[R-(R*,R*)]-α-[1-(methylamino)ethyl]benzyl alcohol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Human experimental study, limitations in design and/or reporting but otherwise adequate for assessment.

Data source

Reference

Reference Type:

publication

Title:

Dose Tolerance and Pharmacokinetic Studies of L (+) Pseudoephedrine Capsules in Man

Author:

Dickerson J.

Year:

1978

Bibliographic source:

European Journal of Clinical Pharmacology 14, 253-259

Materials and methods

Objective of study:

toxicokinetics

other: Dose Tolerance

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Dose tolerance and pharmacokinetic studies of pseudoephedrine sustained action capsules were performed in thirty-three adult male subjects who received either 120 mg or 150 mg capsules every twelve hours for seven consecutive days in a double-blind parallel design study.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

[R-(R*,R*)]-α-[1-(methylamino)ethyl]benzyl alcohol

EC Number:

206-292-8

EC Name:

[R-(R*,R*)]-α-[1-(methylamino)ethyl]benzyl alcohol

Cas Number:

321-97-1

Molecular formula:

C10H15NO

IUPAC Name:

(1R,2R)-2-(methylamino)-1-phenylpropan-1-ol

Details on test material:

- Name of test material (as cited in study report): L (+) Pseudoephedrine
- Substance type: 120 mg or 150 mg capsules
- Manufacturer: DV Pharmaceutical Company, St. Louis, Missouri, and supplied by Burroughs Wellcome Company.

Radiolabelling:

no

Test animals

Species:

human

Details on test animals or test system and environmental conditions:

- Test subjects: Thirty-four male volunteers
- Age at study initiation: between 19 and 30 years
- Mean weight: 120 mg exposure group = 74.7 kg (SD 12), 150 mg exposure group = 71.1 kg (SD 8.6)

The subjects were in good physical and mental health as determined by a baseline rnedical history, physical examination and clinical Iabaratory tests (hemoglobin,hematocrit, white blood cell count with differential, platelets, serum glucose, urea nitrogen, uric acid, cholesterol, phosphorus, alkaline phosphatase, total bilirubin, glutamic oxalacetic transarninase and urinalysis). Subjects who smoked were not disqualified from this study. Of the 34 subjects there were 3 smokers (2 of whom smoked only occasionally) and one occasional pipe-smoker. Recent chronic use of any drug disqualified a volunteer from entering the trial. Drug and alcohol use during the trial was prohibited.

Administration / exposure

Route of administration:

oral: capsule

Duration and frequency of treatment / exposure:

Capsules were taken every twelve hours throughout seven test days (fourteen doses).

Doses / concentrations

Remarks:

Doses / Concentrations:
120 mg or 150 mg per capsule

No. of animals per sex per dose / concentration:

34

Control animals:

no

Details on study design:

- Design: a double-blind parallel design with each subject randomly assigned to either a pseudoephedrine 120 mg or 150 mg sustained action capsule test group.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, plasma, urine
- Time and frequency of sampling: Blood samples, 10 min prior to the ingestion of each capsule and, at four and eight hours following the first dose on days 1, 3, 5, and 7 of the study. Plasma samples, on day 8 of the study at 12, 14, 16, 18, and 20 h after the last dose of drug. Urine samples (for pH) prior to the initiation of treatment, every 24 h during the study, and at 20 h after the last dose of the drug.
- Other: Sitting blood pressure and pulse rates were taken five minutes before each blood sample was drawn. If these measurements were abnormal, blood pressure and pulse rate were again taken after a 15 min rest period but before a blood sampie was drawn. Abnormal pulse rate was defined as a rate greater than 100 beats per minute or where there was more than a 25% difference from the mean of pulse rates taken at baseline and zero hour. An abnormal blood pressure was defined as more than a 30 mm Hg difference in systolic pressure and more than a 20 mm Hg difference in diastolic pressure from the mean taken at baseline and zero hour. The clinical Iabaratory evaluations made prior to the initiation of the study (baseline evaluation) were repeated at 0 h, and at 72 and 168 h after the initial drug dose.
- Other: Each subject was evaluated for the presence or absence of side effects by means of an indirect questionnaire which the subject answered at baseline, 0 h, and every twelve hours thereafter. All spontaneous responses were also noted. If any response suggested central nervous system stimulation, vertigo or mydriasis, dysuria, gastric distress or cardiovascular effects, more specific inquiry was made as to the actual type of effect that was experienced and the onset, severity (mild, moderate or severe) and duration. Whether or not the effect was drug related was evaluated by one of the investigators, and was defined as being definitely, probably, possibly or not related to the drug.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Mean 120 mg group:
- Steady state concentration: 447 ng/mL (SD 116)
- ratio of the volume of distribution to the administered dose absorbed (V/F) = 2.64 L/kg (SD 0.87)
Mean 150 mg group:
- Steady state concentration: 510 ng/mL (SD 133)
- ratio of the volume of distribution to the administered dose absorbed (V/F) = 3.51 L/kg (SD 1.97)

Details on excretion:

Mean 120 mg group:
- t1/2 = 5.9 h (SD 2.2)
Mean 150 mg group:
- t1/2 = 6.8 h (SD 3.9)
The biologic half-life of pseudoephedrine was not dependent on the urine pHs of the subjects studied. The mean urine pH ranged from 5.3 to 6.0 in 27 of the 31 subjects.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Calculations of relative bioavailability suggest that the 120 mg capsule formulation has a 30% greater bioavailability compared to the 150 mg capsule.

Any other information on results incl. tables

Blood pressure
Both groups showed a similar significant and persistent increase over baseline values. Subjects in the 150 mg treatment group had a temporary but significant increase in systolic blood pressure during the 4 to 60 h time period. Both groups showed a significant decline in blood pressure from 170 to 176 h.

Side effects
A large number of side effects which are typical symptoms of central nervous system Stimulation were reported by both treatment groups. The total number of reports of side effects were significantly greater in the higher dose group. The most common reports were those of insomnia, anxiety, tachycardia and anorexia.The latter two effects and dryness of mouth were the most persistent symptoms. The number of subjects experiencing these symptoms did not vary greatly between treatment groups with the exception of tension in the 150 mg group. However, the total number of reports of tension, dryness of mouth, tachycardia, palpitations and anxiety were significantly greater in the 150 mg group.

Symptoms related to time and dose
A significant decline in the mean number of reports of side effects during the 72 to 168 h time period in the lower dose group compared to the 0 to 60 h time period. Subjects in the 150 mg group evaluated their symptoms as being moderate to severe in nature significantly more often than those symptoms in subjects in the 120 mg group. Symptoms were more often evaluated by an investigator under blind conditions as probably or definitely due to the drug in the 150 mg group and as not due to drug in the 120 mg group.

Prematurely discontinuation
One subject (in the 150 mg treatment group) was discontinued from the study prematurely due to primarily excitatory-type effects which increased in number, duration and severity. Symptoms included dry mouth, insomnia, tension, restlessness, dysuria, palpitation, anxiety, and vertigo, the occurrence following in that order. His diastolic blood pressure was elevated to 90 mm Hg on two occasions, to 100 mm Hg once and his pulse rate was greater than 25% above the baseline and 0 h mean on three occasions. Symptoms disappeared within 20 h after the last dose. This subject had previously taken pseudoephedrine 60 mg (Sudafed 30 mg tablets) as acute single doses during the past 2 to 3 years with no side effects.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results

Executive summary:

Dose tolerance and pharmacokinetic studies of pseudoephedrine capsules were performed in thirty-three adult male subjects who received either 120 mg or 150 mg every twelve hours for seven consecutive days in a double-blind parallel design study. One subject (in the 150 mg treatment group) was discontinued from the study prematurely due to primarily excitatory-type effects which increased in number, duration and severity. Both groups showed a similar significant and persistent increase in baseline blood pressure values. A large number of side effects which are typical symptoms of central nervous system stimulation were reported by both treatment groups including insomnia, anxiety, tachycardia, anorexia, and dryness of mouth. A placebo effect might account for a portion of these complaints, however a significant decline was seen in the mean number of reports of side effects during the 72 to 168 h time period in the lower dose group compared to the 0 to 60 h time period, while in the high dose group no decline was observed. Mean half-time was 5.9 h and 6.8 h, and mean steady state concentration was 447 and 510 ng/mL for the 120 mg and 150 mg group, respectively. The mean apparent volume of distribution was 2.64 and 3.51 for the 120 mg and 150 mg group respectively. Calculations of relative bioavailability suggest that the 120 mg capsule formulation has a 30% greater bioavailability compared to the 150 mg capsule.