Absorption
Following a 0.03 mg/kg subcutaneous (SC) injection in the thigh of 1.3 mg/mL GENOTROPIN to adult GHD patients, approximately 80% of the dose was systemically available as compared with that available following intravenous dosing. Results were comparable in both male and female patients. Similar bioavailability has been observed in healthy adult male subjects.
In healthy adult males, following an SC injection in the thigh of 0.03 mg/kg, the extent of absorption (AUC) of a concentration of 5.3 mg/mL GENOTROPIN was 35% greater than that for 1.3 mg/mL GENOTROPIN. The mean (± standard deviation) peak (Cmax) serum levels were 23.0 (± 9.4) ng/mL and 17.4 (± 9.2) ng/mL, respectively.
In a similar study involving pediatric GHD patients, 5.3 mg/mL GENOTROPIN yielded a mean AUC that was 17% greater than that for 1.3 mg/mL GENOTROPIN. The mean Cmax levels were 21.0 ng/mL and 16.3 ng/mL, respectively.
Adult GHD patients received two single SC doses of 0.03 mg/kg of GENOTROPIN at a concentration of 1.3 mg/mL, with a one- to four-week washout period between injections. Mean Cmax levels were 12.4 ng/mL (first injection) and 12.2 ng/mL (second injection), achieved at approximately six hours after dosing.
There are no data on the bioequivalence between the 12 mg/mL formulation and either the 1.3 mg/mL or the 5.3 mg/mL formulations.
Metabolism
The metabolic fate of GENOTROPIN involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products are returned to the systemic circulation. The mean terminal half-life of intravenous GENOTROPIN in normal adults is 0.4 hours, whereas subcutaneously administered GENOTROPIN has a half-life of 3.0 hours in GHD adults. The observed difference is due to slow absorption from the subcutaneous injection site.
Special Populations
Pediatric: The pharmacokinetics of GENOTROPIN are similar in GHD pediatric and adult patients.
Gender: No gender studies have been performed in pediatric patients; however, in GHD adults, the absolute bioavailability of GENOTROPIN was similar in males and females.
Race: No studies have been conducted with GENOTROPIN to assess pharmacokinetic differences among races.
Renal or hepatic insufficiency: No studies have been conducted with GENOTROPIN in these patient populations.
Table 2 Mean SC Pharmacokinetic Parameters in Adult GHD Patients | Bioavailability (%) (N=15) | Tmax (hours) (N=16) | CL/F (L/hr × kg) (N=16) | Vss/F (L/kg) (N=16) | T1/2 (hours) (N=16) |
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Tmax = time of maximum plasma concentration CL/F = plasma clearance Vss/F = volume of distribution |
T 1/2 = terminal half-life SD = standard deviation CI = confidence interval |
|
Mean | 80.5 | 5.9 | 0.3 | 1.3 | 3.0 |
(± SD) | * | (± 1.65) | (± 0.11) | (± 0.80) | (± 1.44) |
95% CI | 70.5 – 92.1 | 5.0 – 6.7 | 0.2 – 0.4 | 0.9 – 1.8 | 2.2 – 3.7 |