Pharmacokinetics of Tenofovir Alafenamide When Coadministered With Other HIV Antiretrovirals

Rebecca Begley, PhD; Moupali Das, MD; Lijie Zhong, PhD; John Ling, PhD; Brian P. Kearney, PharmD; Joseph M. Custodio, PhD


J Acquir Immune Defic Syndr. 2018;78(4):465-472. 

In This Article

Abstract and Introduction


Background: Tenofovir alafenamide (TAF), a prodrug of the nucleotide analogue tenofovir (TFV), is an antiretroviral (ARV) agent approved either as a complete regimen [elvitegravir/cobicistat/emtricitabine (F)/TAF, rilpivirine/F/TAF, bictegravir/F/TAF], or for use with other ARVs (F/TAF), for treatment of HIV. TAF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. Disposition of TAF may be altered by comedications that can inhibit or induce P-gp or BCRP transporters. The effects of ARVs on the pharmacokinetics of TAF were evaluated in 3 studies.

Methods: Healthy participants received TAF administered alone or with rilpivirine in study 1, with dolutegravir, ritonavir-boosted atazanavir (ATV + RTV), lopinavir (LPV/RTV), or darunavir (DRV + RTV) in study 2, and with the pharmacokinetic enhancer cobicistat or efavirenz in study 3.

Results: Across the 3 studies, 98 participants received treatment with TAF and a coadministered agent (n = 10–34/cohort). All study treatments were well tolerated. TAF and TFV exposures were unaffected after co-administration with rilpivirine and dolutegravir. Coadministration with P-gp/BCRP inhibitors such as cobicistat or PI-based regimens (ATV + RTV, LPV/r, or DRV + RTV) resulted in a range of 6%–183% increases in TAF and 105%–316% increases in TFV exposure, whereas coadministration with a P-gp inducer, efavirenz, resulted in a 15%–24% decrease in TAF and TFV exposure.

Conclusions: Evaluation of the drug interaction between TAF and other commonly prescribed boosted and unboosted ARVs provides characterization of the susceptibility of TAF and/or TFV pharmacokinetics to inhibitors or inducers of P-gp/BCRP transporters.


More than 25 antiretroviral (ARV) drugs in 6 mechanistic classes have been approved for treatment of HIV infection. These 6 classes include the nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), a fusion inhibitor, a CCR5 antagonist, and integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, ritonavir (RTV) and cobicistat (COBI), are used as pharmacokinetic (PK) enhancers (ie, boosters) to improve the PK profiles of some ARV drugs (eg, PIs and the INSTI elvitegravir).[1]

All recommended ARV regimens for HIV consist of 2 NRTIs plus a third agent: an INSTI, an NNRTI, or a boosted PI. The choice between an INSTI, NNRTI, or PI as the third drug in an initial ARV regimen should be guided by the regimen's efficacy, genetic barrier to resistance, adverse effects profile, and convenience. The patient's comorbidities, concomitant medications, and the potential for drug–drug interactions (DDIs) should also be considered.[1]

The N(t)RTI tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) that has demonstrated high efficacy when administered as a part of an ARV regimen. TAF exhibits greater stability in the intestine and plasma as compared to tenofovir disoproxil fumarate (TDF), providing greater loading into lymphoid cells, including peripheral blood mononuclear cells, before converting to TFV, which is subsequently phosphorylated into the active form, TFV diphosphate. Accordingly, TAF provides potent antiviral activity, with substantially lower circulating levels of TFV, and therefore has an improved bone and renal safety profile as compared with TDF-containing regimens.[2–8]

TAF, in combination with other boosted and unboosted ARVs, is recommended by all major treatment guidelines as part of a regimen or is included in several fixed-dose combination products.[1,9,10] As such, the DDI liabilities for TAF in combination with commonly used ARVs were evaluated to guide use of TAF within ART regimens. TAF is metabolized by the esterases cathepsin A (CatA) and carboxylesterase 1 (CES1) and is a substrate of the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters.[11,12] The CatA and CES1 pathways are not commonly impacted by DDIs; however, the disposition of TAF can be affected by inhibitors of the P-gp or BCRP transporters, or by inducers that target the nuclear receptors pregnane X receptor and constitutive androstane receptor, resulting in induction of the P-gp and BCRP transporters. TFV is not a substrate of P-gp or BCRP but is a substrate of organic anion transporter 1 (OAT1) and OAT3 renal transporters.[13] Exposure of TFV can be affected by comedications that alter TAF bioavailability, or modulators of the OATs.

Dolutegravir (DTG), a potent INSTI, and rilpivirine (RPV), a second-generation NNRTI, are not clinically relevant inhibitors or inducers of P-gp or BCRP[14,15] and are anticipated not to affect the exposure of TAF. The pharmacoenhancer cobicistat (COBI), in addition to being a potent, mechanism-based inhibitor of cytochrome P450 3A4 (CYP3A4), also inhibits P-gp and BCRP transporters[16] and was anticipated to increase TAF bioavailability. The ritonavir-boosted PI regimens, atazanavir (ATV + RTV), lopinavir (LPV/r), and darunavir (DRV + RTV), may inhibit and/or induce P-gp/BCRP;[17–22] the net effect on TAF would depend on the balance of inhibition and induction for each individual PI regimen. Efavirenz (EFV) has been shown to induce P-gp transporters in vitro[23,24] and was anticipated to reduce TAF bioavailability. These agents are not clinically relevant inhibitors of OAT1/3 transporters.[14–16,21,25–27] As such, any effect on TFV PK is anticipated to be secondary to alterations in TAF disposition.

TAF is not anticipated to be a clinically relevant perpetrator of drug interactions on transporters or cytochrome P450 enzymes;[16] accordingly, no effect of TAF on the PK of the coadministered ARV was anticipated.

Phase 1 pharmacokinetic studies were conducted to evaluate potential DDIs when TAF is coadministered with other ARV agents commonly prescribed for HIV treatment and provide insight into the susceptibility of TAF PK to inhibitors or inducers of P-gp/BCRP transporters. In these studies, TAF was either administered alone, or in combination with emtricitabine (FTC). FTC does not affect P-gp and BCRP transporters and was not anticipated to influence the DDIs evaluated.[28] TAF exhibited potent antiviral activity in a proof of concept phase 1b study over the dose range of 8–40 mg.[29] Doses of TAF used in these studies were 8, 10, 25, or 40 mg; lower doses (8 and 10 mg) were generally used when an increase in TAF exposure was anticipated (ie, with the boosted regimens), and higher doses were used when either no interaction was anticipated (25 mg; ie, with RPV), or a decrease in TAF exposure was anticipated (40 mg; ie, with EFV). TAF PK is linear across this dose range, and the DDI results observed are anticipated to translate to clinically used doses of TAF (10 or 25 mg).