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Mammalian Cell-Derived Somatropin

A Review of its Use in the Management of HIV-Associated Wasting

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Summary

Abstract

HIV-associated wasting, characterised by progressive loss of lean body mass and bodyweight, remains a significant problem in the era of highly active antiretroviral therapy (HAART). Loss of body cell mass, a component of lean body mass, is associated with decreased survival. Somatropin (recombinant human growth hormone) derived from mammalian cells (Serostim®) is the only US FDA-approved treatment indicated to increase lean body mass, bodyweight and physical endurance in HIV-associated wasting.

Somatropin 0.1 mg/kg/day administered subcutaneously for 12 weeks effectively increased work output, bodyweight and lean body mass and improved health-related quality of life (HR-QOL), compared with placebo, and had a generally manageable tolerability profile in a large randomised study in patients with HIV-associated wasting. Potential areas for further research include determination of longer-term efficacy and tolerability, the cost effectiveness of treatment, the optimal somatropin dosage, management of patients after 12 weeks’ therapy and whether maintenance strategies might exist to maintain accrued lean body mass with lower doses of somatropin. Nevertheless, indications to date are that somatropin is likely to have an important role in the treatment of patients with HIV-associated wasting.

Pharmacological Profile

Recombinant mammalian cell-derived somatropin is structurally identical to human pituitary growth hormone and has anticatabolic (protein-sparing) and anabolic (protein-building) properties in patients with HIV-associated wasting receiving supraphysiological doses; somatropin increases lean body mass and bodyweight and decreases body fat (primarily from the trunk rather than the peripheral limbs).

Somatropin has demonstrated stimulatory effects on HIV replication in vitro, but not when antiretroviral agents are added to the culture medium or in clinical trials of somatropin with concurrent antiretroviral therapy. Additionally, somatropin may have some immunostimulatory and haematopoietic growth factor properties.

Pharmacokinetic data on the subcutaneous administration of somatropin in patients with HIV-associated wasting are limited. Absorption is slow and ratelimiting and peak plasma concentration is dose-dependent. The bioavailability of somatropin is ≈70–90% and volume of distribution is 10L.

Somatropin is largely metabolised in the kidney from where amino acids and peptides are returned to the systemic circulation. The elimination half-life was 4.28 hours and renal clearance was 0.0015–0.0018 L/h in patients receiving somatropin 6 mg/day.

Therapeutic Efficacy

The efficacy of subcutaneous somatropin 0.1 mg/kg/day (about 6 mg/day) for 12 weeks in patients with HIV-associated wasting has been demonstrated in placebo-controlled trials. Previous indications of efficacy before the era of highly active antiretroviral therapy (HAART) were confirmed in a large study in which most patients received HAART.

In this study, somatropin 0.1 mg/kg/day was superior to placebo in improving cycle ergometry work output, bodyweight and lean body mass. The same dose administered on alternate days was superior to placebo for increases in bodyweight, lean body mass and work output.

HR-QOL was significantly improved in the placebo-controlled HAART era trial (assessed using the Bristol-Myers Anorexia/Cachexia Recovery Instrument; BACRI) but not in another fully published placebo-controlled trial (using various measures of overall health status adapted from the Medical Outcomes Study) from the pre-HAART era. BACRI results indicated a significant improvement in composite score and all subscores with somatropin 0.1 mg/kg daily or on alternate days compared with placebo.

Tolerability

Somatropin had generally manageable and predictable adverse effects in patients with HIV-associated wasting in clinical trials, with grade 3 or 4 events occurring in 8%, 14% and 34% of the placebo, somatropin alternate-day and daily groups, respectively, in the largest trial. In this trial, the incidences of arthralgia, myalgia, oedema, arthrosis and gynaecomastia were significantly greater with full-dose somatropin than with placebo. Arthralgia, myalgia, oedema, carpal tunnel syndrome, hyperglycaemia and hypertriglyceridaemia were the most common reasons for dosage reductions and/or drug discontinuation. Abnormal fasting glucose levels occurred early in treatment at a similar frequency in both somatropin groups but often had returned to normal range by week 12.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Adis International Limited, Auckland, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    David R. Goldsmith & Antona J. Wagstaff

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Correspondence to David R. Goldsmith.

Additional information

Various sections of the manuscript reviewed by: E.S. Daar, Division of HIV Medicine, David Geffen School of Medicine at UCLA, Torrance, California, USA; H. Jaeger, MUC Research, Munich, Germany; J-C. Melchior, Department of Infectious and Tropical Diseases, Hôpital Raymond Poincaré, Paris, France; N.I. Paton, Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore; B. Polsky, Division of Infectious Diseases, St. Luke’s-Roosevelt Hospital Center, New York, New York, USA; C.R. Steinhart, Mercy Hospital, Miami, Florida, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on somatropin, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘somatropin’ or ‘growth hormone’ and ‘HIV’ or ‘human immunodeficiency’ or ‘AIDS’ or ‘acquired immunodeficiency syndrome’. Searches were last updated 1 February 2006.

Selection: Studies in patients with HIV-associated wasting who received somatropin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Somatropin, HIV-associated wasting, pharmacodynamics, pharmacokinetics, therapeutic use.

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Goldsmith, D.R., Wagstaff, A.J. Mammalian Cell-Derived Somatropin. Drugs 66, 387–401 (2006). https://doi.org/10.2165/00003495-200666030-00014

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