal of the International AIDS Society 2014, 17(Suppl 3):19583
http://www.jiasociety.org/index.php/jias/article/view/19583