14 research outputs found
Investigation of Long-acting Antiretroviral Nanoformulation Pharmacokinetics Using Experimental and Computational Methods
Antiretrovirals (ARVs) can find clinical application for both treatment and prevention of HIV infection. Pre-exposure prophylaxis (PrEP) strategies have been recently introduced to protect individuals who are at high risk of acquiring HIV infection. The majority of existing ARVs are oral formulations which necessitate lifelong daily dosing and suboptimal adherence to this dosing regimen could result in development of viral resistance against treatment. Long-acting injectable (LAI) nanoformulations administered either intramuscularly or subcutaneously could be a valuable pharmacological option. LAIs could potentially simplify dosing regimen, reducing the total amount of drug consumed thus reducing the oral cost of treatment/PrEP and most importantly addressing the problem of suboptimal adherence. The development of novel LAI therapies is complicated by several pharmacological factors including ARV pharmacokinetics and compatibility with existing formulation strategies. The overall aim of this thesis was to investigate and simulate the pharmacokinetics of LAI formulations in order to provide effective tools to inform the future development of formulations. A number of different strategies to investigate the pharmacokinetics of LAI formulations were developed in this thesis. Physiologically based pharmacokinetic (PBPK) modelling represents the mathematical description of anatomical, physiological and molecular processes that define pharmacokinetics in humans. In the recent past, PBPK models have been developed for several disease areas to simulate pharmacokinetics in humans, which currently play an active role in the design of clinical trials and regulatory approvals. In Chapter 2, human adult PBPK models have been developed and validated against clinically available pharmacokinetic data of oral formulations for eight ARVs. These validated models were then used to identify theoretical optimal dose and release rates of LAI formulations for weekly and monthly administration. Clinical studies in paediatric patients encounters ethical issues and possesses concerns during dose optimization. In Chapter 3 and 4, PBPK models have been developed and validated for children and adolescents for existing LAI formulations of cabotegravir and rilpivirine. Doses were optimised for monthly administration such that the plasma concentrations stay over the assumed target concentrations, for paediatric population according to different weight groups recommended by World Health Organisation. In Chapter 5, experimental methods (static release dialysis, sample-and-separate method and dynamic release dialysis) to evaluate the drug release rate from the site of injection were developed. The in vitro release rates were correlated with clinical release rates to obtain a mathematical equation describing the in vitro in vivo extrapolation (IVIVE) in Chapter 6. Novel computational and experimental methods to support the development and optimisation of LAI formulations are required. These findings represent valuable applications of novel methods to simulate and characterise the pharmacology of LAI formulations. The reported findings could help simplify ARV dosing strategies by providing an initial dosing guideline for clinical trials in humans. This approach could improve therapy thus addressing the problem of suboptimal adherence and reduce cost of overall treatment. PBPK models and IVIVE could be an innovative strategy to evaluate drug pharmacokinetics in humans and optimise dose and release rates of novel formulations for LAI HIV therapy
Transdermal delivery with microneedle patches using in silico modelling
Design and qualification of a microneedle array patch PBPK model for transdermal delivery and prediction of ARV pharmacokinetics using this rout
Long-acting injectable formulations for children and adolescents using PBPK modelling
Dose prediction of long-acting cabotegravir and rilpivirine in children and adolescents according to weight categorie
Simulation of long-acting administration of antituberculosis agents using pharmacokinetic modelling
Design and qualify a PBPK model for existing oral anti-TB agents. Predict pharmacokinetics of long-acting nanoformulations of anti-TB agents in adults
Simulating Intestinal Transporter and Enzyme Activity in a Physiologically Based Pharmacokinetic Model for Tenofovir Disoproxil Fumarate
Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (P-glycoprotein), and intestinal degradation (carboxylesterase). However, the influence of luminal pancreatic enzymes is not fully understood. Physiologically based pharmacokinetic (PBPK) modeling has utility for estimating drug exposure from in vitro data. This study aimed to develop a PBPK model that included luminal enzyme activity to inform dose reduction strategies. TDF and tenofovir stability in porcine pancrelipase concentrations was assessed (0, 0.48, 4.8, 48, and 480 U/ml of lipase; 1 mM TDF; 37°C; 0 to 30 min). Samples were analyzed using mass spectrometry. TDF stability and permeation data allowed calculation of absorption rates within a human PBPK model to predict plasma exposure following 6 days of once-daily dosing with 300 mg of TDF. Regional absorption of drug was simulated across gut segments. TDF was degraded by pancrelipase (half-lives of 0.07 and 0.62 h using 480 and 48 U/ml, respectively). Previously reported maximum concentration (Cmax; 335 ng/ml), time to Cmax (Tmax; 2.4 h), area under the concentration-time curve from 0 to 24 h (AUC0–24; 3,045 ng · h/ml), and concentration at 24 h (C24; 48.3 ng/ml) were all within a 0.5-fold difference from the simulated Cmax (238 ng/ml), Tmax (3 h), AUC0–24 (3,036 ng · h/ml), and C24 (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (p<0.05). These data support that TDF absorption is limited by the action of intestinal lipases. Our results suggest that bioavailability may be improved by protection of drug from intestinal transporters and enzymes, for example, by coadministration of enzyme-inhibiting agents or nanoformulation strategies
In Silico Dose Prediction for Long-Acting Rilpivirine and Cabotegravir Administration to Children and Adolescents.
Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3-18Â years) using physiologically-based pharmacokinetic modelling.Whole-body physiologically-based pharmacokinetic models were developed to represent the anatomical, physiological and molecular processes and age-related changes in children and adolescents through allometric equations. Models were validated for long-acting injectable intramuscular cabotegravir and rilpivirine in adults. Subsequently, the anatomy and physiology of children and adolescents were validated against available literature. The optimal doses of monthly administration of cabotegravir and rilpivirine were identified in children and adolescents, to achieve trough concentrations over the target concentrations derived in a recent efficacy trial of the same formulations.Pharmacokinetic data generated through the physiologically-based pharmacokinetic simulations were similar to observed clinical data in adults. Optimal doses of long-acting injectable antiretrovirals cabotegravir and rilpivirine were predicted using the release rate observed for existing clinical formulations, for different weight groups of children and adolescents. The intramuscular loading dose and maintenance dose of cabotegravir ranged from 200 to 600Â mg and from 100 to 250Â mg, respectively, and for rilpivirine it ranged from 250 to 550Â mg and from 150 to 500Â mg, respectively, across various weight groups of children ranging from 15 to 70Â kg.The reported findings represent a rational platform for the identification of suitable dosing strategies and can inform prospective clinical investigation of long-acting injectable formulations in children and adolescents
Enhancement strategies for transdermal drug delivery systems: current trends and applications
Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study
SETTING: Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues. OBJECTIVE: niazid, rifapentine, bedaquiline and delamanid—in adults for treatment for latent tuberculous infection (LTBI). DESIGN: PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution. Combinations of optimal dose and release rates were simulated such that plasma concentrations were maintained over the epidemiological cut-off or minimum inhibitory concentration for the dosing interval. RESULTS: The PBPK model identified 1500 mg of delamanid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration, if a formulation or device can deliver the required release kinetics of 0.001–0.0025 h−1 and 0.0015–0.0025 h−1, respectively. Bedaquiline and isoniazid would require weekly to biweekly intramuscular dosing. CONCLUSION: We identified the theoretical doses and release rates of LAI anti-tuberculosis formulations. Such a strategy could ease the problem of suboptimal adherence provided the associated technological complexities for LTBI treatment are addressed