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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2016
Reliability:
1 (reliable without restriction)
Justification for type of information:
Read across, see justification

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Experiment approved by the Biotrial Ethics committee by the Ministère de l'Enseignement Supérieur et de la Recherche
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Wistar
Sex:
not specified

Administration / exposure

Route of administration:
other: Intravenous or subcutaneous
Vehicle:
not specified
Doses / concentrations
Dose / conc.:
10 mg/kg bw/day (nominal)

Results and discussion

Any other information on results incl. tables

Pharmacokinetic results are presented in a Study Summary Sheet in Appendix 3 of the present Study Report. Following single intravenous or subcutaneous administration of 10mg/kg brivaracetam alone or in combination with EnhanzeTM, brivaracetam was detected at concentrations above the lower limit of detection (ie, LLOQ of 2ng/mL) up to the last sampling time point (ie, 6 hours post-dose for all animals). Following intravenous administration of 10mg/kg brivaracetam, mean peak plasma level (Cmax) and total exposure (AUCinf) were 14950ng/mL and 36393ng.h/mL, respectively. These results were in the same range as the PK parameters observed at the same dose after subcutaneous administrations (ie, mean Cmax and AUCinf values of 12333ng/mL and 39605ng.h/mL, respectively). As the PK profile of rat n°2 was not characteristic of an IV PK profile, likely due to a potential error in dosing route (see Section 3.6, Deviations to Study Plan), with a delayed tmax (tmax=1 hour) and a lower Cmax compared to the other rats in its group, this rat was excluded from the descriptive statistics. When 10mg/kg brivaracetam was subcutaneously administered alone or concomitantly with EnhanzeTM, mean Cmax and AUCinf were similar, with mean values of 12333ng/mL and 12900ng/mL and 39605ng.h/mL and 40577ng.h/mL, respectively. A shorter tmax was observed when brivaracetam was administered in combination with EnhanzeTM than after brivaracetam administration alone, with median tmax of 9 minutes and 30 minutes, respectively. EnhanzeTM seemed to accelerate the absorption process via the subcutaneous route, with tmax values occurring roughly 20 minutes earlier than after the standard brivaracetam subcutaneous administration. Brivaracetam plasma concentrations decreased with a similar elimination half-life for all treatment groups, with a mean value of approximately 2 hours. The inter-individual variability of the main PK parameters (Cmax and AUCs) was low, with CV% ranging between 4.75 and 17.2%.

Applicant's summary and conclusion

Conclusions:
The purpose of the present study was to determine the effect of rHuPH20 (EnhanzeTM Drug Product) on the plasma pharmacokinetics of brivaracetam administered as a single subcutaneous injection to male Wistar rats. For comparison purposes, the pharmacokinetics of brivaracetam was also measured after intravenous administration. On the day of the experiment, rats (n=3 per group) were either administered 10mg/kg brivaracetam intravenously, 10mg/kg brivaracetam subcutaneously, or 10mg/kg brivaracetam+2000U/mL EnhanzeTM Drug Product subcutaneously. Blood samples were taken at 5 min, 10 min, 30 min, 1 h, 3 h and 6 h post-dosing. There was no observable tolerability issue after administration of brivaracetam alone or in combination with EnhanzeTM. Mean Cmax and AUCinf were similar after intravenous and subcutaneous administration of 10 mg/kg brivaracetam (alone). Mean Cmax and AUCinf were also similar whether brivaracetam was administered subcutaneously in combination with EnhanzeTM or alone. EnhanzeTM appeared to accelerate the absorption of brivaracetam administered subcutaneously, with tmax occurring approximately 20 minutes earlier when compared to brivaracetam alone. The mean elimination half-life was similar for the 3 treatment groups. The inter-individual variability of the main PK parameters was low.
Executive summary:

No clinical signs were observed. No sacrifice of animals had to be performed for humane reasons because animals did not show any signs of permanent suffering, pain or fear as described in the OECD guide “Recognition, Assessment and Use of Clinical signs as Humane Endpoints for Experimental Animals in Safety Studies (OECD, 2000)”. 4.2 Pharmacokinetic Results and Conclusions Pharmacokinetic results are presented in a Study Summary Sheet in Appendix 3 of the present Study Report. Following single intravenous or subcutaneous administration of 10mg/kg brivaracetam alone or in combination with EnhanzeTM, brivaracetam was detected at concentrations above the lower limit of detection (ie, LLOQ of 2ng/mL) up to the last sampling time point (ie, 6 hours post-dose for all animals). Following intravenous administration of 10mg/kg brivaracetam, mean peak plasma level (Cmax) and total exposure (AUCinf) were 14950ng/mL and 36393ng.h/mL, respectively. These results were in the same range as the PK parameters observed at the same dose after subcutaneous administrations (ie, mean Cmax and AUCinf values of 12333ng/mL and 39605ng.h/mL, respectively). As the PK profile of rat n°2 was not characteristic of an IV PK profile, likely due to a potential error in dosing route (see Section 3.6, Deviations to Study Plan), with a delayed tmax (tmax=1 hour) and a lower Cmax compared to the other rats in its group, this rat was excluded from the descriptive statistics. When 10mg/kg brivaracetam was subcutaneously administered alone or concomitantly with EnhanzeTM, mean Cmax and AUCinf were similar, with mean values of 12333ng/mL and 12900ng/mL and 39605ng.h/mL and 40577ng.h/mL, respectively. A shorter tmax was observed when brivaracetam was administered in combination with EnhanzeTM than after brivaracetam administration alone, with median tmax of 9 minutes and 30 minutes, respectively. EnhanzeTM seemed to accelerate the absorption process via the subcutaneous route, with tmax values occurring roughly 20 minutes earlier than after the standard brivaracetam subcutaneous administration. Brivaracetam plasma concentrations decreased with a similar elimination half-life for all treatment groups, with a mean value of approximately 2 hours. The inter-individual variability of the main PK parameters (Cmax and AUCs) was low, with CV% ranging between 4.75 and 17.2%.

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