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Original Studies |
Division of Endocrinology (G.M.B.) and the Center for Pediatric Clinical Pharmacology (J.L.), Nemours Children’s Clinic, Jacksonville, Florida 32207; the Division of Endocrinology and Metabolism, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 22908; Veterans Affairs Medical Center (A.I.), Salem, Virginia 24153; and Northwestern University Medical School (G.B., H.M.), Chicago, Illinois 60611
Address all correspondence and requests for reprints to: Dr. George M. Bright, Novo Nordisk Pharmaceuticals, Inc., 100 Overlook Center, Suite 200, Princeton, New Jersey 08540.
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Abstract |
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The new model is comprised of three terms. The first describes plasma GH concentrations from exogenous administration of rhGH according to a one- or a two-compartment model. The second term accounts for basal GH secretion. The third is a cosinor function that describes the oscillatory pattern of basal GH. The composite pharmacokinetic model predicted plasma GH concentrations well (r2 = 0.88–0.97); pharmacokinetic and cosinor parameters had high precision and narrow 95% confidence intervals. The pharmacokinetic parameters were stable and independent.
The mean values and coefficients of variance (SD/mean) of GH pharmacokinetic 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 increased 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 pharmacokinetics in the presence of basal, oscillating, endogenous concentrations without administering a dose of radiolabeled GH. The substantial inter- and intrasubject variance in pharmacokinetic parameters between subjects negates the assumption of a uniform relationship between GH secretion and serum GH concentration and detracts from the utility of a GH concentration cut-off point in GH testing. These findings have implications to the valid appraisal of GH deficiency states, selection of rhGH treatment candidates, and physiological regulation of the GH axis.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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An accurate diagnosis of GH deficiency is of increasing significance, especially given that GH treatment indications have been broadened recently to include both adults and children. The serum GH responses to provocative testing have not been uniformly accurate predictors of recombinant human GH (rhGH) treatment responses in children (3, 4, 5, 6). We, therefore, questioned the accuracy of assessing GH secretion from changes in serum GH concentration. Accordingly, we evaluated the serum GH concentration dependence on GH dose by direct simulation of GH secretory events and frequent sampling for serum GH in 15 healthy, adult, somatostatin-infused subjects. The infused rhGH masses were poorly estimated by deconvolution methods using fixed or variable GH half-lives. Additionally, we found poor correlations between the infused rhGH masses and both measured GH areas under the curve and maximum GH concentration responses (GHmax) (7). We considered that variance in the GH clearances and volumes of distribution between subjects might nullify any simple relationship between secreted GH mass and serum GH. The need for a new GH pharmacokinetic model to assess these parameters was suggested when inspection of the post-rhGH infusion concentration data appeared to contain nonsuppressed basal and oscillatory GH components. There were detectable GH concentrations at time zero and oscillating GH concentrations persisting throughout the 180-min study period. Indeed, several investigators have reported that pulsatile secretion is superimposed upon a low basal pattern of secretion that may be oscillatory rather than episodic (8, 9, 10, 11). We postulated that serum GH concentrations in our subjects reflected multiple components of GH input and that accurate estimation of each subject’s pharmacokinetic parameters would require a composite pharmacokinetic model to account for pulsatile (infused), basal, and oscillatory components.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fifteen healthy adult volunteer subjects participated. After obtaining approval from the Nemours Childrens’ Clinic research committee and the Baptist Medical Center institutional review committee, written informed consent was obtained from 11 women and 4 men. Seven of the women were taking daily oral contraceptives containing 0.025–0.040 mg ethinyl estradiol. The ages averaged 22.6 ± 2.6 yr (mean ± SD), heights averaged 167 ± 8 cm, weights averaged 59.7 ± 10 kg, and body mass indexes averaged 21.0 ± 2.0 kg/m2. All women tested negatively for pregnancy (urinary hCGß test) in the hour before the study.
Clinical procedures
Endogenous GH secretion was suppressed by iv infusion of somatostatin (Octreotide, Sandoz Pharmaceuticals Corp., Hannover, NJ), 100 µg between 0700–0800 h and then 20 µg/h until the completion of the study at 1700 h. No other medications were used during the study. The subjects fasted after midnight, but had water ad libitum during the study hours (0700–1700 h). At 1100 and 1400 h, each subject received an iv rhGH bolus containing either a low (0.44 ± 0.05 µg/kg) or a high (1.2 ± 0.3 µg/kg) dose. Plasma was sampled at 0, 2, 4, 6, 8, 9, 10, 12, 15, 20, 25, 30, 35, 40, 50, 60, 80, 100, 120, 150, and 180 min after the bolus dose was begun at time zero. Blood was collected in ethylenediamine tetraacetate tubes and separated at 4 C, and plasma samples were stored at -80 C until assay. The rhGH used for infusions was therapeutic grade (Nutropin, Genentech, Inc., South San Francisco, CA). Baseline infusions were performed with precalibrated syringe pumps (Razel Scientific Instruments, Stamford, CT), and bolus rhGH doses were administered with Baxter AS40A syringe infusion pumps (Baxter Healthcare Corporation, Deerfield, IL). To obtain accurate measurements of the dose of GH, we weighed the syringes containing the bolus materials on an analytical balance before and after dose administration. The bolus doses were administered as square wave (zero order) pulses over 8 min, the duration of which was selected to mimic that of spontaneously occurring GH secretory events (8).
Deconvolution studies
The deconvolution procedures included one- and two-compartment fits with fixed or variable half-lives and volumes of distribution calculated from body surface area (12, 13). For the fixed half-lives, we used estimates (3.5 min fast component; 20.9 min slow component; fractional amplitude of slow component, 0.63) previously determined in GHRH-stimulated and then somatostatin-suppressed adults (14).
Pharmacokinetic model description
The scheme in Fig. 1
depicts the
disposition of GH during and after exogenous and endogenous input. Our
model assumes that the only source of endogenous input is a basal,
oscillatory secretion of GH. Serum GH concentrations (Cp) at various
times (t) during and after the iv infusion of rhGH were fitted using a
one-compartment (Eq I) or a two-compartment open model (Eq II) assuming
elimination from the central compartment (15). The latter
compartmental assumption was proposed previously (16).
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1 and z are the first order macrorate
constants describing distribution and elimination of GH, respectively,
and are related to the microconstants by: 1 +
z = k12 + k21 +
k10 (15). It should be noted in Eq I
and II that during the
infusion, t = Ti and that after the infusion ends,
Ti becomes a constant; the postinfusion time is t -
Ti.
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The selection of a one- or two-compartment model was based on
visual examination of how well the fitted curve mimicked the observed
data, the reality and SEs of the model parameters, and the
Akaike information criteria (20). The equation using a one-compartment
open model provided least square estimates and SEs of six
parameters: V, K, CB, A, cycle, and tzero. The
equation that used the two-compartment open model provided estimates of
eight parameters: Vc, 1, z,
k21, CB, A, cycle, and tzero.
Calculation of derived pharmacokinetic parameters
The clearance (CL) of GH for the one-compartment model was:
CL = V x K. CL from the two-compartment model was calculated
by:
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Evaluation of model
Eq IV employing either one or two compartments was fitted to
serum GH concentrations as a function of time. Serum concentrations of
GH were weighted in the fit using 1/y2, where y is the
serum concentration. A battery of statistical tools was used to
evaluate our model (19). We evaluated the precision of our model by
examining the parameter coefficients of variation (quotient of the
computer-generated SE and mean of each parameter estimate)
and the univariate 95% confidence intervals of each parameter
estimate. The goodness of fit was evaluated by visual inspection of how
well the model-predicted line mimicked the GH serum concentration
vs. time data and by examining the coefficient of
correlation and the mean SD (S) of the fit. S is defined as
the square root of WRSS/df, where WRSS is the weighted residual sum of
squares, and df is the degrees of freedom. WRSS refers to summed
vertical distances between the model-predicted and observed GH serum
concentrations, and df is the difference between the number of GH
concentration observations and number of parameters in the model (6
for Eq I, 8 for Eq II).
Parameter identifiability is the property of the model that concerns the uniqueness of a set of parameters estimated by the model (19, 21, 22). Parameter identifiability was assessed in three ways. First, the initial estimates of the parameters were varied to determine whether model parameters were stable. Secondly, we assessed the statistical independence of our parameter estimates by examining parameter correlations. These correlations are provided by WinNonLin; values greater than 0.95 suggest that one parameter is dependent on another (19). Thirdly, our model was fitted to serum GH concentration vs. time data that were simulated at increasing CB values. We were interested in determining the CB at which our model could no longer accurately capture other model parameters.
Clinical assays
GH concentrations were assayed in an ultrasensitive chemiluminescence assay with a lower limit of detectability of 0.002 ng/mL as previously described (11). GHBP was assayed at the start of each procedure in each subject and assayed in a previously described gel filtration assay (23).
Statistical analyses
Multiple regression analyses (Statistica, StatSoft, Tulsa, OK) were used to estimate any effects of time, dose, gender, body size, or GHBP concentrations on the pharmacokinetic parameters. Values shown are the mean ± SD unless otherwise specified.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. These GH secretion indexes are
influenced by the clearance and distribution volume of GH, and all
showed considerable scatter around the mean responses. The values of
r2 were 0.55–0.64. The amount of variance in the GH
measurement index not accounted for by the dose of rhGH was then
100 x (1 - r2), or 36–45%. The lack of
uniform dependencies of GH concentrations on rhGH doses suggested
dissimilar values of GH clearance and distribution volume in this
subject group.
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and 4. The finding of basal and oscillatory
GH concentrations at times when only 0.1% of the rhGH dose would have
remained in serum suggested an endogenous source of GH secretion during
our sampling times. We, therefore, fit the GH concentration time series
data to a new pharmacokinetic model that discriminates pulsatile,
basal, and oscillatory components of GH secretion into serum.
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and Figs. 3 and 4). The fits of time
vs. GH concentrations had a range of correlation
coefficients (r2) of 0.88–0.99; unexplained variance in
the fits was then 1–12% (mean, 5%). The precision of the parameters
estimated by the model was acceptable. Parameter coefficients of
variation (CV) were low, and 95% confidence intervals were narrow
(Table 1). Examination of a correlation matrix revealed no statistical
dependence among any of the parameter estimates (data not shown).
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and Table 2). This superior fit afforded by the
two-compartment model was evident by the Akaike information criteria
values (-117 vs. -100) and by the S values (0.0092
vs. 0.0146). However, parameter CV values were considerably
higher and 95% confidence intervals wider (Table 2). The elimination
half-life obtained with the one-compartment model fit was a hybrid of
the half-lives of distribution and elimination obtained with the
two-compartment model fit. More importantly, GH clearances predicted by
both models were similar: 0.243 and 0.235 L/min for the one- and
two-compartment model fits, respectively. Volumes of distribution for
the one- and two-compartment models were 3.8 and 3.9 L, respectively.
Values for CB, cycle, and tzero were also
similar for the two models.
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shows the serum GH concentration
vs. time profile simulated using the pharmacokinetic
parameters from subject 1 and values of CB that were
increased 10- and 100-fold from an initial value of 0.042 to 0.42 and
4.2 ng/mL, respectively. Fitting the two-compartment model to the
simulated GH serum concentrations generated pharmacokinetic parameters
that were the same as our starting parameters. We obtained different
parameter estimates when CB values were increased
1000-fold to 42 ng/mL. Yet the predicted clearance of GH remained
within 10% of the true clearance even at these relatively high
CB values. Although not shown, varying the initial
estimates had little effect on the final estimates of Vc,
1, z, or k21, suggesting that
our model is capable of accurately capturing the pharmacokinetic
parameters of GH after the administration of rhGH, and that these
parameters are stable. Varying initial estimates of CB,
amplitude, cycle, and/or tzero had little effect on derived
parameter of clearance or volume of distribution of GH.
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The pharmacokinetic and cosinor parameters are shown in
Table 3. Mean values for each subject’s
two doses are given because, except for clearance and
CB (see below), there were no differences in parameters
between doses 1 and 2. The ranges in GH pharmacokinetic parameters in
the 15 subjects were: clearance, 0.131–0.469 L/min; volume of
distribution, 1.4–3.9 L; and terminal half-lives, 6.87–24.4 min. The
ranges of the cosinor parameters were: basal concentration
(CB), 0.024–0.331 ng/mL; amplitude, 0.06–1.67; cycle
79–191 minutes; and time shift (acrophase), 13–116 min. There were no
significant differences in Vss, clearance, or half-lives by
gender or estrogen treatment group. In this group of subjects,
clearance, Vss, and elimination rate constants showed no
significant dependence upon weight, height, body mass index, or surface
area. The comparison of parameters for the two doses was assessed by
multiple regression analysis using dose amount and dose number as the
independent variables. These analyses revealed a decrease in clearance
(0.260 ± 0.9 vs. 0.214 ± 0.06 L/min;
P < 0.03) and an increase in CB
(0.200 ± 0.22 vs. 0.33 ± 0.33 ng/mL;
P < 0.05) during the second dose of rhGH. By multiple
regression analysis, the differences were due to the dose number
(i.e. dose 1 vs. dose 2) more than to dose
amount, suggesting that there may be a temporal intrasubject variance
in these parameters. In contrast, no differences (P >
0.05) between dose 1 and dose 2 were found for Vss
(3.73 ± 1.6 vs. 3.31 ± 1.41 L) or the
elimination rate constant, z (0.0661 ± 0.035
vs. 0.0603 ± 0.022 min-1).
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GHBP concentrations were higher in estrogen-treated subjects (1.29 ± 0.24 vs. 0.76 ± 0.14 nmol/L; P < 10-6). A tendency for increased Vss with increasing levels of GHBP was noted, but the relationship fell short of statistical significance (P = 0.06). There were no significant correlations between GHBP concentrations and clearances, plasma elimination rate constants, CB, amplitude, cycle, or tzero. With increasing concentrations of GHBP and when adjusted for dose, there were increases in GHmax (P < 0.037) and GH-AUC (P < 0.048).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Visual examination of serum GH concentration vs. time
profiles at times before and after the rhGH bolus dose revealed the
presence of endogenous, oscillating GH concentrations. Multiple,
contemporaneous components of GH input into the serum can confound the
estimates of GH pharmacokinetic parameters when using models allowing
for only single GH inputs. To obtain accurate estimates we formulated a
composite model that discriminates pulsatile, basal, and oscillatory GH
inputs and used it to fit the GH concentration-time profiles in our
subjects. The examples given in Table 1 and Figs. 2 and 3 indicate that
our model fit the observed serum GH concentration vs. time
data quite well. The correlation coefficients (r2) for the
fits ranged between 0.88–0.99. The models generated stable parameters
with acceptable precision and relatively narrow 95% confidence
intervals. The parameters were not interdependent. Despite increasing
basal concentrations by 100-fold, the model still accurately captured
the other model parameters, thus suggesting that our model is
stable.
A main goal was to develop a model that enabled us to obtain accurate estimates of the pharmacokinetics of GH from exogenous administration of rhGH. As we did not administer a labeled dose of rhGH, we cannot unequivocally determine the accuracy of the pharmacokinetic parameters estimated by our model. However, our model predictions are in excellent agreement with GH parameters published previously. GH clearances from the 30 individual GH boluses ranged from 0.131–0.469 L/min, with a mean overall value of 0.236 L/min, similar to that reported with radioisotopic and nonisotopic methods using bolus or continuous GH infusions (16, 25, 26, 27, 28, 29, 30). Likewise, the volumes of distribution (Vd) ranged between 1.4–3.9 L (mean, 3.46 ± 1.5 L) and were also in good agreement with published values. We therefore conclude that the use of our model can provide useful estimates of the pharmacokinetics of GH in the presence of basal, oscillating endogenous concentrations without administering a dose of radiolabeled GH.
Elimination half-lives in this study ranged between 6.7–25.1 min. The mean half-life was 12.3 ± 4.5 min. These values span those previously reported (8, 14, 27, 30, 31). The half-lives were model dependent. That is, GH half-lives calculated from the one-compartment model were shorter than those calculated from the terminal slope of the two-compartment model. Half-lives calculated from the elimination rate constant, K, for a one-compartment model are probably hybrids of the half-lives of distribution and elimination of the two-compartment model. This raises the question of whether and when to use one or two compartments when fitting serum GH concentration vs. time data. The importance of fitting the one- vs. the two-compartment model to fit serum GH concentration vs. time data depends upon the question asked. To accurately estimate the mass of GH secreted during a pulse or after the administration of a GH secretagogue, one has to know the clearance. Therefore, so long as clearance is accurately estimated, either model can be used.
Although early studies favored the idea that interpulse secretion rates of GH fall to zero (8), more recent studies have a basal, oscillatory secretion rate (9, 10, 11, 12). Thus, our model is consistent with recent studies regarding GH secretion in humans, as monitored during this short term study. The detection of endogenous GH release during the somatostatin infusion and after the administration of rhGH was unexpected and raises several important questions. Is the basal, oscillatory pattern of GH secretion a consequence of administering insufficient doses of somatostatin? Does somatostatin preferentially suppress the secretion of episodic pulses of GH secretion, but suppress to a lesser degree the basal, oscillating pattern? We favor the latter explanation because of earlier studies using somatostatin infusions (32) and because we found no evidence of clearly pulsatile secretion of GH in any of our subjects during the duration of the study. However, the mean periodicity of 121 min approximates that of endogenous GH pulsatility, about 90 min (8), thus allowing the speculation that these oscillations represent dampened GH pulse frequency and amplitude due to somatostatin infusion and/or GH autonegative feedback (33). What are the origin and regulation of this basal, oscillating pattern of GH secretion, and is it physiologically relevant? What neural pathways might subserve this secretion? Finally, what patterns of GH secretion continue in patients receiving GH replacement? These questions may be addressed using the present composite pharmacokinetic model.
We assessed the effects of GHBP on the GH concentration responses to rhGH bolus infusions. The peak serum GH concentration was also found to be directly related to the GHBP concentration. This finding is in general agreement with our previous studies with cortisol (1, 2). Similarly, plasma GH responses to computer-modeled secretory events are also GHBP concentration dependent (34). The dissociation constants indicate that at physiological concentrations the majority of cortisol (35, 36) and GH (37, 38) is bound to their respective binding proteins. The mechanism(s) by which binding proteins may affect the disposition of secreted hormone remains unclear. The half-life of bolus-injected cortisol is directly related to the corticosteroid-binding globulin (CBG) concentration (2). CBG, therefore, increases the mean plasma residence time of cortisol. We find no relationship here between the half-life of GH and the GHBP concentration. Rather, a weak and not quite statistically significant (P = 0.06) increase in the steady state GH volume of distribution was noted with increasing GHBP concentrations. GHBP is the proteolytically cleaved extracellular domain of the GH receptor (39), whereas CBG is not known to reflect any portion of the glucocorticoid receptor or uptake pathway. We postulate that GHBP is a marker of GH receptor activity in the liver and other tissues. Accordingly, high plasma GHBP concentrations probably reflect greater GH receptor availability in various target/uptake tissues, with consequently greater uptake and immediate removal of GH from the blood space. This apparent loss of GH from plasma by receptor uptake, as correlated to and reflected by high GHBP levels, would tend to expand the apparent Vss and thereby produce a positive correlation between apparent GH Vss after injection and GHBP. In contrast, higher amounts of CBG simply increase the amount of cortisol retained in the plasma space and decrease the apparent distribution space for cortisol. In the rat, coinjection of GH and GHBP decreases the apparent distribution volume for GH, at least in experiments in which GH was prebound to GHBP and was thereby less able to distribute to those GH receptors and/or other uptake tissues available at the time (40, 41).
The present study was conducted in healthy young adults. The results suggest that the relationships between secreted GH and serum GH profiles are dissimilar among subjects, and that the dissimilarities are most likely due to variances in GH clearance and distribution volumes. The relationship between secreted GH mass and serum GH concentration is best elucidated with a pharmacokinetic model capable of discerning pulsatile, basal and oscillatory inputs and by the use of subject-specific pharmacokinetic parameters. If further evaluation were also to suggest a diurnal, or other, variability in GH clearance, then subject- and time-specific parameters would be required as well. Further investigation is required to understand how basal and oscillatory GH parameters may change with time, GH pulses, age, various levels of GH sufficiency, and hepatic or renal disorders; in subjects with the everwidening spectrum of GH insensitivity syndromes (42); or with the use of hormonal or other medicinal therapies.
The presence of basal, oscillating, and pulsatile GH inputs and the wide range of intra- and intersubject variance in GH pharmacokinetic parameters negate the assumption of a uniform relationship between GH secretion and serum GH concentration and detracts from the utility of a GH concentration cut-off point in GH testing. These findings have implications for the valid appraisal of GH deficiency states, selection of rhGH treatment candidates, and physiological regulation of the GH axis.
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Footnotes |
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Received October 14, 1998.
Revised April 9, 1999.
Accepted May 21, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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