A Physiologically Based Pharmacokinetic Model Relates the Subcutaneous Bioavailability of Monoclonal Antibodies to the Saturation of FcRn-Mediated Recycling in Injection-Site-Draining Lymph Nodes.

The bioavailability of a monoclonal antibody (mAb) or another therapeutic protein after subcutaneous (SC) dosing is challenging to predict from first principles, even if the impact of injection site physiology and drug properties on mAb bioavailability is generally understood. We used a physiologically based pharmacokinetic model to predict pre-systemic clearance after SC administration mechanistically by incorporating the FcRn salvage pathway in antigen-presenting cells (APCs) in peripheral lymph nodes, draining the injection site. Clinically observed data of the removal rate of IgG from the arm as well as its plasma concentration after SC dosing were mostly predicted within the 95% confidence interval. The bioavailability of IgG was predicted to be 70%, which mechanistically relates to macropinocytosis in the draining lymph nodes and transient local dose-dependent partial saturation of the FcRn receptor in the APCs, resulting in higher catabolism and consequently less drug reaching the systemic circulation. The predicted free FcRn concentration was reduced to 40-45%, reaching the minimum 1-2 days after the SC administration of IgG, and returned to baseline after 8-12 days, depending on the site of injection. The model predicted the uptake into APCs, the binding affinity to FcRn, and the dose to be important factors impacting the bioavailability of a mAb.

Optimal dosing of enoxaparin in overweight and obese children.

AIM: Current enoxaparin dosing guidelines in children are based on total body weight. This is potentially inappropriate in obese children as it may overestimate the drug clearance. Current evidence suggests that obese children may require lower initial doses of enoxaparin, therefore the aim of this work was to characterise the pharmacokinetics of enoxaparin in obese children and to propose a more appropriate dosing regimen. METHODS: Data from 196 unique encounters of 160 children who received enoxaparin treatment doses were analysed. Enoxaparin concentration was quantified using the chromogenic anti factor Xa (anti-Xa) assay. Patients provided a total of 552 anti-Xa samples. Existing published pharmacokinetic (PK) models were fitted and evaluated against our dataset using prediction-corrected visual predictive check plots (pcVPCs). A PK model was fitted using a nonlinear mixed-effects modelling approach. The fitted model was used to evaluate the current standard dosing and identify an optimal dosing regimen for obese children. RESULTS: Published models of enoxaparin pharmacokinetics in children did not capture the pharmacokinetics of enoxaparin in obese children as shown by pcVPCs. A one-compartment model with linear elimination best described the pharmacokinetics of enoxaparin. Allometrically scaled fat-free mass with an estimated exponent of 0.712 (CI 0.66-0.76) was the most influential covariate on clearance while linear fat-free mass was selected as the covariate on volume. Simulations from the model showed that fat-free mass-based dosing could achieve the target anti-Xa activity at steady state in 77.5% and 78.2% of obese and normal-weight children, respectively, compared to 65.2% and 75.5% for standard total body weight-based dosing. CONCLUSIONS: A population PK model that describes the time course of anti-Xa activity of enoxaparin was developed in a paediatric population. Based on this model, a unified dosing regimen was proposed that will potentially improve the success rate of target attainment in overweight/obese patients without the need for patient body size categorisation. Therefore, prospective validation of the proposed approach is warranted.

Role of islatravir in HIV treatment and prevention: an update.

PURPOSE OF REVIEW: To summarize recent updates on the potential role of islatravir for HIV treatment and prevention. RECENT FINDINGS: Islatravir is an investigational antiretroviral agent with unique pharmacologic properties that facilitate flexible dosing regimens. Islatravir has demonstrated potent antiviral activity and a high barrier to resistance when combined with doravirine and lamivudine. A simplified two-drug HIV treatment regimen of islatravir combined with doravirine has also demonstrated comparable efficacy to standard of care three-drug regimens. The long half-life and high potency of islatravir's active metabolite may support its use as a long-acting option for HIV preexposure prophylaxis (PrEP). A once monthly oral dose of islatravir maintains effective concentrations of its active metabolite over the entire dosing interval. Furthermore, an investigational implantable formulation has been projected to provide efficacious concentrations for at least a year and exhibits comparable distribution into vaginal and rectal tissues making it a promising PrEP option for male and female individuals. Islatravir has minimal risks of drug interactions as it is not a substrate, inducer, or inhibitor of major drug metabolizers and transporters. Finally, clinical trials demonstrate islatravir's favorable safety profile revealing only mild and transient adverse events. SUMMARY: Leveraging the unique pharmacological properties of islatravir offers opportunities for simplified HIV treatment regimens and long-acting PrEP making it a valuable addition to the antiretroviral arsenal.

A framework for simplification of quantitative systems pharmacology models in clinical pharmacology.

Quantitative systems pharmacology (QSP) is a relatively new discipline within modelling and simulation that has gained wide attention over the past few years. The application of QSP models spans drug-target identification and validation, through all drug development phases as well as clinical applications. Due to their detailed mechanistic nature, QSP models are capable of extrapolating knowledge to predict outcomes in scenarios that have not been tested experimentally, making them an important resource in experimental and clinical pharmacology. However, these models are complicated to work with due to their size and inherent complexity. This makes many applications of QSP models for simulation, parameter estimation and trial design computationally intractable. A number of techniques have been developed to simplify QSP models into smaller models that are more amenable to further analyses while retaining their accurate predictive capabilities. Different simplification techniques have different strengths and weaknesses and hence different utilities. Understanding the utilities of different methods is essential for selection of the best method for a particular situation. In this paper, we have created an overall framework for model simplification techniques that allows a natural categorisation of methods based on their utility. We provide a brief description of the concept underpinning the different methods and example applications. A summary of the utilities of methods is intended to provide a guide to modellers in their model endeavours to simplify these complicated models.

Reduction of quantitative systems pharmacology models using artificial neural networks.

Quantitative systems pharmacology models are often highly complex and not amenable to further simulation and/or estimation analyses. Model-order reduction can be used to derive a mechanistically sound yet simpler model of the desired input-output relationship. In this study, we explore the use of artificial neural networks for approximating an input-output relationship within highly dimensional systems models. We illustrate this approach using a model of blood coagulation. The model consists of two components linked together through a highly dimensional discontinuous interface, which creates a difficulty for model reduction techniques. The proposed approach enables the development of an efficient approximation to complex models with the desired level of accuracy. The technique is applicable to a wide variety of models and provides substantial speed boost for use of such models in simulation and control purposes.

The Influence of Haemostatic System Maturation on the Dose-Response Relationship of Unfractionated Heparin.

BACKGROUND: Unfractionated heparin (UFH) dosing and monitoring guidelines for children are often extrapolated from adult data. This practice is suboptimal given the inherent differences in haemostatic maturation and drug handling in children compared with adults. OBJECTIVE: The aim of this work was to investigate the impact of haemostatic system maturation on the dose-response relationship of UFH in children. METHODS: A quantitative model for haemostasis in adults was adapted to account for maturation in UFH pharmacokinetic (PK) parameters with and without age-related changes in coagulation factor concentrations. The adult and adapted models were used to predict the time courses of anti-factor Xa activity (aXa) and activated partial thromboplastin time (aPTT) in patients receiving UFH infusion. Predictions from both models were compared with observed aXa and aPTT measurements from 31 paediatric patients receiving UFH during extracorporeal membrane oxygenation (ECMO). RESULTS: The model with maturation for both UFH PK and the haemostatic system had an improved aXa and aPTT predictive performance compared with maturation in UFH PK only and the original adult model. Despite the minor effect of haemostatic system maturation on baseline aPTT, it led to substantial changes in the time course of aPTT sensitivity to UFH. This finding suggests that between-subject variability in clotting factors concentrations is potentially a major contributor to the overall variability of aPTT response to UFH. In addition, time-varying clotting factors concentrations may explain within-subject changes in aPTT sensitivity to UFH. CONCLUSION: We developed the first quantitative systems pharmacology (QSP) model that provides a mechanistic and quantitative basis for linking physiological and pharmacological maturation to UFH effect and response biomarkers. After appropriate clinical validation, the model could be useful for the development of paediatric-specific individualised UFH dosing recommendations.

Revisiting the Pharmacology of Unfractionated Heparin.

Unfractionated heparin (UFH) is a commonly used anticoagulant therapy for the acute treatment and prevention of thrombosis. Its short duration of action, reversibility of effect by protamine sulfate, and extensive clinical experience are some of the advantages that support its use. However, the choice of dose and dosing regimen of UFH remains challenging for several reasons. First, UFH has a narrow therapeutic window and wide variability in the dose-response relationship. Second, its pharmacodynamic (PD) properties are difficult to characterise owing to the complex multidimensional mechanisms of interaction with the haemostatic system. Third, the complex heterogeneous chemical composition of UFH precludes precise characterisation of its pharmacokinetic (PK) properties. This review provides a comprehensive mechanistic approach to the interaction of UFH with the haemostatic system. The effect of chemical structure on its PK and PD properties is quantitatively described, and a framework for characterisation of the dose-response relationship of UFH for the purpose of dose optimisation is proposed.