Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection

Abstract

The use of antiretroviral medications in HIV-negative individuals as pre-exposure prophylaxis (PrEP) is a promising approach to prevent HIV infection. Tenofovir disoproxil fumarate (TDF) and emtricitabine exhibit desirable properties for PrEP including: favourable pharmacokinetics that support infrequent dosing; few major drug-drug or drug-food interactions; an excellent clinical safety record; and pre-clinical evidence for efficacy. Several large, randomized, controlled clinical trials are evaluating the safety and efficacy of TDF and emtricitabine for this new indication. A thorough understanding of variability in drug response will help determine future investigations in the field and/or implementation into clinical care. Because tenofovir and emtricitabine are nucleos(t)ide analogues, the HIV prevention and toxicity effects depend on the triphosphate analogue formed intracellularly. This review identifies important cellular pharmacology considerations for tenofovir and emtricitabine, which include drug penetration into relevant tissues and cell types, race/ethnicity/pharmacogenetics, gender, cellular activation state and appropriate episodic or alternative dosing strategies based on pharmacokinetic principles. The current state of knowledge in these areas is summarized and the future utility of intracellular pharmacokinetics/pharmacodynamics for the PrEP field is discussed.

Figure 1.

Summary of the intracellular disposition of tenofovir and emtricitabine including the transporters and enzymes responsible for the production of tenofovir-DP and emtricitabine-TP. mDNC, mitochondrial deoxynucleotide carrier; 3PGK, 3′-phosphoglycerate kinase; NDPK, nucleotide diphosphate kinase; 5′NT, cytosolic 5′-nucleotidase; dCK, deoxycytidine kinase; dCMK, uridylate-cytidylate kinase; OAT-1 & -3, organic anion transporter 1 & 3; OCT-1 & -2, organic cation transporter 1 & 2; CNT 1, concentrative nucleoside transporter 1; ENT 2, equilibrative nucleoside transporter 2; MRP 1 & 4 & 5, multidrug resistance protein 1 & 4 & 5; BCRP, breast cancer resistance protein; AK, adenylate kinase; dATP, 2′-deoxyadenosine-triphosphate; dCTP, 2′-deoxycytidine-triphosphate; TFV, tenofovir; FTC, emtricitabine; MP, monophosphate; DP, diphosphate; TP, triphosphate.

Figure 2.

Half-lives for intracellular triphosphates (TPs) (top bars) and plasma (bottom bars) for tenofovir (TFV), emtricitabine (FTC), didanosine (ddI), lamivudine (3TC), abacavir (ABC), zidovudine (ZDV) and stavudine (d4T). Note, the intracellular triphosphate for didanosine is dideoxyadenosine-TP and that for abacavir is carbovir-TP. QD, once daily.

Figure 3.

Predicted tenofovir (TFV)-DP accumulation to steady state in humans with three different dosing strategies: daily TDF (QD); TDF every three days (Q3D); and weekly TDF (Q7D). See text for parameters used for simulation.

Figure 4.

Theoretical concentration-effect profile for tenofovir (TFV) and emtricitabine (FTC) for HIV prevention, including potential sources of pharmacokinetic–pharmacodynamic variability. The sigmoid curves define the main drug effects of HIV prevention and toxicity. The horizontal arrows represent factors that influence the positions of the curves and the horizontal arrow on the x-axis represents factors that influence the intracellular drug and endogenous nucleotides. Identified sources of variability are discussed in the text.