scholarly journals Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir

2020 ◽  
Author(s):  
Parul Patel ◽  
Zhengyu Xue ◽  
Karen S King ◽  
Laura Parham ◽  
Susan Ford ◽  
...  
Keyword(s):  
Dose Adjustment ◽  
Total Bilirubin ◽  
Safety Data ◽  
Integrase Inhibitor ◽  
Clinical Development ◽  
Hiv Integrase ◽  
Two Phase ◽  
Functional Variants ◽  
Maximum Change ◽  
Long Acting

Abstract Background Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure. Objectives To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks). Methods Plasma cabotegravir PK was assessed in 346 UGT-genotyped participants with and without UGT1A1 functional variants across six studies (four Phase I and two Phase II) of oral cabotegravir, including 215 HIV-infected participants who received oral cabotegravir followed by cabotegravir LA. Changes from baseline in total bilirubin and ALT were assessed in one study (LATTE; NCT01641809). Results Statistically significant (P < 0.05) associations were observed between UGT1A1 genotype and plasma cabotegravir PK parameters, with 28%–50% increases following oral cabotegravir [plasma cabotegravir concentration at the end of the dosing interval (Ctau), 1.50-fold; AUCtau, 1.41-fold; and Cmax, 1.28-fold] and 16%–24% increases following cabotegravir LA administration (48 week Ctau, 1.24-fold; AUCtau, 1.16-fold; and Cmax, 1.18-fold) among those with low-versus-normal genetically predicted UGT1A1 activity. A statistically significant (P < 10−5) association between predicted UGT1A1 activity and maximum change in total bilirubin was also observed (2.45-fold asymptomatic increase for low versus normal) without a corresponding change in ALT. Conclusions This modest increase in oral and parenteral cabotegravir exposure associated with a reduced function of UGT1A1 is not considered clinically relevant based on accumulated safety data; no dose adjustment is required.

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 Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV-infected adults

2019 ◽  
Vol 75 (3) ◽  
pp. 648-655 ◽  
Author(s):  
Scott L Letendre ◽  
Anthony Mills ◽  
Debbie Hagins ◽  
Susan Swindells ◽  
Franco Felizarta ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Steady State ◽  
Antiviral Activity ◽  
Plasma Concentrations ◽  
Integrase Inhibitor ◽  
Virological Suppression ◽  
Hiv Integrase ◽  
Long Acting ◽  
Hiv 1

Abstract Background Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression. Objectives To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352). Methods Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA <50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays. Results Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA <50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA <2 copies/mL in CSF. Conclusions A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.

scholarly journals Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection

2014 ◽  
Vol 59 (1) ◽  
pp. 397-406 ◽  
Author(s):  
Tomokazu Yoshinaga ◽  
Masanori Kobayashi ◽  
Takahiro Seki ◽  
Shigeru Miki ◽  
Chiaki Wakasa-Morimoto ◽  
...  
Keyword(s):  
Synergistic Effects ◽  
Integrase Inhibitor ◽  
Culture Conditions ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Hiv Replication ◽  
Data Set ◽  
Long Acting ◽  
Anti Hiv

ABSTRACTGSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. Thein vitroantiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC50) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC50relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC50for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier INSTIs, RAL, and elvitegravir (EVG). The collective data set supports further clinical development of GSK1265744.

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
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