1500 ♂= 1957 ó; ♀= 1930 ó ♂ ≈28; ♀ ≈28 4 weeks (continuous IV infusion) NCD1540 200 ♂= 168; ♀= 518 ♂ ≈2; ♀ ≈7 600 ♂= 578; ♀= 992 ♂ ≈8; ♀ ≈14 1000 ♂= 710; ♀= 3061 ♂ ≈10; ♀ ≈44 13 weeks (gavage) PSM0813 50 ♂= 70.7*; ♀= 121* (0-12h) ♂ ≈2; ♀ ≈3 100 ♂= 99.5*; ♀= 251* (0-12h) ♂ ≈3; ♀ ≈7 200 ♂= 177*; ♀= 440* (0-12h) ♂ ≈5; ♀ ≈13 400 ♂= 317*; ♀= 743* (0-12h) ♂ ≈9; ♀ ≈21 26 weeks (diet + gavage) PSM1029 100 (diet) + 50 (gavage) ♂= 65.2; ♀= 144 ♂ ≈1; ♀ ≈2 100 (diet) + 130 (gavage) ♂= 116; ♀= 196 ♂ ≈2; ♀ ≈3 100 (diet) + 350 (gavage) ♂= 257; ♀= 464 ♂ ≈4; ♀ ≈7 Species Study duration Dose AUC0–24h or AUC0–τ (μg∙h/mL) Exposure ratio# Rat (Wistar; 104 weeks (diet + gavage; 52-wk sampling) NCD1305 150 ♂= 84.7; ♀= 121 ♂ ≈1; ♀ ≈2 230 ♂= 124; ♀= 197 ♂ ≈2; ♀ ≈3 450 ♂= 333; ♀= 529 ♂ ≈5; ♀ ≈8 700 ♂= 510; ♀= 635 ♂ ≈7; ♀ ≈9 Dog (Beagle) 4 (gavage) TA0660 6 ♂ & ♀= 14.7* ♂ & ♀ ≈0.4 15ˢ ♂ & ♀= 31.5* ♂ & ♀ ≈1 37.5 ♂ & ♀= 75.1* ♂ & ♀ ≈2 94 ♂ & ♀= 263* ♂ & ♀ ≈8
(CD-1) 13 Weeks PO 450 ♂=4.06ˢ; ♀=3.11 ♂≈1; ♀≈1 ♂≈0.3; ♀≈0.3 675 ♂=9.45; ♀=11.2 ♂≈3; ♀≈3 ♂≈1; ♀≈1 1000 ♂=20.3; ♀=25.7 ♂≈6; ♀≈7 ♂≈2; ♀≈2 Mouse (CD-1) 104 Weeks PO 400 ♂=2.75ˢ; ♀=2.67 ♂≈1; ♀≈1 ♂≈0.2; ♀≈0.2 550 ♂=5.3; ♀=4.38 ♂≈2; ♀≈1 ♂≈0.5; ♀≈0.4 700 ♂=8.99; ♀=8.97 ♂≈36; ♀≈3 ♂≈1; ♀≈1 Rat (Wistar) 4 IV infusion 200 ♂=4.17; ♀=12.4 ♂≈1; ♀≈4 ♂≈0.4; ♀≈1 600 ♂=14.1ˢ; ♀=22.2 ♂=4; ♀≈6 ♂≈1 ♀≈2 1000 ♂=16.6; ♀=70.8 ♂≈5; ♀≈20 ♂≈2; ♀≈6 Rat (Wistar) 26 Weeks PO 150 ♂=1.68; ♀=3.11 ♂≈0.5; ♀≈1 ♂≈0.1; ♀≈0.3 230 ♂=4.11; ♀=5.98 ♂≈1; ♀≈2 ♂≈0.4; ♀≈0.5 450 ♂=7.86ˢ; ♀=12.3 ♂≈2; ♀≈4 ♂≈1; ♀≈1 Rat (Wistar) 52 Weeks PO (104 week study) 150 ♂=2.39; ♀=3.05 ♂≈1; ♀≈1 ♂≈0.2; ♀≈0.3 230 ♂=3.61; ♀=5.1 ♂≈1.0; ♀≈2 ♂≈0.3; ♀≈0.4 450 ♂=10.2; ♀=13.7 ♂≈3; ♀≈4 ♂≈0.9; ♀≈1.2 700 ♂=14.1ˢ; ♀=16.0 ♂=4; ♀≈5 ♂≈1; ♀≈1 Dog (Beagle) 26 Weeks PO 15 2.82 ≈1 ≈0.2 37.5 6.19 ≈2 ≈0.5 75 14.7 ≈4 ≈1
NCD1540 Rat (Wistar) 4 Weeks IV infusion 200 ♂=117; ♀=112 ♂≈8 ♀≈8 ♂≈2; ♀≈2 600 ♂=352ˢ; ♀=323 ♂≈25; ♀≈23 ♂≈6; ♀≈6 1000 ♂=658; ♀=517 ♂≈47; ♀≈37 ♂≈11; ♀≈9 PSM1029 Rat (Wistar) 26 Weeks PO 150 ♂=75.4; ♀=82.6 ♂≈5; ♀≈6 ♂≈1; ♀≈1 230 ♂=151; ♀=151 ♂≈11; ♀≈11 ♂≈3; ♀≈3 450 ♂=276ˢ; ♀=276 ♂≈20; ♀≈20 ♂≈5; ♀≈5 NCD1305 Rat (Wistar) 52 Weeks PO (104 week 150 ♂=102; ♀=92.7 ♂≈7; ♀≈7 ♂≈2; ♀≈2 230 ♂=167; ♀=154 ♂≈12; ♀≈11 ♂≈3; ♀≈3 450 ♂=337; ♀=347 ♂≈24; ♀≈25 ♂≈6; ♀≈6 700 ♂=476ˢ; ♀=449 ♂≈34; ♀≈32 ♂≈8; ♀≈8 PSM1013 Dog (Beagle) 26 Weeks PO 15 28.5 ≈2 ≈0.5 37.5 59.9 ≈4 ≈1.0 75 106 ≈8 ≈2 NCD1543 Dog (Beagle) 4 IV infusion 30 70.9 ≈5 ≈1 100 161 ≈11 ≈3 150/200 305 ≈22 ≈5 PSM1101 Monkey 4 Weeks PO 300 649 ≈46 ≈11 600 1069 ≈76 ≈19 900 1231 ≈87 ≈21 PSM1140 Monkey 39 Weeks PO 300 ≈729 ≈52 ≈13 600 ≈1054 ≈75 ≈18 900 ≈1458 ≈103 ≈25 * at termination unless otherwise noted. # Healthy volunteer data from Study No. N01109 for 200 mg PO dose – AUC= 14.1 μg.h/mL, severe renal impairment data - AUC= 57.5 μg.h/mL
NCD1982 Rat (Wistar) 13 week continuous IV infusion 500 ♂=268; ♀=289 ♂=161; ♂≈8; ♀≈8 1000 ♂=605; ♀=775 ♂≈17; ♀≈22 2000 ♀=1818 ♂≈34; ♀≈51 * at study termination unless otherwise noted. # Healthy volunteer data from Study No. N01109 for 200 mg PO dose – AUC= 1.67 μg.h/mL, severe renal impairment data - AUC= 35.8 μg.h/mL Relative exposure margins for metabolite ucb-102933-1 in adults TK data for this metabolite are available in the animal studies, it is generally not found in humans. It is of important as a biomarker for hepatic porphyria in animals, particularly in dogs. 12: Relative exposure margins for metabolite ucb-107092-1. Study Species Study duration Route Brivaracetam Dose (mg/kg/day) AUC0–24h or AUC0–τ Exposure ratio# PSM1256 (CD-1) 13 Weeks PO 450 ♂=22.5 ♀=11.5 Generally not found in humans 675 ♂=56.5 ♀=28.7 Generally not found in humans 1000 ♂=86.4 ♀=69.9 Generally not found in humans PSM1029 Rat (Wistar) 26 Weeks PO 150 ♂=3.67 ♀=3.66 Generally not found in humans 230 ♂=6.87 ♀=6.02 Generally not found in humans 450 ♂=16.3 ♀=14.4 Generally not found in humans PSM1013 26 Weeks 15 11.8 Generally not in humans
Dog (Beagle) PO 37.5 40.8 Generally not found in humans 75 117 Generally not found in humans PSM1101 Monkey 4 PO 300 ≈9 Generally not found in humans 600 ≈18 Generally not found in humans 900 ≈18 Generally not found in humans PSM1140 Monkey 39 Weeks PO 300 ≈40 Generally not in humans 600 ≈227 Generally not in humans 900 ≈376 Generally not found in humans * at study termination unless otherwise noted. Relative exposure margins for brivaracetam and its metabolites in juveniles Brivaracetam is not recommended for use in children <16 years of age. Although studies in juvenile animals were performed, no human AUC data for this developmental stage were submitted. Thus, relevant AUC ratios cannot be calculated. It should be noted that in juvenile animals (rats and dogs) total plasma exposure was generally similar to exposure in adult animals, except at PND 4 where approximately a 4X higher exposure was achieved in juvenile rats compared with adults. Relevant toxicokinetic data of brivaracetam and its metabolites in juvenile rats are shown below (NOAEL = 600 mg/kg/day). Table 13: PK parameter values of ucb 34714 and its metabolites in juvenile Wistar rats (male & female) after repeat administration of ucb 34714. Key toxicokinetic data for brivaracetam in juvenile dogs are shown below. 14: Mean PK parameter values of ucb 34714 in male & female juvenile beagle dogs after single and repeat oral administration of ucb 34714.
N01069 - Multi-dose N01067 N01079 * Bioequivalence† - Single dose N01185 N01256a N01256b EP0007 N01287 N01296 N01075 * * * * * * * Food effect N01075 N01287 * * PK in special populations Target population - Multi-dose N01258 § Hepatic impairment N01111 * Renal impairment N01109 * Neonates/infants/children/ adolescents N01263 * Elderly- Single dose and - Multi-dose N01118 * Japanese- Single dose N01209a * Japanese- Multi-dose N01209b * Genetic/ gender related PK CYP2C19 polymorphism CYP2C8 activity CYP4A activity N01209a N01259 N01261 * * * PK interactions Ethanol EP0041 * Oral Contraceptive pill N01080 N01282 * * Carbamazepine N01081 N01133 § * * Phenytoin N01082 * Phenytoin N01172 § * Phenytoin N01135 § *
Table 20: Submitted pharmacodynamic studies. PD Subtopic Study ID * Primary Pharmacology Effect on Seizures N01114 § N01193 § N01252 § N01253 § N01254 § N01358 § N01125 § N01199 § N01379 § * * * * * * * * * Effect on evoked pain Subjective drug effects Photosensitive epileptiform discharges N01079 N01295 N01069 § * * * Secondary Pharmacology Effect on Saccadic eye movements N01066 EP0041 *
Smooth pursuit eye movements Adaptive tracking Effect on Number task Effect on Choice Reaction Time Effect on Tapping Test Effect on ARCI 49 Effect on Bond and Lader’s VAS Effect on Pharmacodynamic EEG Effect on Neurological Assessments Visual verbal learning test Essential tremor Post-herpetic neuralgia Myoclonus of ULD Myoclonus of ULD EP0041 EP0041 N01066 N01066 N01079 N01066 N01066 N01069 N01118 N01079 N01295 N01066 N01067 N01118 EP0041 N01079 N01066 N01295 N01069 § N01067 N01118 EP0041 EP0041 N01129 N01162 N01187 N01236 * * * * * * * * * * * * * * * * * * * PD Interactions levetiracetam CL0027 § ethanol EP0041 Population PD and PK-PD analyses Healthy subjects Target population CL0027 * * Indicates the primary aim of the study. § Subjects who would be eligible to receive the drug if approved for the proposed indication. ‡ And adolescents if applicable.
RMP reviewer comment Notwithstanding to the evaluation of the nonclinical and clinical aspects of the Safety Specification (SS), the summary of safety concerns is considered acceptable in the context of this application. It is noted that the PI for injectable Briviact advises of AEs associated with intravenous administration: IV administration was associated with infusion site pain in 2.8% of the patients. The sponsor should provide details, if any, of other reports of adverse events specifically associated with injection of Briviact. Pharmacovigilance plan Proposed pharmacovigilance activities In the EU-RMP, the sponsor proposes routine and additional pharmacovigilance for the identified/potential risks and missing information presented in the Summary of Safety Concerns. Table 28: Proposed pharmacovigilance activities. Safety concern Planned action(s) Important identified risks Suicidality (class label for anticonvulsant products) - Routine pharmacovigilance, with targeted suicidality questionnaire Important potential risks Neutropenia - Routine pharmacovigilance, with targeted using severe blood dyscrasias questionnaire Worsening of seizures (as an anticonvulsant product) - Routine pharmacovigilance, with targeted using drug-induced seizure aggravation questionnaire Abuse potential (as a CNS-active product) - Routine pharmacovigilance, with targeted using drug dependence, abuse, and diversion questionnaire Missing information Data during pregnancy and lactation - Routine pharmacovigilance, with targeted using pregnancy questionnaire - Participation in and sponsorship of EURAP and North American AED Pregnancy Registry – protocols for EURAP and the AED Registry include ‘possible’ activities to follow-up the children Data in paediatrics (i.e. preterm neonates to children aged 16 years) including data on neurodevelopment - Routine pharmacovigilance - Head circumference measurements in all paediatric studies as per protocol and as agreed in the approved Paediatric Investigation Plan (PIP) up