Dag Nilsson

Distribution of Zolmitriptan into the CNS in Healthy Volunteers

AbstractObjective: Triptans are highly effective in the treatment of migraine. Both central and peripheral mechanisms of action have been suggested. Until now, firm data about the passage of triptans into the CNS in humans have been lacking. The aim of the current study was to evaluate, using positron emission tomography (PET), the uptake and distribution of zolmitriptan into the CNS after intranasal administration. Subjects and methods: Eight healthy volunteers, five males and three females (mean ages 23 and 26 years, respectively), were included. Radioactive [carbonyl-11C]zolmitriptan was infused intravenously for 5 minutes on two occasions: once alone, and once 30–40 minutes after intranasal administration of unlabelled zolmitriptan 5mg. PET was used to measure the concentration of labelled zolmitriptan in the brain, from the start of the tracer infusion for 90 minutes. Regional cerebral blood volume was determined with [15O]carbon monoxide. In addition, an MRI scan was performed to obtain anatomical information.The PET images were analysed quantitatively for different areas of the brain, generating [11C]zolmitriptan time-activity data corrected for circulating tracer activity. The rate of uptake of intranasal zolmitriptan into the CNS was estimated by kinetic modelling using the PET data. Results: PET data from this study demonstrate a rapid dose-proportional uptake of [11C]zolmitriptan into the brain. Significant concentrations of [11C]zolmitriptan were found in all brain regions studied. Calculated CNS concentrations after intranasal zolmitriptan administration showed a gradual increase, reaching about 2nM (0.5 μg/L) 30 minutes after administration and 3.5nM (1.0 μg/L), or one-fifth of the plasma concentration, 1 hour after administration. Five minutes after zolmitriptan administration, the mean CNS concentration had already reached 0.5nM, which is higher than in vitro values for initiation of the agonistic action on 5-HT1B/1D receptors. Conclusion: This study demonstrates by direct measurements that zolmitriptan enters the brain parenchyma in humans, achieving an uptake rate and concentration compatible with a central mode of action.

Safety, tolerability and pharmacokinetics of escalating doses of NXY-059 in healthy young and elderly subjects.

ABSTRACT Objective: NXY-059 is a novel, free-radical trapping, neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischaemic stroke. This study evaluated the safety, tolerability and pharmacokinetics of NXY-059 in the unbound steady-state plasma concentration (Cuss) exposure range of 50-300 μmol/L in healthy young and elderly subjects. Research design and methods: The primary objective of this two-centre, randomised, double-blind, placebo-controlled, dose-escalating study was to investigate the safety and tolerability, including renal function parameters and vasoirritative effects, of 8‐h and 72‐h intravenous infusions of NXY‐059 in healthy young (20–45 years) and elderly (55–75 years) male and female subjects. The secondary objective of the study was to evaluate the pharmacokinetics of 8‐h and 72‐h intravenous infusions of NXY‐059 in these subjects, using blood and urine samples taken during and after NXY‐059 infusion as well as the doses administered. Results: Of the 104 healthy volunteers who participated in the study, 72 were young and 32 were elderly. The type and incidence of adverse events in NXY‐059 and placebo subjects were similar, although headache was more common in the NXY‐059 group. Renal function was not altered in either group. Thrombophlebitis was reported in two elderly subjects: one receiving NXY-059 and one receiving placebo. A proportional relationship between AUC and dose for the 8‐h and 72‐h infusions was observed, and clearance did not change with dose. Conclusions: NXY-059 was well tolerated at all plasma concentrations tested in both the young and elderly subjects, and no safety concerns were raised. Linear pharmacokinetics were observed following 8‐h and 72‐h infusions of NXY‐059 at doses resulting in an average Cuss in the 52–317 µmol/L range.

Pharmacokinetics of 8-hour intravenous infusion of NXY-059: A phase I, randomized, double-blind (within dose panels), placebo-controlled study in healthy Chinese volunteers

BACKGROUND NXY-059 is a free radical-trapping neuroprotectant that has been reported to reduce infarct size and preserve brain function in experimental models of acute ischemic stroke. NXY-059 administered as an 8- or 72-hour IV infusion has been reported to be well tolerated in healthy young (age, 20-45 years) and older (55-75 years) white volunteers. NXY-059 is no longer in development following a lack of efficacy found in a Phase III trial in patients with acute ischemic stroke. OBJECTIVES The primary objectives of this study were to determine the pharmacokinetic (PK) properties of an 8-hour IV infusion of NXY-059 in healthy Chinese volunteers and to compare those data with those previously reported in the white population, therefore exploring any differences in PK properties between the 2 ethnic groups. Secondary objectives were to evaluate PK linearity and tolerability. METHODS This Phase I, randomized, double-blind (within dose panels), placebo-controlled study was conducted at Peking Union Medical College Hospital, Beijing, China. Healthy male and female Chinese volunteers aged 20 to 45 years were recruited. NXY-059 was administered as a continuous 8-hour IV infusion, starting with a 1-hour loading dose (dosing rate, 3 x maintenance infusion rate) followed by a 7-hour maintenance dose infusion. Subjects were randomly assigned, in a 3:1 ratio, to receive doses calculated (based on creatinine clearance in individual subjects) to achieve 1 of 3 concentration targets, or inactive vehicle (sodium chloride; placebo). The target unbound plasma NXY-059 concentrations during constant rate infusion (steady state) (Cu(ss)) in the 3 dose panels were 100,200, and 300 micromol/L. An explorative bridging analysis was used to compare PK data from this study with those previously reported in the white population. Linearity of NXY-059 PK properties was assessed. Tolerability was assessed using adverse events (spontaneous reporting, study staff observation, and open questioning), physical examination, including vital sign measurement; and electrocardiography and laboratory analysis. RESULTS Thirty-six subjects were randomized (mean age, 32 years [range, 20-41 years]; mean body mass index, 22.6 kg/m(2) [range, 20-26 kg/m(2)]). The target exposures of NXY-059 were achieved (mean [SD] Cu(ss) values, 98.3 [8.9], 202.1 [18.3], and 287.9 [25.4] micromol/L, respectively). Steady-state concentrations appeared to have been reached after 4 hours. From the bridging analysis, comparison of PK properties in the 27 Chinese volunteers versus those in 28 white volunteers found similar total plasma clearance of NXY-059 (estimated Chinese:white clearance ratio, 1.077 [95% CI, 1.009-1.150]). There were no apparent differences in other PK parameters between the 2 ethnic groups. The PK properties of NXY-059 in Chinese volunteers were suggestive of linearity. A total of 7 adverse events were reported, all of mild intensity, in the NXY-059 and placebo groups (thirst and polyuria [each in 2 subjects who received NXY-059 and 1 subject who received placebo]; urinary tract infection [1 subject who received NXY-059]). CONCLUSIONS The results from the present study suggest that the PK properties of NXY-059 were similar in the Chinese and historical white healthy volunteer populations.

NXY-059 Does Not Affect Bleeding Time in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled, 3-Period Crossover Phase I Study

NXY‐059 is a novel free radical–trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. It is the first neuroprotectant to demonstrate a reduction in global disability in a phase III clinical trial, as measured by the modified Rankin Scale. Any effect of NXY‐059 on hemostasis may be important when treating stroke patients. This phase I randomized, double‐blind, placebo‐controlled, 3‐period crossover study compared the effect of NXY‐059, desmopressin, and placebo on bleeding time, platelet aggregation, and adhesion in 30 healthy volunteers. NXY‐059 did not prolong bleeding time compared with placebo: mean (SD) time for NXY‐059, 369.5 seconds (125.0 seconds) versus placebo, 369.1 seconds (136.0 seconds). There were no significant effects on platelet aggregation or adhesion. At a mean unbound plasma concentration (Cuss) of 335 μmol/L, NXY‐059 was well tolerated, with no major safety concerns identified. In conclusion, NXY‐059 does not appear to affect primary hemostasis.

A Study of Organic Acid Transporter‐Mediated Pharmacokinetic Interaction Between NXY‐059 and Cefuroxime

N is a novel, free-radical-trapping neuroprotectant that, until recently, was in clinical development for the treatment of acute ischemic stroke based on effects seen in experimental animal models. NXY-059 is eliminated primarily by renal excretion, and initial studies have shown that approximately 30% is via active tubular secretion. A phase I study has demonstrated that the active tubular secretion of NXY-059 occurs through an organic acid transporter (OAT). The half-life of NXY-059 is approximately 4 hours in healthy subjects. The antibiotic cefuroxime has a half-life of approximately 66 minutes and is eliminated renally, with approximately 45% accounted for by an OAT. The relatively large fraction of cefuroxime eliminated via an OAT compared with most other drugs makes it a suitable model drug to study any effect of NXY-059 on this transporter. Furthermore, the clinical dose of cefuroxime is relatively high (1.5 g or approximately 3.5 mmol), resulting in concentrations that can potentially saturate the OAT and thereby affect the active elimination of NXY-059. The primary objectives of this study were to explore the effect of NXY-059 on the renal clearance (CLR) of the model drug cefuroxime and, vice versa, to estimate the degree of interaction to be expected with NXY-059 when coadministered with other drugs mainly eliminated by the kidney, with some contribution from active transportation by OAT.

Autoradiographic Mapping of 5-HT1B/1D Binding Sites in the Rhesus Monkey Brain Using [carbonyl-11C]zolmitriptan

Zolmitriptan is a serotonin 5-HT1B/1D receptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [11C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [11C]zolmitriptan in Rhesus monkey brain using whole hemisphere in vitro autoradiography with [11C]zolmitriptan as a radioligand. In saturation studies, [11C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95–5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT1 receptor antagonists, [11C]zolmitriptan binding was blocked by selective 5-HT1B and 5-HT1D ligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT1A receptor antagonist.

Active Renal Secretion of NXY-059, a Novel Neuroprotectant, Is Mediated via an Organic Acid Transporter

N (disufenton sodium) is a novel, freeradical–trapping neuroprotectant, which, until recently, was in clinical development for the treatment of acute ischemic stroke based on effects seen in experimental animal models. Phase 1 studies in healthy subjects receiving intravenous (iv) infusions of NXY-059 demonstrated that it is mainly eliminated unchanged by renal excretion. Furthermore, these data indicated that passive tubular reabsorption of NXY-059 does not occur because renal clearance (CLR) was insensitive to changes in pH and urine flow rate. Analysis of CLR data indicated that approximately 30% of renal elimination is a result of active secretion in the kidney. A study undertaken in subjects with renal impairment indicated that plasma clearance of NXY-059 correlated highly to kidney function measured as glomerular filtration rate (GFR). The study concluded that the contribution of nonrenal clearance to the overall clearance of NXY-059 was negligible. The purpose of this study was to further characterize the active renal excretion of NXY-059. NXY-059 is a disulfonate salt with both of its pKa values less than 2. At physiological pH of the blood, most of NXY-059 will exist in the unprotonated form and will be ionized as an acid. Therefore, NXY-059 would be a likely candidate for secretion by an active (carrier-mediated and energy-dependent) organic acid transport system. However, because the N-oxide moiety of NXY-059 also carries a partial positive charge, the possibility also exists that NXY-059 could be secreted by an active transporter for organic bases. Probenecid and cimetidine were used as model inhibitors in this study to further characterize the renal excretory mechanisms of NXY-059 because these drugs are known to be inhibitors of renal systems that transport organic acids and bases, respectively. In addition, inulin was used for monitoring GFR during the study.

A phase 1, placebo-controlled, randomised, double-blind (within dose panels) study evaluating the safety, tolerability and pharmacokinetics of intravenous NXY-059 in Japanese subjects

ABSTRACT Objective: NXY‑059 has a proposed mechanism of action of free-radical trapping and has been studied in clinical trials based on positive effects seen in experimental models of acute ischaemic stroke. This study evaluated the safety, tolerability and pharmacokinetics of NXY‑059 in healthy Japanese male subjects compared with previous data from healthy Caucasian subjects. Research design and methods: The primary objective of this phase 1, double-blind, randomised, placebo-controlled, dose-escalating study was to evaluate the safety and tolerability of an 8- or 24‑h intravenous infusion of NXY-059 targeting an unbound plasma concentration of 25–300 μmol/L in healthy Japanese male subjects (20–45 years). NXY‑059 pharmacokinetics were also assessed, and any differences in pharmacokinetics between Japanese and previously studied Caucasian subjects (20–45 years) were explored. Results: NXY‑059 was generally well tolerated and no safety concerns were identified. There was a similar incidence of adverse events between subjects receiving NXY‑059 or placebo, and no obvious trend towards an increased incidence of adverse events with increasing doses of NXY‑059 was observed. In addition, there was no evidence of any vasoirritative effects or changes in renal function. The tolerability profile was similar in Caucasian subjects. The pharmacokinetic results indicate proportional exposure of 8‑h and 24‑h infusions of NXY‑059 resulting in mean unbound steady state plasma concentrations up to 417 μmol/L and 379 μmol/L, respectively. Plasma clearance values for NXY‑059 were similar in both Japanese and Caucasian subjects. Conclusions: This study suggests that the tolerability and pharmacokinetics of NXY‑059 in healthy Japanese male subjects and Caucasians are similar.

Effect of NXY-059, a novel neuroprotectant, on the pharmacokinetics of a single dose of digoxin in healthy subjects

ABSTRACT Objective: NXY-059 is a novel free-radical trapping neuroprotectant. Digoxin treatment is common in acute ischaemic stroke, the intended patient population for NXY‑059. Since both digoxin and NXY‑059 are eliminated primarily renally, with a substantial contribution by active renal secretion, and because digoxin has a narrow therapeutic window, this open, randomised, crossover, two-period study investigated whether NXY‑059 affects the pharmacokinetics (PK) of digoxin. Research design and methods: Twenty-two healthy subjects received 0.5 mg oral digoxin 2 h after the start of 60‑h intravenous infusions of NXY‑059 and placebo separated by a 14-day washout. Blood and urine were collected for 60 h. Digoxin concentrations were measured by a novel liquid chromatography–mass spectrometry assay. Main outcome measures: The ratio of the geometric mean (90% confidence interval) between NXY‑059 and placebo for the digoxin area under the concentration-versus-time curve was 0.91 (0.83–0.99) and was within the predefined range for no interaction (0.80–1.25). No safety concerns were raised in the study. No serious adverse events were recorded. The most common adverse event was headache with similar frequencies in the two treatments. Conclusions: NXY‑059 had no clinically significant effect on the PK of digoxin.