Biodistribution and Radiation Dosimetry for the Novel SV2A Radiotracer [(18)F]UCB-H: First-in-Human Study.

PURPOSE: [(18)F]UCB-H is a novel radiotracer with a high affinity for synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in synaptic vesicles. SV2A is the binding site of levetiracetam, a "first-in-class" antiepileptic drug with a distinct but still poorly understood mechanism of action. The objective of this study was to determine the biodistribution and radiation dosimetry of [(18)F]UCB-H in a human clinical trial and to establish injection limits according to biomedical research guidelines. Additionally, the clinical radiation dosimetry results were compared to estimations in previously published preclinical data. PROCEDURES: Dynamic whole body positron emission tomography/X-ray computed tomography (PET/CT) imaging was performed over approximately 110 min on five healthy male volunteers after injection of 144.5 ± 7.1 MBq (range, 139.1-156.5 MBq) of [(18)F]UCB-H. Major organs were delineated on CT images, and time-activity curves were obtained from co-registered dynamic PET emission scans. The bladder could only be delineated on PET images. Time-integrated activity coefficients were calculated as area under the curve using trapezoidal numerical integration. Urinary excretion data based on PET activities including voiding was also simulated using the dynamic bladder module of OLINDA/EXM. The radiation dosimetry was calculated using OLINDA/EXM. RESULTS: The effective dose to the OLINDA/EXM 70-kg standard male was 1.54 × 10(-2) ± 6.84 × 10(-4) millisieverts (mSv)/MBq, with urinary bladder wall, gallbladder wall, and the liver receiving the highest absorbed dose. The brain, the tracer's main organ of interest, received an absorbed dose of 1.89 × 10(-2) ± 2.32 × 10(-3) mGy/MBq. CONCLUSIONS: This first human dosimetry study of [(18)F]UCB-H indicated that the tracer shows similar radiation burdens to widely used common clinical tracers. Single injections of at maximum 672 MBq for US practice and 649 MBq for European practice keep radiation exposure below recommended limits. Recently published preclinical dosimetry data extrapolated from mice provided satisfactory prediction of total body and effective dose but showed significant differences in organ absorbed doses compared to human data.

Comparison of plasma and saliva concentrations of levetiracetam following administration orally as a tablet and as a solution in healthy adult volunteers.

OBJECTIVE: Concentrations in saliva, as an alternative to concentrations in blood, can be advantageous for the monitoring of antiepileptic agents. This study assesses the relationship between saliva and plasma concentrations of levetiracetam after administration orally as a solution and as a tablet. The possibility that saliva concentrations of the drug are altered by contamination in the buccal cavity was also examined. METHODS: 4 healthy male subjects received a single 750 mg oral dose of levetiracetam as a 10% solution and 4 subjects received three 250 mg tablets (750 mg). Levetiracetam concentrations in plasma and saliva were monitored for 24 hours post dose. RESULTS: In subjects receiving the levetiracetam solution, maximum saliva concentrations were observed at the first collection point (15 min) after administration and these were 19-74 times higher than corresponding plasma levels. The mean saliva/plasma ratio rapidly decreased thereafter, becoming stable after 4 hours. In subjects receiving tablets, levetiracetam concentration profiles for saliva paralleled the plasma concentration profiles with a fairly constant saliva/plasma concentration ratio throughout the 24-hour sampling period. A significant linear correlation between levetiracetam saliva and plasma concentrations was demonstrated (Pearson r = 0.88; p < 0.001 for tablet (n = 35) and r = 0.87; p < 0.001 for solution at times > or = 4 hours post-dose (n = 20)). The saliva to plasma concentration ratio was 1.11 (95% confidence interval: 0.99 - 1.22) following tablet intake, and 1.55 (95% CI: 1.34 1.77) following oral solution (> or = 4 hours post dose). CONCLUSIONS: Using saliva to monitor therapeutic exposure to levetiracetam is feasible beginning 15 minutes after tablet intake but beginning 4 hours after intake of an oral solution.

Evaluation of pharmacokinetic interaction between cetirizine and ritonavir, an HIV-1 protease inhibitor, in healthy male volunteers.

BACKGROUND: Serious adverse effects have been observed with some non-sedative H1-antihistamines (terfenadine and astemizole) when they were associated with drugs known to inhibit their metabolism. However, this is not a class effect, and this interaction should be considered on a case-by-case basis. The aim of this study was to evaluate the potential of pharmacokinetic interaction between cetirizine and ritonavir, the most potent cytochrome P450 (CYP) inhibitor. METHODS: An open-label, single-center, one-sequence crossover pharmacokinetic study was conducted in three running periods: cetirizine (CTZ) alone, ritonavir (RTV) alone and then CTZ plus RTV. For each period, steady-state pharmacokinetics were obtained. RTV and CTZ plasma concentrations were determined using validated liquid chromatography methods. The statistical method was based on a 90% confidence interval (CI) for the ratio of population geometric means (combination/drug alone) for each drug and for each parameter [area under the plasma concentration versus time curve (AUC(0-tau,ss)), value of maximum plasma concentration (C(max,ss))] and compared to bioequivalence ranges 80-125% and 70-143% for AUC(0-tau,ss) and C(max,ss), respectively. RESULTS: Among the 17 male subjects enrolled (26.4 +/- 8.6 years), 16 completed the study (1 withdrawal after the first period). The RTV pharmacokinetic parameter values were not affected by CTZ co-treatment. With RTV, a 42% increase in the CTZ AUC(0-tau,ss) (3406 versus 4840 microgh/l, 90% CI of 128-158%), a 53% increase in the CTZ elimination half-life (7.8 h versus 11.9 h, P = 0.001), a slight increase (15%) in the CTZ apparent volume of distribution (V(d,ss)/f) (34.7 l versus 39.8 l, P = 0.035), a 29% decrease in the CTZ apparent total body clearance (49.9 ml/min versus 35.3 ml/min, P < 0.001) and bioequivalent C(max,ss) (374 microg/l versus 408 microg/l) were observed. No serious drug related adverse effects were notified. CONCLUSIONS: CTZ does not significantly affect the pharmacokinetic parameters of RTV, and the association does not, thus, require a modification of the dosage of the protease inhibitor. The increased extent of exposure to CTZ in healthy subjects, in the presence of RTV administered at high doses, remained in the same range as previously observed in the elderly or in mildly renally impaired subjects.

Dose-response effect of levetiracetam 1000 and 2000 mg/day in partial epilepsy.

PURPOSE: To evaluate the efficacy, dose-response, tolerability, and withdrawal effects of levetiracetam (Keppra) as adjunctive therapy in adult patients with partial epilepsy. METHODS: In this European multicenter, double-blind, randomized, cross-over trial, levetiracetam 1000 or 2000 mg/day given in two divided doses was compared to placebo as add-on therapy in 324 patients with refractory partial seizures with or without secondary generalization. This trial consisted of six periods: an 8- or 12-week baseline, a treatment period A (4-week titration and 12-week evaluation), a treatment period B (4-week titration and 12-week evaluation), and a withdrawal period. During each evaluation period (A and B), patients received two of the three possible treatment regimens. RESULTS: This study provides additional information on dose-response effects and withdrawal phenomena and confirms the responder and seizure freedom rates previously reported in the parallel part of the study (Epilepsia 41 (2000) 1179-1186). Both doses of levetiracetam significantly decreased mean partial seizure frequency compared with placebo (P<0.001), and significantly more patients receiving levetiracetam had > or = 50 and > or = 75% reductions in partial seizure frequency (1000 mg, P=0.004 and P=0.043, respectively; 2000 mg P=0.001 and P<0.001, respectively). In addition, 5.5% (10/183) of patients receiving levetiracetam 1000 mg/day and 6.3% (11/175) of patients receiving levetiracetam 2000 mg/day were seizure-free during the corresponding evaluation period, compared with 1.2% (2/172) of patients on placebo. A within-patient comparison revealed a significantly greater responder rate for the higher levetiracetam dose (P=0.018). The most commonly reported adverse effects (> or = 5% and more frequent in one of the groups with levetiracetam) were headache, asthenia, infection, somnolence, pharyngitis, dizziness, and pain. No withdrawal-related adverse events were reported during the cross-titration period. CONCLUSIONS: Levetiracetam was effective and well-tolerated and decreased seizure frequency in a dose-dependent manner, with no evidence of typical withdrawal-related adverse events or rebound phenomena after withdrawal or down-titration.

Long-term continuation of levetiracetam in patients with refractory epilepsy.

The long-term continuation (retention) rate, efficacy, and safety data of the new antiepileptic drug levetiracetam (LEV) was evaluated in all patients with epilepsy exposed to the drug during its developmental program (n = 1,422). The retention rate was estimated to be 60% after 1 year and 32% after 5 years. Thirty-nine percent (512/1,325) of patients had a seizure reduction of > or =50%, and 13% (183/1,422) became seizure-free for at least 6 months. LEV seems an effective and well tolerated new antiepileptic drug.

Double-blind study to assess the efficacy of chlorproguanil given alone or in combination with chloroquine for malaria chemoprophylaxis in an area with Plasmodium falciparum resistance to chloroquine, pyrimethamine and cycloguanil.

In this study the efficacy of chlorproguanil (20 mg base weekly) was compared in schoolchildren with that of chloroquine (200 mg base weekly) and that of both drugs combined (20 mg base + 200 mg base weekly). The double blind trial was performed in the rice field area of the Ruzizi valley in Burundi, where Plasmodium falciparum is widely resistant to chloroquine, and where pyrimethamine resistance with cycloguanil cross-resistance had been demonstrated. After 17 weeks, when the trial was ended, 60% breakthroughs had been observed among the children taking chloroquine, 72% among those under chlorproguanil and 61% among those under chlorproguanil and chloroquine. In children weighing between 15 and 24 kg, the failure rate was significantly higher in those treated with chlorproguanil than in the group treated with chloroquine. No difference in efficacy was observed in children weighing 25 to 39 kg. There was no significant increase of efficacy when chlorproguanil was given in association with chloroquine. The mean titre of fluorescent antibodies was the same in each treated group on week 5 and week 15. The comparison of these data with the infection rates in non-protected children suggests that malaria could not be prevented with any of the drug regimens utilized in the study.