Pharmacokinetics and pharmacodynamics of GH: dependence on route and dosage of administration

Keller, Alexandra; Wu, Zida; Kratzsch, Juergen; Keller, E; Blum, Werner; Kniess, Astrid; Preiss, R; Teichert, Jens; Strasburger, Christian J.; Bidlingmaier, Martin

doi:10.1530/eje-07-0057

Cited by 51 publications

(29 citation statements)

References 31 publications

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“…A similar result was found recently after subcutaneous administration of recombinant human growth hormone. [24] The lack of involvement of bodyweight and sex in the IIV of population pharmacokinetic parameters of this model supports the use of fixed dosing and confirms the appropriateness of the deep subcutaneous route of administration for both sexes.…”

Section: Discussionsupporting

confidence: 57%

Population Pharmacokinetic Analysis of Lanreotide Autogel® in Healthy Subjects

Trocóniz¹,

Cendros²,

Peraire³

et al. 2009

Clinical Pharmacokinetics

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Abstractneuroendocrine tumours. The objective of this study was to develop a pharmacokinetic model for the sustainedrelease formulation lanreotide Autogel ® after deep subcutaneous administration in healthy subjects, and to explore the potential effect of covariates, especially sex and dose. Subjects and methods:This was an open-label, single-centre, randomized, dose-ranging, parallel-group study, with a follow-up period of 4-7 months following drug administration in healthy subjects. Healthy Caucasian subjects aged 18-45 years were included. Subjects received a rapid intravenous bolus of 7 µg/kg of an immediate-release formulation of lanreotide (lanreotide IRF). After a 3-day washout period, participants were randomized to receive a single deep subcutaneous injection of lanreotide Autogel ® at a dose of 60, 90 or 120 mg. Pharmacokinetic and statistical analysis: Blood samples for lanreotide determination were obtained during the first 12 hours after the intravenous bolus injection and during the 4-to 7-month follow-up period after deep subcutaneous administration of lanreotide Autogel ® . Data after intravenous and subcutaneous administration were fitted simultaneously using the population approach in NONMEM ® version VI software. The model was validated externally using data from patients with acromegaly. Results: In total, 50 healthy subjects (24 women and 26 men) received a single intravenous dose of lanreotide IRF. Of these, 38 subjects (18 women and 20 men) received a single subcutaneous dose of lanreotide Autogel ® 3 days after intravenous lanreotide IRF. The disposition of lanreotide was described by a three-compartment open model. The estimates of the total volume of distribution and serum clearance were 15.1 L and 23.1 L/h, respectively. The estimates of interindividual variability were <40%. To evaluate lanreotide Autogel ® pharmacokinetics, the absorption rate was modelled to decrease exponentially as a function of the natural logarithm of time. The absolute bioavailability after deep subcutaneous administration of lanreotide Autogel ® was 63%. The rate of absorption and bioavailability of lanreotide Autogel ® were independent of the administered dose in the range from 60 to 120 mg, and no significant effect of covariates (sex, dose, age or bodyweight) was found (p > 0.05). Conclusions: Population analysis allows a full description of the disposition of lanreotide after rapid intravenous bolus administration of lanreotide IRF (7 µg/kg) and the pharmacokinetics of lanreotide Autogel ® after a single deep subcutaneous injection (60, 90 or 120 mg) in healthy subjects. The model-based simulations provide support for the feasibility of extending the dosing interval for lanreotide Autogel ® to 56 days when given at 120 mg. The absorption profile of lanreotide Autogel ® was independent of the dose and was not affected by sex. Backgroundmeters, the design included a rapid intravenous bolus injection of an immediate-release formulation of lanreotide (lanreotide IRF).

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Section: Discussionsupporting

confidence: 57%

Population Pharmacokinetic Analysis of Lanreotide Autogel® in Healthy Subjects

Trocóniz¹,

Cendros²,

Peraire³

et al. 2009

Clinical Pharmacokinetics

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“…The sensitivity of the IGF1, IGFBP3, and NEFA parameters has its limitations to detect differences. Although NEFA serum levels show a significant rise after GH administration, the changes in IGF1 and IGFBP3 serum levels brought about by rhGH at the dose tested are relatively low compared with baseline concentrations (26). The increase in serum levels of IGF1 stayed within the upper normal range, and did not accumulate to reach acromegalic values after the single-dose rhGH administration (27).…”

Section: Pharmacodynamicsmentioning

confidence: 86%

“…Therefore, it is difficult to assess whether rhGH treatment might also contribute to these complaints in this setting as described earlier (26,28). Nevertheless, adverse events were similar regarding the number, type, and intensity in all treatment groups.…”

Section: Side Effectsmentioning

confidence: 87%

Bioequivalence between novel ready-to-use liquid formulations of the recombinant human GH Omnitrope and the original lyophilized formulations for reconstitution of Omnitrope and Genotropin

Fuhr

Tuculanu

Berghout

et al. 2010

European Journal of Endocrinology

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Objective: Two strengths of a novel ready-to-use liquid preparation of the recombinant human GH (rhGH) Omnitrope were developed to increase the convenience for the patients. Design: Omnitrope 3.3 mg/ml solution or Omnitrope 6.7 mg/ml solution was compared to Omnitrope 5 mg/ml powder and Genotropin 5 mg/ml powder in terms of pharmacokinetics, pharmacodynamics, safety, and local tolerance after a single s.c. dose of 5 mg. Methods: Two randomized, double-blind, single-dose, three-way crossover studies were carried out in 36 young healthy volunteers each. Endogenous GH secretion was suppressed with a 25-h continuous i.v. infusion of octreotide (40 mg/h) starting 1 h before rhGH administration. Results: Pharmacokinetic parameters were similar for the three treatments in both studies respectively. Bioequivalence criteria were met for area under the concentration-time curve (AUC) and C max . Likewise, the pharmacodynamic parameters for IGF1, IGF-binding protein 3, and non-esterified fatty acid were similar for all preparations. No differences in adverse events were observed between groups. Conclusions: Omnitrope 3.3 mg/ml solution, 6.7 mg/ml solution, and 5 mg/ml powder, and Genotropin 5 mg/ml powder are bioequivalent, have similar pharmacokinetic and pharmacodynamic profiles, and are equally safe. Overall, the products can be considered to be therapeutically interchangeable.

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“…The 20-kDa hGH isoform cross-reacts with all capture mAbs but does not interfere in any of the 4 sandwich assays, because the epitope recognized by the labeled antibody AK569 includes amino acids missing in the 20-kDa isoform. This has implications for future developments of other methods to detect hGH dopingbecause injection of rhGH leads to suppression of the 20-kDa hGH isoform (24,32 ), immunoassays specifically measuring 20-kDa hGH could be used as an independent measure to confirm rhGH administration.…”

Section: Discussionmentioning

confidence: 99%

“…We analyzed additional leftover serum samples from a study in recreational athletes (10 men, 10 women) receiving single injections of rhGH at different doses (moderate dose, 0.033 mg/kg; high dose, 0.083 mg/kg). Details of the protocol and participants of this study have been published (24 ). In 24 samples from this study, hGH concentrations in the pitA and/or pitB assay were below the functional sensitivity.…”

Section: Subjects and Samplesmentioning

confidence: 99%