Cerebrospinal fluid penetration of the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, pexidartinib.

PURPOSE: Pexidartinib (PLX3397) is a colony-stimulating factor-1 receptor (CSF-1R) inhibitor under clinical evaluation for potential CNS tumor treatment. This study aims to evaluate plasma pharmacokinetic parameters and estimate CNS penetrance of pexidartinib in a non-human primate (NHP) cerebrospinal fluid (CSF) reservoir model. METHODS: Five male rhesus macaques, each with a previously implanted subcutaneous CSF ventricular reservoir and central venous lines, were used. NHPs received a single dose of 40 mg/kg pexidartinib (human equivalent dose of 800 mg/m2), administered orally as 200 mg tablets. Serial paired samples of blood and CSF were collected at 0-8, 24, 48, and 72 h. Pexidartinib concentrations were assayed by Integrated Analytical Solutions, Inc. (Berkeley, CA, USA) using HPLC/MS/MS. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. RESULTS: Samples from four NHPs were evaluable. Average (± SD) plasma PK parameters were as follows: Cmax = 16.50 (± 6.67) µg/mL; Tmax = 5.00 (± 2.58) h; AUClast = 250.25 (± 103.76) h*µg/mL; CL = 0.18 (± 0.10) L/h/kg. In CSF, pexidartinib was either quantifiable (n = 2), with Cmax values of 16.1 and 10.1 ng/mL achieved 2-4 h after plasma Tmax, or undetected at all time points (n = 2, LLOQCSF = 5 ng/mL). CONCLUSION: Pexidartinib was well-tolerated in NHPs, with no Grade 3 or Grade 4 toxicities. The CSF penetration of pexidartinib after single-dose oral administration to NHPs was limited.

Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates.

PURPOSE: Describe and compare the central nervous system pharmacology of the platinum analogues, cisplatin, carboplatin, and oxaliplatin and develop a pharmacokinetic model to distinguish the disposition of active drug from inert platinum species. EXPERIMENTAL DESIGN: Oxaliplatin (7 or 5 mg/kg), cisplatin (2 mg/kg), or carboplatin (10 mg/kg) was given i.v. Serial plasma and cerebrospinal fluid (CSF) samples were collected over 24 hours. Plasma ultrafiltrates were prepared immediately. Platinum concentrations were measured using atomic absorption spectrometry. Areas under the concentration x time curve were derived using the linear trapezoidal method. CSF penetration was defined as the CSF AUC(0-24)/plasma ultrafiltrate AUC(0-24) ratio. A four-compartment model with first-order rate constants was fit to the data to distinguish active drug from inactive metabolites. RESULTS: The mean +/- SD AUCs in plasma ultrafiltrate for oxaliplatin, cisplatin, and carboplatin were 61 +/- 22, 18 +/- 6, and 211 +/- 64 micromol/L hour, respectively. The AUCs in CSF were 1.2 +/- 0.4 micromol/L hour for oxaliplatin, 0.56 +/- 0.08 micromol/L hour for cisplatin, and 8 +/- 2.2 mumol/L hour for carboplatin, and CSF penetration was 2.0%, 3.6%, and 3.8%, respectively. For oxaliplatin, cisplatin, and carboplatin, the pharmacokinetic model estimated that active drug accounted for 29%, 79%, and 81% of platinum in plasma ultrafiltrate, respectively, and 25%, 89%, and 56% of platinum in CSF, respectively. The CSF penetration of active drug was 1.6% for oxaliplatin, 3.7% for cisplatin, and 2.6% for carboplatin. CONCLUSIONS: The CSF penetration of the platinum analogues is limited. The pharmacokinetic model distinguished between active drug and their inactive (inert) metabolites in plasma and CSF.

Incorporation of an enrichment program into a study protocol involving long-term restraint in macaques.

Nonhuman primates might experience stress during periods of restraint associated with research procedures. In an attempt to minimize such stress, the authors describe an enrichment program they designed for use with restrained adult male rhesus macaques.

Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates.

PURPOSE: Cisplatin, carboplatin, and oxaliplatin are chemically reactive anticancer drugs with modest activity in brain tumors. Previously, we have demonstrated that drug exposure in cerebrospinal fluid (CSF) for these platinum analogs is <5% of the plasma ultrafiltrate (UF) drug exposure in nonhuman primates. Microdialysis is a minimally invasive in vivo method for sampling small molecules in the blood and tissue extracellular fluid (ECF). The purpose of this study was to estimate the penetration of platinum analogs into the brain ECF. METHODS: We measured free concentrations of cisplatin, carboplatin, and oxaliplatin in ECF of brain, muscle, and blood of nonhuman primates using microdialysis and compared ECF platinum concentrations in blood and brain to plasma UF and CSF concentrations obtained using conventional sampling methods. RESULTS: For all three platinum analogs, AUC(0-4h) for microdialysis sampling from the vein was similar to standard plasma UF sampling. The median AUC(0-4h) ratio for vein to plasma UF was 1.1 (range, 0.9-1.4). The platinum analogs had limited distribution (<5%) to the CSF and brain ECF. CSF penetration predicts for the limited penetration of the platinum analogs into brain ECF, but concordance between CSF and brain ECF measurements was poor. CSF oxaliplatin concentrations (AUC(0-4h), 0.4-0.9 microM h) were substantially lower than brain ECF concentrations (AUC(0-4h), 2.0-8.6 microM h). CONCLUSIONS: The penetration of platinum analogs into CSF and brain is limited. The differences in the CNS penetrations among the three platinum analogs are not clinically significant. For cisplatin and carboplatin, CSF penetration appears to be a surrogate for brain extracellular free drug exposure.

The serum and cerebrospinal fluid pharmacokinetics of anakinra after intravenous administration to non-human primates.

Anakinra improves the central nervous system manifestations of neonatal-onset multisystem inflammatory disease, which is mediated by IL-1beta oversecretion. The cerebrospinal fluid (CSF) penetration of the IL-1 receptor antagonist anakinra was studied in rhesus monkeys after intravenous doses of 3 and 10 mg/kg. Drug exposure (area under concentration-time curve) in CSF was 0.28% of that in serum. The average CSF concentration at 3 mg/kg was 1.8 ng/mL, which is 30-fold higher than endogenous CSF levels of IL-1Ra. The CSF penetration was not dose-dependent, indicating that the CSF penetration was not saturated in the 3 to 10 mg/kg dose range.

Zidovudine concentration in brain extracellular fluid measured by microdialysis: steady-state and transient results in rhesus monkey.

We measured zidovudine concentrations in blood, muscle, and brain extracellular fluid (ECF) by microdialysis and in serum ultrafiltrate and cerebrospinal fluid (CSF) samples during a continuous intravenous infusion (15 mg/kg/h) and after bolus dosing (50-80 mg/kg over 15 min) in nonhuman primates to determine whether CSF drug penetration is a valid surrogate for blood-brain barrier penetration. Recovery was estimated in vivo by zero net flux for the continuous infusion and retrodialysis for the bolus dosing. In vivo recovery was tissue-dependent and was lower in brain than in blood or muscle. Mean (+/-S.D.) steady-state blood, muscle, and brain zidovudine concentrations by microdialysis were 112 +/- 63.8, 105 +/- 51.1, and 13.8 +/- 10.4 microM, respectively; and steady-state serum ultrafiltrate and CSF concentrations were 81.2 +/- 40.2 and 14.1 +/- 8.0 microM, respectively. Brain ECF penetration (microdialysis brain/blood ratio) and CSF penetration (standard sampling CSF/serum ratio) at steady state were 0.13 +/- 0.06 and 0.17 +/- 0.02, respectively. With bolus dosing the mean (+/-S.D.) zidovudine area under concentration-time curve (AUC) normalized to a dose of 80 mg/kg was 577 +/- 103 microM. h in blood, 528 +/- 202 microM. h in muscle, and 108 +/- 74 microM. h in brain (brain/blood ratio of 0.18 +/- 0.10) by microdialysis. Serum ultrafiltrate AUC was 446 +/- 72 microM. h and the CSF AUC was 123 +/- 4.7 microM. h (CSF/serum ratio of 0.28 +/- 0.06). In conclusion, recovery was tissue-dependent. CSF and brain ECF zidovudine concentrations were comparable at steady state, and the corresponding AUCs were comparable after bolus injection. Thus, zidovudine penetration in brain ECF and CSF in nonhuman primates is limited to a similar extent, presumably by active transport, as in other species.