[2-(Isopropoxycarbonyloxy)-benzoyl]-benzoylperoxide

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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

Objective of study:

other: Pharmacokinetics

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

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

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

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.

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.

Preliminary studies:

n.a.

Details on absorption:

Not applicable

Details on distribution in tissues:

Not applicable

Details on excretion:

Not applicable

Metabolites identified:

yes

Details on metabolites:

CD08465 = carbonate moiety
CD0345 = salicylic acid

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 AUC_inf extrapolation to infinity was above 20%

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.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2010-10-01 to 2011-05-15

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Objective of study:

other: pharmacokinetis profile

Qualifier:

according to guideline

Guideline:

other: USA/FDA Guideline for the format & content of the non clinical pharmacology/ toxicology section of an application. US Department of Health and Human Services, FDA

Version / remarks:

adopted February 1997

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: ICH guideline M3(R2) (Guidance on non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals

Version / remarks:

adopted 11 June 2009

Deviations:

no

GLP compliance:

yes

Specific details on test material used for the study:

- Batch No.: 8542 for intravenous formulation and 8622 for oral formulation
- Purity: Conform
- Expiry date / reanalysis date: 30.12.2010
- Appearance/description: White powder
- Storage conditions: Temperature/Brown flasks/Protection from light

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Details on species / strain selection:

The rat is one of the rodent species commonly used for conducting research in pharmacology and toxicology and usually recommended by regulatory authorities as a test system for drug safety evaluation. This strain has been widely and extensively used in evaluation studies, hence sufficient background data exist to support interpretation of results.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, L’Arbresle, France
- Age at study initiation: approximately 9 weeks old
- Weight at study initiation: 155 to 314 g
- Housing: Animals were housed individually in Makrolon Type III H cages. The cage was covered by a lid in stainless steel. Each cage contains dust-free sawdust

- Diet (e.g. ad libitum): Ad libitum, Standard pelleted complete diet (Diet reference A04C, S.A.F.E., Augy, France)
- Water (e.g. ad libitum): Ad libitum, Filtered mains drinking water (0.22 μm)
- Acclimation period: 2 weeks

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

Route of administration:

other: intravenous, oral, dermal

Details on exposure:

Method of administration
Intravenous route: Animals were treated by intravenous injection (bolus) via the caudal vein at a dosing volume of 1 mL/kg. Before administration, the animals were lightly anaesthetized with isoflurane.
Oral route: Animals were treated orally by gavage using plastic syringe fitted with a metal cannula at a dosing volume of 10 mL/kg.
Dermal route: Animals were treated by topical application at a dosing volume of 2 mL/kg. The day before administration, treatment area was clipped free from hair, as close to the skin as possible, with an electric clipper.

Justification of the route of administration: The intravenous administration was used as reference. The oral administration was selected to determine the exposure to CD08467 metabolite and to evaluate the possibility to use this route of administration for the next toxicology studies. The dermal route was selected because it is the intended route for clinical use.

Duration and frequency of treatment / exposure:

Each animal from intravenous administration group received a single dose on Day 1. Each animal from oral administration group received a single dose on Day 9 and each animal from dermal administration group received a single dose on Day 10.

Dose / conc.:

1 mg/kg bw/day

Remarks:

Intravenous route

Dose / conc.:

20 mg/kg bw/day

Remarks:

Oral route

Dose / conc.:

100 mg/kg bw/day

Remarks:

Dermal route

No. of animals per sex per dose / concentration:

2 animals / time-point for each route of administration

Control animals:

not specified

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 was chosen assuming an oral bioavalability of 5%. The concentration of CD08467 in dermal formulation is the intended concentration used in human.

- Rationale for animal assignment (if not random): The animals were individually marked on the day following their arrival with a transponder implanted in the sub-cutaneous tissue (Type Réseaumatique implants ISO 12 mm, Bernay, France). This automatic system gives to each animal an individual number (stock number). No randomization was applied and allocation was done before administration.

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): blood
After the single dosing, blood samples (approximately 2.0 mL) were collected into lithium
heparin tubes under isoflurane anesthesia from the retro-orbital venous plexus of each animal for plasma levels analysis. After blood collection, the test tubes, identified at least by the study number, test item code, animal numbers, gender, route, day of blood collection and sampling time, were gently shaken manually for approximately 10 seconds and maintained in ice. Each blood sample was centrifuged (10 minutes at 1620 G, at +4 °C) then separated into tubes without anticoagulant. The collected plasma was splitted into two polypropylene tubes and frozen at approximately – 80 °C until their analysis. The animals were killed without necropsies by CO2 after the only blood sampling. The remainder carcasses were eliminated according to the corresponding procedure.

- Time and frequency of sampling: blood: See table 1 in box “Any other information on materials & methods incl. tables”

Statistics:

not applicable

Preliminary studies:

Not applicable

Details on absorption:

Not applicable

Details on distribution in tissues:

Not applicable

Details on excretion:

Not applicable

Metabolites identified:

yes

Details on metabolites:

CD08465 = carbonate moiety
CD0345 = salicylic acid

Mortality: No animal was found dead. On the day of dosing, one male presented crust on the neck.

Plasma concentration

CD08465

After one single CD08467 intravenous administration, CD08465 plasma concentrations were low with individual values ranging from 2 ng/mL to approximately 43.6 ng/mL, irrespective of the sex. CD08465 plasma concentrations were quantified up to 4 h and 24 h post-dosing in females and in males, respectively.

After one single CD08467 oral administration, CD08465 plasma concentrations were quantifiable up to 4 h and 8 h post-dosing in females and in males.

After one single CD08467 dermal application, CD08465 plasma concentrations were very low with individual values ranging from 2 ng/mL to 25 ng/mL, whatever the sex.

CD0345

After one single CD08467 intravenous administration at 1 mg/kg, a slow decrease of CD0345 plasma concentrations was observed with quantifiable concentrations up to 4h post-dosing in females and males, respectively.

After one single CD08467 oral administration, CD0345 plasma concentrations were quantifiable up to 8 h and 24 h post-dosing, in females and in males, whatever the sex.

After one single CD08467 dermal application, CD0345 plasma concentrations were quantifiable up to 24 h post-dosing, in both sexes.

Pharmacokinetic parameters: CD08465

 

Intravenous administration

After one single intravenous administration of CD08467 at 1 mg/kg, maximum plasma concentrations were 35.2 ng/mL and 20.6 ng/mL in female and male rats, respectively. The exposure, corresponding to AUC0-4 h and AUC0-24 h in females and in males respectively, was approximately 49 ng.h/mL in females and 41 ng.h/mL in males.

Due to plasma concentration profiles, several pharmacokinetic parameters, like terminal half-life, clearance and volume of distribution, could not be evaluated in males.

In females, the volume of distribution at steady state (Vdss) was approximately 36 L/kg, representing approximately 1200 fold the plasma volume in rats and demonstrating a very high distribution of the compound.

The elimination was moderate with elimination half-life of approximately 1.6h in females. The systemic plasmatic clearance was 16.8 L/h/kg in females, representing approximately 156% of the cardiac plasma flow output in rats and indicating a very high clearance of the compound.

 

Oral administration

After one single CD08467 oral administration at 20 mg/kg, exposure to CD08465, expressed as AUC0-4 h and AUC0-8 h in females and in males respectively, was approximately 66 ng.h/mL in females and 26 ng.h/mL in males. The apparition of CD08465 was rapid with maximum plasma concentrations observed 0.5 h and 0.25 h post-dosing in females and in males, respectively.

The exposure to CD08465 after CD08467 oral administration was lower than the exposure

observed after CD08467 intravenous administration, as evidenced by an exposure ratio PO/IV (extrapolated from AUC0-2h) of 0.08 in females and 0.04 in males.

 

Topical administration

After one single CD08467 dermal application at 100 mg/kg, CD08465 systemic exposure was 5.49 ng.h/mL in females (expressed as AUC0-2 h) and 148 ng.h/mL in males (expressed as AUC0-24 h). The apparition of CD08465 was very variable with maximum plasma concentrations observed 1h post-dosing in females and 24 h post-dosing in males.

The exposure to CD08465 after dermal administration was very lower than the exposure observed after CD08467 intravenous administration, demonstrated by an exposure ratio Dermal/IV (extrapolated from AUC0-2h) of 0.002 in females and 0.005 in males.

 

Pharmacokinetic parameters: CD0345

 

Intravenous administration

After one single intravenous administration of CD08467 at 1 mg/kg, the exposure to CD0345, expressed as AUC0-4 h, was 3 340 ng.h/mL and 2 170 ng.h/mL in females and in males, respectively. The apparition of CD0345 was rapid with maximum plasma concentrations observed 0.25 and 0.083 h post-dosing in females and in males, respectively.

Due to plasma concentration profiles, several pharmacokinetic parameters, like terminal half-life, clearance and volume of distribution, could not be evaluated in females.

In males, the volume of distribution at steady state (Vdss) was approximately 0.64 L/kg, representing approximately 21 fold the plasma volume in rats and demonstrating a moderate distribution of the compound. The apparent elimination half-life of approximately 1 h in males was short. The systemic plasmatic clearance was 0.43 L/h/kg in males, representing approximately 4% of the cardiac plasma flow output in rats and indicating a low clearance of the compound.

 

Oral administration

After one single CD08467 oral administration at 20 mg/kg, CD0345 systemic exposure was

163 000 ng.h/mL in females (expressed as AUC0-8 h) and 131 000 ng.h/mL in males (expressed as AUC0-24 h). The apparition of CD0345 was relatively slow with maximum plasma concentrations observed 4 h and 2 h post-dosing, in females and in males, respectively.

The exposure to CD0345 was similar between intravenous and oral administration in males, as evidenced by an exposure ratio PO/IV (extrapolated from AUC0-4 h) close to 1. The exposure to CD0345 was very higher after CD08467 oral administration than the exposure observed after CD08467 intravenous administration in females, demonstrated by an exposure ratio PO/IV (extrapolated from AUC0 -0 -'h) of approximately 2.8.

 

Topical administration

After one single CD08467 dermal application at 100 mg/kg, the apparition of CD0345 was slow with maximum plasma concentrations observed 24h post-dosing, whatever the sex. The exposure to CD0345, expressed as AUC0-24 h, was 45 500 ng.h/mL and 6 720 ng.h/mL in females and in males, respectively.

The exposure to CD0345 after CD08467 dermal administration was very lower than the exposure observed after CD08467 intravenous administration, demonstrated by an exposure ratio Dermal/IV (extrapolated from AUC0 -‘h) of approximately 0.007 and 0.003 in females and in males, respectively.

Sex effect

Based on AUC0-2 h of CD08465, a sex effect was observed in rats. The exposures to CD08465 were higher in females than in males after CD08467 intravenous and oral administration while the exposure to CD08465 was lower in females than in males after dermal application. Based on AUC0-4 h of CD0345, a sex effect was observed in rats, with higher exposure in females than in males, whatever the route of the administration.

 

Metabolite exposure

Based on plasma concentrations and on the exposure to CD08467 metabolites, CD0345 was the preponderant metabolite demonstrated by an exposure to CD0345 higher than the exposure of CD08465, whatever the sex and the route of administration.

 

Conclusions:

In conclusion, CD0345 was the predominant metabolite demonstrated by an exposure to CD0345 higher than the exposure to CD08465 regardless of sex and the route of administration.

Executive summary:

In this study, the pharmacokinetic profiles of main CD08467 metabolites, CD08465 (carbonate moiety) and CD0345 (salicylic acid), in male and female Wistar rats after single CD08467 administration by intravenous, oral or dermal route at 1, 20 and 100 mg/kg, respectively. Animals were treated by intravenous injection (bolus) via the caudal vein, by oral route via gavage or by dermal application. Pharmacokinetic analysis was performed from mean plasma concentrations using a noncompartmental approach. The results were observed as follows:

After one single CD08467 intravenous administration in rats, the appearance of both metabolites was rapid. After one single CD08467 oral administration, the appearance of CD08465 was rapid and slower for CD0345. After one single CD08467 dermal administration, the appearance of CD08465 was very variable and slow for CD0345. The exposures to CD08465 were higher in females than in males after CD08467 intravenous and oral administration while the exposure to CD08465 was lower in females than in males after dermal application. The exposure to CD0345 was higher in females than in males regardless of route of administration. CD0345 was the predominant metabolite demonstrated by an exposure to CD0345 higher than the exposure to CD08465 regardless of sex and the route of administration.

Description of key information

Pharmacokinetic profiles of key CD08467 metabolites were determined in two studies, one conducted in rats and the other conducted in Göttingen® minipigs. In the rat study, animals were administered with the test item CD08467 orally, intravenously or dermally, whereas in the Göttingen® minipig study the animals were exposed only orally or dermally. In both studies, it was shown that CD08467 rapidly decomposes to CD08465 (carbonate moiety) and CD0345 (salicylic acid) with its rate of decomposition dependent on the sex and route of administration. After intravenous administration, the appearance of both metabolites was rapid, whereas after oral or dermal administration of CD08467, the formation and elimination of its two metabolites were slower than these observed after intravenous administration. In both studies, CD0345 was the predominant metabolite regardless of sex and route of administration.