Single and multiple dose pharmacokinetics of methionyl growth hormone in children with idiopathic growth hormone deficiency.
The pharmacokinetics (PK) of methionyl GH (metGH) were characterized in 20 newly diagnosed GH-deficient children (19 males; 12.9 +/- 3.3 yr old; initial height, 138.8 +/- 16.2 cm; weight, 32.1 +/- 13.1 kg) after the first dose (FD) of metGH and again after 4-5 weeks of multiple dosing (MD). All subjects received a total metGH dose of 0.3 mg/kg.week by sc administration, but were randomized to receive the drug daily (D; n = 12; dose, 0.043 mg/kg) or three times per week (TIW; n = 8; dose, 0.1 mg/kg). After drug administration, repeated blood samples (n = 14) were obtained over a 10-h period. Concentrations of metGH from each sample were determined using a monoclonal antibody radiometric assay (range of linearity, 0.5-40.0 ng/ml; coefficient of variation, less than 4%). Plasma concentration vs. time data were curve fit using a nonlinear weighted least squares algorithm which permitted calculation of the following PK parameters (mean +/- SEM; FD vs. MD group): elimination rate constant (0.23 +/- 0.04 vs. 0.25 +/- 0.04 h-1), absorption rate constant (0.43 +/- 0.05 vs. 0.48 +/- 0.04 h-1), elimination half-life (t1/2; 3.01 vs. 2.77 h), total plasma clearance (CL/F; 0.32 +/- 0.02 vs. 0.54 +/- 0.09 L/h.kg), and apparent volume of distribution (VDss/F; 2.2 +/- 0.14 vs. 3.15 +/- 0.28 L/kg). Both the CL/F and VDss/F of metGH were significantly greater when data from the entire study population were compared on the basis of FD vs. MD administration. With the exception of a larger VDss/F in subjects who received daily (3.6 +/- 0.4 L/kg) vs. TIW metGH (2.4 +/- 0.2 L/kg), no significant differences were found for the PK parameters between the D and TIW dosing groups. In all subjects, absorption of metGH was slow, with an average time to reach maximum concentration (Tmax) of 4.4 h and an absorption t1/2 that ranged from 1.4-1.8 h. Proportionality was also found between the dose and the area under the plasma concentration vs. time curve, suggesting dose-independent PK of metGH. Our data demonstrate that the PK of metGH after sc administration to children are markedly different from those previously reported in adults and, also, do not vary as a consequence of dosing schedule (i.e. D vs. TIW). The apparent increase in CL/F and VDss/F for met GH with multiple dosing may reflect concentration-dependent changes in plasma binding of the drug or, alternatively, represent the effect of increased body mass on the pharmacokinetics of GH.
Kearns
G L
GL
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock 72205-7199.
Kemp
S F
SF
Frindik
J P
JP
D000293:Adolescent; D002648:Child; D004305:Dose-Response Relationship, Drug; D006130:Growth Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D013006:Growth Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000172:deficiency / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D019382:Human Growth Hormone; D006801:Humans; D008297:Male
D019382:Human Growth Hormone; D013006:Growth Hormone