2-amino-2-methylpropanol

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Remarks:

clinical trial

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

Pamabrom is an Over The Counter (OTC) diuretic agent which is an AMP salt of 8-bromotheophylline, CAS No. 606-04-2.
It is an equimolar mixture of 74.4% w/w 8-Bromotheophylline (CAS No. 10381-75-6) and 25.6% w/w 2-amino-2-methylpropan-1-ol (AMP, CAS No. 124-68-5). Clinical data on this test material can be used for AMP safety assessment based on the AMP/Pamabrom bioequivalence study (see Basic Toxicokinetics /IUCLID §7.1.1) which indicated that Pamabrom's AMP, and AMP as is, were equivalent in terms of AUC0-t, AUC0-inf and AUC0-168h. Pamabrom doses can be converted into equivalent AMP doses based on the AMP content of 25.6% w/w in this drug and assuming a patient weight of 70 kg when not indicated.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

toxicity to reproduction: other studies

Remarks:

cross-reference to human clinical trials under IUCLID section 7.10.3

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1953 to 2016

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Pamabrom is an Over The Counter (OTC) diuretic agent which is an AMP salt of 8-bromotheophylline, CAS No. 606-04-2.
It is an equimolar mixture of 74.4% w/w 8-Bromotheophylline (CAS No. 10381-75-6) and 25.6% w/w 2-amino-2-methylpropan-1-ol (AMP, CAS No. 124-68-5). Clinical data on this test material can be used for AMP safety assessment based on the AMP/Pamabrom bioequivalence study (see Basic Toxicokinetics /IUCLID §7.1.1) which indicated that Pamabrom's AMP, and AMP as is, were equivalent in terms of AUC0-t, AUC0-inf and AUC0-168h. Pamabrom doses can be converted into equivalent AMP doses based on the AMP content of 25.6% w/w in this drug and assuming a patient weight of 70 kg when not indicated.

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

see details under each of the Cross-referenced summaries

GLP compliance:

no

Type of method:

in vivo

Specific details on test material used for the study:

see details under each of the 4 Cross-referenced summaries

Species:

other: humans

Details on test animals or test system and environmental conditions:

see details under each of the Cross-referenced summaries

Route of administration:

oral: capsule

Duration of treatment / exposure:

NOAELs cover 3 days to 17 weeks depending on clinical trial (+ one Klimisch-4 trial summary where treatment duration was not indicated).
see details under each of the Cross-referenced summaries

Dose descriptor:

NOAEL

Effect level:

>= 2.2 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

male/female

Basis for effect level:

clinical signs

Remarks on result:

other: Study 1), NOAEL covers 3 to 17 weeks depending on patient

Dose descriptor:

NOAEL

Effect level:

>= 2.9 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 2), 28 days

Dose descriptor:

NOAEL

Effect level:

>= 1.5 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 3), variable treatment regime, mean 2 weeks

Dose descriptor:

NOAEL

Effect level:

>= 0.32 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 4), 3-day treatment in 189 patients

Dose descriptor:

NOAEL

Effect level:

>= 5.9 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 5), 5-7 days, pregnant women

Key result

Dose descriptor:

NOAEL

Effect level:

>= 2.9 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 5), total of 2-week treatment in 9 patients who failed to loose weight, pregnant women

Key result

Dose descriptor:

NOAEL

Effect level:

>= 2.2 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 6), unknown treatment duration and schedule, pregnant women

for summary of repeat-dose effects, see 7.5.1 consolidated summary or individual summaries under 7.10.3

Reproductive effects:

Studies 1) and 2) No adverse clinical effects related to reproduction were reported.

Study 3): The only effects were therapeutic (benefic): normalisation of symptoms of premenstrual tension (menstrual cycle length, amount of flow).

Study 4): The only effects were therapeutic (benefic): normalisation of symptoms of menstrual pain.

Study 5): No adverse effects on gravidity, gestation, fetal movement.

Study 6): No adverse effects reported during pregnancy.

Executive summary:

Pamabrom is an Over The Counter (OTC) diuretic agent which is an AMP salt of 8-bromotheophylline, CAS No. 606-04-2. It is an equimolar mixture of 74.4% w/w 8-Bromotheophylline (CAS No. 10381-75-6) and 25.6% w/w 2-amino-2-methylpropan-1-ol (AMP, CAS No. 124-68-5).

Six clinical studies are available on pamabrom. NOAELs are expressed in AMP based on pamabrom posology and AMP content. They inform on absence of reproductive toxicity. In all cases the below-listed NOAELs were the maximum tested dose:

1) Trial in severe cardiac failure patients (Doherty et al, 1953): Patients (n=19) were given pamabrom at 300 to 900 mg/day for 5 to 137 days. This study did not mention specific monitoring of reproductive endpoints, but included reporting of any clinical effects. No clinical effects related to reproduction were reported. Isolated occurence of maculopapular rash from 4th week of treatment (1/18 patients) and diarrhea from day 120 of treatment (1/18 patients). The NOAEL was >= 2.2 mg AMP/kg bw/day x 2 to 17 weeks depending on patient.

2) Trial in women with premenstrual tension - Preliminary study (McGavack et al, 1956): oral treatment (n=9) up to 800 mg pamabrom for 4 weeks (28-days) in women with menstrual cycles. This study did not mention specific monitoring of reproductive endpoints, but included reporting of any clinical effects. No adverse effect. The NOAEL was >= 2.9 mg AMP/kg bw/day x 4 weeks.

3) Trial in women with premenstrual tension - Main study (McGavack et al, 1956): oral treatment (n=43) with 100 to 400 mg pamabrom per day, provided in 1 to 14 successive treatment cycles (mean 2-3 treatment cycles per group) of 3-10 days before start of menstruation, mean cumulated treatment duration 2 weeks. This study included reporting of any clinical effects and notably symptoms of premenstrual tension (menstrual cycle length, amount of flow). No adverse effect: the only effects were therapeutic (benefic): normalisation of symptoms of premenstrual tension (menstrual cycle length, amount of flow). The NOAEL was >= 1.5 mg AMP/kg bw/day x 2 weeks (mean: variable treatment regime).

4) Trial in women with primary dysmenorrhea (Ortiz et al, 2016): n=189 women with mean age 21 years were given 75 mg pamabrom daily for 3 days, in combination with various other drugs. The study involved monitoring of adverse clinical effects and multiple efficacy endpoints (menstrual pain reduction, symptoms of dysmenorrhea, overall clinical response). The only effects related to reproduction were therapeutic (benefic): normalisation of symptoms of menstrual pain. The NOAEL was >= 0.32 mg AMP/kg bw/day x 3 days.

5) Trial in pregnant women (Patterson, 1958): >22 week pregnant women with edema classified as mild pre-eclampsia (n=38) were given orally 800 mg of pamabrom daily for 5-7 days. Then, (n=9) patients who failed to loose weight were again given orally 1600 mg of pamabrom daily for 5-7 days. Study covered gravidity, gestation, changes in fetal movement. No adverse effects. The NOAEL was >= 5.9 mg AMP/kg bw/day x 1 week (if considering only the second treatment cycle), and >= 2.9 mg AMP/kg bw/day x 2 weeks (if considering both treatment cycles in patients treated twice).

6) Trial in pregnant women (James et al, 1957): In 180 pregnant women with edema treated with pamabrom for unknown duration (Klimisch 4 study), no adverse effects were reported up to 12 tablets/day and an average of 8-10 tablets/day. The max. NOAEL was >= 2.2 mg AMP/kg bw/day and in most patients it was >=1.6 mg AMP/kg bw/day.

For repeat-dose toxicity information, please refer to each of the referenced study summaries.

Considering all data, the most robust human NOAEL for reproductive toxicity comes from study 4) (Patterson, 1958) since it is the most robust study in pregnant women and it included monitoring of pregnancy and fetal movement. The NOAEL was >= 2.9 mg AMP/kg bw/day x 2 weeks in patients treated twice. Results from Study 6) (James et al, 1957) are consistent with this conclusion.

Cross-reference 2

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

cross-reference to human clinical trials under IUCLID section 7.10.3

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1953 to 2016

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Pamabrom is an Over The Counter (OTC) diuretic agent which is an AMP salt of 8-bromotheophylline, CAS No. 606-04-2.
It is an equimolar mixture of 74.4% w/w 8-Bromotheophylline (CAS No. 10381-75-6) and 25.6% w/w 2-amino-2-methylpropan-1-ol (AMP, CAS No. 124-68-5). Clinical data on this test material can be used for AMP safety assessment based on the AMP/Pamabrom bioequivalence study (see Basic Toxicokinetics /IUCLID §7.1.1) which indicated that Pamabrom's AMP, and AMP as is, were equivalent in terms of AUC0-t, AUC0-inf and AUC0-168h. Pamabrom doses can be converted into equivalent AMP doses based on the AMP content of 25.6% w/w in this drug and assuming a patient weight of 70 kg when not indicated.

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

see details under each of the Cross-referenced summaries

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

see details under each of the Cross-referenced summaries

Species:

other: humans

Details on test animals or test system and environmental conditions:

see details under each of the Cross-referenced summaries

Route of administration:

oral: capsule

Duration of treatment / exposure:

NOAELs cover 3 days to 17 weeks depending on clinical trial (+ one Klimisch-4 trial summary where treatment duration was not indicated).
see details under each of the Cross-referenced summaries

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Study 1):
- Only 2/18 patients showed effects likely attributable to pamabrom since they cleared after treatment cessation: Patient n° 14 (600 mg x 67 days then 900 mg x 70 days) developed mild diarrhea after 120 days of treatment, Patient n° 11 (600 mg x 24 days) developed maculopapular rash over 4th treatment week.
- 8/18 patients showed no effects of pamabrom treatment (patients N° 4,7,8,12,13,15,16,18 treated for 13-70 days at 600 to 900 mg/day), and we can also consider patient n°14 until diarrhea appeared on day 120 (600 mg x 67 days + 900 mg x 52 days before diarrhea).
- 8/18 patients showed adverse reactions which cannot be interpreted concerning relationship
with Pamabrom treatment because of the severe cardiac failure, co-treatment with highly toxic
mercurial diuretics in most patients, and often missing information about recovery upon cessation of pamabrom treatment.

Study 2): No toxic effects noted.

Study 3): The only effects were therapeutic (benefic): variable "degree of improvement" of the premenstrual tension condition (less water retention, nervous symptoms, acne, headache, breast engorgement, gastrointestinal symptoms, pelvic pain). No toxic effects.

Study 4): Only 6/189 2 (3%) patients reported minor "adverse" effects, among which only 3/189 were not similar to symptoms already present before treatment in this ill population (primary dysmenorrhea): somnolence (one case), dizziness (one case), increased thirst (one case).

Study 5): The only effects were therapeutic (benefic): edema reduction or persistence. No toxic effects.

Study 6): A few patients complained of nausea, vomiting, etc. due to pregnancy. The only effects were therapeutic (benefic): edema reduction or persistence. No toxic effects.

Mortality:

no mortality observed

Description (incidence):

All 6 studies: no deaths reported

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Studies 1), 3), 5) and 6): The only effects were therapeutic (benefic): weight reduction /less weight gain /less "water retention" in some patients.

Studies 2) and 4) do not include any information

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Description (incidence and severity):

Study 2) investigated but no results provided

Not assessed in other studies

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

study 2): no adverse effect

Not assessed in other studies

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

study 2): no adverse effect

Not assessed in other studies

Endocrine findings:

not examined

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Study 1): 7/18 patients showed no adverse effects at medical examination; other effects observed cannot be interpreted due to illness and co-treatment with toxic mercurial drugs.

Study 2): no adverse effect

Studies 3) and 4) did not include urinalysis

Study 5): The only effects were therapeutic (benefic): changes in electrolytes.

Study 6): The only effects were therapeutic (benefic): albuminuria was reduced or eliminated.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Description (incidence and severity):

Reproduction endpoints:

Studies 1) and 2) No adverse clinical effects related to reproduction were reported.

Study 3): The only effects were therapeutic (benefic): normalisation of symptoms of premenstrual tension (menstrual cycle length, amount of flow).

Study 4): The only effects were therapeutic (benefic): normalisation of symptoms of menstrual pain.

Study 5): No adverse effects on gravidity. gestation, changes in fetal movement.

Study 6): No adverse effects reported during pregnancy.

Dose descriptor:

NOAEL

Effect level:

>= 2.2 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

male/female

Basis for effect level:

clinical signs

Remarks on result:

other: Study 1), NOAEL covers 3 to 17 weeks depending on patient

Key result

Dose descriptor:

NOAEL

Effect level:

>= 2.9 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 2), 28 days

Dose descriptor:

NOAEL

Effect level:

>= 1.5 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 3), variable treatment regime, mean 2 weeks

Dose descriptor:

NOAEL

Effect level:

>= 0.32 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 4), 3-day treatment in 189 patients, only 3 reported minor effects

Dose descriptor:

NOAEL

Effect level:

>= 5.9 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 5), 5-7 days, pregnant women

Dose descriptor:

NOAEL

Effect level:

>= 2.9 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 5), total of 2-week treatment in 9 patients who failed to loose weight, pregnant women

Dose descriptor:

NOAEL

Effect level:

>= 2.2 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Remarks:

AMP (supplied as Pamabrom)

Sex:

female

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

Study 6), unknown treatment duration and schedule, pregnant women

Critical effects observed:

no

see details under each of the Cross-referenced summaries

Conclusions:

see details under each of the Cross-referenced summaries

Executive summary:

Pamabrom is an Over The Counter (OTC) diuretic agent which is an AMP salt of 8-bromotheophylline, CAS No. 606-04-2. It is an equimolar mixture of 74.4% w/w 8-Bromotheophylline (CAS No. 10381-75-6) and 25.6% w/w 2-amino-2-methylpropan-1-ol (AMP, CAS No. 124-68-5).

Six clinical studies are available on pamabrom. NOAELs are expressed in AMP based on pamabrom posology and AMP content.

They inform on absence of repeat-dose adverse effects, in all cases the below-listed NOAELs were the maximum tested dose:

1) Trial in severe cardiac failure patients (Doherty et al, 1953): Patients (n=19) were given pamabrom at 300 to 900 mg/day for 5 to 137 days. This study included clinical signs, edema, degree of cardiac failure, subjective improvement. Only 2/18 patients reported adverse effects potentially related to pamabrom upon longer treatment: 1/18 case of maculopapular rash (4th week of treatment) and 1/18 case of diarrhea (day 120 of treatment). A third patient stopped treatment after 2 weeks due to therapeutic success. The NOAEL was >= 2.2 mg AMP/kg bw/day x 2 to 17 weeks depending on patient.

2) Trial in women with premenstrual tension - Preliminary study (McGavack et al, 1956): oral treatment (n=9) up to 800 mg pamabrom for 4 weeks (28-days) in women with menstrual cycles. This study included general examination for toxic effects. No adverse effect. The NOAEL was >= 2.9 mg AMP/kg bw/day x 4 weeks.

3) Trial in women with premenstrual tension - Main study (McGavack et al, 1956): oral treatment (n=43) with 100 to 400 mg pamabrom per day, provided in 1 to 14 successive treatment cycles (mean 2-3 treatment cycles per group) of 3-10 days before start of menstruation, mean cumulated treatment duration 2 weeks. This study included general examination and monitoring of degree of improvement of premenstrual tension (less water retention, nervous symptoms, acne, headache, breast engorgement, gastrointestinal symptoms, pelvic pain, menstrual cycle length, amount of flow). No adverse effect: the only effects were therapeutic (benefic): normalisation of symptoms of premenstrual tension (menstrual cycle length, amount of flow). The NOAEL was >= 1.5 mg AMP/kg bw/day x 2 weeks (mean: variable treatment regime).

4) Trial in women with primary dysmenorrhea (Ortiz et al, 2016): n=189 women with mean age 21 years were given 75 mg pamabrom daily for 3 days, in combination with various other drugs. The study involved monitoring of adverse clinical effects and multiple efficacy endpoints (menstrual pain reduction, symptoms of dysmenorrhea, overall clinical response). The only effects were minor effects in 3/189 patients (somnolence, dizziness and increased thirst, 1 case each) and normalisation of symptoms of menstrual pain. The NOAEL was >= 0.32 mg AMP/kg bw/day x 3 days.

5) Trial in pregnant women (Patterson, 1958): >22 week pregnant women with edema classified as mild pre-eclampsia (n=38) were given orally 800 mg of pamabrom daily for 5-7 days. Then, (n=9) patients who failed to loose weight were again given orally 1600 mg of pamabrom daily for 5-7 days. This study included monitoring of edema before and after treatment, nausea, vomiting, edema, changes in vision, headache, miscellaneous side effects, blood pressure, daily intake and output of fluids, gravidity, gestation, fetal movement. No adverse effects. The NOAEL was >= 5.9 mg AMP/kg bw/day x 1 week (if considering only the second treatment cycle), and>= 2.9 mg AMP/kg bw/day x 2 weeks (if considering both treatment cycles in patients treated twice).

6) Trial in pregnant women (James et al, 1957): In 180 pregnant women with edema treated with pamabrom for unknown duration (Klimisch 4 study), no adverse effects were reported up to 12 tablets/day and an average of 8-10 tablets/day. The max. NOAEL was >= 2.2 mg AMP/kg bw/day and in most patients it was >=1.6 mg AMP/kg bw/day.

Considering all data, the most robust human NOAEL for repeat-dose toxicity comes from study 2) (preliminary study by McGavack et al, 1956) since this is the only study monitoring hematology and blood biochemistry. The NOAEL was >= 2.9 mg AMP/kg bw/day x 4 weeks.

Cross-reference 3

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Aug 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

Pamabrom is a diuretic agent. This is 2-amino-2-methylpropanol 8-bromotheophyllinate, CAS No. 606-04-2. It is an equimolar mixture of 74.4% w/w 8-Bromotheophylline (CAS No. 10381-75-6) and 25.6% w/w 2-amino-2-methylpropan-1-ol (CAS No. 124-68-5). Clinical data on this test material are provided in IUCLID section 7.10.3 and can be used for AMP safety assessment based on this AMP/Pamabrom bioequivalence study which indicated that Pamabrom and AMP were equivalent in terms of AUC0-t, AUC0-inf and AUC0-168h. Pamabrom doses can be converted into equivalent AMP doses based on the AMP content of 25.6% w/w in this drug.

Objective of study:

toxicokinetics

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

AMP- 95% AMP in water
Pamabrom - Equimolar mixture of AMP and 8-bromotheophylline

Radiolabelling:

no

Species:

rat

Strain:

Fischer 344

Details on species / strain selection:

Fischer 344 (F344/NHsd) from Envigo RMS, Inc

Sex:

male

Details on test animals or test system and environmental conditions:

Species
Rat
Number and Sex
12 males
Strain and Source
Fischer 344 (F344/NHsd) from Envigo RMS, Inc.
Acclimation
At least 3 days
Weight at Dose Administration
250 to 325 g
Age at Dose Administration
9 to 15 weeks
Housing
During acclimation and test period, animals will be group housed (up to five
animals/cage/group) in polycarbonate cages with hardwood chip bedding.
Animals may be individually housed for study-related procedures or behavioral or health
reasons.
Feed
Certified Rodent Diet #2016C and/or 2016CM (Envigo RMS, Inc.) will be provided ad
libitum, except as specified under dosing procedures.
Water
Ad libitum, provided fresh daily
Environment
Environmental controls for the animal room will be set to maintain a temperature of 20 to
26°C, a relative humidity of 50 ± 20%, and a 12-hour light/12-hour dark cycle. The
12-hour dark cycle may be interrupted to accommodate study procedures.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Single oral dose
Dose Preparation and Analyses
The test articles will be prepared in water at Covance. The pH of the AMP dose
formulation will be adjusted to approximately pH 7 with HCl (Saghir 2008). The pH of
the Pamabrom dose formulation will be recorded and adjusted to approximately pH 7, as
needed.
Triplicate sets of two aliquots (1 mL; top, middle and bottom) of each formulation will be
taken and stored at approximately 5°C until analysis. Analysis of the dose formulations
will be conducted at Covance-Salt Lake City. Any dose formulations remaining
following administration will be stored at approximately 5°C.
Dose Procedures
Individual doses will be calculated based on body weights recorded on the day of dose
administration.
Fasting
All animals will be fasted overnight through approximately 4 hours postdose.
Dose Administration
The oral dose will be administered via a gavage needle.

Duration and frequency of treatment / exposure:

Single oral dose

Remarks:

AMP:
Target dose 12.5 mg/kg, Target Dose Conc (Mg/ml)= 2.5 ; Target Dose Vol (ml/kg) = 5

Pamabrom:
Target dose 50 mg/kg ( equivalent to 12.5 mg/kg AMP), Target Dose Conc (Mg/ml)= 10; Target Dose Vol (ml/kg) =5

No. of animals per sex per dose / concentration:

6 animals per test material

Control animals:

no

Details on study design:

The purpose of this study is to determine the pharmacokinetics of AMP after a single oral
dose of AMP or Pamabrom to rats.

Details on dosing and sampling:

Single oral dose of AMP or Pamabrom in water.
Dose Preparation and Analyses
The test articles will be prepared in water at Covance. The pH of the AMP dose
formulation will be adjusted to approximately pH 7 with HCl (Saghir 2008). The pH of
the Pamabrom dose formulation will be recorded and adjusted to approximately pH 7, as
needed.
Triplicate sets of two aliquots (1 mL; top, middle and bottom) of each formulation will be
taken and stored at approximately 5°C until analysis. Analysis of the dose formulations
will be conducted at Covance-Salt Lake City. Any dose formulations remaining
following administration will be stored at approximately 5°C.
Dose Procedures
Individual doses will be calculated based on body weights recorded on the day of dose
administration.
Fasting
All animals will be fasted overnight through approximately 4 hours postdose.
Dose Administration
The oral dose will be administered via a gavage needle.
Sample Collection
Blood
Blood (approximately 0.3 mL) will be collected via a jugular vein via syringe and needle
and transferred into tubes containing K2EDTA anticoagulant from each animal predose
and at approximately 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours
postdose.
Blood will be maintained on wet ice, in chilled cryoracks, or at approximately 5°C prior
to centrifugation to obtain plasma. Centrifugation will begin within 30 minutes of
collection. Plasma will be placed into 96-well tubes and maintained on dry ice prior to
storage at approximately-70°C.

Statistics:

Statistical Analyses
Bioequivalence of Pamabrom and AMP will be evaluated. Dose normalized PK
parameters Cmax, AUC0-24, AUC0-t, AUC0-inf, and AUC0-168 will be natural log
transformed (ln) prior to analysis. Due to measureable AMP plasma levels beyond
24 hours for some animals, the AUC0-24 values are not useful for calculating
bioequivalence and will not be included in the report. A two-sample t-test will be used
to analyze each of the parameters. Treatment means and the difference for the group
comparison, along with the associated 90% confidence interval for the difference, will be
estimated on the ln-scale. These will be back transformed to generate geometric means
and a geometric mean ratio for the group comparison, along with the associated 90%
confidence interval. Results will be presented as Pamabrom/AMP.

Preliminary studies:

A single dose study at the highest approved dose will generally be adequate for the demonstration of bioequivalence.
The extent of product bioavailability is estimated by the area under the blood concentration vs time curve (AUC).
For a single dose bioequivalence study, AUC should be calculated from time 0 (predose) to the last sampling time associated with quantifiable drug concentration AUC(0-LOQ). The comparison of the test and reference product value for this noninfinity estimate provides the closest approximation of the measure of uncertainty (variance) and the relative bioavailability estimate associated with AUC(0-INF), the full extent of product bioavailability
Results:
Dose normalized PK parameters Cmax, AUC0-t, AUC0-inf and AUC0-168 were natural log transformed (ln) prior to analysis. A two-sample t-test was used to analyze each of the parameters. Treatment means and the difference for the group comparison, along with the associated 90% confidence interval for the difference, were estimated on the ln-scale. These were back transformed to generate geometric means and a geometric mean ratio for the group comparison, along with the associated 90% confidence interval.

Metabolites identified:

no

Conclusions:

The results indicated that Pamabrom and AMP were equivalent for AUC0-t, AUC0-inf and AUC0-168, justifying the use of Pamabrom data for read across to AMP.
The bioequivalence results showed the 90% confidence interval was from 1.050 to 1.465
for Cmax, from 0.921 to 1.177 for AUC0-t, from 0.848 to 1.099 for AUC0-inf and from
0.929 to 1.177 for AUC0-168.

Data source

Reference

Reference Type:

publication

Title:

Evaluation of a Diuretic Substance in the Management of Mild Pre-Eclampsia - a report of 47 clinical trials.

Author:

Patterson RE, Baer H

Year:

1958

Bibliographic source:

American Journal of Obstetrics and Gynecology,. 76(6):1264-67, 1958.

Materials and methods

Study type:

other: clinical trial of a drug

Endpoint addressed:

repeated dose toxicity: oral

developmental toxicity / teratogenicity

Principles of method if other than guideline:

- Principle of test: 38 patients, repeated trial at two times higher dose on 9 of them = total of 47 trials

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

8-bromotheophylline

EC Number:

233-846-6

EC Name:

8-bromotheophylline

Cas Number:

10381-75-6

Molecular formula:

C7H7BrN4O2

IUPAC Name:

8-Bromotheophylline

Constituent 2

Reference substance name:

2-amino-2-methylpropanol

EC Number:

204-709-8

EC Name:

2-amino-2-methylpropanol

Cas Number:

124-68-5

Molecular formula:

C4H11NO

IUPAC Name:

2-amino-2-methylpropan-1-ol

Details on test material:

Drug name: NeoBromth

Specific details on test material used for the study:

Supplied in 200 mg tablets marketed as Predema by the Brayten Pharmaceutical Co., Chattanooga, Tenn.

Method

Type of population:

other: ill patients (clinical trial)

Subjects:

Pregnant women (>22 week pregnancy) with edema classified as mild pre-eclampsia

Route of exposure:

oral

Reason of exposure:

intentional

Exposure assessment:

measured

Remarks:

based on drug posology

Details on exposure:

38 patients were given orally 800 mg (split in 4 doses per day) of pamabrom daily for 5-7 days
then, 9 patients who failed to loose weight were again given orally 1600 mg (split in 4 doses per day) of pamabrom daily for 5-7 days

Examinations:

Special charts were kept on all patients, giving the age, parity, gravidity. gestation, usual weight, history of previous pregnancies, urine albumin (before and after treatment on outpatients, daily on inpatients), urinary sodium, chloride, potassium, creatinine (before treatment and on the fifth or seventh day of treatment of inpatients), blood pressure (before, during, and after treatment), daily intake and output of fluids (on inpatients), edema before and after treatment, indication of nausea, vomiting, changes in vision, changes in fetal movement, headache, and miscellaneous side effects.

Results and discussion

Clinical signs:

None of the 47 trials (38 patients dosed at 800 mg/day + 9 patients failing to loose weight dosed again at 1600 mg/day, doses in pamabrom) showed any toxic effects from the drug. The only effects were therapeutic effects or effects related to the pre-existing edema condition (weight changes, edema reduction or persistence, changes in urinary electrolytes).

Results of examinations:

No side effects

Effectivity of medical treatment:

Effective in treating edema of pregnancy

Applicant's summary and conclusion

Conclusions:

In >22-week pregnant women with mild pre-eclampsia, the oral 1-week NOAEL covering gestation and repeated dose toxicity is at least 5.9 mg AMP/kg bw/day.

Executive summary:

Pamabrom is an Over The Counter (OTC) diuretic agent which is an AMP salt of 8-bromotheophylline, CAS No. 606-04-2. It is an equimolar mixture of 74.4% w/w 8-Bromotheophylline (CAS No. 10381-75-6) and 25.6% w/w 2-amino-2-methylpropan-1-ol (AMP, CAS No. 124-68-5).

Pamabrom daily oral doses up to 1600 mg (split in 4 doses) for 5-7 days caused no side effects on general condition, renal and liver function in >22 week pregnant women with mild pre-eclampsia. This is equivalent to 410 mg AMP/patient/day i.e. 5.9 mg AMP/kg bw/day. This is a human NOAEL.