Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV

2021 ◽  
Author(s):  
M Neyens ◽  
H M Crauwels ◽  
J J Perez-Ruixo ◽  
S Rossenu
Keyword(s):  
Population Pharmacokinetics ◽  
Healthy Subjects ◽  
Phase Iii ◽  
Intramuscular Administration ◽  
Population Pharmacokinetic ◽  
People Living With Hiv ◽  
Concentration Data ◽  
Flip Flop ◽  
Long Acting ◽  
Living With Hiv

Abstract Objectives To characterize the population pharmacokinetics of the rilpivirine long-acting (LA) formulation after intramuscular administration. Methods Rich and sparse rilpivirine plasma concentration data were obtained from seven clinical studies. In total, 18 261 rilpivirine samples were collected from 986 subjects (131 healthy subjects from Phase I studies and 855 people living with HIV from Phase IIb/III studies). Doses ranged from 300 to 1200 mg, as single-dose or multiple-dose regimens (every 4 or 8 weeks). In Phase III studies, an initiation injection of 900 mg followed by continuation injections of 600 mg every 4 weeks was used. Non-linear mixed-effects modelling was performed using NONMEM® software. Results A one-compartment model with linear elimination and two parallel absorption pathways (fast and slow) with sequential zero-first-order processes adequately captured rilpivirine flip-flop pharmacokinetics after intramuscular administration of the LA formulation. The estimated apparent elimination half-life of rilpivirine LA was 200 days. None of the evaluated covariates (age, body weight, BMI, sex, race, health status and needle length) had a clinically relevant impact on rilpivirine pharmacokinetics. Conclusions The population pharmacokinetic model suitably describes the time course and associated variability of rilpivirine plasma concentrations after rilpivirine LA intramuscular administration. The monthly regimen consists of an oral lead-in period (rilpivirine 25 mg tablets once daily for 4 weeks), followed by an initiation injection of 900 mg rilpivirine LA, then 600 mg rilpivirine LA continuation injections monthly. The absence of a clinically relevant effect of covariates on rilpivirine pharmacokinetics suggests that rilpivirine LA dose adjustments for specific subgroups are not warranted.

scholarly journals Population Pharmacokinetic Analysis of Fevipiprant in Healthy Subjects and Asthma Patients using a Tukey’s g-and-h Distribution

Drug Research ◽  
2021 ◽  
Author(s):  
Xinting Wang ◽  
Christian Bartels ◽  
Swarupa Kulkarni ◽  
Ramachandra Sangana ◽  
Monish Jain ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Compartment Model ◽  
Skewed Distribution ◽  
Phase Iii ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Concentration Data ◽  
First Order ◽  
Two Compartment Model ◽  
Asthma Patients

Abstract Aim The objective of this analysis was to characterize the population pharmacokinetics (PK) of fevipiprant in asthma patients and to evaluate the effect of baseline covariates on the PK of fevipiprant. Methods PK data from 1281 healthy subjects or asthma patients were available after single or once daily dosing of fevipiprant. Population PK analysis was conducted to describe fevipiprant plasma concentration data using a non-linear mixed effect modeling approach. Results Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. Exploration of fevipiprant PK in the population from the phase III studies revealed an over-dispersed and skewed distribution. This unusual distribution was described using Tukey’s g-and-h distribution (TGH) on the between-subject variability of apparent clearance (CL/F). The model identified a significant impact of disease status on CL/F, with the value in healthy subjects being 62% higher than that in asthma patients. Bodyweight, age and renal function showed statistically significant impact on fevipiprant clearance; however, compared with a typical asthma patient, the simulated difference in steady-state exposure was at most 16%. Conclusion Fevipiprant PK was described by a two-compartment model with first-order absorption and first-order elimination. The TGH distribution was appropriate to describe the over-dispersed and skewed PK data as observed in the current studies. Asthma patients had approximately 37% higher exposure than healthy subjects did. Other covariates changed exposure by at most 16%.

Factors associated with interest in a long-acting HIV regimen: perspectives of people living with HIV and healthcare providers in four European countries

2021 ◽  
pp. sextrans-2020-054648
Author(s):  
Babatunde Akinwunmi ◽  
Daniel Buchenberger ◽  
Jenny Scherzer ◽  
Martina Bode ◽  
Paolo Rizzini ◽  
...  
Keyword(s):  
Unmet Needs ◽  
Resource Constraints ◽  
Hiv Treatment ◽  
Transmission Risk ◽  
People Living With Hiv ◽  
Privacy Concerns ◽  
Medical Needs ◽  
Suboptimal Adherence ◽  
Long Acting ◽  
Living With Hiv

ObjectivesA novel long-acting regimen (LAR) of cabotegravir and rilpivirine for HIV treatment requires dosing every 2 months instead of daily. We assessed what proportion of people living with HIV and physicians would be interested in trying and offering LAR respectively and why.Methods688 people living with HIV on treatment, and 120 HIV physicians completed web-based surveys in Germany, Italy, the UK and France during 2019. Balanced description of a hypothetical LAR regarding efficacy, administration and possible side effects were provided. The hypothetical long-acting injections were assumed to be cost-neutral to current daily oral antiretrovirals. Interest of people living with HIV in trying (‘very’/’highly’) and physicians’ willingness to offer (‘definitely’/’probably’) this LAR in different situations, with perceived benefits/concerns was measured.ResultsOf people living with HIV, 65.8% were interested in trying LAR. The majority (~80%–90%) of those with unmet needs felt LAR would help, including those with strong medical needs (malabsorption and interfering gastrointestinal conditions), suboptimal adherence, confidentiality/privacy concerns and emotional burden of daily dosing. Of physicians, percentage willing to offer LAR varied situationally: strong medical need (dysphagia, 93.3%; malabsorption, 91.6%; interfering gastrointestinal issues, 90.0%; central nervous system disorders, 87.5%); suboptimal adherence (84.2%); confidentiality/privacy concerns (hiding medications, 86.6%) and convenience/lifestyle (84.2%). People living with HIV liked LAR for not having to carry pills when travelling (56.3%); physicians liked the increased patient contact (54.2%). Furthermore, 50.0% of people living with HIV perceived LAR would minimise transmission risk and improve their sexual health. The most disliked attribute was scheduling appointments (37.2%) and resource constraints (57.5%) for people living with HIV and physicians, respectively. Physicians estimated 25.7% of their patients would actually switch.ConclusionProviders and people living with HIV viewed the described LAR as addressing several unmet needs. Alternative treatment routes and especially LAR may improve adherence and quality of life.

scholarly journals 2497. Women’s Perspectives on and Experiences with Long-acting Injectable Anti-retroviral Therapy in the United States and Spain: the Potential Role of Gender in Patient Preferences

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S866-S866
Author(s):  
Andrea R Mantsios ◽  
Miranda Murray ◽  
Tahilin Sanchez Karver ◽  
Wendy Davis ◽  
David Margolis ◽  
...  
Keyword(s):  
United States ◽  
The United States ◽  
Phase Iii ◽  
Future Research ◽  
People Living With Hiv ◽  
Full Time ◽  
Daily Lives ◽  
Provider Perspectives ◽  
Long Acting ◽  
Trial Participants

Abstract Background Adherence to antiretroviral therapy (ART) to treat HIV remains a critical global health challenge given its relationship with individual health outcomes and population-level transmission. Given barriers associated with oral ART adherence, and considerations of patients’ preferences, long-acting injectable (LA) ART (cabotegravir + rilpivirine) is under development and has been shown to be non-inferior to daily oral ART in Phase III trials. While most of the trial participants have been men, as LA ART gets closer to becoming available for routine clinical use, it is critical to understand how this option is perceived by women. Methods We conducted in-depth interviews with 67 individuals, 53 people living with HIV (PLHIV) and 14 healthcare providers, in 11 sites in the United States and Spain participating in Phase III LA ART trials (ATLAS, ATLAS 2-M and FLAIR). Twenty percent (10/53) of trial participants interviewed were women. Interviews explored patient and provider perspectives and experiences with LA ART, and appropriate candidates and recommendations to support use. Interviews were audio-recorded, transcribed and coded using thematic content analysis. Results Overall, several salient themes emerged regarding participant’s generally positive experiences transitioning from daily oral ART to injectable ART including: the importance of the clinical efficacy of LA ART, the ability to learn to manage injection side-effects over time, and the “freedom” reportedly afforded by LA ART logistically and psychosocially. Women interviewed shared many of the aforementioned positive perceptions of LA ART but also had some unique perspectives. Female participants discussed how LA ART was easier to integrate into their daily lives including managing their multiple roles and responsibilities, which often involved working full-time and taking care of themselves as well as their family and children. Conclusion Similar to all participants, female participants had generally positive views of LA ART. However, the gendered nature of their daily lives also led to some unique perspectives on why and how they were satisfied with LA ART that merits further exploration in future research. Disclosures All authors: No reported disclosures.

scholarly journals Population Pharmacokinetics of Amikacin in Adult Patients with Cystic Fibrosis

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Sílvia M. Illamola ◽  
Hoa Q. Huynh ◽  
Xiaoxi Liu ◽  
Zubin N. Bhakta ◽  
Catherine M. Sherwin ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Population Pharmacokinetics ◽  
Drug Disposition ◽  
Adult Patients ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Concentration Data ◽  
First Order ◽  
Dosing Regimens ◽  
Pulmonary Exacerbations

ABSTRACTPractitioners commonly use amikacin in patients with cystic fibrosis. Establishment of the pharmacokinetics of amikacin in adults with cystic fibrosis may increase the efficacy and safety of therapy. This study was aimed to establish the population pharmacokinetics of amikacin in adults with cystic fibrosis. We used serum concentration data obtained during routine therapeutic drug monitoring and explored the influence of patient covariates on drug disposition. We performed a retrospective chart review to collect the amikacin dosing regimens, serum amikacin concentrations, blood sampling times, and patient characteristics for adults with cystic fibrosis admitted for treatment of acute pulmonary exacerbations. Amikacin concentrations were retrospectively collected for 49 adults with cystic fibrosis, and 192 serum concentrations were available for analysis. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling with the first-order conditional estimation method. A two-compartment model with first-order elimination best described amikacin pharmacokinetics. Creatinine clearance and weight were identified as significant covariates for clearance and the volume of distribution, respectively, in the final model. Residual variability was modeled using a proportional error model. Typical estimates for clearance, central and peripheral volumes of distribution, and intercompartmental clearance were 3.06 liters/h, 14.4 liters, 17.1 liters, and 0.925 liters/h, respectively. The pharmacokinetics of amikacin in individuals with cystic fibrosis seems to differ from those in individuals without cystic fibrosis. However, further investigations are needed to confirm these results and, thus, the need for variations in amikacin dosing. Future pharmacodynamic studies will potentially establish the optimal amikacin dosing regimens for the treatment of acute pulmonary exacerbations in adult patients with CF.

Dolutegravir Population Pharmacokinetics in a Real-Life Cohort of People Living With HIV Infection

2019 ◽  
Vol 41 (4) ◽  
pp. 444-451 ◽  
Author(s):  
François Parant ◽  
Patrick Miailhes ◽  
Florence Brunel ◽  
Marie-Claude Gagnieu
Keyword(s):  
Hiv Infection ◽  
Population Pharmacokinetics ◽  
Real Life ◽  
People Living With Hiv ◽  
Living With Hiv

scholarly journals Reasons People Living with HIV Might Prefer Oral Daily Antiretroviral Therapy, Long-Acting Formulations, or Future HIV Remission Options

2020 ◽  
Vol 36 (12) ◽  
pp. 1054-1058
Author(s):  
Karine Dubé ◽  
Danielle M. Campbell ◽  
Kelly E. Perry ◽  
John T. Kanazawa ◽  
Parya Saberi ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
People Living With Hiv ◽  
Long Acting ◽  
Living With Hiv

scholarly journals Patient-Reported Outcomes in ATLAS and FLAIR Participants on Long-Acting Regimens of Cabotegravir and Rilpivirine Over 48 Weeks

2020 ◽  
Vol 24 (12) ◽  
pp. 3533-3544 ◽  
Author(s):  
Miranda Murray ◽  
Antonio Antela ◽  
Anthony Mills ◽  
Jenny Huang ◽  
Hans Jäger ◽  
...  
Keyword(s):  
Treatment Satisfaction ◽  
Oral Therapy ◽  
Oral Treatment ◽  
Patient Reported Outcome ◽  
Treatment Preference ◽  
People Living With Hiv ◽  
Injection Site Reactions ◽  
Patient Reported ◽  
Long Acting ◽  
Living With Hiv

AbstractThe phase 3 ATLAS and FLAIR studies demonstrated that maintenance with Long-Acting (LA) intramuscular cabotegravir and rilpivirine is non-inferior in efficacy to current antiretroviral (CAR) oral therapy. Both studies utilized Patient-Reported Outcome instruments to measure treatment satisfaction (HIVTSQ) and acceptance (ACCEPT general domain), health status (SF-12), injection tolerability/acceptance (PIN), and treatment preference. In pooled analyses, LA-treated patients (n = 591) demonstrated greater mean improvements from baseline than the CAR group (n = 591) in treatment satisfaction (Week 44, + 3.9 vs. +0.5 HIVTSQs-points; p < 0.001) and acceptance (Week 48, +8.8 vs. +2.0 ACCEPT-points; p < 0.001). The acceptability of injection site reactions (PIN) significantly improved from week 5 (2.10 points) to week 48 (1.62 points; p < 0.001). In both studies, ≥ 97% of LA group participants with recorded data preferred LA treatment compared with prior oral therapy. These results further support the potential of a monthly injectable option for people living with HIV seeking an alternative to daily oral treatment.

Population pharmacokinetic modeling and simulations of dopamine Dd2 receptor occupancy of long-acting intramuscular risperidone-ISM

2016 ◽  
Vol 33 (S1) ◽  
pp. S572-S572
Author(s):  
J. Llaudó ◽  
L. Anta ◽  
I. Ayani ◽  
J. Martínez-González ◽  
I. Gutierro ◽  
...  
Keyword(s):  
Steady State ◽  
Dopamine D2 Receptor ◽  
Plasma Concentrations ◽  
Phase Iii ◽  
Population Pharmacokinetic ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Population Pharmacokinetic Modeling ◽  
Population Pk ◽  
Long Acting

IntroductionRisperidone-ISM is a new long-acting intramuscular formulation intended to achieve sustained plasma concentrations over 4 weeks without oral supplementation. The clinical efficacy to risperidone has been associated with 65–80% occupancy of dopamine D2 receptor (D2RO) and a mean Cmax between 7.5 ng/mL and 80 ng/mL.AimUse a population PK/PD model to predict the PK and the D2RO for Risperidone-ISM in schizophrenic patients and to characterize the relationship among doses, in order to guide dose selection for a future Phase-III trial.MethodsA population PK/PD analysis for Risperidone-ISM using Monolix software was conducted based on 6641 plasma samples from two Phase-I studies (17 healthy subjects and 31 schizophrenic subjects, respectively) and 1 Phase-II study (60 schizophrenic subjects). Simulations were subsequently undertaken predicting the steady state PK and D2RO after multiple Risperidone-ISM doses administered every 28 days for 12 weeks.ResultsDoses of 75 and 100 mg, administered either in gluteal or deltoid muscle, were predicted to result in median Cmax and Ctrough that stayed between 7.5 ng/mL and 80 ng/mL. At steady state 75 mg and 100 mg dose (gluteal) achieved a D2RO average [min–max] of 70.8% [61.4–80.4] and 74.3% [66.2–82.1], respectively; a 75-mg and 100-mg dose (deltoid) achieved a D2RO average [min–max] of 69.3% [56.5–80.3] and 73.0% [61.8–82.1], respectively. The model estimated that the 65% D2RO occurs within first 8 h after treatment.ConclusionsSimulations were carried out supporting doses of 75 mg and 100 mg Risperidone-ISM to show the greatest efficacy and safety potential to be assessed in the future Phase-III trial.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Optimizing gentamicin dosing in different pediatric age groups using population pharmacokinetics and Monte Carlo simulation

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Ragia H. Ghoneim ◽  
Abrar K. Thabit ◽  
Manar O. Lashkar ◽  
Ahmed S. Ali
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Population Pharmacokinetics ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Concentration Data ◽  
Once Daily ◽  
Dosing Regimens ◽  
Gentamicin Concentration

Abstract Introduction The use of once daily dosing of aminoglycosides in pediatrics is increasing but studies on dose optimization targeting the pediatric population are limited. This study aimed to derive a population pharmacokinetic model of gentamicin and apply it to design optimal dosing regimens in pediatrics. Methods Population pharmacokinetics of gentamicin in pediatrics was described from a retrospective chart review of plasma gentamicin concentration data (peak/ trough levels) of pediatric patients (1 month − 12 years), admitted to non-critically ill pediatrics. Monte Carlo simulations were performed on the resulting pharmacokinetic model to assess the probability of achieving a Cmax/MIC target of 10 mg/L over a range of gentamicin MICs of 0.5–2 mg/L and once daily gentamicin dosing regimens. Results: A two-compartment model with additive residual error best described the model with weight incorporated as a significant covariate for both clearance and volume of distribution. Monte Carlo simulations demonstrated a good probability of target attainment even at a MIC of 2 mg/L, where neonates required doses of 6-7 mg/kg/day and older pediatrics required lower daily doses of 4–5 mg/kg/day while maintaining trough gentamicin concentration below the toxicity limit of 1 mg/L. Conclusion: Once daily dosing is a reasonable option in pediatrics that allows target attainment while maintaining trough gentamicin level below the limits of toxicity.

scholarly journals Population Pharmacokinetic and Pharmacodynamic Analysis To Evaluate a Switch to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate in People Living with HIV-1

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Pavan Vaddady ◽  
Bhargava Kandala ◽  
Ka Lai Yee
Keyword(s):  
Transcriptase Inhibitor ◽  
Population Pharmacokinetic ◽  
People Living With Hiv ◽  
Shift Trial ◽  
Treatment Naïve ◽  
Post Hoc ◽  
Living With Hiv ◽  
Reverse Transcriptase Inhibitor ◽  
Parameter Values ◽  
Hiv 1

ABSTRACT Doravirine is a non-nucleoside reverse transcriptase inhibitor for treatment of human immunodeficiency virus type 1 (HIV-1) infection. A population pharmacokinetic (PK) model for treatment-naive participants in doravirine clinical studies was updated with data from switch participants in the DRIVE-SHIFT trial and used to estimate individual post hoc PK parameter values and evaluate the efficacy exposure-response relationship. The results support the 100-mg dose for people living with HIV switching to a doravirine-based regimen (This study has been registered at ClinicalTrials.gov under ClinicalTrials registration no. NCT02397096.)

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