Long‐acting injectable Cabotegravir: How drug concentrations could help guide patient management

Castillo‐Mancilla, José; Anderson, Peter L.

doi:10.1111/bcp.15410

Cited by 2 publications

(4 citation statements)

References 9 publications

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“…Finally, the PBPK model simulated the ideal clinical scenario in which all virtual individuals received the injection in the muscle, whereas real-world data have shown injection site variability [ 31 ]. Thus, our model does not reproduce the variability reported in real-world studies [ 25 , 32 , 33 ], which was not always explained by differences in BMI [ 34 ]. As matter of fact, young and older individuals with similar BMIs may have different tissue distributions [ 35 ] which may increase the risk of receiving the injection in the adipose tissue rather than the muscle.…”

Section: Discussionmentioning

confidence: 63%

“…As matter of fact, young and older individuals with similar BMIs may have different tissue distributions [ 35 ] which may increase the risk of receiving the injection in the adipose tissue rather than the muscle. Moreover, the variability could be related to changes in blood flow [ 33 , 34 ]. Thus, further data are needed to investigate the source of variability in the pharmacokinetics of LA injectables together with the related drug response in both young and older PWH.…”

Section: Discussionmentioning

confidence: 99%

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Drug Exposure of Long-Acting Cabotegravir and Rilpivirine in Older People With Human Immunodeficiency Virus: A Pharmacokinetic Modeling Study

Bettonte,

Berton,

Stader

et al. 2024

Open Forum Infectious Diseases

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Background The life expectancy of people with human immunodeficiency virus (PWH) has significantly increased, thanks to combined antiretrovirals with improved potency and tolerability. One further step has been achieved with the development of long-acting (LA) injectable antiretrovirals, which allow for infrequent dosing. However, the pharmacokinetics of LA antiretrovirals has been poorly characterized in older PWH, as they are generally excluded from trials. We performed virtual studies using physiologically based pharmacokinetic (PBPK) modeling to determine the anticipated exposure of LA cabotegravir/rilpivirine in older individuals. Methods Our PBPK model was verified against available observed data for LA cabotegravir and rilpivirine. Cohorts of virtual individuals aged 20–50, 50–65, or 65–85 years were generated to simulate the exposure of LA cabotegravir/rilpivirine for each age group. The fold changes in trough concentration (Cmin) and in drug exposure (area under the time-concentration curve [AUC]) were determined for older relative to young individuals. Results The verified PBPK models predicted an increase in exposure within the 0.8–1.25 fold range for monthly LA cabotegravir/rilpivirine. The Cmin and AUC were predicted to be 29% and 26% higher in older compared with young adults for LA cabotegravir administered bimonthly (every 2 months) and 46% and 41% higher for LA rilpivirine bimonthly. The Cmin and AUC of LA cabotegravir and rilpivirine were predicted to be modestly increased in female compared with male individuals for all age groups. Conclusions LA cabotegravir/rilpivirine exposure and trough concentrations are predicted to be higher in older than in young PWH; thus, older adults could have a lower risk to present suboptimal concentrations during the dosing interval.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Drug Exposure of Long-Acting Cabotegravir and Rilpivirine in Older People With Human Immunodeficiency Virus: A Pharmacokinetic Modeling Study

Bettonte,

Berton,

Stader

et al. 2024

Open Forum Infectious Diseases

View full text Add to dashboard Cite

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“…The real-world studies, including controlled clinical trials, have shown a large interindividual variability in drug concentrations. 21,44 This variability relates to factors that were not included in the model, such as the ventrogluteal injection site (i.e., in realworld practice, the injected drug does not always reach the muscle but can be deposited in the subcutaneous tissue), injection technique (i.e., a longer needle length needs to be used in obese individuals which is not always done in practice), and split injections (i.e., splitting the injected dose was shown to increase the drug absorption). 45,46 The sensitivity analysis demonstrated that the drug release from the depot is influenced by the physicochemical properties of the drug and by the physiology of the injection site.…”

Section: Discussionmentioning

confidence: 99%

“…The predictions were within twofold of the observed clinical data; however, the population variability was underpredicted by the model as it assumes that the drug always reaches the muscle. The real‐world studies, including controlled clinical trials, have shown a large interindividual variability in drug concentrations 21,44 . This variability relates to factors that were not included in the model, such as the ventrogluteal injection site (i.e., in real‐world practice, the injected drug does not always reach the muscle but can be deposited in the subcutaneous tissue), injection technique (i.e., a longer needle length needs to be used in obese individuals which is not always done in practice), and split injections (i.e., splitting the injected dose was shown to increase the drug absorption) 45,46 …”

Section: Discussionmentioning

confidence: 99%

Development of a physiologically‐based pharmacokinetic model to simulate the pharmacokinetics of intramuscular antiretroviral drugs

Bettonte,

Berton,

Battegay

et al. 2024

CPT Pharmacom & Syst Pharma

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There is growing interest in the use of long‐acting (LA) injectable drugs to improve treatment adherence. However, their long elimination half‐life complicates the conduct of clinical trials. Physiologically‐based pharmacokinetic (PBPK) modeling is a mathematical tool that allows to simulate unknown clinical scenarios for LA formulations. Thus, this work aimed to develop and verify a mechanistic intramuscular PBPK model. The framework describing the release of a LA drug from the depot was developed by including both the physiology of the injection site and the physicochemical properties of the drug. The framework was coded in Matlab® 2020a and implemented in our existing PBPK model for the verification step using clinical data for LA cabotegravir, rilpivirine, and paliperidone. The model was considered verified when the simulations were within twofold of observed data. Furthermore, a local sensitivity analysis was conducted to assess the impact of various factors relevant for the drug release from the depot on pharmacokinetics. The PBPK model was successfully verified since all predictions were within twofold of observed clinical data. Peak concentration, area under the concentration‐time curve, and trough concentration were sensitive to media viscosity, drug solubility, drug density, and diffusion layer thickness. Additionally, inflammation was shown to impact the drug release from the depot. The developed framework correctly described the release and the drug disposition of LA formulations upon intramuscular administration. It can be implemented in PBPK models to address pharmacological questions related to the use of LA formulations.

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Long‐acting injectable Cabotegravir: How drug concentrations could help guide patient management

Cited by 2 publications

References 9 publications

Drug Exposure of Long-Acting Cabotegravir and Rilpivirine in Older People With Human Immunodeficiency Virus: A Pharmacokinetic Modeling Study

Drug Exposure of Long-Acting Cabotegravir and Rilpivirine in Older People With Human Immunodeficiency Virus: A Pharmacokinetic Modeling Study

Development of a physiologically‐based pharmacokinetic model to simulate the pharmacokinetics of intramuscular antiretroviral drugs

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