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Original Article |
Department of Internal Medicine (J.D.V., S.M.A., W.S.E.), Division of Endocrinology, General Clinical Research Center, Center for Biochemical Technology, University of Virginia School of Medicine, Charlottesville, Virginia 22908-2020; and Medizinische Klinik (M.B., Z.W., C.J.S.), Klinikum der Ludwig-Maximilians Universität-Innenstadt, Ziemssenstrasse 1, 80336 Muenchen, Germany
Address all correspondence and requests for reprints to: J. D. Veldhuis, M.D., Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Mayo Medical and Graduate School of Medicine, 200 First Street SW, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.
Abstract
Organs that respond to and metabolize GH are enriched in cognate high-affinity receptors. However, whether isologous receptors mediate the de facto access of ligand to cellular degradative pathways is not known. To address this query, we assessed the distribution and whole-body elimination kinetics of (endogenous and exogenous) GH before and after administration of a novel, potent, and selective recombinant human (rh) GH receptor antagonist peptide, pegvisomant. Sixteen healthy young adults (nine men and seven women) participated in a double-blind, prospectively randomized, within-subject cross-over study. The intervention comprised a single sc injection of placebo vs. a high dose of pegvisomant (1 mg/kg sc) timed 62 and 74 h before the overnight sampling and daytime infusion sessions, respectively. The half-life, metabolic clearance rate (MCR), and distribution volume of GH were quantitated by way of: 1) deconvolution analysis of serum GH concentration time series collected every 10 min for 10 h; 2) exponential regression analysis of the decay of GH concentrations after a 6-min iv pulse of rhGH (1 and 10 µg/kg); 3) calculation of the MCR during constant iv infusion of rhGH (0.5 and 5.0 µg/kg every 2 h); and 4) exponential fitting of the elimination time-course of GH concentrations following cessation of each constant infusion. Concentrations of GH and pegvisomant were measured in separate, noncross-reactive, two-site monoclonal, immunofluorometric assays. Pegvisomant concentrations averaged 4860 ± 480 µg/liter (±SEM) across the infusion interval, thus exceeding low steady state GH concentrations by 3000-fold. Inhibitory efficacy of the GH receptor antagonist peptide was affirmed by way of a 34% reduction in the serum total IGF-I concentration, i.e., from 257 ± 37 (placebo) to 170 ± 24 (drug) µg/liter (P < 0.001); and a reciprocal 77% elevation of the (10-h) mean GH concentration, i.e., from 1.3 ± 0.23 (placebo) to 2.3 ± 0.42 (drug) µg/liter (P = 0.003). ANOVA disclosed that prior administration of pegvisomant (compared with placebo) did not alter: 1) the calculated half-life (minutes) of secreted GH, which averaged 15 ± 1.3 (placebo) and 14 ± 0.69 (drug); 2) the half-time of disappearance (minutes) of an iv pulse of rhGH, 15 ± 1.0 (placebo) and 13 ± 0.5 (drug) (for the 10 µg/kg dose); 3) the distribution volume (milliliters per kilogram) of rhGH, 59 ± 6.2 (placebo) and 58 ± 3.5 (drug); 4) the steady state GH concentration (micrograms per liter) attained during constant iv infusion of rhGH (at a rate of 5 µg/kg every 2 h), 18.2 ± 2.4 (placebo) and 18.3 ± 2.3 (drug); 5) the half-life (minutes) of elimination of GH from equilibrium, 16 ± 0.98 (placebo) and 16 ± 1.8 (drug); and 6) the steady state MCR (liters per kilogram per day) of rhGH, 3.8 ± 0.32 (placebo) and 3.5 ± 0.31 (drug). In ensemble, the present data refute the a priori postulate that vascular-accessible GH receptors determine the in vivo pseudoequilibrium kinetics of GH disappearance in the human.
POLYPEPTIDE HORMONES, such as GH, supervise cellular growth and differentiation by activating ligand-specific, high-affinity transmembrane receptors (1, 2). Nuclear magnetic resonance spectroscopy and x-ray crystallography indicate that one molecule of GH engages two membrane-associated receptors (3, 4, 5). The sequential binding and dimerization reactions require high-affinity epitopes in core helices of the GH protein (6). A conformationally unique trimeric complex initiates intracellular signaling events that culminate in altered gene expression (5, 7, 8). Occupied receptors undergo internalization, dissociation from ligand, and recycling to the cell membrane (8). In the human, tissue metalloproteinases generate a soluble, high-affinity GH-binding protein (GHBP) as a proteolytic fragment of the extracellular domain of the parent receptor (9). GHBP binds GH and certain GH analogs with high affinity (10), thereby either limiting or enhancing the tissue actions of this agonist.
The liver and kidneys metabolize a substantial fraction of GH (11, 12, 13, 14, 15, 16, 17, 18). Both organs maintain an abundance of high-affinity GH receptors, which mediate adsorptive endocytosis and direct GH to lysosomal degradation (19, 20). In this light, a recent clinical study postulated that reduced metabolic clearance of GH in patients with type I diabetes mellitus is due to impaired GH receptor function (21). However, available data neither document nor refute a role for GH receptors in the whole-body elimination of GH (22). For example, the only analysis of the half-life of endogenous GH in (three) patients with profound loss-of-function mutations of the GH receptor was limited technically by a 30-min sampling interval (23).
Advances in genetic engineering have allowed the construction of recombinant peptidyl analogs of GH, which attach to the GH receptor and disable ligand-specific intracellular signaling (7, 8). One biosynthetic GH receptor antagonist protein, pegvisomant (B2036-PEG), contains eight amino acid substitutions in the primary binding motif and a single mutation in a critical receptor-dimerization site (glycine 
valine 120) (7, 10, 24). Administration of this potent (oligopegylated) drug lowers IGF-I concentrations significantly in healthy adults and normalizes IGF-I production in more than 95% of patients with acromegalic disease (25, 26, 27, 28, 29). Innovative agents in this class offer important therapeutic and investigational probes of metabolic and neuroendocrine processes mediated by the GH receptor or systemic IGF-I availability (27, 30, 31, 32). The present study uses pegvisomant to test the hypothesis that GH receptors mediate the whole-body clearance of GH.
Materials and Methods
Clinical protocol
Seven women (mean age, 25 yr; range, 19–32 yr) and nine men (mean age, 26 yr; range, 18–44 yr) participated after providing written, informed, and voluntary consent approved by the Human Investigation Committee and General Clinical Research Center (GCRC) Advisory Committee of the University of Virginia. The Food and Drug Administration authorized an investigator-initiated new drug application for this study. Subjects were recruited from the local community and reimbursed for participation. Blood sampling and infusion sessions were conducted 2–6 d after the onset of menses in separate months in women and 4–6 wk apart in men. A negative pregnancy test was verified immediately before drug or saline injection. Volunteers were of normal weight, i.e., median body mass index 25 kg/m2 (range, 22–29) in men and 24 kg/m2 (range, 20–29) in women. Each subject had unremarkable screening biochemical tests of endocrine, metabolic, hepatic, renal, and hematological function. A subset of subjects participated in an earlier analysis of the effect of pegvisomant on the pulsatile mode of GH secretion (30).
The study design comprised a prospectively randomized, placebo-controlled, double-blind, within-subject cross-over intervention. Volunteers received an injection of the investigational GH receptor antagonist drug pegvisomant (1 mg/kg sc) and placebo (saline) as outpatients at 0800 h.
Subjects were admitted to the GCRC in the evening 2.5 d after the outpatient injection. Cannulae were inserted into contralateral forearm veins to allow concurrent blood sampling and infusion procedures. Volunteers received a standardized meal at 1800 h [8 kcal/kg in women and 10 kcal/kg in men (55% carbohydrate, 15% fat, and 30% protein)] and then remained fasting overnight. Blood samples (0.75 ml) were withdrawn every 10 min for 10 h beginning at 2200 h; the latter onset time is 62 h after drug/placebo injection. Serum GH concentration time series were used for deconvolution analysis (below).
The next morning at 0800 h (72 h after the outpatient injection), octreotide (100 µg) was infused continuously sc over 1 h. This dose was repeated at 5-h intervals to suppress GH secretion (15, 18). Blood was sampled (0.75 ml) every 5 min beginning at 0800 h for a total of 18 h (until 0200 h) to monitor suppression of endogenous GH (0800–1000 h) and the subsequent elimination kinetics of exogenous (rh) GH (1000–0200 h). Four consecutive iv infusion protocols were carried out beginning at 1000 h, 2 h after initiating the octreotide infusion (and 74 h after administering pegvisomant or saline), 1400 h, 1800 h, and 2200 h. The four randomly ordered study paradigms comprised an iv pulse (6-min square-wave injection) of 1 and 10 µg/kg rhGH (i/ii) and a constant iv infusion of 0.5 and 5.0 µg/kg rhGH delivered by Harvard infusion pump over 120 min (iii/iv). Continuous infusions were preceded by a 6-min iv bolus loading dose of rhGH (equivalent in amount to the subsequent constant infusion dose).
Volunteers were provided standardized meals (above) at 0800, 1200, and 1700 h and remained in the GCRC overnight. Breakfast was provided in the morning before discharge.
Kinetic analyses
Five complementary kinetic analyses were used. First, deconvolution analysis was applied to quantitate pulsatile (and basal) GH secretion and the endogenous GH half-life based on the (10-h) overnight serum GH concentration profile (33, 34). Second, nonequilibrium kinetics of GH elimination was determined by monoexponential regression analysis following the bolus iv injection of rhGH over 6 min (15, 18). The distribution volume (milliliters per kilogram) was calculated as 1000-fold the quotient of the injected dose of rhGH (micrograms per kilogram) and the peak serum GH concentration (micrograms per liter). Third, the equilibrium metabolic clearance rate (MCR) (liters per kilogram per day) of GH was computed using the mean serum GH concentration measured over the last 30 min of each continuous infusion, based on the algebraic relationship: MCR = infusion rate/mean concentration (35). Presumptive equilibrium was defined by a nonsignificant slope of the linear regression of GH concentrations on time across the last 30 min. Fourth, the half-life of elimination of GH following cessation of each constant infusion was determined by monitoring the decay of serum GH concentrations from equilibrium. And fifth, the equilibrium GH half-life during the constant infusion was calculated from the algebraic relationship: half-life = (ln 2) (volume of distribution)/MCR.
Statistical analysis
Statistical assessments among groups were made by repeated-measures ANOVA applied to the logarithms of kinetic measures. The post hoc Tukey’s procedure was applied to contrast means. Statistical power exceeded 90% (ß error less than 0.10) for detecting a 30% interventional (drug) effect among groups assuming P = 0.05.
Linear regression analysis was applied to examine the relationship between GH half-life and the peak (after bolus injection) or mean (overnight and constant infusion) GH concentration.
Nonlinear (exponential) regression analysis was used to relate the MCR to the corresponding GH concentration observed at apparent steady state (35, 36). Data are presented as the mean ± SEM.
Hormone assays
GH concentrations were quantitated in duplicate by a two-site immunofluorometric assay, which does not cross-react with pegvisomant peptide at drug concentrations as high as 50,000 µg/liter. The assay standard was 22 kDa rhGH. Samples from a given volunteer were analyzed in one run to obviate interassay variance. Intra- and interassay coefficients of variation ranged from 4.2–6.5% and 6.2–8.7%, respectively.
IGF-I concentrations were quantitated in sera collected at 0800 h on the morning of infusion by RIA after acid-ethanol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA). The intra- and interassay coefficients of variation were 8.8% and 10.3%.
Immunofluorometric assay of pegvisomant
Pegvisomant concentrations were determined by a new two-site immunofluorometric assay. The capture and indicator monoclonal antibodies (mAbs) (10A7 and 6F1) were raised against rhGH and selected for cross-reactivity with the mutated protein (25–50% less than with GH). Because of 1,000- to 10,000-fold higher concentrations of injected antagonist than GH and 100-fold predilution of all samples, any interference by GH is negligible. Microtiter plates were coated with mAb 10A7 (0.5 µg/well) by overnight incubation. Pegvisomant standards and diluted sera were added (50 µl/well) and incubated for 3 h at room temperature. Indicator antibody (biotinylated mAb 6F1, 0.05 µg/well) was added for 12 h after washing, followed by further incubation with Europium-labeled streptavidin for 15 min. After a final washing step, enhancement solution was applied for 10 min, and fluorescence emission intensity was quantitated by time-resolved fluorometry (Wallac, Inc., Turku, Finland). Within-assay variability averaged 6.2% and 7.4% at a pegvisomant concentration of 1000 µg/liter and 4000 µg/liter, respectively. Between-assay variability at the same concentrations was 7.2% and 8.1%, respectively. This assay reads approximately 40% lower than that of Endocrine Sciences, Inc. Laboratory (Calabasa Hills, CA).
Pegvisomant concentrations were determined in each subject on serum samples collected at 62, 74, and 86 h after drug injection. The foregoing times reflect the onset of overnight blood sampling and the first and last infusions session, respectively.
Results
No subjects experienced clinically significant adverse events following the injection of saline, rhGH, pegvisomant, and/or octreotide. Two volunteers reported a transient stinging sensation at the site of sc pegvisomant injection, and four noted nausea and abdominal cramps after sc octreotide administration. One individual received pegvisomant inadvertently by iv infusion over 1 h without sequelae and was restudied 4 wk later according to the indicated protocol (above).
Pegvisomant concentrations (micrograms per liter) averaged 4310 ± 460 (at 62 h), 4580 ± 470 (at 74 h), and 4860 ± 480 (at 86 h) after drug injection (P = NS for a test of time trend by ANOVA). The foregoing values are approximately 3000-fold higher than the mean serum GH concentration measured during the constant infusion of a low dose of rhGH (below).
Pegvisomant-induced blockade of GH receptor function was affirmed by a 34% decline in the fasting serum total IGF-I concentration, i.e., 257 ± 37 (placebo) vs. 170 ± 24 (pegvisomant) µg/liter (P < 0.001). Concomitantly, the mean (10-h overnight) GH concentration rose by 77%, i.e., 1.3 ± 0.23 (placebo) vs. 2.3 ± 0.42 (drug) µg/liter (P = 0.003). Figure 1
illustrates the reciprocal relationship between changes in mean (10-h) serum IGF-I and GH concentrations. The youngest (19 yr old) woman studied had the highest serum IGF-I concentration, which was in the normal late-pubertal range (37).
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). The half-life of secreted GH averaged 15 ± 1.3 min (placebo) and 14 ± 0.69 min (pegvisomant). Values did not differ by drug intervention or by gender (Table 1).
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). The volume of distribution (milliliters per kilogram) of GH was 3-fold, independent of rhGH dose, prior drug intervention and gender (Table 1). Figure 3 presents individual GH half-lives following each bolus injection of rhGH in relation to the peak GH concentration attained concomitantly. Data are identified further by rhGH dose, drug intervention, and gender. Linear regression analysis revealed that GH half-life was not affected by the peak GH concentration attained after the bolus.
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). The relationship is depicted by an inverse curvilinear (exponential) regression of calculated MCR on observed steady state GH concentration in the group of 16 subjects (Fig. 4). In particular, the MCR decreased toward a finite (asymptotic) minimum as the GH concentration increased. Statistical comparisons showed that prior pegvisomant administration and gender did not influence this relationship (tabulated data deleted at reviewer’s request).
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) (group data). Figure 5 presents individual GH half-lives in relation to the starting (steady state) serum GH concentration. There was no linear relationship between the latter two variables.
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reports group mean values and Fig. 6 individual data. Values are represented by type of intervention, rhGH infusion rate, and gender. In a subset comparison in women, administration of pegvisomant, compared with placebo, reduced the equilibrium half-life of rhGH infused at the low rate by 45% (P = 0.022) (Fig. 7).
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The present clinical investigation demonstrates that administration of a potent, selective, and long-acting GH receptor antagonist peptide does not alter the elimination kinetics of endogenously secreted or exogenously infused rhGH in healthy young adults. This conclusion is strengthened by documentation of a 3000-fold higher serum concentration of the GH receptor inhibitory drug than of infused rhGH; reciprocal suppression of IGF-I concentrations and unleashing of GH secretion; highly specific (nondrug-reactive), double-monoclonal immunofluorometric assay of GH; analytical corroboration by 5-fold independent kinetic models; and, adequate statistical power (>90%) to detect a 30% change in GH half-life.
The accompanying experiments indicate that access of systemic GH to degradative pathways does not depend on a rate-limiting gatekeeping function of GH receptors. One possible exception is the pegvisomant-induced reduction in the equilibrium GH half-life inferred during the constant low-dose iv infusion of rhGH in women. The latter finding predicted a 1.45-fold more rapid exit of GH from the circulation in the presence of the mutated GH analog. The precise basis for this (paradoxical) effect is unknown. However, the unpegylated recombinant GH analog can compete with 22 kDa GH for binding to recombinant GHBP in vitro (10). Assuming that the majority of injected pegvisomant molecules contain several polyethylene-glycol adducts and that only small amounts of unpegylated peptide are generated in vivo by metabolism, then any competition between drug and native hormone would be more readily detectable at low circulating GH concentrations. Putative in vivo displacement of rhGH by depeglylated peptide would elevate free GH concentrations, and thereby (on analytical grounds) accelerate the availability of GH to tissue elimination processes (17, 23). Why this postulated scenario was not detectable in men is not clear.
The current analyses indicate that the MCR of continuously infused rhGH decreases asymptotically with rising serum GH concentrations (Fig. 4). On the other hand, we found that the plasma half-life of GH does not differ significantly across the same range of systemic GH concentrations (Table 1). Constancy of the plasma half-life but not the MCR could denote that the rate of exit of GH from the circulation is already maximal at the lowest serum GH concentration studied here (
1.5 µg/liter). The mechanisms that control egress of GH from plasma are not known but evidently do not involve pegvisomant-inhibitable steps. In counterpoint, the whole-body MCR of GH is concentration dependent and apparently saturable at high physiological GH concentrations. Saturability signifies the emergence of (unknown) rate-limiting process(es). According to the present data, the maximal rate of (whole-body) metabolism of GH is governed by reactions operating outside plasma and by inference is independent of the GH receptor. Importantly, at true steady state, the MCR is determined jointly by the half-life and distribution volume (17, 35). Therefore, based on the accompanying data, we postulated that the prominent concentration dependence of the MCR of GH implies time-delayed and rate-limiting uptake and irreversible loss of GH in extravascular sites (e.g. hepatic reticulothelial and renal tubular cells) and/or time evolution (rather than true steady state) of the calculated GH distribution volume over the course of a 2-h iv infusion. The first notion could account for the fact that the particular mode (duration and/or amount) of acute iv delivery of GH impacts kinetic estimates (18). The second inference would explain the continuing rise in serum GH concentrations during a 4-h iv infusion of this protein (37).
The postulate that molecules of secreted or infused GH gain access to extravascular disposal sites slowly would be consistent with independent experiments showing that insulin, LH, leptin, transferrin, and low-density lipoprotein each achieve equilibrium in lymphatic, interstitial, intraocular, and/or cerebrospinal fluid only after significant time delays (38, 39, 40, 41). Tissue hormone accumulation is important because cerebrospinal fluid concentrations of GH increase in a dose-dependent fashion in hyposomatotropic adults sampled at the end of 1 yr of replacement therapy (42). Thus, more detailed clinical investigations will be required to delineate the rate of de facto transfer of GH into the brain as well as other pivotal target organs.
As an indirect estimate of intravascular and total-body (sum of intra- and extravascular) GH distributional spaces, we extrapolated the set of 16 MCRs to infinite and zero serum GH concentrations (Fig. 4). This analysis forecast (asymptotically approximated) intravascular and total-body GH distribution volumes of 32 ± 4.3 ml/kg and 345 ± 15 ml/kg, respectively. The former GH distribution volume mirrors the plasma space (30 ml/kg), whereas the latter exceeds the sum of the vascular (70 ml/kg) and interstitial (210 ml/kg) spaces by 65 ml/kg (43). Inasmuch as incomplete equilibration after short-term infusion of GH (above) would force underestimation of the total-body distribution volume, any unaccounted for space probably exceeds 65 ml/kg. Available data cannot rule out some estimation artifact because of partial retention of immunoreactive GH fragments in the circulation. However, a more plausible interpretation is that GH accumulates within cells. Indeed, the intracellular space is several-fold larger than the unexplained deficit. Although cellular uptake of GH would seem to require the homonymous receptor, pegvisomant treatment did not alter estimates of either the intravascular or whole-body distribution of GH.
The curvilinear relationship between the MCR and GH concentration allowed an analogous limit-based approximation of the half-life of plasma free (GHBP-unbound) and dissociably bound GH. To this end, we assumed an equilibrium relationship MCR = (ln 2/half-life) x (distribution volume), an observed (pseudoequilibrium) GH distribution volume of 69 ± 8 ml/kg, and an exponentially extrapolated maximal and minimal MCR of 21 ± 3.5 and 2.0 ± 0.4 liters/kg per day, respectively. The foregoing analytical approach predicted a lower-bound half-life of free GH of 2.0 ± 0.33 min. This minimum (floor) value is consistent with an earlier analytical inference that free GH half-lives range from 2 to 5 min (23). The same extrapolation strategy forecast an upper-bound half-life of dissociably bound GH of 21 ± 4.1 min. This maximum (ceiling) value approximates the half-time of in vitro dissociation of GH from the GH-GHBP complex (23). By way of comparison, the directly determined half-life of total GH averaged 15 min (range, 12–17 min) across the four study paradigms (Table 1). Notably, a 3000-fold excess of GH receptor antagonist over rhGH in plasma did not increase the extrapolated half-life of either free or dissociably bound GH. Indeed, pegvisomant shortened the half-life of total GH monitored at low GH concentrations. The foregoing data are consistent with the analytical prediction that relative partitioning of GH between apparently free and dissociably bound fractions in plasma influences GH elimination kinetics.
In summary, the accompanying analyses indicate that activity of the GH receptor is not a primary determinant of the intra- and extravascular distribution or the elimination of GH in healthy adults. However, GH distributes slowly into remote tissues. Whether comparable inferences apply to other protein hormones is not yet known.
Acknowledgments
We thank Elizabeth Lovestrand, Olivia Veldhuis, Adrienne Gauthier, Margaret Kidd, and Kandace Bradford for assisting in the preparation of the manuscript; Paula P. Azimi for assisting in deconvolution analysis, data management, and graphics; Sandra Jackson and the nursing staff at the University of Virginia GCRC for conducting the research protocols; and Dr. Robert Davis at Sensus Drug Development Corp. (Austin, TX) for donating pegvisomant used under investigator-initiated Food and Drug Administration Investigative New Drug.
Footnotes
This work was supported in part by NIH Grants MO1-RR00847 to the GCRC and RO1-AG14799-05 and AG19695-01 (to J.D.V.).
Abbreviations: GHBP, GH-binding protein; mAb, monoclonal antibody; MCR, metabolic clearance rate; rh, recombinant human.
Received November 28, 2001.
Accepted September 2, 2002.
References
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, Men; •, women. The highest IGF-I concentration occurred in a 19-yr-old woman. Data are the mean ± SEM (n = 16; 7 women and 9 men). P values reflect paired statistical contrasts (see Materials and Methods).
, women.
