Integrated Experimental and Computational Approaches for the Prediction of Drug-Drug Interactions

People living with HIV (PLWH) are highly susceptible to drug-drug interactions (DDIs) due to the increased risk of coinfections and comorbidities. Antiretroviral (ARV) drugs used for the treatment of HIV can be both victims and perpetrators of DDIs with potential effects on drug exposure leading to reduced efficacy and toxicity. Transporters have been identified as key mediators of drug pharmacokinetics however their role in DDIs remains unclear due to our current paucity of knowledge. The complexities surrounding the clinical management of DDIs in PLWH is further hindered by a lack of evidence-based guidance for many drug combinations. The aim of this thesis was to utilise in vitro and in silico techniques to explore the role of transporters in DDIs as well as investigate the magnitude of potential DDIs in PLWH that currently have no clinical data to support their management. Uptake and efflux transporters facilitate the clearance of drugs in the liver however, due to the complex interplay with enzymes along with non-specific probe substrates and inhibitors, their role in clinically relevant DDIs have not been fully elucidated. In vitro and in silico techniques can be applied synergistically to investigate hepatic transporter-mediated DDIs. Chapter 2 describes the development and verification of a cryopreserved suspension primary human hepatocyte (SPHH) in vitro assay used to calculate the hepatic intrinsic clearance and inhibition constant (Ki) of the well-known organic anion transporting polypeptides (OATP) 1B1 and 1B3 substrate and inhibitor, pitavastatin (PIT) and rifampicin (RIF). This in vitro data was then utilised in Chapter 3 in a physiologically based pharmacokinetic (PBPK) model to simulate the DDI between PIT and RIF and was successfully verified against observed data. Chapter 4 applied the verified in vitro-in silico framework to assess the role of transporters in the complex DDI between the hepatitis C (HCV) NS3/4A protease inhibitor (PI) grazoprevir (GZR) and HIV PIs atazanavir (ATV), darunavir (DRV) and ritonavir (RTV), testing the suitability of the framework in a clinically relevant DDI scenario. Additionally, chapter 5 utilised SPHHs from elderly donors in vitro alongside an enzyme-linked immunosorbent assay (ELISA) to investigate the effect of age on transporter expression and activity. Furthermore, in chapter 6 an enzyme induction PBPK model was developed and verified to predict the magnitude of DDI between high dose once monthly (QMT) RIF and dolutegravir (DTG) 50mg twice-daily for the treatment of leprosy in PLWH as there is currently no evidence-based guidance to support their clinical management. There is a demand for paralleled clinical management and research of DDIs in PLWH. These findings represent a potential in vitro-in silico framework utilising a non-drug specific IVIVE correction factor for the investigation of hepatic uptake transporters in DDIs. Additionally, these findings could help fill the knowledge gap on the role of older age in transporter expression and activity, providing key research in this underrepresented population. The reported findings could also help support the clinical management of DDIs in high dose QMT RIF regimens, presenting in silico assessment strategies for concomitant antiretroviral therapy

Evaluating Islatravir Administered Via Microneedle Array Patch for Long-Acting HIV Pre-exposure Prophylaxis Using Physiologically Based Pharmacokinetic Modelling

Background and objectivesTechnologies for long-acting administration of antiretrovirals (ARVs) for the prevention and treatment of HIV are at the forefront of research initiatives aiming to tackle issues surrounding drug adherence with the current standard of once-daily oral administration. Islatravir (ISL) is an emerging ARV that shows promising characteristics for long-acting prevention and treatment both orally as well as through alternative routes of administration. Microneedle array patches (MAPs) are a pain-free and discreet transdermal delivery technology that offer extended-release administration of nanoparticulate drugs. This study aimed to utilise physiologically based pharmacokinetic (PBPK) modelling to predict the pharmacokinetics resulting from ISL administered via MAP and to identify key MAP characteristics required to sustain effective concentrations over extended dosing intervals.MethodsA PBPK model describing the conversion of ISL to ISL-triphosphate (ISL-TP) and its whole-body disposition was developed and verified against observed clinical data for orally administered ISL in healthy adults. An intradermal PBPK model was integrated with the ISL PBPK model to predict the dose and nanoparticle release rate required for MAP administration strategies capable of achieving a minimum ISL-TP target concentration of 0.05 pmol/106 PBMCs over extended dosing intervals. MAP design was limited to a maximum therapeutic area of 20 cm2 with a dose loading of 4.09 mg/cm2 and a minimum duration of 3 months. Due to the lack of available clinical data, a range of nanoparticle release rates and MAP bioavailability scenarios were simulated to provide an overview of potential clinical outcomes.ResultsThe ISL PBPK model was successfully verified, with predicted vs observed ratios falling within 0.5-2-fold. ISL MAP doses ranging from 15 to 80 mg were predicted to sustain ISL-TP concentrations above the minimum target concentration at 3, 6 and 12 months after administration. Nanoparticle release rate and MAP bioavailability were found to have a major impact on whether dosing strategies achieved the criteria. Minimum doses of 15 mg and 60 mg with a nanoparticle release rate of 0.0005 h-1 and bioavailability ranging from 25 to 100% were predicted to achieve effective ISL-TP concentrations up to 3 and 6 months, respectively. Doses of 15 mg and 30 mg with a nanoparticle release rate of 0.0005 h-1 were also able to attain the target concentration up to 6 months after MAP administration, albeit with a minimum bioavailability of 75% and 50%, respectively. Furthermore, when simulating a bioavailability of 100%, an 80 mg ISL MAP was predicted to sustain ISL-TP concentrations above the minimum target concentration up to 12 months after administration.ConclusionsThe ISL PBPK model successfully predicted ISL and ISL-TP pharmacokinetics across a range of orally administered regimens. The integrated intradermal PBPK model outlined optimal MAP dose and nanoparticle release rates for effective ISL-TP concentrations up to 12 months, providing justification for further investigation of ISL as a candidate for MAP administration

Predicting Drug-Drug Interactions between Rifampicin and Ritonavir-Boosted Atazanavir Using PBPK Modelling

ObjectivesThe aim of this study was to simulate the drug-drug interaction (DDI) between ritonavir-boosted atazanavir (ATV/r) and rifampicin (RIF) using physiologically based pharmacokinetic (PBPK) modelling, and to predict suitable dose adjustments for ATV/r for the treatment of people living with HIV (PLWH) co-infected with tuberculosis.MethodsA whole-body DDI PBPK model was designed using Simbiology 9.6.0 (MATLAB R2019a) and verified against reported clinical data for all drugs administered alone and concomitantly. The model contained the induction mechanisms of RIF and ritonavir (RTV), the inhibition effect of RTV for the enzymes involved in the DDI, and the induction and inhibition mechanisms of RIF and RTV on the uptake and efflux hepatic transporters. The model was considered verified if the observed versus predicted pharmacokinetic values were within twofold. Alternative ATV/r dosing regimens were simulated to achieve the trough concentration (Ctrough) clinical cut-off of 150 ng/mL.ResultsThe PBPK model was successfully verified according to the criteria. Simulation of different dose adjustments predicted that a change in regimen to twice-daily ATV/r (300/100 or 300/200 mg) may alleviate the induction effect of RIF on ATV Ctrough, with > 95% of individuals predicted to achieve Ctrough above the clinical cut-off.ConclusionsThe developed PBPK model characterized the induction-mediated DDI between RIF and ATV/r, accurately predicting the reduction of ATV plasma concentrations in line with observed clinical data. A change in the ATV/r dosing regimen from once-daily to twice-daily was predicted to mitigate the effect of the DDI on the Ctrough of ATV, maintaining plasma concentration levels above the therapeutic threshold for most patients

The biological challenges and pharmacological opportunities of orally administered nanomedicine delivery

Introduction Nano-scale formulations are being developed to improve the delivery of orally administered medicines, and the interactions between nanoformulations and the gastrointestinal luminal, mucosal and epithelial environment is currently being investigated. The mucosal surface of the gastrointestinal tract is capable of trapping and eliminating large particles and pathogens as part of the natural defences of the body, it is becoming clearer that nanoformulation properties such as particle size, charge, and shape, as well as mucous properties such as viscoelasticity, thickness, density, and turn-over time are all relevant to these interactions. However, progress has been slow to utilise this information to produce effective mucous-penetrating particles. Areas covered This review focuses on delivery method of nanomedicines both into and across the gastrointestinal mucosal surface, and aims to summarise the biological barriers that exist to successful oral nanomedicine delivery and how these barriers may be investigated and overcome. Expert commentary Despite successes in the laboratory, no nanotechnology-enabled products are currently in clinical use which either specifically target the intestinal mucous surface or cross the epithelial barrier intact. New nanomedicine-based treatments of local diseases (intestinal cancer, inflammation, infection) and systemic diseases are advancing towards clinical use, and offer genuine opportunities to improve therapy

Drug-Drug Interactions in People Living With HIV at Risk of Hepatic and Renal Impairment: Current Status and Future Perspectives

Despite the advancement of antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV), drug–drug interactions (DDIs) remain a relevant clinical issue for people living with HIV receiving ART. Antiretroviral (ARV) drugs can be victims and perpetrators of DDIs, and a detailed investigation during drug discovery and development is required to determine whether dose adjustments are necessary or coadministrations are contraindicated. Maintaining therapeutic ARV plasma concentrations is essential for successful ART, and changes resulting from potential DDIs could lead to toxicity, treatment failure, or the emergence of ARV‐resistant HIV. The challenges surrounding DDI management are complex in special populations of people living with HIV, and often lack evidence‐based guidance as a result of their underrepresentation in clinical investigations. Specifically, the prevalence of hepatic and renal impairment in people living with HIV are between five and 10 times greater than in people who are HIV‐negative, with each condition constituting approximately 15% of non‐AIDS‐related mortality. Therapeutic strategies tend to revolve around the treatment of risk factors that lead to hepatic and renal impairment, such as hepatitis C, hepatitis B, hypertension, hyperlipidemia, and diabetes. These strategies result in a diverse range of potential DDIs with ART. The purpose of this review was 2‐fold. First, to summarize current pharmacokinetic DDIs and their mechanisms between ARVs and co‐medications used for the prevention and treatment of hepatic and renal impairment in people living with HIV. Second, to identify existing knowledge gaps surrounding DDIs related to these special populations and suggest areas and techniques to focus upon in future research efforts

Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly

Medication use is highly prevalent with advanced age, but clinical studies are rarely conducted in the elderly, leading to limited knowledge regarding age-related pharmacokinetic changes.; The objective of this study was to investigate which pharmacokinetic parameters determine drug exposure changes in the elderly by conducting virtual clinical trials for ten drugs (midazolam, metoprolol, lisinopril, amlodipine, rivaroxaban, repaglinide, atorvastatin, rosuvastatin, clarithromycin and rifampicin) using our physiologically based pharmacokinetic (PBPK) framework.; PBPK models for all ten drugs were developed in young adults (20-50 years) following the best practice approach, before predicting pharmacokinetics in the elderly (≥ 65 years) without any modification of drug parameters. A descriptive relationship between age and each investigated pharmacokinetic parameter (peak concentration [C; max; ], time to C; max; [t; max; ], area under the curve [AUC], clearance, volume of distribution, elimination-half-life) was derived using the final PBPK models, and verified with independent clinically observed data from 52 drugs.; The age-related changes in drug exposure were successfully simulated for all ten drugs. Pharmacokinetic parameters were predicted within 1.25-fold (70%), 1.5-fold (86%) and 2-fold (100%) of clinical data. AUC increased progressively by 0.9% per year throughout adulthood from the age of 20 years, which was explained by decreased clearance, while C; max; , t; max; and volume of distribution were not affected by human aging. Additional clinical data of 52 drugs were contained within the estimated variability of the established age-dependent correlations for each pharmacokinetic parameter.; The progressive decrease in hepatic and renal blood flow, as well as glomerular filtration, rate led to a reduced clearance driving exposure changes in the healthy elderly, independent of the drug

In vitro assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel

OBJECTIVES: The World Health Organization recommends that all countries adopt dolutegravir-based antiretroviral therapy as the preferred regimen for all individuals living with HIV. Levonorgestrel is a commonly used hormonal contraceptive, which undergoes drug–drug interactions with some antiretrovirals, but the potential interaction between dolutegravir and levonorgestrel has not been examined. We aimed to evaluate cytochrome P450 (CYP)-mediated levonorgestrel metabolism and quantify the effects of dolutegravir on levonorgestrel apparent intrinsic clearance (CL(int.app.)) and CYP gene expression. METHODS: In vitro CYP-mediated CL(int.app.) of levonorgestrel was quantified using a recombinant human CYP (rhCYP) enzyme system. A primary human hepatocyte model of drug metabolism was used to assess the effects of dolutegravir on (1) levonorgestrel CL(int.app.), using liquid chromatography-tandem mass spectrometry, and (2) the expression of specific CYP enzymes, using quantitative real-time polymerase chain reaction. RESULTS: Levonorgestrel clearance was mediated by multiple rhCYPs, including rhCYP3A4. Under control conditions, levonorgestrel CL(int.app.) was 22.4 ± 5.0 μL/min/10(6) hepatocytes. Incubation with 43.1 nM of unbound dolutegravir elevated levonorgestrel CL(int.app.) to 31.4 ± 7.8 μL/min/10(6) hepatocytes (P = 0.168), while 142.23 nM increased levonorgestrel CL(int.app.) to 37.0 ± 2.9 μL/min/10(6) hepatocytes (P = 0.012). Unbound dolutegravir ≥ 431 nM induced expression of CYP3A4 (≥ two-fold) in a dose-dependent manner, while 1.44 μM of unbound dolutegravir induced CYP2B6 expression 2.2 ± 0.3-fold (P = 0.0004). CONCLUSIONS: In summary, this in vitro study suggests that dolutegravir has the potential to increase hepatic clearance of levonorgestrel by inducing both CYP3A and non-CYP3A enzymes. The observed in vitro dolutegravir–levonorgestrel drug–drug interaction should be further examined in clinical studies

Repository Describing an Aging Population to Inform Physiologically Based Pharmacokinetic Models Considering Anatomical, Physiological, and Biological Age-Dependent Changes

Aging is characterized by anatomical, physiological, and biological changes that can impact drug kinetics. The elderly are often excluded from clinical trials and knowledge about drug kinetics and drug-drug interaction magnitudes is sparse. Physiologically based pharmacokinetic modeling can overcome this clinical limitation but detailed descriptions of the population characteristics are essential to adequately inform models.; The objective of this study was to develop and verify a population database for aging Caucasians considering anatomical, physiological, and biological system parameters required to inform a physiologically based pharmacokinetic model that included population variability.; A structured literature search was performed to analyze age-dependent changes of system parameters. All collated data were carefully analyzed, and descriptive mathematical equations were derived.; A total of 362 studies were found of which 318 studies were included in the analysis as they reported rich data for anthropometric parameters and specific organs (e.g., liver). Continuous functions could be derived for most system parameters describing a Caucasian population from 20 to 99 years of age with variability. Areas with sparse data were identified such as tissue composition, but knowledge gaps were filled with plausible qualified assumptions. The developed population was implemented in Matlab; ®; and estimated system parameters from 1000 virtual individuals were in accordance with independent observed data showing the robustness of the developed population.; The developed repository for aging subjects provides a singular specific source for key system parameters needed for physiologically based pharmacokinetic modeling and can in turn be used to investigate drug kinetics and drug-drug interaction magnitudes in the elderly

Analysis of Clinical Drug-Drug Interaction Data To Predict Magnitudes of Uncharacterized Interactions between Antiretroviral Drugs and Comedications

Despite their high potential for drug-drug interactions (DDI), clinical DDI studies of antiretroviral drugs (ARVs) are often lacking, because the full range of potential interactions cannot feasibly or pragmatically be studied, with some high-risk DDI studies also being ethically difficult to undertake. Thus, a robust method to screen and to predict the likelihood of DDIs is required. We developed a method to predict DDIs based on two parameters: the degree of metabolism by specific enzymes, such as CYP3A, and the strength of an inhibitor or inducer. These parameters were derived from existing studies utilizing paradigm substrates, inducers, and inhibitors of CYP3A to assess the predictive performance of this method by verifying predicted magnitudes of changes in drug exposure against clinical DDI studies involving ARVs. The derived parameters were consistent with the FDA classification of sensitive CYP3A substrates and the strength of CYP3A inhibitors and inducers. Characterized DDI magnitudes (; n; = 68) between ARVs and comedications were successfully quantified, meaning 53%, 85%, and 98% of the predictions were within 1.25-fold (0.80 to 1.25), 1.5-fold (0.66 to 1.48), and 2-fold (0.66 to 1.94) of the observed clinical data. In addition, the method identifies CYP3A substrates likely to be highly or, conversely, minimally impacted by CYP3A inhibitors or inducers, thus categorizing the magnitude of DDIs. The developed effective and robust method has the potential to support a more rational identification of dose adjustment to overcome DDIs, being particularly relevant in an HIV setting, given the treatment's complexity, high DDI risk, and limited guidance on the management of DDIs

Effect of ageing on antiretroviral drug pharmacokinetics using clinical data combined with modelling and simulation

The impact of ageing on antiretroviral pharmacokinetics remains uncertain, leading to missing dosing recommendations for elderly people living with human immunodeficiency virus (HIV: PLWH). The objective of this study was to investigate whether ageing leads to clinically relevant pharmacokinetic changes of antiretrovirals that would support a dose adjustment based on the age of the treated PLWH.; Plasma concentrations for 10 first-line antiretrovirals were obtained in PLWH ≥55 years, participating in the Swiss HIV Cohort Study, and used to proof the predictive performance of our physiologically based pharmacokinetic (PBPK) model. The verified PBPK model predicted the continuous effect of ageing on HIV drug pharmacokinetics across adulthood (20-99 years). The impact of ethnicity on age-related pharmacokinetic changes between whites and other races was statistically analysed.; Clinically observed concentration-time profiles of all investigated antiretrovirals were generally within the 95% confidence interval of the PBPK simulations, demonstrating the predictive power of the modelling approach used. The predicted decline in drug clearance drove age-related pharmacokinetic changes of antiretrovirals, resulting in a maximal 70% [95% confidence interval: 40%, 120%] increase in antiretrovirals exposure across adulthood. Peak concentration, time to peak concentration and apparent volume of distribution were predicted to be unaltered by ageing. There was no statistically significant difference of age-related pharmacokinetic changes between studied ethnicities.; Dose adjustment for antiretrovirals based on the age of male and female PLWH is a priori not necessary in the absence of severe comorbidities considering the large safety margin of the current first-line HIV treatments