Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration

Abstract

Subcutaneous administration of biologics is highly desirable; however, incomplete bioavailability after sc administration remains a major challenge. In this work we investigated the effects of excipient dependent hyper-osmolarity on lymphatic uptake and plasma exposure of rituximab as a model protein. Using Swiss Webster (SW) mice as our animal model, we compared the effects of NaCl, mannitol and, O-Phospho-L-Serine (OPLS) on plasma concentration of rituximab over 5 days after sc administration. We observed an increase in plasma concentrations in animals administered rituximab in hypertonic buffer solutions, as compared to isotonic buffer. Bioavailability, as estimated by our pharmacokinetic model, increased from 29% in isotonic buffer to 54% in hypertonic buffer containing NaCl, to almost complete bioavailability in hypertonic buffers containing high dose OPLS or mannitol. This improvement in plasma exposure is due to improved lymphatic trafficking as evident from the increase in the fraction of dose trafficked through the lymph node in the presence of hypertonic buffers. The fraction of the dose trafficked through the lymphatic, as estimated by the model, increased from 0.05 % in isotonic buffer to 13% in hyper-tonic buffer containing NaCl to about 30% for hypertonic buffers containing high dose OPLS and mannitol. Our data suggests that hypertonic solutions may be a viable option to improve sc bioavailability.

Anatomical, Physiological, and Experimental Factors Affecting the Bioavailability of sc-Administered Large Biotherapeutics

“…In our own work, we found a relationship between increased buffer tonicity and improved bioavailability of subcutaneously administered rituximab in a mouse model . Furthermore, our data suggest that the effect of buffer hypertonicity on rituximab bioavailability is excipient specific.…”

“…4,24 In our own work, we found a relationship between increased buffer tonicity and improved bioavailability of subcutaneously administered rituximab in a mouse model. 25 Furthermore, our data suggest that the effect of buffer hypertonicity on rituximab bioavailability is excipient specific. We found that mannitol, a neutral excipient, performed better than the negatively charged O-phospho-L-serine at equal tonicities.…”

“…We found that mannitol, a neutral excipient, performed better than the negatively charged O‐phospho‐L‐serine at equal tonicities. The enhanced bioavailability was associated with enhanced lymph node uptake of rituximab . We propose that hypertonic buffers perturb the isotonicity of the interstitial space altering the formation and reabsorption of interstitial fluid at the postcapillary beds.…”

“…The enhanced bioavailability was associated with enhanced lymph node uptake of rituximab. 25 We propose that hypertonic buffers perturb the isotonicity of the interstitial space altering the formation and reabsorption of interstitial fluid at the postcapillary beds. The draining of excess interstitial fluid by the lymphatics enhances bulk movement of fluid through the sc space carrying with it the protein from the injection site through to the lymphatic.…”

Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics

“…Recently, it is reported that formulation may also affect the bioavailability of SC administered protein therapeutics. Fathallah et al [30] have described a significant increase in the bioavailability of SC administered rituximab when administered in a hypertonic buffer solution, because of an increase in the amount of protein that traffics through the lymph system.…”