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

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.

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 (C_max) and time to achieve C_max for GH and IGF-I. Thereafter, weekly serum concentrations were measured and compared with baseline. C_max 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.

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

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

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