Absorption Kinetics of Subcutaneously Administered Ceftazidime in Hypoperfused Guinea Pigs.

BACKGROUND: Pneumonia is the most common cause of death in patients with severe motor and intellectual disabilities (SMID), and intravenous ceftazidime (CAZ) is a widely used treatment for such infections. However, intravenous administration in patients with SMID may be difficult because of insufficient vascular development. OBJECTIVES: The aim of our study was to determine the feasibility of subcutaneous drug administration by mentholated warm compresses (WMCs) as an alternative delivery method for ceftazidime in patients with SMID. METHODS: CAZ was subcutaneously administered to the abdominal region of naphazoline-treated hypoperfused guinea pigs, which were used as a hemodynamic model of patients with SMID. MWCs or warm compresses (WCs) were applied to the injection site to increase blood flow. We calculated the cumulative CAZ absorption over time by using the deconvolution method. RESULTS: Application of MWCs or WCs increased blood flow at the administration site and increased CAZ plasma levels. Application of MWCs or WCs after subcutaneous CAZ injection led to higher CAZ plasma levels than the mutant prevention concentration for a longer period than was observed for CAZ administration without the application of MWCs or WCs. CONCLUSIONS: The application of MWCs or WCs enhanced subcutaneous CAZ absorption by increasing blood flow. MWCs and WCs are considered to be safe and routine methods to induce defecation after surgery on the digestive system; thus, the combination of these methods and subcutaneous CAZ administration is a potential method for treating pneumonia in patients with SMID.

Biorelevant subcutaneous in vitro test predicts the release of human and fast acting insulin formulations.

The administration of insulins by subcutaneous injection is nowadays widely prevalent. The injection site is located below the dermis and composed of cells and the extracellular matrix formed of a network of macromolecules such as hyaluronic acid and collagen. Following an injection, the insulins from the formulated products are timely released as drug molecules from the injection site into systemic circulation. In this publication, we show the development of an in vitro setup utilizing a hydrogel composed of a special collagen-hyaluronic acid mixture that mimics the extracellular matrix. Another setup was used for differentiation of the commercially available and research insulin formulations by determining the in vitro permeation characteristics with the results that were correlated with the human in vivo data. Significant differentiation was achieved at 90 % confidence level between the permeation curves of insulin glulisine containing formulations (U100 and a concentrated research formulation), while in case of the insulin lispro containing formulations (U100 and U200) the permeation curves showed similarity. These results demonstrated that the in vitro setup may be used as a tool for formulation development and drug candidate profiling as it is able to differentiate or show similarities between the agglomeration states and concentration of the active pharmaceutical ingredients.

Predicting the clinical subcutaneous absorption rate constant of monoclonal antibodies using only the primary sequence: a machine learning approach.

Subcutaneous injections are an increasingly prevalent route of administration for delivering biological therapies including monoclonal antibodies (mAbs). Compared with intravenous delivery, subcutaneous injections reduce administration costs, shorten the administration time, and are strongly preferred from a patient experience point of view. An understanding of the absorption process of a mAb from the injection site to the systemic circulation is critical to the process of subcutaneous mAb formulation development. In this study, we built a model to predict the absorption rate constant (ka), which denotes how fast a mAb is absorbed from the site of administration. Once trained, our model (enabled by the XGBoost algorithm in machine learning) can predict the ka of a mAb following a subcutaneous injection using in silico molecular properties alone (generated from the primary sequence). Our model does not need clinically observed plasma concentration-time data; this is a novel capability not previously achieved in predictive pharmacokinetic models. The model also showed improved performance when benchmarked against a recently reported mechanistic model that relied on clinical data to predict subcutaneous absorption of mAbs. We further interpreted the model to understand which molecular properties affect the absorption rate and showed that our findings are consistent with previous studies evaluating subcutaneous absorption through direct experimentation. Taken altogether, this study reports the development, validation, benchmarking, and interpretation of a model that can predict the clinical ka of a mAb using its primary sequence as the only input.

Multiscale pharmacokinetic modeling of systemic exposure of subcutaneously injected biotherapeutics.

Subcutaneously injected formulations have been developed for many biological products including monoclonal antibodies (mAbs). A knowledge gap nonetheless remains regarding the absorption and catabolism mechanisms and kinetics of a large molecule at the administration site. A multiscale pharmacokinetic (PK) model was thus developed by coupling multiphysics simulations of subcutaneous (SC) absorption kinetics with whole-body pharmacokinetic (PK) modeling, bridged by consideration of the presystemic clearance by the initial lymph. Our local absorption simulation of SC-injected albumin enabled the estimation of its presystemic clearance and led to the whole-body PK modeling of systemic exposure. The local absorption rate of albumin was found to be influential on the PK profile. Additionally, nineteen mAbs were explored via this multiscale simulation and modeling framework. The computational results suggest that stability propensities of the mAbs are correlated with the presystemic clearance, and electrostatic charges in the complementarity-determining region influence the local absorption rate. Still, this study underscores a critical need to experimentally determine various biophysical characteristics of a large molecule and the biomechanical properties of human skin tissues.

A Two-Pore Physiologically Based Pharmacokinetic Model to Predict Subcutaneously Administered Different-Size Antibody/Antibody Fragments.

Quantitative modeling of the subcutaneous absorption processes of protein therapeutics is challenging. Here we have proposed a "two-pore" PBPK model that is able to simultaneously characterize plasma PK of different-size protein therapeutics in mice. The skin compartment is evolved to mechanistically account for the absorption pathways through lymph and blood capillaries, as well as local degradation at the SC injection site. The model is developed using in-house plasma PK data generated following subcutaneous administration of 6 different-size protein therapeutics (13-150 kDa) in mice. The model was able to capture plasma PK of all molecules following intravenous and subcutaneous administration relatively well. From the observed plasma PK profiles, as well as from the model simulation result, several important PK descriptors were found to be dependent on protein size for FcRn nonbinding molecules. A positive correlation was found between Tmax and protein size. A "U" shape relationship was found between Cmax and protein size. Negative correlations were observed between bioavailability (F) and local degradation rate (kdeg,SC), and F and protein size. Pathway analysis of the model was conducted for the subcutaneous absorption process, and continuous relationships were established between the percentage of absorption through lymphatic and vascular pathways and protein size. This PBPK model could serve as a platform for the development of different-size protein therapeutics and will be scaled up to humans for translational studies in the future.

Influence of physiochemical properties on the subcutaneous absorption and bioavailability of monoclonal antibodies.

Many therapeutic monoclonal antibodies (mAbs) were initially developed for intravenous (IV) administration. As a means to improve mAb drug-ability and the patient experience, subcutaneous (SC) administration is an increasingly important delivery route for mAbs. Unlike IV administration, bioavailability limitations for antibodies have been reported following SC injection and can dictate whether a mAb is administered via this parenteral route. The SC bioavailability of antibodies has been difficult to predict, and it can be variable and partial, with values ranging from ~50% to 100%. The mechanisms leading to the incomplete bioavailability of some mAbs relative to others are not well understood. There are some limited data that suggest the physiochemical properties inherent to a mAb can contribute to its SC absorption, bioavailability, and in vivo fate. In this study, we evaluated the integrated influence of multiple mAb physiochemical factors on the SC absorption and bioavailability of six humanized mAbs in both rats and cynomolgus monkeys. We demonstrate the physiochemical properties of mAbs are critical to their rate and extent of SC absorption. The combination of high positive charge and hydrophobic interaction significantly reduced the rate of the evaluated mAb's SC absorption and bioavailability. Reduction or balancing of both these attributes via re-engineering the mAbs restored desirable properties of the molecules assessed. This included reduced association with SC tissue, improvements in mAb absorption from the SC space and overall SC bioavailability. Our findings point to the importance of evaluating the relative balance between various physiochemical factors, including charge, hydrophobicity, and stability, to improve the SC drug-ability of mAbs for selecting or engineering mAbs with enhanced in vivo absorption and bioavailability following SC administration.

Incidência e eventos adversos da hipodermóclise no idoso em cuidados paliativos / Incidencia y eventos adversos de hipodermoclisis en ancianos en cuidados paliativos / Incidence and adverse events of hypodermoclysis in the elderly in palliative care

Objetivo: estimar a incidência, tempo de ocorrência de eventos adversos e tempo de permanência da hipodermóclise no idoso Método: Pesquisa realizada com 127 idosos em cuidados paliativos. A avaliação da hipodermóclise foi realizada a cada 24 horas até a ocorrência do evento. Realizou-se análise descritiva, calculando as proporções e a taxa de incidência por 100 punções/pacientes. Resultados: A taxa de incidência dos eventos adversos foi de 22,8% para a hipodermóclise e 27% para os indivíduos em uso de hipodermóclise. O cateter permaneceu em média quatro dias, sendo no mínimo um dia e no máximo 15 dias; a chance de eventos adversos no primeiro dia foi de 6%, de 28% no quinto dia e 48% no décimo. Conclusão: Incidência de eventos adversos foi pequena e localizada; tempo médio da permanência do cateter no local de inserção foi de quatro dias e as probabilidades de apresentar complicações aumentaram no decorrer dos dias.

Objective: to estimate the incidence, time of occurrence of adverse events and time of permanence of hypodermoclysis in the elderly. Method: Research carried out with 127 elderly people in Palliative Care. Assessment of hypodermoclysis was performed every 24 hours until the event occurred. Descriptive analysis was performed, proportions and incidence rate were calculated per 100 punctures/patients. Results: The incidence rate of adverse events was 22.8% for hypodermoclysis and 27% for individuals using hypodermoclysis. The catheter remained for an average of 4 days, with a minimum of 1 day and a maximum of 15 days; the chance of adverse events on the 1st day was 6%, 28% on the 5th day and 48% on the 10th. Conclusion: The incidence of adverse events was small and localized; mean time of catheter permanence at the insertion site was 4 days and the probability of presenting complications increased over the days.

Objetivo: estimar la incidencia, tiempo de ocurrencia de eventos adversos y tiempo de permanencia de la hipodermoclisis en ancianos Método: Investigación realizada con 127 ancianos en Cuidados Paliativos. La evaluaciónde la hipodermoclisis se realizó cada 24 horas hasta que ocurrió el evento. Se realizó análisis descriptivo, se calcularon proporciones y tasa de incidencia por 100 punciones/pacientes. Resultados: La tasa de incidencia de eventos adversos fue del 22,8 % para la hipodermoclisis y del 27 % para los individuos que usaban la hipodermoclisis. El catéter permaneció en promedio 4 días, con un mínimo de 1 día y un máximo de 15 días; la probabilidad de eventos adversos el primer día fue del 6 %, del 28 % el quinto día y del 48 % el décimo. Conclusión: La incidencia de eventos adversos fue pequeña y localizada; el tiempo medio de permanencia del catéter en el sitio de inserción fue de 4 días y la probabilidad de presentar complicaciones aumentó con el transcurso de los días.

A Bottom-Up Whole-Body Physiologically Based Pharmacokinetic Model to Mechanistically Predict Tissue Distribution and the Rate of Subcutaneous Absorption of Therapeutic Proteins.

The ability to predict subcutaneous (SC) absorption rate and tissue distribution of therapeutic proteins (TPs) using a bottom-up approach is highly desirable early in the drug development process prior to clinical data being available. A whole-body physiologically based pharmacokinetic (PBPK) model, requiring only a few drug parameters, to predict plasma and interstitial fluid concentrations of TPs in humans after intravenous and subcutaneous dosing has been developed. Movement of TPs between vascular and interstitial spaces was described by considering both convection and diffusion processes using a 2-pore framework. The model was optimised using a variety of literature sources, such as tissue lymph/plasma concentration ratios in humans and animals, information on the percentage of dose absorbed following SC dosing via lymph in animals and data showing loss of radiolabelled IgG from the SC dosing site in humans. The resultant model was used to predict t max and plasma concentration profiles for 12 TPs (molecular weight 8-150 kDa) following SC dosing. The predicted plasma concentration profiles were generally comparable to observed data. t max was predicted within 3-fold of reported values, with one third of the predictions within 0.8-1.25-fold. There was no systematic bias in simulated C max values, although a general trend for underprediction of t max was observed. No clear trend between prediction accuracy of t max and TP isoelectric point or molecular size was apparent. The mechanistic whole-body PBPK model described here can be applied to predict absorption rate of TPs into blood and movement into target tissues following SC dosing.