Appraisal of growth hormone (GH) secretion: Evaluation of a composite pharmacokinetic model that discriminates multiple components of GH input

Criteria for a diagnosis of GH deficiency include inadequate GH secretion a s assessed by provocative testing. The changes in serum GH concentration in such tests, however, do not uniformly predict treatment responses. We ques tioned whether the changes in serum GH have a uniform dependence among subj ects on the mass of secreted GH. We simulated spontaneous GH secretory even ts with bolus infusions of recombinant human GH (rhGH) in 15 somatostatin-i nfused adult subjects. Maximum serum GH responses, the GH areas under the c urve, and GH mass calculated from deconvolution techniques are all indexes of GH secretion influenced by GH clearance and distribution volume. In this group, these indexes showed a nonuniform dependence on the known GH dose. Despite somatostatin infusion, we found evidence for low level basal GH sec retion with oscillatory characteristics that may have influenced the GH con centration dependence on GH dose. We then developed and evaluated a new pha rmacokinetic model to account for pulsatile, basal, and oscillatory inputs to the serum GH concentration profile. The new model is comprised of three terms. The first describes plasma GH co ncentrations from exogenous administration of rhGH according to a one- or a two-compartment model. The second term accounts for basal GH secretion. Th e third is a cosinor function that describes the oscillatory pattern of bas al GH. The composite pharmacokinetic model predicted plasma GH concentratio ns well (x(2) = 0.88-0.97); pharmacokinetic and cosinor parameters had high precision and narrow 95% confidence intervals. The pharmacokinetic paramet ers were stable and independent. The mean values and coefficients of variance (SD/mean) of GH pharmacokineti c parameters in our 15 subjects were: clearance, 0.236 L/min (24%); volume of distribution, 3.46 L (30%); and terminal half-life, 12.3 min (37%). The values for the cosinor parameters were: basal concentration, 0.22 ng/mL (85 %); amplitude, 0.758 (50%); cycle, 121 min (27%); and time shift (acrophase ), 60.3 min (53.6%). During the 9-h study, clearance decreased from 0.259 /- 0.09 to 0.214 +/- 0.06 L/min (P < 0.03), and basal concentration increas ed from 0.20 +/- 0.22 to 0.33 +/- 0.33 ng/mL (P < 0.5). We conclude that our model can provide useful estimates of GH pharmacokinet ics in the presence of basal, oscillating, endogenous concentrations withou t administering a dose of radiolabeled GH. The substantial inter- and intra subject variance in pharmacokinetic parameters between subjects negates the assumption of a uniform relationship between GH secretion and serum GH con centration and detracts from the utility of a GH concentration cut-off poin t in GH testing. These findings have implications to the valid appraisal of GH deficiency states, selection of rhGH treatment candidates, and physiolo gical regulation of the GH axis.