Drug interaction profile of the HIV integrase inhibitor cabotegravir: assessment fromin vitrostudies and a clinical investigation with midazolam

Xenobiotica ◽  
2015 ◽  
Vol 46 (5) ◽  
pp. 445-456 ◽  
Author(s):  
Melinda J. Reese ◽  
Gary D. Bowers ◽  
Joan E. Humphreys ◽  
Elizabeth P. Gould ◽  
Susan L. Ford ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Clinical Investigation ◽  
Integrase Inhibitor ◽  
Hiv Integrase

Antiretroviral concentrations in the presence and absence of valproic acid

2020 ◽  
Vol 75 (7) ◽  
pp. 1969-1971
Author(s):  
A Calcagno ◽  
J Cusato ◽  
M Ferrara ◽  
A De Nicolò ◽  
A Lazzaro ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Drug Interaction ◽  
Plasma Concentrations ◽  
Integrase Inhibitor ◽  
Major Effect ◽  
Therapeutic Drug ◽  
Hiv Integrase ◽  
Drug Drug Interaction ◽  
Underlying Mechanisms ◽  
Protein Displacement

Abstract Objectives An unexpected drug–drug interaction has been recently reported between dolutegravir, an HIV integrase inhibitor, and valproic acid. Despite there being several potential underlying mechanisms, plasma protein displacement has been suggested. The aim of this study was to assess plasma concentrations of several antiretrovirals when administered with or without valproic acid. Methods We performed a therapeutic drug monitoring registry analysis and identified patients concomitantly taking antiretrovirals and valproic acid and without clinical affecting conditions or interacting drugs. Results One hundred and thirty-four patients were identified. Median (IQR) age and BMI were 49.7 years (45–56) and 23.4 kg/m2 (20.8–26.3) and 78 were male (58.2%). Despite small groups, we observed no major effect on antiretroviral exposure, even when considering highly protein-bound compounds (such as etravirine), with the exception of dolutegravir trough concentrations [median (IQR) = 132 ng/mL (62–227) in individuals on valproic acid versus 760 ng/mL (333–1407) in those not receiving valproic acid]. Conclusions Valproic acid does not have a major effect on antiretrovirals other than dolutegravir. The mechanism of this unexpected drug–drug interaction may be the combination of protein displacement, reduced absorption and CYP3A4 induction.

Novel Second Generation HIV Integrase Inhibitor-DOLUTEGRAVIR: An Emerging Weapon Against HIV

2017 ◽  
Vol 14 (3) ◽  
pp. 354-371 ◽  
Author(s):  
Vivek Jain ◽  
Diksha Gupta ◽  
Ashutosh Pareek ◽  
Yashumati Ratan
Keyword(s):  
Second Generation ◽  
Integrase Inhibitor ◽  
Hiv Integrase

scholarly journals No difference in HIV-1 integrase inhibitor resistance between CSF and blood compartments

2021 ◽  
Author(s):  
Basma Abdi ◽  
Mouna Chebbi ◽  
Marc Wirden ◽  
Elisa Teyssou ◽  
Sophie Sayon ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Routine Care ◽  
Biological Data ◽  
Recombinant Form ◽  
Hiv Integrase ◽  
Resistance Mutations ◽  
Clinical Routine ◽  
Inhibitor Resistance ◽  
Hiv 1

Abstract Background Little is known about HIV-1 integrase inhibitor resistance in the CNS. Objectives This study aimed to evaluate integrase inhibitor resistance in CSF, as a marker of the CNS, and compare it with the resistance in plasma. Methods HIV integrase was sequenced both in plasma and CSF for 59 HIV-1 patients. The clinical and biological data were collected from clinical routine care. Results Among the 59 HIV-1 patients, 32 (54.2%) were under antiretroviral (ARV) treatment. The median (IQR) HIV-1 RNA in the plasma of viraemic patients was 5.32 (3.85–5.80) and 3.59 (2.16–4.50) log10 copies/mL versus 4.79 (3.56–5.25) and 3.80 (2.68–4.33) log10 copies/mL in the CSF of ARV-naive and ARV-treated patients, respectively. The patients were mainly infected with non-B subtypes (72.2%) with the most prevalent recombinant form being CRF02_AG (42.4%). The HIV-1 integrase sequences from CSF presented resistance mutations for 9/27 (33.3%) and 8/32 (25.0%) for ARV-naive (L74I, n = 3; L74I/M, n = 1; T97A, n = 1; E157Q, n = 4) and ARV-treated (L74I, n = 6; L74M, n = 1; T97A, n = 1; N155H, n = 1) patients, respectively. Integrase inhibitor resistance mutations in CSF were similar to those in plasma, except for 1/59 patients. Conclusions This work shows similar integrase inhibitor resistance profiles in the CNS and plasma in a population of HIV-1 viraemic patients.

Radiosynthesis of the HIV integrase inhibitor [18F]MK-0518 (Isentress)

2010 ◽  
pp. n/a-n/a ◽  
Author(s):  
Wenping Li ◽  
Wayne Thompson ◽  
Thorsten Fisher ◽  
John S. Wai ◽  
Daria Hazuda ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Hiv Integrase

scholarly journals Quantum Mechanical-Based Stability Evaluation of Crystal Structures for HIV-Targeted Drug Cabotegravir

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7178
Author(s):  
Yanqiang Han ◽  
Hongyuan Luo ◽  
Qianqian Lu ◽  
Zeying Liu ◽  
Jinyun Liu ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Ab Initio ◽  
Crystal Structures ◽  
Structure Prediction ◽  
Hiv Infections ◽  
Integrase Inhibitor ◽  
Hiv Integrase ◽  
Stability Evaluation ◽  
The Stability ◽  
Long Acting

The long-acting parenteral formulation of the HIV integrase inhibitor cabotegravir (GSK744) is currently being developed to prevent HIV infections, benefiting from infrequent dosing and high efficacy. The crystal structure can affect the bioavailability and efficacy of cabotegravir. However, the stability determination of crystal structures of GSK744 have remained a challenge. Here, we introduced an ab initio protocol to determine the stability of the crystal structures of pharmaceutical molecules, which were obtained from crystal structure prediction process starting from the molecular diagram. Using GSK744 as a case study, the ab initio predicted that Gibbs free energy provides reliable further refinement of the predicted crystal structures and presents its capability for becoming a crystal stability determination approach in the future. The proposed work can assist in the comprehensive screening of pharmaceutical design and can provide structural predictions and stability evaluation for pharmaceutical crystals.

scholarly journals Synthesis of the spiroketal core of integramycin

2013 ◽  
Vol 9 ◽  
pp. 2446-2450
Author(s):  
Evgeny V Prusov
Keyword(s):  
Integrase Inhibitor ◽  
Protecting Groups ◽  
Hiv Integrase ◽  
Acylation Reaction ◽  
Synthetic Strategy

A concise synthetic strategy towards the spiroketal core of the HIV-integrase inhibitor integramycin (1) was developed. The required ketone precursor was efficiently constructed from two simple and easily accessible subunits by means of a hydrozirconation/copper catalyzed acylation reaction. The effects of different protecting groups on the spiroketalization step were also investigated.

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