Lymphatic Absorption of Subcutaneously Administered Proteins: Influence of Different Injection Sites on the Absorption of Darbepoetin Alfa Using a Sheep Model

Kota, Jagannath; Machavaram, Krishna K.; McLennan, Danielle N; Edwards, Glenn A.; Porter, Christopher John; Charman, Susan A.

doi:10.1124/dmd.107.015669

Cited by 62 publications

(63 citation statements)

References 21 publications

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“…The anatomic site of injection had a major impact on both the rate and extent of absorption, which is consistent with pharmacokinetic studies for other proteins (Beshyah et al, 1991;Macdougall et al, 1991;Kota et al, 2007). An inverse correlation was found between the dose level and rituximab bioavailability, and it was hypothesized to result from saturation of neonatal Fc receptor (FcRn)-mediated protective binding at the absorption site.…”

Section: Introductionsupporting

confidence: 62%

Mechanisms of Subcutaneous Absorption of Rituximab in Rats

Kagan

Mager

2012

Drug Metab Dispos

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Absorption of monoclonal antibodies (mAbs) after s.c. injection results from the interplay among several kinetic processes. The aims of this study were to investigate the absorption mechanisms of rituximab in rats by using slow s.c. infusion and coadministration with nonspecific IgG or hyaluronidase, and to evaluate the predictive performance of the pharmacokinetic model previously developed to describe the nonlinear absorption behavior of mAbs. Rituximab serum concentrations were measured after s.c. coadministration with nonspecific IgG and hyaluronidase to rats. Several dose levels and different injection sites were evaluated. For the back site, 6.5-and 2.6-fold decreases in the area under the concentration-time curve were obtained after coadministration with IgG for 1 and 10 mg/kg doses compared with administration of rituximab alone. For the abdomen, only a minor reduction in concentrations was observed. Hyaluronidase increased the rate of s.c. absorption and the bioavailability (1.9-and 1.6-fold for the back and the abdomen injection of 10 mg/kg). Our previously established pharmacokinetic model provided excellent predictions of the effect of nonspecific IgG on rituximab absorption. In conclusion, the magnitude of the effect of absorption modifiers is dependent on the site of injection and the dose level of rituximab. Pharmacokinetic profiles further support the hypothesis that neonatal Fc receptormediated transport is a major determinant of s.c. absorption of mAbs.

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Section: Introductionsupporting

confidence: 62%

Mechanisms of Subcutaneous Absorption of Rituximab in Rats

Kagan

Mager

2012

Drug Metab Dispos

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“…In larger animals such as sheep, it was possible to recover a significant amount of the subcutaneous dose in the thoracic duct lymph even when injection sites other than lower hind legs were used (Kota et al, 2007). One possible reason is that in sheep, one can cannulate the thoracic duct at a position very close to where it enters the systemic circulation (Kota et al, 2007).…”

Section: Lymphatic Transport After Subcutaneous Administrationmentioning

confidence: 99%

Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

Wang¹,

Chen²,

Shen³

et al. 2012

Drug Metab Dispos

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ABSTRACT:The mechanism underlying subcutaneous absorption of macromolecules and factors that can influence this process were studied in rats using PEGylated erythropoietins (EPOs) as model compounds. Using a thoracic lymph duct cannulation (LDC) model, we showed that PEGylated EPO was absorbed from the subcutaneous injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. After subcutaneous administration, the serum exposure was reduced by ϳ70% in LDC animals compared with that in the control animals, and most of the systemically available dose was recovered in the lymph. In both LDC and intact rats, the total radioactivity recoveries in excreta after subcutaneous administration were high (70-80%), indicating that catabolism, not poor absorption, was the main cause for the observed low bioavailability (30-40%). Moreover, catabolism of PEGylated EPO was found with both rat subcutaneous tissue homogenate and lymph node cell suspensions, and a significant amount of dose-related breakdown fragments was found in the lymph of LDC rats. In addition, the bioavailability of PEGylated EPOs was shown to be 2-to 4-fold lower in "fat rats," indicating that physiologic features pertinent to lymphatic transport can have a profound impact on subcutaneous absorption. Limited studies in dogs also suggested similar subcutaneous absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is probably conserved among commonly used preclinical species, e.g., rats and dogs, and that mechanistic understanding of the subcutaneous absorption mechanism and associated determinants should be helpful in biologic drug discovery and development.

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“…[23] The site of administration also plays a major role in delivering therapeutic payloads to the lymphatics where a higher accumulation of injected formulation in lymphatics is noted when injected subcutaneously (SC) as compared to the IV. [24] Any macromolecules or nanoscale drug delivery systems injected IV are limited to the vascular space and do not partition into the interstitium. Thus, their uptake into the lymphatics is limited.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Doddapaneni

Kyryachenko

Chagani

et al. 2015

Journal of Controlled Release

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Metastatic Melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NP) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NP are similarly sized (~ 48nm), with neutral, partially charged, or fully charged surface. The NP are able to load ~ 2mg/mL of each drug and are stable for 24 h. The NP are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NP were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NP are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NP are efficacious at the proximal LN, while the fully charged NP have no effect on either LN. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NP have the highest potential in treating metastatic melanoma. GRAPHICAL ABSTRACT

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Lymphatic Absorption of Subcutaneously Administered Proteins: Influence of Different Injection Sites on the Absorption of Darbepoetin Alfa Using a Sheep Model

Cited by 62 publications

References 21 publications

Mechanisms of Subcutaneous Absorption of Rituximab in Rats

Mechanisms of Subcutaneous Absorption of Rituximab in Rats

Lymphatic Transport and Catabolism of Therapeutic Proteins after Subcutaneous Administration to Rats and Dogs

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

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