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Tenofovir Lower in Plasma, Higher in PBMCs, With TAF Versus TDF
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16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 26-28, 2015, Washington, DC
Mark Mascolini
Tenofovir alafenamide (TAF), the investigational tenofovir prodrug, yields lower plasma tenofovir levels but higher intracellular tenofovir-diphosphate (TFV-DP) concentrations than tenofovir disoproxil fumarate (TDF), according to results of a three-study analysis [1]. The findings reinforce earlier data and could explain why signals of bone and kidney toxicity favored TAF over TDF in two phase 3 trials [2].
Gilead Sciences designed TAF to maximize TFV-DP concentrations in the cells HIV targets and to minimize tenofovir levels in plasma, in which it can travel to other cells and tissues and cause side effects. Trials to date showed that TAF puts tenofovir where it's wanted and that it matches TDF in antiviral action when combined in a once-daily pill with elvitegravir, cobicistat, and emtricitabine (E/C/F/TAF) taken as a first regimen. Two identical phase 3 studies in antiretroviral-naive populations found the E/C/F/TAF pill noninferior to E/C/F/TDF (Stribild), with 92% in the TAF arm and 90% in the TDF arm reaching a viral load below 50 copies through 48 weeks [2].
To confirm that TAF targets peripheral blood mononuclear cells (PBMCs) and spares plasma better than TDF, Gilead investigators combined results from the two phase 3 trials [2] and an earlier phase 2 study of E/C/F/TAF and Stribild. All trials had a pharmacokinetic substudy to measure steady-state concentrations of tenofovir and TFV-DP (the active form of the drug) at or between weeks 4 and 8.
The plasma-level analysis involved 55 people taking E/C/F/TAF and 36 taking TDF in Stribild. The PBMC analysis focused on 31 people taking TAF and 19 taking TDF. TAF dosed at 10 mg in this once-a-day coformulation is equivalent to 25 mg of solo TAF because cobicistat inflates TAF levels by inhibiting intestinal P-glycoprotein.
Tenofovir concentrations in plasma proved 91% lower with the TAF coformulation than with TDF in Stribild (geometric mean ratio [GMR] for tenofovir area under the concentration-time curve [AUC] 8.90, 90% confidence interval [CI] 8.20 to 9.65). Maximum concentrations of tenofovir in plasma averaged 17.4 ng/mL with TAF and 420 ng/mL with TDF (GMR 15.0, 90% CI 13.5 to 16.7).
Levels of TFV-DP in PBMCs stood 4.4-fold higher with TAF than with TDF (geometric mean AUC 12.2 ng*h/mL versus 2.79 ng*h/mL; GMR for AUC 437, 90% CI 286 to 669).
A safety analyses of the two phase 3 double-blind, double-dummy trials demonstrated significantly lower 48-week gains in serum creatinine with TAF than TDF (average 0.08 versus 0.11 mg/dL) and significantly smaller drops in estimated glomerular filtration rate (average 6.6 versus 11.2 mL/min) [2,3]. No one in the TAF arms versus 4 in the TDF arms (0.5%) dropped out because of kidney side effects.
Hip bone mineral density (BMD) fell significantly less with TAF than TDF through 48 weeks (-0.66% versus -2.95%), as did spine BMD (-1.30% versus -2.86%) [2,3]. Two markers of bone turnover--C-telopeptide and P1NP---rose significantly less with TAF than with TDF.
CROI: Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate - (02/27/15)
CROI: Tenofovir Alafenamide (TAF) in a Single-Tablet Regimen in Initial HIV-1 Therapy - (02/26/15)
CROI: Gilead Announces Phase 3 Results for Investigational Once-Daily Single Tablet HIV Regimen Containing Tenofovir Alafenamide (TAF) - (02/27/15)
CROI: Safety of Tenofovir Alafenamide in Renal Impairment - (02/27/15)
References
1. Custodio J, Garner W, Callebaut C, et al. The pharmacokinetics of tenofovir and tenofovir diphosphate following administration of tenofovir alafenamide versus tenofovir disoproxil fumarate. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. May 26-28, 2015. Washington, DC. Abstract 6.
2. Sax PE, Wohl D, Yin MT. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. Published Online April 16, 2015. http://dx.doi.org/10.1016/S0140-6736(15)60616-X
3. Sax PE, Saag MS, Yin MT, et al. Renal and bone safety of tenofovir alafenamide vs tenofovir disoproxil fumarate. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 143LB.
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