PMID- 37522811
OWN - NLM
STAT- MEDLINE
DCOM- 20231127
LR  - 20240305
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Linking)
VI  - 89
IP  - 12
DP  - 2023 Dec
TI  - Intramuscular cabotegravir and rilpivirine concentrations after switching from 
      efavirenz-containing regimen.
PG  - 3618-3628
LID - 10.1111/bcp.15867 [doi]
AB  - AIMS: Intramuscular cabotegravir/rilpivirine (IM CAB/RPV) are metabolized by 
      UGT1A1/CYP3A4. Efavirenz induces both enzymes; therefore, switching from an 
      efavirenz-containing regimen to IM CAB/RPV could possibly result in suboptimal 
      levels. Due to their long dosing interval, clinical studies with IM CAB/RPV are 
      challenging. We used physiologically based pharmacokinetics (PBPK) modelling to 
      simulate the switch from efavirenz to IM CAB/RPV. METHODS: First, we developed 
      the drug models and verified the performance of the PBPK model to predict the 
      pharmacokinetics of IM cabotegravir, IM rilpivirine and efavirenz by comparing 
      the simulations against observed clinical data. Second, we verified the ability 
      of the model to predict the effect of residual induction with observed data for 
      the switch from efavirenz to dolutegravir or rilpivirine. Finally, we generated a 
      cohort of 100 virtual individuals (20-50 years, 50% female, 18.5-30 kg/m(2) ) to 
      simulate IM CAB/RPV concentrations after discontinuing efavirenz in extensive and 
      slow metabolizers of efavirenz. RESULTS: IM CAB concentrations were predicted to 
      decrease by 11% (95% confidence interval 7-15%), 13% (6-21%) and 8% (0-18%) at 
      day 1, 7 and 14 after efavirenz discontinuation. CAB concentrations were 
      predicted to remain above the minimal efficacy threshold (i.e., 664 ng/mL) 
      throughout the switch period both in extensive and slow metabolizers of 
      efavirenz. Similarly, IM RPV concentrations were modestly decreased with the 
      lowest reduction being 10% (6-14%) on day 7 post last efavirenz dose. CONCLUSION: 
      Our simulations indicate that switching from an efavirenz-containing regimen to 
      IM CAB/RPV does not put at risk of having a time window with suboptimal drug 
      levels.
CI  - (c) 2023 The Authors. British Journal of Clinical Pharmacology published by John 
      Wiley & Sons Ltd on behalf of British Pharmacological Society.
FAU - Bettonte, Sara
AU  - Bettonte S
AUID- ORCID: 0000-0002-7532-7898
AD  - Division of Infectious Diseases and Hospital Epidemiology, Departments of 
      Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
AD  - Faculty of Medicine, University of Basel, Basel, Switzerland.
FAU - Berton, Mattia
AU  - Berton M
AUID- ORCID: 0000-0001-9450-2228
AD  - Division of Infectious Diseases and Hospital Epidemiology, Departments of 
      Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
AD  - Faculty of Medicine, University of Basel, Basel, Switzerland.
FAU - Stader, Felix
AU  - Stader F
AUID- ORCID: 0000-0002-4223-6754
AD  - Certara UK Limited, Sheffield, UK.
FAU - Battegay, Manuel
AU  - Battegay M
AUID- ORCID: 0000-0002-6638-3679
AD  - Division of Infectious Diseases and Hospital Epidemiology, Departments of 
      Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
AD  - Faculty of Medicine, University of Basel, Basel, Switzerland.
FAU - Marzolini, Catia
AU  - Marzolini C
AUID- ORCID: 0000-0002-2312-7050
AD  - Division of Infectious Diseases and Hospital Epidemiology, Departments of 
      Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.
AD  - Faculty of Medicine, University of Basel, Basel, Switzerland.
AD  - Department of Molecular and Clinical Pharmacology, University of Liverpool, 
      Liverpool, UK.
LA  - eng
GR  - 188504/Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen 
      Forschung/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230816
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - FI96A8X663 (Rilpivirine)
RN  - JE6H2O27P8 (efavirenz)
RN  - HMH0132Z1Q (cabotegravir)
RN  - 0 (Anti-Retroviral Agents)
RN  - 0 (Benzoxazines)
RN  - 0 (Anti-HIV Agents)
SB  - IM
MH  - Humans
MH  - Female
MH  - Male
MH  - Rilpivirine/therapeutic use
MH  - *HIV Infections/drug therapy
MH  - Anti-Retroviral Agents/therapeutic use
MH  - Benzoxazines/therapeutic use
MH  - *Anti-HIV Agents/pharmacokinetics
OTO - NOTNLM
OT  - PBPK modelling, pharmacokinetics
OT  - drug-drug interaction
OT  - efavirenz
OT  - long-acting cabotegravir
OT  - long-acting rilpivirine
EDAT- 2023/07/31 13:08
MHDA- 2023/11/27 12:41
CRDT- 2023/07/31 09:53
PHST- 2023/07/17 00:00 [revised]
PHST- 2023/01/19 00:00 [received]
PHST- 2023/07/26 00:00 [accepted]
PHST- 2023/11/27 12:41 [medline]
PHST- 2023/07/31 13:08 [pubmed]
PHST- 2023/07/31 09:53 [entrez]
AID - 10.1111/bcp.15867 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2023 Dec;89(12):3618-3628. doi: 10.1111/bcp.15867. Epub 2023 
      Aug 16.