madmoe
Donating Member
Peak GH Serum times post injection
Bros, I have been getting a lot of PMs about GH Peak times and WHY 3-4 HOURS POST INJECTION FOR TESTING. HERE IT IS:
--------------------
http://www.biomedcentral.com/1472-6904/7/10
Research article
Pharmacokinetics of recombinant human growth hormone administered by cool.click™ 2, a new needle-free device, compared with subcutaneous administration using a conventional syringe and needle
Chris Brearley1, Anthony Priestley2, James Leighton-Scott2 and Michel Christen3*
* Corresponding author: Michel Christen michel.christen@merckserono.net
Author Affiliations
1 Clinical Research, Serono International SA, 1211 Geneva, Swizerland
2 LCG Bioscience, Bourn Hall, Bourn, Cambridge CB3 7TR, UK
3 Patients Care Technologies Center of Expertise, Merck Serono International SA, 1211 Geneva, Switzerland
For all author emails, please log on.
BMC Clinical Pharmacology 2007, 7:10 doi:10.1186/1472-6904-7-10
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1472-6904/7/10
Received: 8 December 2006
Accepted: 8 October 2007
Published: 8 October 2007
© 2007 Brearley et al.; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
Growth hormone (GH) is used to treat growth hormone deficiency (GHD, adult and paediatric), short bowel syndrome in patients on a specialized diet, HIV-associated wasting and, in children, growth failure due to a number of disorders including Turner's syndrome and chronic renal failure, and in children born small for gestational age. Different brands and generic forms of recombinant human growth hormone (r-hGH) are approved for varying indications in different countries. New ways of administering GH are required because the use of a needle and syringe or a device where a patient still has to insert the needle manually into the skin on a daily basis can lead to low adherence and sub-optimal treatment outcomes. The objective of this study was to assess the relative bioavailability of r-hGH (Saizen®, Merck Serono) administered by a new needle-free device, cool.click™ 2, and a standard needle and syringe.
Methods
The study was performed with 38 healthy volunteers who underwent pituitary somatotrope cell down-regulation using somatostatin, according to a randomized, two-period, two-sequence crossover design. Following subcutaneous administration of r-hGH using cool.click™ 2 or needle and syringe, pharmacokinetic parameters were analysed by non-compartmental methods. Bioequivalence was assessed based on log-transformed AUC and Cmax values.
Results
The 90% confidence intervals for test/reference mean ratio of the plasma pharmacokinetic variables Cmax and AUC0-inf were 103.7–118.3 and 97.1–110.0, respectively, which is within the accepted bioequivalence range of 80–125%. r-hGH administered by cool.click™ 2 is, therefore, bioequivalent to administration by needle and syringe with respect to the rate and extent of GH exposure. Treatment using cool.click™ 2 was found to be well tolerated. With cool.click™ 2 the tmax was less (3.0 hours) than for needle and syringe delivery (4.5 hours), p = 0.002 (Friedman test), although this is unlikely to have any clinical implications.
Conclusion
These results demonstrate that cool.click™ 2 delivers subcutaneous r-hGH exposure that is bioequivalent to the conventional mode of injection. The new device has the additional advantage of being needle-free, and should help to increase patient adherence and achieve good therapeutic outcomes from r-hGH treatment.
Background
Growth hormone deficiency (GHD) affects both children and adults, and clinical manifestations vary depending on the age of onset [1]. Children present with short stature and low growth rate [2], while adults have altered body composition and metabolism with reduced physical performance [3]. At all ages, quality of life is impaired [4,5].
For many years, replacement therapy using exogenous human growth hormone (GH) has been used successfully to treat children with GHD [6], and has more recently benefited adult patients with GHD [7]. GH is now produced using recombinant DNA technology [8], and is also used to treat growth failure due to a number of other disorders including Turner's syndrome [9-11] and chronic renal failure [12], and in children born small for gestational age [13].
Conventional GH therapy for GHD was originally developed as a daily subcutaneous injection using a standard needle and syringe. However, many patients (a large proportion of who are children and adolescents) find that using needles is painful and this provokes fear of the injection procedure, resulting in potential non-adherence and sub-optimal therapy. Efforts have focused on finding alternative means of administering GH to patients. Delivery devices such as pre-filled syringes, manual injector pens, auto-injectors, injectors with hidden needles and needle-free devices have been introduced in an attempt to improve dosing accuracy and flexibility, ease-of-use, convenience, adherence and patient-friendliness [14-19]. However, the majority of injections still require manual insertion of the needle into the skin by the patient.
Needle-free devices have been introduced for GH therapy, having already been used for some time to administer insulin to patients with diabetes mellitus [20] although, in the latter case, local reactions may have limited more widespread acceptance. These devices expel the liquid preparation of the hormone through a small disposable nozzle at high pressure so that it is forced through the skin and dispersed in the subcutaneous region. This mode of administration is as effective as a conventional injection [21,22], but has the added advantage of reduced adverse psychological effects [23].
In response to feedback regarding a wish for simplification of dose selection and improvement of the ergonomics of the present device, the next-generation cool.click™ 2 needle-free injection device for administration of r-hGH has now been developed by Merck Serono (an affiliate of Merck KGaA, Darmstadt, Germany). The new device is similar to the current version of cool.click™, with the additional benefit that it allows dosing in milligrams. The original cool.click™ device allowed dosing only by volume, which meant clinicians had to convert from mass (milligrams r-hGH prescribed) to volume (millilitres of solution to be injected), a procedure that could be further complicated by the fact that different volumes of solvent could be used during reconstitution of the Saizen® powder for injection. In addition, the reading of the cool.click™ linear analogue dosing scale could be difficult – a vertical scale had to be aligned with a horizontal scale to set the required injection volume. In cool.click™ 2, this analogue scale has been replaced by a digital LCD dose readout. Lastly, compared with the original device, cool.click™ 2 is quieter in operation and has a modified design for ease of use and to facilitate handling by children (with smaller hands).
The main objective of this study (Study No. 25821) was to demonstrate that r-hGH administration using the cool.click™ 2 needle-free delivery device was bioequivalent to injection with a standard syringe and needle, the reference standard mode of injection.
Methods
Subjects
Healthy male volunteers with pituitary somatotrope cell down-regulation were screened for eligibility, for recruitment into the study. To be eligible for inclusion, subjects were required to fulfil the following criteria: age 21–50 years; have a body weight greater than 60 kg and a body mass index (BMI) in the range of 22–30 kg/m2; have vital signs in the normal range; and must have agreed to use barrier contraception during the study and for 3 months following completion of the post-study visit. A subject was not entered into the study if he had evidence of any surgical or medical condition that might have interfered with the pharmacokinetics of the investigational medicinal product or if he had received any investigational drug in the 12 weeks prior to dosing.
Study design
The study was designed as a phase I, randomized, open-label, two-period, two-sequence crossover study. Treatment started within 21 days of screening. Each study period lasted 3 days, with a washout period of at least 7 days between drug administrations. The subjects were randomly assigned to one of two treatment sequences. Subjects were allocated a randomization number in sequential, chronological order immediately prior to first dose administration, in accordance with the randomization list supplied by the sponsor (Serono).
The first treatment sequence received a 0.5 mL (2.92 mg) subcutaneous dose of r-hGH (Saizen®, Merck Serono) administered by standard needle and syringe (period 1) followed by administration of the same dose of rhGH using the cool.click™ 2 needle-free injection device (period 2). The second treatment sequence received 0.5 mL (2.92 mg) r-hGH administered by the cool.click™ 2 device (period 1) followed by administration of the same dose of r-hGH using a standard needle and syringe (period 2).
The protocol was approved by the local research ethics committee and conducted in accordance with the Declaration of Helsinki and good clinical practice. Subjects gave written informed consent to participate in the study.
Experimental procedures
The subjects remained in the clinical unit from 16 hours before dosing until 30 hours post-dose. To down-regulate endogenous GH sufficiently to enable accurate assessment of serum GH concentration-time profiles, somatostatin (3 mg) was given intravenously by continuous infusion for 25 hours (corresponding to a rate of approximately 1.75 μg/kg body weight/hour), commencing 1 hour prior to dosing with r-hGH to allow pituitary somatotrope cell down-regulation to be established.
Subcutaneous injections of GH were administered alternately to the left or right lower external abdominal wall with the subject in a relaxed sitting position. A different location on the external abdominal wall was used for the cool.click™ 2 needle-free injection device. The abdominal wall below the umbilicus was divided into two areas; one injection was to be administered in each area. The second injection had to be administered at least 10 cm from the first one. Each injection site was clearly circled with a permanent marker prior to dosing.
The 0.5 mL (2.92 mg) dose of r-hGH administered yielded serum hGH concentrations that remained above the limit of quantification of the hGH assay (Euro/DPC Ltd., UK; lower limit of quantification = 3.1 mIU/L) for a sufficient period to enable accurate assessment of the serum hGH concentration-time profile. Blood samples for determination of PK serum hGH concentrations were taken immediately prior to dosing and at 1, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 18 and 24 hours post-dosing in both treatment periods.
Data management and analysis methods
Serum concentrations of GH were analysed for each subject by non-compartmental methods using WinNonLin® Professional 4.1 (Pharsight, USA).
The following pharmacokinetic parameters were computed: area under the serum concentration-time curve from time zero to the last quantifiable concentration (AUC0-last); area under the serum concentration-time curve extrapolated to infinity (AUC0-inf); peak serum concentration (Cmax); time of peak serum concentration (tmax); and elimination half-life (t1/2).
The areas under the GH concentration-time curves were calculated according to the log-linear trapezoidal rule [26].
Bioequivalence was assessed according to EU Guideline CPMP/EWP/QWP/1401/98 and the FDA Code of Federal Regulations. Following logarithmic transformation, an analysis of variance (ANOVA, SAS®) was performed on GH metrics (Cmax, AUC0-last, AUC0-inf and tmax) of the full analysis population. There were no imputations for missing data. The ANOVA model consisted of the logarithmically transformed Cmax parameter as the response variable with factors for sequence, subject nested in sequence, period and mode of administration (treatment). Using an average bioequivalence approach, a 90% confidence interval (CI) for the true ratio test (needle-free device) to reference (needle injection) of the means of the two treatments was produced from this model and compared with the equivalence acceptance limits 80–125%.
Based on data from previous Serono r-hGH studies, when the sample size in each sequence group is 15 (and the total sample size is 30), a crossover design has a 90% power to demonstrate equivalence within the acceptance limits of 80–125%, assuming that the expected ratio of means was 1.000, the crossover ANOVA, MSE (ln scale) was 0.250 [the SD differences, σd (ln scale) were 0.354], that data were analysed in the natural log scale using t-tests for differences in means, and that each t-test was made at the 5% level. Taking into account a potential drop-out rate of approximately 20%, it was estimated that approximately 38 subjects were required to complete this study.
The pharmacokinetic analysis population consisted of all 38 subjects (100%) who were randomized into this study and who had evaluable pharmacokinetic data for both periods.
Results
Thirty-eight healthy male volunteers completed the study. Demographic and baseline characteristics for each subject (Table 1) were in compliance with specific inclusion and exclusion criteria. There were no major protocol deviations, no subjects dropped out and no subjects were withdrawn.
Table 1. Summary of baseline subject demographic data
The ANOVA model assumptions were met satisfactorily and there was no significant sequence effect (p = 0.980). The mean ± SD serum concentration vs time profiles for GH following administration of 2.92 mg of r-hGH by either the needle-free device, cool.click™ 2, or by needle injection were generally similar throughout the 25-hour blood-monitoring period (Figure 1). Geometric mean values for AUC0-inf, AUC0-last and t1/2 were similar between the two administration methods (Table 2). The maximum serum GH concentrations (Cmax) of 18–20 ng/mL were observed 3–4.5 hours (tmax) after drug administration (Table 2, Figure 1).
Bros, I have been getting a lot of PMs about GH Peak times and WHY 3-4 HOURS POST INJECTION FOR TESTING. HERE IT IS:
--------------------
http://www.biomedcentral.com/1472-6904/7/10
Research article
Pharmacokinetics of recombinant human growth hormone administered by cool.click™ 2, a new needle-free device, compared with subcutaneous administration using a conventional syringe and needle
Chris Brearley1, Anthony Priestley2, James Leighton-Scott2 and Michel Christen3*
* Corresponding author: Michel Christen michel.christen@merckserono.net
Author Affiliations
1 Clinical Research, Serono International SA, 1211 Geneva, Swizerland
2 LCG Bioscience, Bourn Hall, Bourn, Cambridge CB3 7TR, UK
3 Patients Care Technologies Center of Expertise, Merck Serono International SA, 1211 Geneva, Switzerland
For all author emails, please log on.
BMC Clinical Pharmacology 2007, 7:10 doi:10.1186/1472-6904-7-10
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1472-6904/7/10
Received: 8 December 2006
Accepted: 8 October 2007
Published: 8 October 2007
© 2007 Brearley et al.; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
Growth hormone (GH) is used to treat growth hormone deficiency (GHD, adult and paediatric), short bowel syndrome in patients on a specialized diet, HIV-associated wasting and, in children, growth failure due to a number of disorders including Turner's syndrome and chronic renal failure, and in children born small for gestational age. Different brands and generic forms of recombinant human growth hormone (r-hGH) are approved for varying indications in different countries. New ways of administering GH are required because the use of a needle and syringe or a device where a patient still has to insert the needle manually into the skin on a daily basis can lead to low adherence and sub-optimal treatment outcomes. The objective of this study was to assess the relative bioavailability of r-hGH (Saizen®, Merck Serono) administered by a new needle-free device, cool.click™ 2, and a standard needle and syringe.
Methods
The study was performed with 38 healthy volunteers who underwent pituitary somatotrope cell down-regulation using somatostatin, according to a randomized, two-period, two-sequence crossover design. Following subcutaneous administration of r-hGH using cool.click™ 2 or needle and syringe, pharmacokinetic parameters were analysed by non-compartmental methods. Bioequivalence was assessed based on log-transformed AUC and Cmax values.
Results
The 90% confidence intervals for test/reference mean ratio of the plasma pharmacokinetic variables Cmax and AUC0-inf were 103.7–118.3 and 97.1–110.0, respectively, which is within the accepted bioequivalence range of 80–125%. r-hGH administered by cool.click™ 2 is, therefore, bioequivalent to administration by needle and syringe with respect to the rate and extent of GH exposure. Treatment using cool.click™ 2 was found to be well tolerated. With cool.click™ 2 the tmax was less (3.0 hours) than for needle and syringe delivery (4.5 hours), p = 0.002 (Friedman test), although this is unlikely to have any clinical implications.
Conclusion
These results demonstrate that cool.click™ 2 delivers subcutaneous r-hGH exposure that is bioequivalent to the conventional mode of injection. The new device has the additional advantage of being needle-free, and should help to increase patient adherence and achieve good therapeutic outcomes from r-hGH treatment.
Background
Growth hormone deficiency (GHD) affects both children and adults, and clinical manifestations vary depending on the age of onset [1]. Children present with short stature and low growth rate [2], while adults have altered body composition and metabolism with reduced physical performance [3]. At all ages, quality of life is impaired [4,5].
For many years, replacement therapy using exogenous human growth hormone (GH) has been used successfully to treat children with GHD [6], and has more recently benefited adult patients with GHD [7]. GH is now produced using recombinant DNA technology [8], and is also used to treat growth failure due to a number of other disorders including Turner's syndrome [9-11] and chronic renal failure [12], and in children born small for gestational age [13].
Conventional GH therapy for GHD was originally developed as a daily subcutaneous injection using a standard needle and syringe. However, many patients (a large proportion of who are children and adolescents) find that using needles is painful and this provokes fear of the injection procedure, resulting in potential non-adherence and sub-optimal therapy. Efforts have focused on finding alternative means of administering GH to patients. Delivery devices such as pre-filled syringes, manual injector pens, auto-injectors, injectors with hidden needles and needle-free devices have been introduced in an attempt to improve dosing accuracy and flexibility, ease-of-use, convenience, adherence and patient-friendliness [14-19]. However, the majority of injections still require manual insertion of the needle into the skin by the patient.
Needle-free devices have been introduced for GH therapy, having already been used for some time to administer insulin to patients with diabetes mellitus [20] although, in the latter case, local reactions may have limited more widespread acceptance. These devices expel the liquid preparation of the hormone through a small disposable nozzle at high pressure so that it is forced through the skin and dispersed in the subcutaneous region. This mode of administration is as effective as a conventional injection [21,22], but has the added advantage of reduced adverse psychological effects [23].
In response to feedback regarding a wish for simplification of dose selection and improvement of the ergonomics of the present device, the next-generation cool.click™ 2 needle-free injection device for administration of r-hGH has now been developed by Merck Serono (an affiliate of Merck KGaA, Darmstadt, Germany). The new device is similar to the current version of cool.click™, with the additional benefit that it allows dosing in milligrams. The original cool.click™ device allowed dosing only by volume, which meant clinicians had to convert from mass (milligrams r-hGH prescribed) to volume (millilitres of solution to be injected), a procedure that could be further complicated by the fact that different volumes of solvent could be used during reconstitution of the Saizen® powder for injection. In addition, the reading of the cool.click™ linear analogue dosing scale could be difficult – a vertical scale had to be aligned with a horizontal scale to set the required injection volume. In cool.click™ 2, this analogue scale has been replaced by a digital LCD dose readout. Lastly, compared with the original device, cool.click™ 2 is quieter in operation and has a modified design for ease of use and to facilitate handling by children (with smaller hands).
The main objective of this study (Study No. 25821) was to demonstrate that r-hGH administration using the cool.click™ 2 needle-free delivery device was bioequivalent to injection with a standard syringe and needle, the reference standard mode of injection.
Methods
Subjects
Healthy male volunteers with pituitary somatotrope cell down-regulation were screened for eligibility, for recruitment into the study. To be eligible for inclusion, subjects were required to fulfil the following criteria: age 21–50 years; have a body weight greater than 60 kg and a body mass index (BMI) in the range of 22–30 kg/m2; have vital signs in the normal range; and must have agreed to use barrier contraception during the study and for 3 months following completion of the post-study visit. A subject was not entered into the study if he had evidence of any surgical or medical condition that might have interfered with the pharmacokinetics of the investigational medicinal product or if he had received any investigational drug in the 12 weeks prior to dosing.
Study design
The study was designed as a phase I, randomized, open-label, two-period, two-sequence crossover study. Treatment started within 21 days of screening. Each study period lasted 3 days, with a washout period of at least 7 days between drug administrations. The subjects were randomly assigned to one of two treatment sequences. Subjects were allocated a randomization number in sequential, chronological order immediately prior to first dose administration, in accordance with the randomization list supplied by the sponsor (Serono).
The first treatment sequence received a 0.5 mL (2.92 mg) subcutaneous dose of r-hGH (Saizen®, Merck Serono) administered by standard needle and syringe (period 1) followed by administration of the same dose of rhGH using the cool.click™ 2 needle-free injection device (period 2). The second treatment sequence received 0.5 mL (2.92 mg) r-hGH administered by the cool.click™ 2 device (period 1) followed by administration of the same dose of r-hGH using a standard needle and syringe (period 2).
The protocol was approved by the local research ethics committee and conducted in accordance with the Declaration of Helsinki and good clinical practice. Subjects gave written informed consent to participate in the study.
Experimental procedures
The subjects remained in the clinical unit from 16 hours before dosing until 30 hours post-dose. To down-regulate endogenous GH sufficiently to enable accurate assessment of serum GH concentration-time profiles, somatostatin (3 mg) was given intravenously by continuous infusion for 25 hours (corresponding to a rate of approximately 1.75 μg/kg body weight/hour), commencing 1 hour prior to dosing with r-hGH to allow pituitary somatotrope cell down-regulation to be established.
Subcutaneous injections of GH were administered alternately to the left or right lower external abdominal wall with the subject in a relaxed sitting position. A different location on the external abdominal wall was used for the cool.click™ 2 needle-free injection device. The abdominal wall below the umbilicus was divided into two areas; one injection was to be administered in each area. The second injection had to be administered at least 10 cm from the first one. Each injection site was clearly circled with a permanent marker prior to dosing.
The 0.5 mL (2.92 mg) dose of r-hGH administered yielded serum hGH concentrations that remained above the limit of quantification of the hGH assay (Euro/DPC Ltd., UK; lower limit of quantification = 3.1 mIU/L) for a sufficient period to enable accurate assessment of the serum hGH concentration-time profile. Blood samples for determination of PK serum hGH concentrations were taken immediately prior to dosing and at 1, 2, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 18 and 24 hours post-dosing in both treatment periods.
Data management and analysis methods
Serum concentrations of GH were analysed for each subject by non-compartmental methods using WinNonLin® Professional 4.1 (Pharsight, USA).
The following pharmacokinetic parameters were computed: area under the serum concentration-time curve from time zero to the last quantifiable concentration (AUC0-last); area under the serum concentration-time curve extrapolated to infinity (AUC0-inf); peak serum concentration (Cmax); time of peak serum concentration (tmax); and elimination half-life (t1/2).
The areas under the GH concentration-time curves were calculated according to the log-linear trapezoidal rule [26].
Bioequivalence was assessed according to EU Guideline CPMP/EWP/QWP/1401/98 and the FDA Code of Federal Regulations. Following logarithmic transformation, an analysis of variance (ANOVA, SAS®) was performed on GH metrics (Cmax, AUC0-last, AUC0-inf and tmax) of the full analysis population. There were no imputations for missing data. The ANOVA model consisted of the logarithmically transformed Cmax parameter as the response variable with factors for sequence, subject nested in sequence, period and mode of administration (treatment). Using an average bioequivalence approach, a 90% confidence interval (CI) for the true ratio test (needle-free device) to reference (needle injection) of the means of the two treatments was produced from this model and compared with the equivalence acceptance limits 80–125%.
Based on data from previous Serono r-hGH studies, when the sample size in each sequence group is 15 (and the total sample size is 30), a crossover design has a 90% power to demonstrate equivalence within the acceptance limits of 80–125%, assuming that the expected ratio of means was 1.000, the crossover ANOVA, MSE (ln scale) was 0.250 [the SD differences, σd (ln scale) were 0.354], that data were analysed in the natural log scale using t-tests for differences in means, and that each t-test was made at the 5% level. Taking into account a potential drop-out rate of approximately 20%, it was estimated that approximately 38 subjects were required to complete this study.
The pharmacokinetic analysis population consisted of all 38 subjects (100%) who were randomized into this study and who had evaluable pharmacokinetic data for both periods.
Results
Thirty-eight healthy male volunteers completed the study. Demographic and baseline characteristics for each subject (Table 1) were in compliance with specific inclusion and exclusion criteria. There were no major protocol deviations, no subjects dropped out and no subjects were withdrawn.
Table 1. Summary of baseline subject demographic data
The ANOVA model assumptions were met satisfactorily and there was no significant sequence effect (p = 0.980). The mean ± SD serum concentration vs time profiles for GH following administration of 2.92 mg of r-hGH by either the needle-free device, cool.click™ 2, or by needle injection were generally similar throughout the 25-hour blood-monitoring period (Figure 1). Geometric mean values for AUC0-inf, AUC0-last and t1/2 were similar between the two administration methods (Table 2). The maximum serum GH concentrations (Cmax) of 18–20 ng/mL were observed 3–4.5 hours (tmax) after drug administration (Table 2, Figure 1).
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