Plasma and cerebrospinal fluid pharmacokinetics of valproic acid after oral administration in non-human primates.

PURPOSE: Valproic acid (VPA), a widely used antiepileptic, also inhibits histone deacetylase (HDAC), and is undergoing evaluation as an anti-cancer agent. We studied the pharmacokinetics of VPA in the plasma and cerebrospinal fluid (CSF) in a non-human primate model that is highly predictive of human CSF penetration to determine if levels of VPA required to inhibit HDAC in in vivo models can be attained. METHODS: Oral VPA, 75 mg/kg, was administered to four non-human primates. Serial samples of blood (n = 4) and CSF (n = 3) were obtained for pharmacokinetic studies of total and free VPA. Plasma and CSF VPA concentrations were measured using the commercially available Abbott AxSYM VPA assay reagent system (Abbott Laboratories, Abbott Park, IL, USA). The resultant plasma and CSF data were evaluated using pharmacokinetic modeling methods. RESULTS: At a dose of 75 mg/kg, the maximum plasma concentration of VPA was 130.1 +/- 70.6 microg/ml (mean +/- standard deviation) for total drug and 53.3 +/- 44.4 microg/ml for free drug. The mean plasma area under the curve (AUC) for total drug was 680 +/- 233 microg/ml h and for free drug 146 +/- 89 microg/ml hr. The maximum CSF concentration occurred 2-3 h after administration and was 28.2 +/- 18.6 microg/ml. The CSF AUC for VPA was 108 +/- 52 microg/ml h. The CSF penetration of VPA was 12.9 +/- 5.1% for total drug and 57.0 +/- 8.7% for free drug. Disappearance from the plasma followed non-linear kinetics with a V (max) of 321.2 +/- 65.6 microg/kg/min and a K (m) of 17.2 +/- 13.7 mg/l. CONCLUSION: Valproic acid deserves further study for the treatment of CNS tumors given its high CSF penetration after oral dosing coupled with the anti-tumor activity observed in preclinical studies.

Plasma and cerebrospinal fluid pharmacokinetics of nelarabine in nonhuman primates.

INTRODUCTION: Nelarabine is a water-soluble prodrug of the cytotoxic deoxyguanosine analog ara-G, to which it is rapidly converted in vivo by adenosine deaminase. Nelarabine has shown activity in the treatment of T-cell malignancies, especially T-cell acute lymphoblastic leukemia. Preliminary data suggested that nelarabine might penetrate into the CSF. We therefore studied the CSF penetration of nelarabine and ara-G in a nonhuman primate model that has been highly predictive of anticancer drug distribution in humans. METHODS: Nelarabine (35 mg/kg, approximately 700 mg/m2) was administered over 1 h through a surgically implanted central venous catheter to four nonhuman primates. Blood (four animals) and ventricular CSF (three animals) samples were obtained at intervals for 24 h for determination of nelarabine concentrations, which were measured by HPLC-mass spectrometry. RESULTS: The nelarabine plasma AUC (median+/-s.d.) was 2,820+/-1,140 microM min and the ara-G plasma AUC was 20,000+/-8,100 microM min. The terminal half-life of nelarabine in plasma was 25+/-5.2 min and clearance was 42+/-61 ml/min/kg. The terminal half-life of ara-G in plasma was 182+/-45 min. In CSF the terminal half-life of nelarabine was 77+/-28 min and of ara-G was 232+/-79 min. The AUCcsf:AUCplasma was 29+/-11% for nelarabine and 23+/-12% for ara-G. CONCLUSION: The excellent CSF penetration of nelarabine and ara-G supports further study of the contribution of nelarabine to the prevention and treatment of CNS leukemia.

Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates.

PURPOSE: Pemetrexed, a multi-targeted antifolate that disrupts synthesis of both purines and pyrimidines, is approved for use in malignant pleural mesothelioma and non-small cell lung cancer. Pemetrexed is currently being evaluated for anti-tumor activity in a variety of solid and central nervous system tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of pemetrexed in a non-human primate model that is highly predictive of human CSF penetration. METHODS: Pemetrexed, 20 mg/kg (400 mg/m2), was administered intravenously to four non-human primates. Serial blood samples were obtained from all animals and serial CSF samples were obtained from three animals. Plasma and CSF concentrations of pemetrexed were measured using LC/MS/MS and the resulting concentration versus time data were evaluated using model independent and dependent methods. RESULTS: Pemetrexed disappearance from plasma was best described by a two compartment model with a mean distribution half-life of 13.8 +/- 3.2 min and an elimination half-life of 70.0 +/- 16.0 min. The volume of distribution of and the clearance from the central compartment were 0.066 +/- 0.017 l/kg and 3.6 +/- 0.6 ml/min/kg, respectively. Peak CSF concentrations occurred 40-71 min after the start of the infusion with an average of 0.26 +/- 0.15 microM. CONCLUSION: The CSF penetration of pemetrexed was less than 2% (range 0.33-1.58%), suggesting that it should be used in conjunction with other CNS preventive strategies when used in the treatment of malignancies with a predilection for CNS or leptomeningeal metastases.

Plasma and cerebrospinal fluid pharmacokinetics of clofarabine in nonhuman primates.

INTRODUCTION: Clofarabine (2-chloro-2'fluoro-2'-deoxy-9-beta-d-arabinofuranosyladenine) is a purine nucleoside analogue that is active in the treatment of acute leukemia. We studied the pharmacokinetics and cerebrospinal fluid penetration of clofarabine in a nonhuman primate model. METHODS: A dose of 2.3 mg/kg of clofarabine was given i.v. over 2 hours to each of four animals. Plasma and cerebrospinal fluid (CSF) samples were obtained at specified intervals and the clofarabine concentration determined by reverse-phase high-pressure liquid chromatography with mass spectroscopy. RESULTS: The median clofarabine clearance was 17 mL/min/kg (range, 15-20), the median plasma area under the concentration-time curve was 452 mumol/L minutes (range, 380-487), and the median terminal half-life was 105 minutes (range, 78-138). Concentrations of clofarabine in CSF could not be modeled reliably because the terminal rate constant was not well defined. The median CSF penetration was 5% (range, 3-26%). CONCLUSION: Clofarabine penetrates into the CSF only modestly, but the concentrations obtained may approach those that are cytotoxic in vitro. Evaluation of the contribution of clofarabine to central nervous system preventive therapy should be considered in future studies.

Plasma and cerebrospinal fluid pharmacokinetics of imatinib after administration to nonhuman primates.

PURPOSE: Imatinib mesylate (Gleevec, Glivec, STI571, imatinib) is a potent tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. The role of imatinib in the treatment of malignant gliomas and other solid tumors is being evaluated. We used a nonhuman primate model that is highly predictive of the cerebrospinal fluid penetration of drugs in humans to study the pharmacokinetics of imatinib in plasma and cerebrospinal fluid (CSF) after i.v. and p.o. administration. EXPERIMENTAL DESIGN: Imatinib, 15 mg/kg i.v. over 30 min (n = 3) or 30 mg/kg p.o. (n = 3), was administered to nonhuman primates. Imatinib was measured in serial samples of plasma and CSF using high-pressure liquid chromatography with UV absorbance or mass spectroscopic detection. Pharmacokinetic parameters were estimated using model-independent methods. RESULTS: Peak plasma imatinib concentrations ranged from 6.4 to 9.5 microM after i.v. dosing and 0.8 to 2.8 microM after p.o. dosing. The mean +/-SD area under the plasma concentration versus time curve was 2480 +/-1340 microM.min and 1191 +/-146 microM.min after i.v. and p.o. dosing, respectively. The terminal half-life was 529 +/-167 min after i.v. dosing and 266 +/-88 min after p.o. dosing. After i.v. dosing the steady state volume of distribution was 5.9 +/-2.8 liter/kg, and the total body clearance was 12 +/-5 ml/min/kg. The mean peak CSF concentration was 0.25 +/-0.07 microM after i.v. dosing and 0.07 +/-0.04 microM after p.o. dosing. The mean CSF:plasma area under the plasma concentration versus time curve ratio for all of the animals was 5% +/-2%. CONCLUSIONS: There is limited penetration of imatinib into the CSF of nonhuman primates after i.v. and p.o. administration.

Plasma and cerebrospinal fluid pharmacokinetics of rebeccamycin (NSC 655649) in nonhuman primates.

PURPOSE: The rebeccamycins, indolocarbazole topoisomerase I poisons originally discovered in actinomycetes, have shown activity in vitro against a range of adult and pediatric tumors. The derivative NSC 655649 (diethylaminoethyl analog of rebeccamycin, or DEAE rebeccamycin) is currently undergoing early-phase human studies and has shown some signs of antitumor activity. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of NSC 655649 after systemic administration in a nonhuman primate model that is predictive of anticancer drug behavior in humans. DESIGN: A dose of 400 mg/m2 was infused over 1 h to three rhesus monkeys. Serial blood and CSF samples were collected. Rebeccamycin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic analysis was performed using compartmental and noncompartmental methods. RESULTS: A two-compartment or three-compartment model described rebeccamycin pharmacokinetics in plasma adequately. In two animals, the three-compartment model provided a better fit, and in one animal, the two-compartment model was better. The terminal half-life was 730+/-410 min, the AUC was 3130+/-425 microM min, and the clearance was 190+/-25 ml/min/m2. Rebeccamycin was below the limit of quantitation in all CSF samples. The animals had some nausea and agitation during and shortly after the infusion that responded to treatment with prochlorperazine or diazepam. Otherwise, rebeccamycin was well tolerated with minimal toxicity. CONCLUSION: Rebeccamycin penetrates poorly into the CSF following an intravenous infusion. Therefore, systemically administered rebeccamycin is unlikely to be an important agent for the treatment of leptomeningeal tumors. Because the drug is associated with local irritation at injection sites, it is not an ideal candidate for development as an intrathecal agent. However, the role of rebeccamycin in the treatment of parenchymal brain tumors should be determined in clinical trials.

Plasma and cerebrospinal fluid pharmacokinetics of SU5416 after intravenous administration in nonhuman primates.

PURPOSE: SU5416 is a small, lipophilic synthetic molecule that selectively inhibits the tyrosine kinase activity of the VEGF receptor Flk-1/KDR. The role of this agent in brain tumors is currently being investigated. Pharmacokinetic studies of SU5416 have been performed in humans; however, there have been no studies of its penetration in the cerebrospinal fluid (CSF). We studied the pharmacokinetics of SU5416 in plasma and CSF after intravenous (i.v.) administration using a nonhuman primate model that is highly predictive of the CSF penetration in humans. EXPERIMENTAL DESIGN: SU5416 (85 mg/m(2), about 3.8 mg/kg) was administered i.v. over 20 min to four nonhuman primates. Serial plasma and CSF samples were obtained prior to, during, and after completion of the infusion for determination of SU5416 concentrations. SU5416 was measured in plasma and CSF using high-performance liquid chromatography (HPLC). Concentration-versus-time data were modeled using model-independent and model-dependent methods. RESULTS: Peak plasma concentrations ranged from 6.3 to 14.5 microM and the mean plasma AUC was 620+/-180 microM.min. Disappearance of SU5416 from the plasma was best described by a one-compartment model with a half-life of 39+/-2.9 min. The volume of distribution was 36+/-11 l/m(2) and the clearance was 0.62+/-0.2 l/min per m(2). SU4516 was not quantifiable in the CSF. CONCLUSIONS: There is minimal penetration of SU5416 into the CSF after i.v. administration. The very low CNS exposure to SU5416 after i.v. dosing suggests that this agent is not optimal for the treatment of leptomeningeal tumors.

Plasma and cerebrospinal fluid pharmacokinetics of depsipeptide (FR901228) in nonhuman primates.

PURPOSE: Acetylation of histones by histone acetyl transferases (HATs) leads to transcriptional activation, while histone deacetylase (HDAC) activity leads to transcriptional repression. Abnormalities of histone acetylation are associated with the malignant phenotype. Depsipeptide (FR901228) inhibits HDAC and has shown anticancer activity in preclinical models. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics of depsipeptide in a nonhuman primate model that is highly predictive of human CSF penetration. DESIGN: Depsipeptide was administered intravenously at a dose of 10 mg/m(2) over 4 h to three different animals. Serial blood samples were obtained from all animals and serial CSF samples were obtained from two animals. Plasma and CSF concentrations of depsipeptide were measured using liquid chromatography/tandem mass spectrometry. Concentration-versus-time data were modeled using model-independent and model-dependent methods. RESULTS: The peak plasma concentration (median+/-SD) was 245+/-50 n M and occurred within the first 2 h of the infusion. The terminal half-life was 205+/-315 min, the AUC extrapolated to infinity was 50+/-15 micro M.min, and the total body clearance was 350+/-65 ml/min/m(2). In the two animals that had CSF sampling performed, the CSF peak concentration was 3.6 n M in one animal and 2.3 n M in the other, and the CSF half-lives were 250 and 325 min. The CSF penetration of depsipeptide (AUC(CSF):AUC(plasma)) was 2% in each animal. Observed changes included anorexia, fatigue, elevation of creatine phosphokinase (CPK) enzyme levels (muscle fraction), and transient early leukopenia. All animals recovered without sequelae. CONCLUSIONS: Although the CSF exposure to depsipeptide after intravenous administration was only 2%, CSF concentrations approached the IC(50) of depsipeptide in vitro for some tumors. Systemic administration of this agent may be useful for the treatment of leptomeningeal tumors.

Plasma and cerebrospinal fluid pharmacokinetic study of BNP1350 in nonhuman primates.

PURPOSE: BNP1350 (7-[(2-trimethylsilyl)ethyl]-20(S)-camptothecin, karenitecin), a highly lipophilic camptothecin, a high percentage of which is maintained in the active lactone form under physiologic conditions, has recently entered clinical trials in adults and children. BNP1350 has shown significant preclinical antitumor activity against a wide variety of adult and pediatric tumor cell lines. This study was undertaken to define the pharmacokinetics of BNP1350 in both plasma and cerebrospinal fluid (CSF) in a nonhuman primate model. METHODS: Four nonhuman primates with indwelling Ommaya reservoirs received BNP1350, 0.1 mg/kg i.v, administered as a 60-min infusion. Frequent plasma and CSF samples were obtained for quantitation of BNP1350 concentrations using reverse-phase high-pressure liquid chromatography (HPLC). RESULTS: Disappearance of the lactone form from the plasma was biexponential with a mean distribution half-life of 57.5 min (CV +/-33%) and an elimination half-life of 457 min (CV +/-24%). The volume of distribution for the central compartment was 1.36 l/kg (CV +/-27%) and clearance from the central compartment was 10.6 ml/kg per minute (CV +/-28%). The peripheral compartment volume of distribution was 1.96 l/kg (CV +/-8.4%). Peak CSF lactone concentration, which occurred at 12 to 25 min after the end of the infusion, was 0.33 n M (CV +/-71%). CONCLUSIONS: The ratio of the CSF AUC to the plasma AUC was less than 5% (range 0.4% to 3.0%), similar to other highly protein-bound topoisomerase inhibitors such as 9-aminocamptothecin and SN-38 (the active metabolite of irinotecan).

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.

Plasma and cerebrospinal fluid pharmacokinetics of thalidomide and lenalidomide in nonhuman primates.

PURPOSE: Thalidomide, originally developed as a sedative, was subsequently identified to have antiangiogenic properties. Lenalidomide is an antiangiogenic and immunomodulatory agent that has been utilized in the treatment of patients with brain tumors. We studied the pharmacokinetics and cerebrospinal fluid (CSF) penetration of thalidomide and lenalidomide in a nonhuman primate model. METHODS: A dose of 50 mg of thalidomide or 20 mg of lenalidomide was administered once orally to each of three rhesus monkeys. Plasma and CSF samples were obtained at specified intervals, and the thalidomide or lenalidomide concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods. CSF penetration was calculated as area under the concentration-time curve (AUC) CSF/AUC plasma. RESULTS: For thalidomide, the median apparent clearance (Cl/F) was 2.9 mL/min/kg, the median plasma AUC was 80 µM h, and the median terminal half-life (t(½)) was 13.3 h. For lenalidomide, the median Cl/F was 8.7 mL/min/kg, the median AUC was 9 µM h, and the median t(½) was 5.6 h. Thalidomide was detected in the CSF of all animals, with a median penetration of 42%. Lenalidomide was detected in the CSF of 2 of 3 animals, with a CSF penetration of 11% in each. CONCLUSION: Thalidomide and lenalidomide penetrate into the CSF after oral administration of clinically relevant doses. Plasma exposure to lenalidomide was similar in our model to that observed in studies involving children who have brain tumors. These results support further development of lenalidomide for the treatment of central nervous system malignancies.

Plasma and cerebrospinal fluid pharmacokinetics of ABT-888 after oral administration in non-human primates.

PURPOSE: ABT-888 inhibits poly(ADP-ribose) polymerase (PARP) and may enhance the efficacy of chemotherapy and radiation in CNS tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of ABT-888 in a non-human primate (NHP) model that is highly predictive of human CSF penetration. METHODS: ABT-888, 5 mg/kg, was administered orally to three NHPs. Serial blood and CSF samples were obtained. Plasma and CSF concentrations of ABT-888 were measured using LC/MS/MS, and the resulting concentration versus time data were evaluated using non-compartmental and compartmental PK methods. RESULTS: The CSF penetration of ABT-888 was 57+/-7% (mean+/-SD). The peak ABT-888 concentration in the plasma was 0.62+/-0.18 microM. Plasma and CSF AUC0-infinity were 3.7+/-1.7 and 2.1+/-0.8 microM h. PARP inhibition in peripheral blood mononuclear cells was evident 2 h after ABT-888 administration. CONCLUSION: The CSF penetration of ABT-888 after oral administration was 57%. Plasma and CSF concentrations were in the range that has been shown to inhibit PARP activity in vivo in humans.

Plasma and cerebrospinal fluid pharmacokinetics of tasidotin (ILX-651) and its metabolites in non-human primates.

PURPOSE: To evaluate the plasma and cerebrospinal fluid (CSF) pharmacokinetics and CSF penetration of tasidotin and metabolites in a nonhuman primate model. METHODS: Tasidotin 0.75 mg/kg was administered intravenously. The plasma and CSF concentrations of tasidotin and its metabolites were determined. Pharmacokinetic parameters were estimated using model-independent and model-dependent methods. RESULTS: The mean (+/-SD) CSF:plasma AUC ratio for tasidotin was 1.1 +/- 0.4. For tasidotin, tasidotin-C-carboxylate and desprolyl-tasidotin-C-carboxylate the plasma AUCs (mean +/- SD) were 30 +/- 10, 54 +/- 19 and 12 +/- 2 microM min, and apparent plasma half-lives were 27 +/- 4, 229 +/- 73 and 100 +/- 29 min. The plasma clearance of tasidotin was 44 +/- 14 ml/min/kg. The CSF AUC and half-life of tasidotin was 28 +/- 10 microM min and 96 +/- 40 min. The model-dependent plasma clearance was 35 ml/min/kg for tasidotin and 2 ml/min/kg for tasidotin-C-carboxylate. CONCLUSIONS: Tasidotin penetrates into the CSF well and further evaluation of its activity in the treatment of central nervous system malignancies should be considered.