title: Plasma Tenofovir, Emtricitabine, and Rilpivirine and Intracellular Tenofovir Diphosphate and Emtricitabine Triphosphate Pharmacokinetics following Drug Intake Cessation.
abstract: Pharmacokinetic (PK) data describing a prolonged time course of antiretrovirals in plasma and peripheral blood mononuclear cells (PBMCs) are important for understanding and managing late or missed doses and to assess the appropriateness of compounds for preexposure prophylaxis (PrEP). This study aimed to evaluate the PK of coformulated tenofovir disoproxil fumarate (DF), emtricitabine, and rilpivirine in plasma and of the intracellular (IC) anabolites tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) in healthy volunteers up to 9 days after drug cessation. Individuals received daily tenofovir DF-emtricitabine-rilpivirine (245/200/25 mg) for 14 days. Drug intake was stopped, and serial sampling occurred prior to the final dose and up to 216 h (9 days) after stopping drug intake. Concentrations were quantified and PK parameters calculated. Eighteen volunteers completed the study. The terminal elimination plasma half-lives for tenofovir and emtricitabine over 216 h (geometric mean [90% confidence interval]) were higher than those seen over 0 to 24 h (for tenofovir, 31 h [27 to 40 h] versus 13.3 h [12.5 to 15.1 h]; for emtricitabine, 41 h [36 to 54 h] versus 6.4 h (5.9 to 7.6 h]). Model-predicted IC half-lives (0 to 168 h) were 116 h (TFV-DP) and 37 h (FTC-TP). The plasma rilpivirine concentration at 216 h was 4.5 ng/ml (4.2 to 6.2 ng/ml), and half-lives over 0 to 216 h and 0 to 24 h were 47 h (41 to 59 h) and 35 h (28 to 46 h), respectively. These data contribute to our understanding of drug behavior following treatment interruption; however, adherence to therapy should be promoted. Validated plasma and IC target concentrations are necessary to allow interpretation with respect to sustained virus suppression or HIV prevention. (The trial was conducted in accordance with the Declaration of Helsinki [EudraCT 2012-002781-13].).
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom laurad@liv.ac.uk.
authors.forename: Laura
authors.initials: L
authors.lastname: Dickinson
authors.affiliation: St Stephen's Centre, Chelsea & Westminster Foundation Trust, London, United Kingdom.
authors.forename: H Manisha
authors.initials: HM
authors.lastname: Yapa
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom St Stephen's Centre, Chelsea & Westminster Foundation Trust, London, United Kingdom.
authors.forename: Akil
authors.initials: A
authors.lastname: Jackson
authors.affiliation: St Stephen's Centre, Chelsea & Westminster Foundation Trust, London, United Kingdom.
authors.forename: Graeme
authors.initials: G
authors.lastname: Moyle
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Else
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Alieu
authors.initials: A
authors.lastname: Amara
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.affiliation: St Stephen's Centre, Chelsea & Westminster Foundation Trust, London, United Kingdom.
authors.forename: Zeenat
authors.initials: Z
authors.lastname: Karolia
authors.affiliation: St Stephen's Centre, Chelsea & Westminster Foundation Trust, London, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Higgs
authors.affiliation: St Stephen's Centre, Chelsea & Westminster Foundation Trust, London, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068679:Emtricitabine / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control; D006801:Humans; D008875:Middle Aged; D010755:Organophosphates / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068696:Rilpivirine / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068698:Tenofovir / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D010755:Organophosphates; C583447:tenofovir diphosphate; D000068698:Tenofovir; D000068696:Rilpivirine; D000068679:Emtricitabine; D000225:Adenine