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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-02-09 to 2012-09-06
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Objective of study:
other: Pharmacokinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
- Principle of test: Assessment of the pharmacokinetic profile of CD08467 metabolites, CD08465 (carbonate moiety) and CD0345 (salicylic acid), in male Göttingen® minipigs after a single intravenous or a single oral administration of CD08467 at 1 mg/kg and 20 mg/kg, respectively.
- Short description of test conditions: Four animals received a single intravenous administration by slow bolus at a dosing volume of 1 mL/kg then a single oral administration by gavage at a dosing volume of 10 mL/kg after a washout period of 11 days.
- Parameters analysed / observed: Pharmacokinetic analysis was performed from individual plasma concentrations using a non-compartmental approach
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
[2-(Isopropoxycarbonyloxy)-benzoyl]-benzoylperoxide
EC Number:
814-835-0
Cas Number:
1310672-91-3
Molecular formula:
C18H16O7
IUPAC Name:
[2-(Isopropoxycarbonyloxy)-benzoyl]-benzoylperoxide
Specific details on test material used for the study:
- Source: UGLC
- Batch No.: 11.00664
- Appearance: White powder
- Purity: 98.3 % a/a
- Storage conditions: Between +2 °C and +8 °C and protected from light
- Expiry date: 09/02/2012
Radiolabelling:
no

Test animals

Species:
miniature swine
Strain:
other: Göttingen® minipig
Details on species / strain selection:
The Göttingen minipig was selected as test system because it is a non-rodent species commonly used for conducting research in pharmacology and toxicology. In addition, this species has been widely and extensively used in dermal evaluation studies, hence sufficient background data exist to support interpretation of results.
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Ellegaard, Dalmose, Denmark
- Age at study initiation: approximately 3 - 4 months
- Weight at study initiation: 7.75 to 8.07 kg
- Housing: Animals were housed in pens containing wood shavings for bedding material. Each 2 m² pen contained one minipig.

- Diet (e.g. ad libitum): pelleted complete diet, as specified by the breeder (Ellegaard) according to the animal’s age. The rations were given twice a day as equal amounts. In addition, animals received a piece of fruit (given by hand as a reward) daily.
- Water (e.g. ad libitum): Yes, tap water (0.45 µm filter), ad libitum
- Acclimation period: 2 weeks
- Fasting: The animals were fasted overnight before each administration of the test item and were fed about 4 h after drug administration

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): 15 to 20
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
other: intravenous and oral
Vehicle:
other: PEG400/EtOH/NaCl 0.9% (70/10/20, w/w/w) (intravenous) and 4% PG/0.2% Lutrol L44 (poloxamer)/0.1% CMC in purified water (oral)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
CD08467 was supplied as weighed raw material (Drug Substance). The drug substance was reconstituted in the vehicle used for intravenous and oral route to obtain final dosage forms at required concentrations (1 mg/mL and 2 mg/mL, respectively) by the supplying department.
The dosage form preparation was manufactured once for each form and delivered as ready-to-use formulations.

Dose administered:
In order to adjust the volume of administration, the animals were weighed the day before the drug administration. The administration devices containing the test item preparation were weighed before and after administration in order to calculate the actual delivered dose for each animal.
Duration and frequency of treatment / exposure:
Each animal received a single intravenous dose on Day 1 followed by a washout period of 11 days then a single oral administration on Day 13.
Doses / concentrationsopen allclose all
Dose / conc.:
1 mg/kg bw/day (nominal)
Remarks:
1/ Intravenous route (slow bolus)
Dose / conc.:
20 mg/kg bw/day (nominal)
Remarks:
2/ Oral route (gavage)
No. of animals per sex per dose / concentration:
4 males per dose group
Control animals:
no
Positive control reference chemical:
n.a.
Details on study design:
- Dose selection rationale: The dose level determination for intravenous administration was based on the maximum solubility of CD08467 in the intravenous vehicle. The dose level for oral administration is the same as that used in a previous pharmacokinetic study performed in Wistar rat with the same compound.

- Rationale for animal assignment (if not random): No randomization was applied and an individual experimental number was arbitrarily given to each animal. This number was written on an identification card placed on the pen.
Details on dosing and sampling:
DOSING

Intravenous route
Animals were treated with a single intravenous injection as slow bolus (performed in approximately 1 minute maximum) at a dosing volume of 1 mL/kg. The day before drug administration, each animal used for the intravenous administration was tranquilized by the administration of Stresnil at 8 mg/kg then anaesthetized by isoflurane inhalation prior to place a catheter in one ear of each animal. Just after the set-up of the catheter, a physiological solution was used for flushing the catheter (approximately 1 mL, equivalent to the catheter dead volume). The day of the intravenous administration, a flush of 1 mL of physiological solution was performed just preceding the drug administration.
Oral route
Animals were treated by a single oral administration (gavage) using a plastic syringe fitted with an esophageal cannula. Immediately after dosing, tap water was used for flushing the cannula (approximately 5 mL, equivalent to the cannula dead volume) in order to administer entirely the test item.

PHARMACOKINETIC EVALUATION

Blood collection
Blood samples were taken from all animals at the following time points:
Intravenous administration: 0.16, 0.33, 0.5, 1, 2, 4, 6, 8, 10 and 24 h post-dosing
Oral administration: before dosing (0h), 0.16, 0.33, 0.5, 1, 2, 4, 6, 8, 10, 24 and 48 h post-dosing

Bioanalysis
Only CD08465 and CD0345 concentrations were measured in plasma samples. Plasma CD08465 concentrations were analyzed by a non-validated LC-MS/MS method referenced RDS.03.MIP.4907-A.R002 with a limit of quantification of 0.5 ng/mL. Plasma CD0345 concentrations were analyzed by a non-validated LC-MS/MS method referenced RDS.03.MIP.4907-B.R003 with a limit of quantification of 150 ng/mL.

ACCEPTANCE CRITERIA

Acceptance criteria for specificity of the method
Analyzed compound: Individual interference no greater than 20% of the signal at the LOQ.
Internal standard: Individual interference no greater than 5% of the signal at working concentration.

Acceptance criteria for calibration samples
Individual bias of the back-calculated values within ± 20% of the theoretical values for at least 2/3 of the values and with at least 6 calibration levels within the acceptance criteria.

Acceptance criteria for QC samples
Individual bias within ± 20% of the theoretical values for at least 2/3 of the values, with the exception of QC at low level, which was within ± 25%.

Acceptance criteria for study samples
Values were reported when the results from calibration and QC samples were within the pre-defined acceptance range.
Statistics:
Descriptive statistics (mean, SD and CV%) of plasma concentrations and pharmacokinetic parameters of CD0345 and CD08465 were calculated for each route of administration using Kinetica 4.3TM from unrounded individual values.

Results and discussion

Preliminary studies:
n.a.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Not applicable
Details on distribution in tissues:
Not applicable
Details on excretion:
Not applicable

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
CD08465 = carbonate moiety
CD0345 = salicylic acid

Any other information on results incl. tables

Mortality/Morbidity: No mortality was observed during the study.

Clinical signs: Before the intravenous administration, one male presented a priapism probably due to the administration of Stresnil®. This clinical sign had no impact on the pharmacokinetic results. The priapism disappeared on Day 2.

Plasma concentration: Following a single intravenous administration of CD08467, a rapid decrease of plasma CD0345 concentrations was observed with quantifiable concentration up to 2 h. Plasma CD08465 concentrations were quantifiable up to 10 h. After an oral administration of CD08467, plasma concentrations of CD0345 and CD08465 were quantifiable up to 10 h.

Pharmacokinetic parameters:

CD0345: Following a single intravenous administration of CD08467 at 1 mg/kg, the formation of CD0345 was rapid with the mean maximum plasma concentration of 2500 ± 245 ng/mL observed at 0.16 h (first time point). The exposure to CD0345, expressed as AUCinf, was 1790 ± 317 ng.h/mL. CD0345 was rapidly eliminated, demonstrated by an apparent elimination half-life of 0.5h.

Following a single oral administration of CD08467 at 20 mg/kg, the mean maximum plasma concentration of 9090 ± 1350 ng/mL was observed 4 h post-dosing. The exposure to CD0345, expressed as AUCinf, was 50 500 ng.h/mL. The apparent elimination half-life of CD0345 was 3 h. The exposure to CD0345 after oral CD08467 administration was higher than the exposure observed after intravenous CD08467 administration, as evidenced by an exposure ratio PO/IV of 1.45 ± 0.20.

CD08465: Following a single intravenous administration of CD08467 at 1 mg/kg, maximum plasma concentrations of CD08467 was observed at 0.16 h. The exposure to CD08465, expressed as AUClast, was low compared to the exposure to CD0345, with mean value of 22.3 ± 6.32 ng.h/mL. Due to plasma concentration profiles (AUCextra > 20%), some pharmacokinetic parameters could not be accurately determined and were not reported.

Following a single oral administration of CD08467 at 20 mg/kg, the formation of CD08465 was variable with individual maximum plasma concentrations observed between 0.16 h and 2 h post-dosing. The exposure to CD08465, expressed as AUCinf, was 154 ± 56 ng.h/mL. The apparent elimination half-life of CD08465 was 2 h. The exposure to CD08465 after oral CD08467 administration was lower than the exposure observed after intravenous CD08467 administration, as evidenced by an exposure ratio PO/IV of 0.350 ± 0.168.

See also Table 1 below.

Table 1: Mean  ± SD pharmacokinetic parameters observed in male minipigs after intravenous or oral administration

Sex Male
Compound CD0345 CD08465
Administration route Intravenous Oral Intravenous Oral
Dose (mg/kg) 1 20.0 1.00 20.0
Cmax (ng/mL) 2500± 245 9090 ± 1350 14.3 ± 2.33 39.2 ± 17.1
Tmax (h) (a) 0.160 4.00 0.160 1.00
tlast (h) (a) 2.00 10.0 10.0 10.0
AUClast (ng.h/mL) 1610 ± 362 50800 ± 4240 22.3 ± 6.32 146 ± 52.1
AUCinf (ng.h/mL) 1790 ± 317 50500 ± NC NR 154 ± 55.8
AUCextra (%) 11.1 ± 5.65 1.76 ± NC NR 5.05 ± 3.01
MRT (h) 0.787 ± 0.0960 4.86 ± NC NR 3.77 ± 1.12
t1/2 (h) 0.504 ± 0.0791 3.01 ± NC NR 1.99 ± 0.372
Exposure ratio PO/IV NA 1.45 ± 0.196 NA 0.350 ± 0.168

(a) Mediane values

NA: Not Applicable

NC: Not calculated (since these parameters were accurately determined for two animals, only)

NR: Not reported since the percentage of AUCinf extrapolation to infinity was above 20%

Applicant's summary and conclusion

Conclusions:
In this study, after an intravenous administration of CD08467, the formation of its two metabolites, CD0345 (salicylic acid) and CD08465 (carbonate moiety) was rapid. The exposure to CD0345 was much higher than that to CD08465. After an oral administration of CD08467, the formation and elimination of its two metabolites were much slower than these observed after intravenous administration. The exposure to CD0345 and CD08465 after the oral administration of CD08467 demonstrated a potential absorption of CD08467 and/or an absorption of its both metabolites. CD0345 was the predominant metabolite.
Executive summary:

In this study, the pharmacokinetic profiles of main CD08467 metabolites, CD08465 (carbonate moiety) and CD0345 (salicylic acid) were assessed in Göttingen minipigs after a single intravenous or a single oral administration of CD08467 at 1 mg/kg and 20 mg/kg, respectively. Four animals received a single intravenous administration by slow bolus at a dosing volume of 1 mL/kg then a single oral administration by gavage at a dosing volume of 10 mL/kg after a washout period of 11 days. Pharmacokinetic analysis was performed from individual plasma concentrations using a non-compartmental approach.

After an intravenous administration of CD08467, the formation of its two metabolites, CD0345 (salicylic acid) and CD08465 (carbonate moiety) was rapid. The exposure to CD0345 was much higher than that to CD08465. After an oral administration of CD08467, the formation and elimination of its two metabolites were much slower than these observed after intravenous administration. CD0345 was the predominant metabolite, whatever the administration route.