Factrel Pharmacology, Pharmacokinetics, Studies, Metabolism - gonadorelin

Factrel Pharmacology, Pharmacokinetics, Studies, Metabolism - gonadorelin

CLINICAL PHARMACOLOGY

Factrel has been shown to have gonadotropin-releasing effects upon the anterior pituitary. The range for normal baseline LH levels, as determined from the literature, is 5-25 mIU/mL in postpubertal males, and postpubertal and premenopausal females. The standard used is the Second International Reference Preparation HMC. This range may not correspond in each laboratory performing the assay since the concentration of LH in normal individuals varies with different assay methods. The normal responses to Factrel analyzed from the results of clinical studies included:

1. LH peak (mIU/mL)
   (highest LH value post-Factrel administration)
2. Maximum LH increase (mIU/mL)
   (peak LH value LH baseline value)
3. LH percent response
   peak LH baseline LH   ×  100%
          baseline LH
4. Time to peak (minutes)
   (time required to reach LH peak value)

Normal adult subjects were shown to have these LH responses following Factrel administration by subcutaneous or intravenous routes.

1.   MALE ADULTS:
   
   1. Subcutaneous Administration
      The results are based on 18 tests in males between the ages of 18-42 years, inclusive:
      
      1. LH peak: mean 60.3 ± 26.2 mIU/mL
         100% >= 24.0 mIU/mL
           90% >= 32.8 mIU/mL
      2. Maximum LH increase: mean 46.7 ± 20.8 mIU/mL
         100% >= 12.3 mIU/mL
           90% >= 20.9 mIU/mL
      3. LH percent response: mean 437 ± 243% range: 66-1853%
          90% >= 188%
      4. Time to peak: mean 34 ± 13 min
   2. Intravenous Administration
      The results are based on 26 tests in males between the ages of 19-58 years, inclusive:
      
      1. LH peak: mean 63.8 ± 40.3 mIU/mL
         100% >= 12.6 mIU/mL
           90% >= 26.0 mIU/mL
      2. Maximum LH increase: mean 51.3 ± 35.2 mIU/mL
         100% >=  7.4 mIU/mL
           90% >= 14.8 mIU/mL
      3. LH percent response: mean 481 ± 184% range: 67-2139%
          90% >= 142%
      4. Time to peak: mean 27 ± 14 min
   
   In males older than 50 years, the LH baseline and peak levels tend to be higher; however, the maximum LH increases do not differ in regard to age.
   
   
2.   FEMALE ADULTS:
   
   1. Subcutaneous Administration
      The results are based on 38 tests in females between the ages of 19-36 years, inclusive:
      
      1. LH peak: mean 67.9 ± 27.5 mIU/mL
         100% >= 12.5 mIU/mL
           90% >= 39.0 mIU/mL
      2. Maximum LH increase: mean 52.8 ± 26.4 mIU/mL
         100% >=  7.5 mIU/mL
           90% >= 23.8 mIU/mL
      3. LH percent response: mean 374 ± 221% range: 108-981%
          90% >= 185%
      4. Time to peak: mean 71.5 ± 49.6 min
   2. Intravenous Administration
      The results are based on 31 tests in females between the ages of 20-35 years, inclusive:
      
      1. LH peak: mean 57.6 ± 36.7 mIU/mL
         100% >= 20.0 mIU/mL
           90% >= 24.6 mIU/mL
      2. Maximum LH increase: mean 44.5 ± 31.8 mIU/mL
         100% >=  7.5 mIU/mL
           90% >= 16.2 mIU/mL
      3. LH percent response: mean 356 ± 282% range: 60-1300%
          90% >= 142%
      4. Time to peak: mean 36 ± 24 min

The Factrel tests on which the normal female responses are based were performed in the early follicular phase of the menstrual cycle (Days 1-7).

In menopausal and postmenopausal females, the baseline LH levels are elevated and the maximum LH increases are exaggerated when compared with the premenopausal levels.

Patients with clinically diagnosed or suspected pituitary and/or hypothalamic dysfunction were often shown to have subnormal or no LH responses following Factrel administration. For example, in clinical tests of 6 patients with known postpubertal panhypopituitarism, and 11 patients with Prader-Willi syndrome, 100% showed subnormal responses or no rise in LH. Subnormal responses to the Factrel test also were observed in 21 (95%) of 22 patients with prepubertal panhypopituitarism. In 19 patients with Sheehan's syndrome, 16 (84%) had a subnormal response. In the Factrel test in 44 patients with Kallmann's syndrome, 33 (77%) had subnormal LH responses.