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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 7 3234-3240
Copyright © 2004 by The Endocrine Society

Pharmacokinetic and Pharmacodynamic Characteristics of a Long-Acting Growth Hormone (GH) Preparation (Nutropin Depot) in GH-Deficient Children

S. F. Kemp, P. J. Fielder, K. M. Attie, S. L. Blethen, E. O. Reiter, K. M. Ford, M. Marian, L. N. Dao, H. J. Lee and P. Saenger

Arkansas Children’s Hospital, University of Arkansas for Medical Sciences (S.F.K.), Little Rock, Arkansas 72202; Genentech, Inc. (P.J.F., K.M.A., S.L.B., M.M., L.N.D.), South San Francisco, California 94080; Alkermes, Inc. (K.M.F., H.J.L.), Cambridge, Massachusetts 02139; Baystate Medical Center Children’s Hospital, Tufts University School of Medicine (E.O.R.), Springfield, Massachusetts 01199; and Montefiore Medical Center (P.S.), Bronx, New York 10461

Address all correspondence and requests for reprints to: Stephen F. Kemp, M.D., Ph.D., University of Arkansas for Medical Sciences at Arkansas Children’s Hospital, 800 Marshall Street, Springer Building, Arkansas Children’s Hospital, Little Rock, Arkansas 72202. E-mail: KempStephenF{at}uams.edu.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Long-term GH replacement therapy is indicated for children with growth failure due to GH deficiency (GHD). We evaluated the feasibility of administering a long-acting GH preparation [Nutropin Depot (somatropin, rDNA origin) for injectable suspension] to prepubertal children with GHD by examining pharmacokinetic and pharmacodynamic response parameters after single or multiple doses. Data were collected from three studies involving 138 children treated with Nutropin Depot 0.75 mg/kg once per month, 0.75 mg/kg twice per month, or 1.5 mg/kg once per month. Twenty-two patients underwent intensive sampling to estimate mean peak serum GH concentrations (Cmax) and time to achieve Cmax for GH and IGF-I. Thereafter, weekly serum concentrations were measured and compared with baseline. Cmax and area under the curve were approximately proportional to the dose administered. Fractional area under the curve data indicate that at least 50% of GH exposure occurs during the first 2 d after administration. Serum GH levels remained above 1 µg/liter for 11–14 d. IGF-I levels remained above baseline for 16–20 d, but increases were not proportional to dose. After multiple doses over a 6-month period, peak and trough concentrations showed no progressive accumulation of GH, IGF-I, or IGF binding protein-3. Nutropin Depot administration once or twice per month provides serum levels of GH and IGF-I expected to promote growth, without accumulation of GH, IGF-I, or IGF binding protein-3, in children with GHD.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
SINCE THE INTRODUCTION of recombinant human GH (rhGH) in 1985, thousands of children with growth failure due to GH deficiency (GHD) have achieved positive height outcomes with GH replacement therapy. Despite the proven efficacy and safety of daily injections, this regimen has been burdensome for some patients and their families. In one study, 50% of pediatric patients failed to comply with all aspects of a prescribed GH treatment plan (1). The perceived complexity of the regimen, including the time required for drug preparation and administration, may be a factor influencing patient acceptance (2). A simplified dosing schedule may improve patient and caregiver acceptance and, ultimately, improve compliance and growth outcomes in problem patients. To this end, a prolonged-release formulation of GH [somatropin (rDNA origin) for injectable suspension, Nutropin Depot] has been developed to be administered by sc injection either once or twice per month.

Early studies of GH disposition indicate that pharmacokinetic (PK) parameters of pituitary-derived and biosynthetic forms of GH are similar (3, 4). In a study of children (n = 6) receiving im injections of pituitary-derived GH, Frasier et al. (5) reported mean plasma concentration-vs.-time data that suggested an apparent delay in absorption, with time to maximum concentration (Tmax) of approximately 3 h. More recently, Kearns et al. (6) reported a similarly slow absorption of GH after single and multiple sc doses of recombinant methionyl GH (somatrem for injection, Protropin) in children with GHD (mean Tmax, 4.4 h). Peak GH concentrations and area under the curve (AUC) estimations were proportional to the dose administered; however, AUC values decreased significantly with repeated daily dosing. Increases in total plasma clearance and apparent volume of distribution also were observed after the administration of multiple methionyl GH doses.

Nutropin Depot is a long-acting formulation of somatropin using the ProLease (Alkermes, Inc., Cambridge, MA) depot drug delivery system. This system is comprised of micronized particles of zinc-stabilized rhGH embedded in biocompatible, biodegradable microspheres made of poly D/L lactide coglycolide copolymer. Bioactive rhGH is released from the microspheres initially by diffusion, followed by both diffusion and polymer degradation. Ultimately, the poly D/L lactide coglycolide copolymer undergoes hydrolysis to form lactic acid and glycolic acid, which are either cleared by the kidney or further degraded, primarily to carbon dioxide and water (7).

Recently, Cook et al. (8) evaluated the PK and pharmacodynamic (PD) responses after administration of single doses of Nutropin Depot in adult men and women with GHD. However, to date, there have been no published studies examining these parameters in children with GHD. In this paper, we present PK data describing the absorption and exposure characteristics of Nutropin Depot administered once or twice per month in prepubertal patients with GHD. In addition, we examine the PD responses to Nutropin Depot administration, as determined by alterations in IGF-I, IGF binding protein-3 (IGFBP-3), and GH binding protein (GHBP) serum concentrations.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Written informed consent from a parent or legal guardian was required for all study participants. The clinical diagnosis of GHD was determined by each investigator using criteria defined by expert consensus (9), with the recognition that there is variation in clinical practice in diagnosing GHD (10). There were no specific auxological criteria for inclusion; it was required that each patient be prepubertal (Tanner stage 1), have had GHD documented (at each investigator’s site) by peak GH concentrations less than 10 µg/liter in response to two pharmacological tests of GH secretory capacity (insulin-induced hypoglycemia, arginine, clonidine, or levodopa), and have a bone age of 9 yr or less (girls) or 10 yr or less (boys). For patients who had not previously received GH (naive patients), a height at least 2 SD values below the mean for age- and sex-matched controls was required. Children with multiple hormonal deficiencies had to be stabilized on levothyroxine and/or hydrocortisone for at least 6 months before enrollment. Patients previously treated with GH were required to have been on continuous GH therapy (at an average dose of 0.25–0.35 mg/kg·wk, administered six to seven times per week) for at least 1 yr before entering the study. A 7-d washout period was established for these patients.

Patients were excluded from study entry if they had growth failure related to causes other than GHD; had diabetes mellitus; received anabolic agents; or currently were being treated with methylphenidate or cyproheptadine. In addition, hypothalamic-pituitary tumors diagnosed or treated within the previous year, known bleeding disorders, or known allergy or sensitivity to any component of the ProLease rhGH formulation were exclusions to study participation.

PK data were collected as part of three clinical trials evaluating Nutropin Depot in pediatric patients (Table 1Go): a phase I/II PK/PD multiple-dose study (study 1), a phase III multiple-dose trial (study 2), and an extension of studies 1 and 2 (study 3). All three clinical trials were conducted in the United States. Sixty-four children with GHD (38 previously treated and 26 naive to GH therapy) were enrolled in study 1, a 12-center, open-label study. Fifty-two of these patients (29 previously treated and 23 naive) completed this 6-month study. An additional 74 naive patients with GHD were enrolled in study 2, a 27-center, open-label study (11). Sixty-nine patients completed this 6-month study. Patients in both studies who completed 6 months of treatment were offered the option of continuing therapy in an open-ended extension study (data not shown).


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  		TABLE 1. Summary of PK-PD studies in GHD children

 
Study treatment

Nutropin Depot is designed to be administered by sc administration once or twice per month. The diluent used to suspend the microspheres is an isotonic aqueous solution of carboxymethylcellulose sodium salt, polysorbate 20, sodium chloride, and water for injection (12). After reconstitution, Nutropin Depot was administered sc into the arm, abdomen, thigh, or buttock, using a 21-gauge (1/2-in.) needle.

The doses for study 1 were determined by evaluating the GH, IGF-I, and safety responses to an initial dose of 0.75 mg/kg once per month (for two treatments) given to previously treated (n = 6) and naive (n = 6) children. This dose represents approximately 60% of the total daily dose of rhGH given over a 30-d period. Subsequently, the dosing regimens were expanded, and patients were randomly assigned to receive either 0.75 mg/kg once per month, 0.75 mg/kg twice per month, or 1.5 mg/kg once per month. In study 2, patients were randomized to receive either 0.75 mg/kg twice per month or 1.5 mg/kg once per month. These dosage regimens were continued during participation in the extension study (study 3).

Study assessments

All patients underwent a history and physical examination (which included height and weight determinations, Tanner staging, and inspection of the injection site) at baseline and once per month for the first 6 months.

In study 1, PK and PD investigations were undertaken in all 52 patients completing the first 6 months of study. Mean serum concentrations of GH, as well as biological markers of GH activity (IGF-I, GHBP, and IGFBP-3) were determined at baseline and on d 1, 7, 14, 15 (predose for 0.75 mg/kg twice per month), 21, and 28 (predose for once per month dosing) during each treatment cycle. A subset of 22 patients, receiving either 0.75 or 1.5 mg/kg once per month, was selected for intensive sampling of GH and IGF-I serum concentrations. These patients stayed in the clinical research unit for 48 h, where serum samples were collected every 6 h. Subsequently, samples for the determination of serum GH and IGF-I concentrations were collected twice weekly for one treatment cycle from naive patients and for two treatment cycles from previously treated patients. GHBP and IGFBP-3 concentrations were determined at baseline, 24 h, and weekly thereafter. Serum concentrations of GH, IGF-I, GHBP, and IGFBP-3 were obtained during the initial release (0–2 d) and prolonged-release (2–14 or 2–28 d) phases. During study 2, trough serum concentrations of GH, IGF-I, and IGFBP-3 were measured in 74 naive children with GHD, at baseline and at 3 and 6 months after treatment with Nutropin Depot 0.75 mg/kg twice per month or 1.5 mg/kg once per month. Similarly, trough levels of GH and IGF-I were determined every 3 months in 95 patients treated in the extension study (study 3).

Bioanalytical methods

Quantitation of serum GH, IGF-I, IGFBP-3, and GHBP concentrations. In all studies, assays for serum GH, IGF-I, GHBP, and IGFBP-3 concentrations were performed at Esoterix, Inc. (Calabasas Hills, CA). Serum GH concentrations were determined using an immunochemiluminometric method. This double monoclonal antibody-based sandwich assay measures only 22-kDa GH, exhibiting no cross-reactivity with other GH forms. This assay has a 0.05 µg/liter limit of detection, and linearity was established in the 0.05–50 µg/liter concentration range. Interassay and intraassay coefficients of variation were 11 and 5.7%, respectively, at 7.8 µg/liter. This assay is not calibrated to a World Health Organization (WHO) International Standard for rhGH, although it does recover WHO IS 80/505, which is pituitary-derived at approximately 100%. Serum concentrations of total IGF-I were measured using an IGF-I by Extraction RIA kit from Nichols Institute Diagnostics (San Juan Capistrano, CA; cat. no. 40-2100). The assay standards were calibrated to the WHO International Reference Reagent for IGF-I immunoassays (87/518). This assay has a range of 0.3–4.8 µg/liter and interassay and intraassay coefficients of variation of 5.2 and 2.4%, respectively, at 0.53 µg/liter. IGFBP-3 concentrations were measured using the RIA method developed by Esoterix, Inc., with a range of 0.188–12 mg/liter, a limit of quantitation of 0.43 mg/liter, and interassay and intraassay coefficients of variation of 7.8 and 5.1%, respectively, at 2.7 mg/liter. Serum concentrations of total GHBP were determined using a monoclonal antibody-based immunoprecipitation assay with a range of 125-5000 pmol/liter and interassay and intraassay coefficients of 12% (at 972 pmol/liter) and 9% (at 991 pmol/liter), respectively.

PK and statistical analysis

PK parameters for GH and IGF-I were estimated using standard noncompartmental analyses. In patients undergoing intensive sampling, these included the observed maximum concentration (Cmax), the observed Tmax, area under the serum concentration-time curve from 0 to 28 d (AUC0–28 d), and fractional AUCs for d 0–2, 2–7, 7–14, and 14–28. All AUCs were calculated using the linear trapezoidal method. Baseline values for all assayed samples were defined as the value at the fasting time point before the first dose was administered. For GH analysis, none of the parameters were corrected for baseline values. Cmax and AUC calculations for IGF-I were performed using both baseline-corrected and uncorrected values.

The number of days that GH concentrations were above 1 µg/liter and the number of days that IGF-I levels were above baseline were defined by the first of two consecutive time points in which concentrations were lower than the designated values. In addition, the median time for return to baseline levels was calculated for GH, IGF-I, and IGFBP-3.

In study 2, a paired t test was used to evaluate the change in GH, IGF-I, and IGFBP-3 from baseline to month 3, baseline to month 6, and month 3 to month 6 within each dose group. Statistical significance was determined when P < 0.05. This analysis was based on subjects with measurements at all three time points.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Demographic and baseline data for 138 study patients from studies 1 and 2 are summarized in Table 2Go. All four groups were similar in age, sex, and baseline growth parameters. Thirty-eight patients in study 1 have been previously treated with daily GH therapy, for an average of 2.9 yr (range, 0.9–6.3 yr). All patients in study 2 were naive to GH therapy. Data for two subjects were excluded from the mean data analysis for the intensively sampled group. These two subjects had GH concentrations with several values that appeared markedly inconsistent with the rest of the data and were most likely anomalous.


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  		TABLE 2. Baseline characteristics1

 
PK parameters

Single-dose (intensive sampling) GH data (from study 1). Mean (±SD) GH serum concentration-vs.-time profiles after a single dose of Nutropin Depot (0.75 mg/kg or 1.5 mg/kg) for 20 children who underwent intensive sampling (study 1) are presented in Fig. 1Go. These profiles are characterized by an initial release phase, lasting approximately 48 h, followed by a prolonged-release phase. Serum GH profiles for the two dose groups were parallel over the first 2 wk and proportional to dose. These profiles were similar between previously treated and naive patients (data not shown). Mean (±SD) PK data for GH by dose and treatment history are summarized in Table 3Go. Values for Cmax, Tmax, and AUC0–28 d were similar in previously treated and naive patients at either dose level, except that Cmax was higher in previously treated patients receiving 1.5 mg/kg once per month (n = 2). Cmax and total GH exposure (AUC0–28 d) were approximately proportional to the dose administered. The percentage contribution of the exposure in the first 48 h to total GH AUC ranged from 50–70% and was not markedly different by dose or treatment history. Serum GH concentrations greater than 1 µg/liter persisted for approximately 11–14 d after the administration of either dose.



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  		FIG. 1. Mean (±SD) GH serum concentration-vs.-time profiles in naive and previously treated prepubertal children after a single dose of Nutropin Depot 0.75 mg/kg once per month (n = 12; filled squares) and 1.5 mg/kg once per month (n = 8; open squares). Data are from patients in the intensively sampled set from study 1.

 

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  		TABLE 3. PK summary for GH in intensively sampled subjects (from study 1)1

 
Single-dose (intensive sampling) IGF-I and IGFBP-3 (from study 1). Serum IGF-I concentration-vs.-time profiles for intensively sampled subjects who received Nutropin Depot (0.75 mg/kg or 1.5 mg/kg) are presented in Fig. 2Go. IGF-I concentrations were variable among individual patients and not proportional to dose. Mean IGF-I concentrations were higher in previously treated patients compared with those naive to GH therapy (data not shown). This larger IGF-I response could be due in part to the difference in baseline status between previously treated and naive patients and/or an increased capacity for IGF-I response related to previous GH treatment.



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  		FIG. 2. Mean (±SD) IGF-I serum concentration-vs.-time profiles in naive and previously treated prepubertal children after a single dose of Nutropin Depot 0.75 mg/kg (n = 12; filled squares) and 1.5 mg/kg (n = 8; open squares). Data are from patients in the intensively sampled set from study 1.

 
PK parameters for IGF-I, as determined by intensive sampling after Nutropin Depot administration, are presented in Table 4Go. Mean Cmax increased approximately 2- to 8-fold over baseline values, but was not proportional to the dose administered. IGF-I levels remained above baseline for an average of 16–20 d after dosing.


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  		TABLE 4. PD summary for IGF-I in intensively sampled subjects (from study 1)1

 
IGFBP-3 response after a single dose of Nutropin Depot is shown in Fig. 3Go. The response was similar between dose groups, demonstrating an increase in IGFBP-3 that was sustained for approximately 7 d and returned to baseline by 14 d after GH administration.



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  		FIG. 3. Mean (±SD) IGFBP-3 serum concentration-vs.-time profiles response in naive and previously treated prepubertal children after a single dose of Nutropin Depot 0.75 mg/kg (n = 5; filled squares) or 1.5 mg/kg (n = 8; open squares). Data are from patients in the intensively sampled set from study 1.

 
Multiple-dose GH data over 6 months (study 1). GH serum concentration-vs.-time data after multiple doses of Nutropin Depot administered over a 6-month period are shown in Fig. 4Go. GH serum concentrations were obtained on d 1 and were repeated weekly during the 6-month period. Mean GH concentrations for each dose group were similar among previously treated and naive patients, approximately dose proportional, and generally reproducible at each cycle. Serum GH profiles from d 0 to 14 after administration of 0.75 mg/kg twice per month were very similar to those observed with administration of 0.75 mg/kg once per month. At the end of month 6, GH serum concentrations had returned to near prestudy values in all three dose groups. There was no apparent trend in observed GH levels at 24 h post dose over the 6-month study period. In addition, the 24-h postdose GH levels were not generally different by rhGH treatment history or by cycle and were dose proportional within the dose levels tested. These results indicate that the initial-release phase for Nutropin Depot after repeated sc administration is reproducible in children with GHD and that GH disposition during the initial phase is not significantly affected by previous rhGH exposure or by repeated dosing over 6 months. Repeated administration of Nutropin Depot resulted in minimal accumulation of GH as measured by trough serum concentrations during this time period.



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  		FIG. 4. Mean (±SD) GH serum concentration-vs.-time profiles in naive and previously treated children after multiple doses of Nutropin Depot 0.75 mg/kg once per month (n = 13; filled squares), 1.5 mg/kg once per month (n = 19; open squares), or 0.75 mg/kg twice per month (n = 20; open triangles). Data are from patients in the nonintensively sampled set from study 1. During each dosing cycle, GH levels were determined before dose, 24 h after dose, and on d 7 and 14, as well as on d 21 and 28 in the once per month dose groups.

 
IGF-I and IGFBP-3 data over 6 months (study 1). Figure 5Go shows serum IGF-I concentrations over 6 months of treatment. In general, the increases were variable among subjects and not proportional to the GH dose administered. IGFBP-3 responses were consistent with IGF-I responses. GHBP levels either remained unchanged or declined during Nutropin Depot treatment (data not shown). Comparisons of IGF-I, IGFBP-3, and GHBP by treatment history indicated that 24-h serum levels were lower in the naive group than in previously treated patients, but differences were not statistically significant (data not shown). Observed near peak concentrations (24 h post dose) of all response variables were consistent over the six dosing cycles and returned to baseline values at the end of the study, indicating no progressive accumulation over 6 months of treatment.



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  		FIG. 5. Mean (±SD) IGF-I serum concentration-vs.-time profiles in naive and previously treated children after multiple doses of Nutropin Depot 0.75 mg/kg once per month (n = 13; filled squares), 1.5 mg/kg once per month (n = 19; open squares), or 0.75 mg/kg twice per month (n = 20; open triangles). Data are from patients in the nonintensively sampled set from study 1. During each dosing cycle, IGF-I levels were determined before dose, 24 h after dose, and on d 7 and 14, as well as on d 21 and 28 in the once per month dose groups.

 
Trough concentration data over 6 months (study 2). Mean (±SD) trough concentrations of GH, IGF-I, and IGFBP-3 were determined at baseline, 3 months, and 6 months in naive children receiving Nutropin Depot 0.75 mg/kg twice per month or 1.5 mg/kg once per month. These data are analyzed by dose group and are presented in Table 5Go. As expected, small but significant increases in mean concentrations of serum GH vs. baseline were observed at month 3 and month 6 (3.1 vs. 1.7 µg/liter at baseline; P < 0.05) in the 0.75-mg/kg twice per month dose group; however, mean GH trough serum concentrations were not different between dose groups at 3 or 6 months. Moreover, no additional increase in serum GH concentrations was observed between months 3 and 6 in either dose group, suggesting no progressive accumulation over time. Compared with baseline values, no significant changes in trough IGF-I concentrations were seen in the 1.5-mg/kg once per month group at either month 3 or month 6, although the month 6 value was slightly greater than that of month 3 (P < 0.05). In contrast, patients in the 0.75-mg/kg twice per month group demonstrated a mean trough IGF-I level that was significantly increased over baseline at month 3 (P < 0.05), but remained almost unchanged at month 6, indicating no progressive accumulation. IGFBP-3 trough concentrations at month 3 and month 6 were not significantly elevated over baseline in either dose group, suggesting a return to baseline concentrations between doses. Trough levels of IGFBP-3 and GHBP also remained constant.


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  		TABLE 5. Trough serum GH, IGF-I, and IGFBP-3 concentrations (from study 2)

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
A single sc dose of Nutropin Depot produced a rapid peak of serum GH followed by a slow decline in GH concentration over the remainder of the dosing interval. This initial release of rhGH is likely the result of dissociation of GH from the surface of the microsphere, whereas the prolonged-release phase represents the GH released as the microspheres disintegrate. Using data from the intensively sampled subjects, it was possible to calculate several PK parameters. Cmax values after Nutropin Depot injection (0.75 mg/kg) were similar to those reported after single doses (0.1 mg/kg) of a daily GH formulation, whereas peaks associated with 1.5 mg/kg doses were proportionately higher (6). Tmax ranged from 12–14 h, which is approximately three times longer than what has been reported after a single sc injection of methionyl-GH.

The elimination half-life of GH after sc or im injection has been reported to range between 2.7 and 5 h (5, 6, 13, 14), which suggests that most of the dose is eliminated by 24 h (4–8 half-lives) after administration. After a single injection of Nutropin Depot, serum GH levels remained above 1 µg/liter for 11–14 d. After day 14, GH concentrations were low, but variable. Given that many subjects had demonstrated some endogenous GH secretion and were therefore not completely GH-deficient, we suspect that this variability represents residual endogenous GH secretion in some subjects.

Both GH Cmax and AUC were approximately proportional to the dose of Nutropin Depot administered. The Cmax after the lower dose (0.75 mg/kg once per month) was just slightly more than twice that reported for daily methionyl-GH administered at 0.3 mg/kg·wk (6). In general, it appears that 50–70% of the GH exposure (AUC) occurs over the first 2 d. However, the total GH exposure associated with either dose of Nutropin Depot is estimated to be less than the calculated exposure to daily GH injections, when administered daily at a dosage of 0.3 mg/kg·wk (6). PK modeling estimates that the relative bioavailability of Nutropin Depot is approximately 50% that of daily rhGH. This is likely due to a loss of GH at the injection site, resulting in a lower overall bioavailability. As has been reported previously (11), no progressive increases in either peak or trough levels of GH were observed, indicating that there was no accumulation of GH with continued Nutropin Depot therapy.

Increases in serum concentrations of both IGF-I and IGFBP-3 were observed during Nutropin Depot treatment. Mean IGF-I levels increased approximately 2- to 8-fold over baseline values and remained above baseline for 16–20 d. The observed increases were highly variable among individuals and not proportional to the dose administered. The higher peak IGF-I levels observed in the 0.75 mg/kg once per month group may be related to higher baseline levels compared with the 1.5 mg/kg once per month group (Fig. 2Go). Although the exact reasons for these higher baseline levels are unclear, it is possible that because more of these patients were previously treated with GH, the 7-d washout period was inadequate for a return to pretreatment levels. In addition, patients undergoing intensive study for PK assessment may not have been completely GH deficient. IGF-I levels generally peaked between 1.5 and 3.5 d after Nutropin Depot administration. Because IGF-I levels returned to baseline between doses, the total IGF-I AUC at either dose is likely lower than that achieved with daily GH (Fig. 5Go).

In the phase III study by Reiter et al. (11) examining the effects of the same doses of Nutropin Depot in previously untreated pediatric patients, similar changes in trough levels of GH and IGF-I were observed. Among patients receiving doses of 1.5 mg/kg once per month, GH and IGF-I remained relatively unchanged from baseline during the 6-month study period. In contrast, those receiving doses of 0.75 mg/kg twice per month exhibited significant (but not progressive) rises in both GH and IGF-I levels. These increases did not translate into different growth outcomes between dose groups, however. In a study by Cook et al. (8), the PK and PD characteristics of Nutropin Depot were evaluated in adults with GHD. In this study, patients received single doses of 0.25 or 0.5 mg/kg. Baseline GH and IGF-I levels were considered low, but as in our study, variable. In contrast to results observed in children, GH and IGF-I responses were both gender- and dose-dependent and confirmed that adults have distinct tolerance levels and dosing requirements to achieve safe and effective GH replacement.

In summary, the administration of Nutropin Depot either once or twice per month provides serum levels of GH sufficient to increase growth rates and allow catch-up growth in children with GHD (11, 15). Administration of this preparation results in increased levels of IGF-I and IGFBP-3, with peak levels similar to those achieved with daily GH injections. With continued administration, no accumulation of GH, IGF-I, or IGFBP-3 was observed. From a PK perspective, Nutropin Depot offers clinicians a viable alternative to daily GH injections in children with GHD.


   Acknowledgments
 
The study investigators were Thomas P. Foley, Jr., M.D. (Children’s Hospital of Pittsburgh, Pittsburgh, PA); Mitchell E. Geffner, M.D. (University of California, Los Angeles, Los Angeles, CA); Stephen F. Kemp, M.D., Ph.D. (Arkansas Children’s Hospital, Little Rock, AR); Margaret H. MacGillivray, M.D. (Children’s Hospital of Buffalo, Buffalo, NY); Wayne V. Moore, M.D., Ph.D. (Children’s Mercy Hospital, Kansas City, MO); Thomas Moshang, Jr., M.D. (Children’s Hospital of Philadelphia, Philadelphia, PA); Leslie P. Plotnick, M.D. (Johns Hopkins Hospital, Baltimore, MD); Edward O. Reiter, M.D. (Children’s Hospital-Baystate Medical Center, Springfield, MA); Alan D. Rogol, M.D., Ph.D. (University of Virginia Health Sciences Center, Charlottesville, VA); Paul Saenger, M.D. (Montefiore Medical Center, Bronx, NY); Bernard L. Silverman, M.D. (Children’s Memorial Hospital, Chicago, IL); and David T. Wyatt, M.D. (Children’s Hospital of Wisconsin, Milwaukee, WI).


   Footnotes
 
Genentech, Inc., provided financial support for editorial assistance on this paper.

Abbreviations: AUC, Area under the curve; Cmax, maximum concentration; GHBP, GH binding protein; GHD, GH deficiency; IGFBP-3, IGF binding protein 3; PD, pharmacodynamic; PK, pharmacokinetic; rhGH, recombinant human GH; Tmax, time to achieve Cmax.

Received May 12, 2003.

Accepted March 31, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Smith SL, Hindmarsh PC, Brook CGD 1993 Compliance with growth hormone treatment—are they getting it? Arch Dis Child 68:91–93[Abstract/Free Full Text]
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  4. Wilton P, Sietnieks A 1987 An open-labeled study of the safety, acute metabolic activity and pharmacokinetic profile of a short-term course of recombinant human growth hormone in healthy volunteers. Clin Endocrinol (Oxf) 26:125–128[Medline]
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