The elimination of raltitrexed is triexponential with a prolonged terminal elimination phase. The pharmacokinetic profile is consistent with extensive polyglutamation and intracellular retention of ralitrexed. The three-compartment model presented here may be useful for the analysis of the pharmacokinetics of raltitrexed in humans.

Sorafenib is well tolerated in NHP and measurable in CSF after an IV dose. The CSF penetration of sorafenib is limited relative to total and free drug exposure in plasma.

KNI-272 is a human immunodeficiency virus (HIV) protease inhibitor with potent activity in vitro. We studied the pharmacokinetics of KNI-272 in the plasma and cerebrospinal fluid (CSF) of a nonhuman primate model and after intravenous and oral administration to children with HIV infection. Plasma and CSF were sampled over 24 h after the administration of an intravenous dose of 50 mg of KNI-272 per kg of body weight (approximately 1,000 mg/m2) to three nonhuman primates. The pharmacokinetics of KNI-272 were also studied in 18 children (9 males and 9 females; median age, 9.4 years) enrolled in a phase I trial of four dose levels of KNI-272 (100, 200, 330, and 500 mg/m2 per dose given four times daily). The plasma concentration-time profile of KNI-272 in the nonhuman primate model was characterized by considerable interanimal variability and rapid elimination (clearance, 2.5 liters/h/kg; terminal half-life, 0.54 h). The level of drug exposure achieved in CSF, as measured by the area under the KNI-272 concentration-time curve, was only 1% of that achieved in plasma. The pharmacokinetics of KNI-272 in children were characterized by rapid elimination (clearance, 276 ml/min/m2; terminal half-life, 0.44 h), limited (12%) and apparently saturable bioavailability, and limited distribution (volume of distribution at steady state, 0.11 liter/kg). The concentrations in plasma were maintained above a concentration that is active in vitro for less than half of the 6-h dosing interval. There was no significant increase in CD4 cell counts or decrease in p24 antigen or HIV RNA levels. The pharmacokinetic profile of KNI-272 may limit the drug’s efficacy in vivo. It appears that KNI-272 will play a limited role in the treatment of HIV-infected children.

Background: Cytokine release syndrome (CRS) is a life-threatening complication of effective immunotherapies, particularly chimeric antigen receptor (CAR) T-cells. CRS is characterized by fever, hypotension, cardiac dysfunction, and at times end organ dysfunction and is mediated by elevated cytokines including IL-6, IFN-γ, and TNFα. A mainstay treatment for severe CRS is intravenous (IV) tocilizumab, a humanized, monoclonal antibody against membrane-associated and soluble IL-6 receptor. Most CRS symptoms resolve within hours of a single dose of IV tocilizumab in contrast to neurotoxicities, which are exacerbated or develop de novo after tocilizumab by a mechanism that is not well understood. IL-6 is elevated in the cerebrospinal fluid (CSF) of patients with CRS and neurotoxicity. The CSF penetration of tocilizumab is unknown. The objective of this study is to determine the CSF penetration of tocilizumab after IV administration in a nonhuman primate model. Methods: Four adult male rhesus monkeys (Macaca mulatta) each received 10 mg/kg tocilizumab IV (human equivalent dose of 8 mg/kg). The macaques have an implanted CNS ventricular reservoir for CSF collection and two central venous lines; one for drug administration and a second for sample collection. Serial, paired blood and CSF samples were collected 0-8 hours, 1-3 days, 5 days, & 10 days post-infusion. A fluorescence bridging ELISA was used to determine serum and CSF levels of free tocilizumab (AbD Serotec). Results: Three of the four animals were evaluable. Mean serum Cmax = 1.55 μM (1.20-2.13) and mean CSF Cmax = 0.00065 μM (0.00037-0.00083). Mean serum and CSF Tmax were 10 hours and 48 hours, respectively. Mean serum and CSF half-life were 127 and 339 hours, respectively. Serum AUC (mean) = 63 μM/hour (25-130) while CSF AUC (mean) = 0.099 μM/hour (0.07-0.125). CSF penetration was low with mean CSF:plasma AUC ratio of 0.26%. All samples and standards were plated in triplicate and had a coefficient of variation less than 20%. In one animal, tocilizumab concentrations were markedly lower with no detectable tocilizumab in the serum after 4 hours; results from this study were considered unevaluable. Conclusion: Studies in this nonhuman primate model reveal low CSF penetration of tocilizumab and delayed time to maximum concentration in the CSF, potentially explaining the persistent neurologic toxicity observed in patients with CRS treated with tocilizumab. However, tocilizumab has a long half-life in the CSF, suggesting alternate means of delivery may be beneficial. Free tocilizumab concentrations were extremely low in one out of four animals and may have been due to preexisting inhibitors. Intranasal delivery of tocilizumab may result in significantly higher CSF exposure and provides a convenient route in patients that are otherwise critically ill. Studies of intranasal tocilizumab are ongoing and will be presented. Citation Format: Anandani Nellan, Nalini Jayaprakash, Cindy McCully, Brigitte C. Widemann, Daniel W. Lee, Katherine E. Warren. Plasma and cerebrospinal fluid pharmacokinetics of tocilizumab in a nonhuman primate model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1411.