Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Diagnostic agents, Tests for pituitary function, ATC code: V04CD06 
Mechanism of action

Macimorelin is an orally available peptidomimetic with growth hormone (GH) secretagogue activity similar to ghrelin. Macimorelin stimulates GH release by activating growth hormone secretagogue receptors (GHSR) present in the pituitary and hypothalamus.

Pharmacodynamic effects

GH stimulation
In dose finding studies in healthy subjects, maximum stimulation of GH secretion was achieved following single dose administration of 0.5 mg/kg macimorelin. Maximum GH levels have been observed approximately 45 to 60 minutes after administration of macimorelin.
In a diagnostic study comparing macimorelin with the insulin tolerance test (ITT) stimulated GH concentrations after macimorelin were on average 1.4 fold higher than in the ITT.

Cardiac electrophysiology

The effects of macimorelin on ECG parameters were investigated in a dedicated Thorough QT study that investigated in a 3-way cross-over design with 60 healthy subjects the effects of a supra-therapeutic dose of macimorelin (2 mg/kg, i.e., 4 times the recommended dosage) in comparison with placebo and with moxifloxacin. This study showed a mean baseline- and placebo-adjusted change (upper single-sided 95% confidence interval) in QTcF of 9.6 ms (11.4 ms) at 4 h post-dose (see also section 4.4), which occurred after the mean maximum macimorelin plasma concentration (0.5 h). A similar increase in the QTcF interval was also observed in a single-ascending dose study, which included three dose levels (0.5 mg/kg, 1 mg/kg and 2 mg/kg (2 times and 4 times the recommended dosage, respectively)). All three dose levels studied showed a similar magnitude of QTcF prolongation in the Thorough QT study, suggesting an absence of dose dependent changes. The mechanism for the observed QTcF prolongation is unknown.

Clinical efficacy and safety

The diagnostic efficacy of MACRILEN was established in a randomized, open-label, single dose, cross-over study (AEZS-130-052) comparing the level of agreement between the macimorelin test (MAC) results and insulin tolerance test (ITT) results. Four groups of individuals were evaluated: three groups of adult patients with different pre-test probability of growth hormone deficiency (Group A (high likelihood), Group B (intermediate likelihood), Group C (low likelihood) and healthy control subjects (Group D)).

For both the ITT and the MAC test, serum concentrations of GH were measured at 30, 45, 60 and 90 minutes after administration. The test was considered positive (i.e., growth hormone deficiency (GHD) diagnosed) if the maximum serum GH level observed after stimulation was less than the pre-specified cut-off point of 2.8 ng/mL for the MAC test or 5.1 ng/mL for the ITT.

GH levels were determined centrally with the IDS-iSYS assay (Immunodiagnostic Systems Ltd., UK).

The level of negative and positive agreement between the results of the ITT and the MAC test was used to evaluate the performance of the MAC test.
Negative agreement is the proportion of subjects with a negative ITT (i.e., those who do not have GHD per the ITT) who also have a negative MAC test. With a high level of negative agreement, the MAC test will not wrongly diagnose an individual without GHD per the ITT as having GHD. Positive agreement is the proportion of subjects with a positive ITT (i.e., those who have GHD per the ITT) who also have a positive macimorelin test. With a high level of positive agreement, the MAC test will not wrongly diagnose an individual with GHD per the ITT as not having GHD.

Sensitivity and specificity for both growth hormone stimulation tests (GHSTs) were estimated, assuming all high likelihood AGHD subjects of Group A as ‘true’ AGHD subjects and all healthy matching subjects of Group D as ‘true’ AGHD negative subjects.

Results
One hundred and fifty-seven (157) subjects underwent at least one of the two tests in this study, 59% were male, 41% female and 86% of white origin. The median age was 41 years (range: 18 - 66 years) and body mass index 27.5 kg/m2 (range: 16 – 40 kg/m2). Data on both tests were available for 140 subjects; 38 (27%) in Group A, 37 (26%) in Group B, 40 (29%) in Group C and 25 (18%) in Group D. One out of 154 MAC tests (0.6%) performed failed due to a technical error and 27 out of 157 ITTs (17.2%) performed failed because induction of severe hypoglycemia (i.e., the stimulus) could not be achieved.

The estimates for negative and positive agreement between MAC and the ITT in the overall study population were 94% and 74% with lower 95% confidence interval bounds 85% and 63%, respectively. Negative and positive agreement between MAC and the ITT in subjects with intermediate or low risk (Groups B 
and C) were 93% and 61% with lower 95% confidence interval bounds 80% and 43%, respectively. These results are based on peak GH values (maximum GH concentrations across all measurement timepoints).

Point estimates for sensitivity ranged from 0.87 to 0.90 for the MAC and from 0.97 to 1.0 for the ITT, depending on the inclusion or exclusion of data from not matched Group A subjects, respectively. For both GHSTs, the estimated specificity was 0.96, irrespective of the in/exclusion data from not matched Group A subjects.
Repeatability was tested in a subset of 34 subjects who underwent two MAC tests. Agreement between the result of the first test and the second test was observed in 31 cases (91.2%).

Post-hoc analysis with a cut-off point of 3.0 ng/mL for the ITT

An exploratory analysis was conducted on the performance of the MAC based on an ITT cut-off point of 3.0 ng/mL. The estimates for negative and positive agreement were 95% and 86% with lower 95% confidence interval bounds 87% and 75%, respectively. Repeatability was 97%. Point estimates for sensitivity and specificity were 87% and 96% from not matched Group A subjects, respectively.

Both co-primary endpoints as pre-defined in Study 052 (lower limit of the 95% CI for negative agreement ≥ 75%, lower limit of the 95% CI for positive agreement ≥ 70%) are met when using an ITT cut-off point of 3.0 ng/mL and the pre-defined cut-off point for the MAC of 2.8 ng/mL.

Paediatric population

The EMA has deferred the obligation to submit the results of studies with MACRILEN in one or more subsets of the paediatric population in the diagnosis of growth hormone deficiency (see section 4.2 for information on paediatric use).

Elderly

The pharmacodynamics of macimorelin was not sufficiently evaluated in the elderly population aged > 65 years.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

Macimorelin was absorbed rapidly and the maximum plasma macimorelin concentrations (Cmax) were observed approximately 30 minutes to 1 hour and 10 minutes after oral administration of 0.5 mg/kg macimorelin after fasting for at least 8 hours. A liquid meal decreased the macimorelin Cmax and AUC by 0.42 and 0.5 fold, respectively.

The oral bioavailability may be limited (among others) by first pass metabolism via CYP3A4 (see section 4.5).

Distribution
Macimorelin is moderately bound to plasma proteins. Plasma protein binding decreases with increasing concentrations from 78% at 0.1 µM to 62% at 10 µM.
At the clinically relevant concentration of 0.1 µM (clinical Cmax = 11.2 ng/ml = approx. 0.02 µM), the unbound fraction of macimorelin in human plasma is 22%.

Biotransformation

CYP3A4 is the major enzyme to metabolize macimorelin. Studies to detect macimorelin metabolites did not identify any metabolites.
Elimination

An in vitro human liver microsomes study showed that CYP3A4 is the major enzyme to metabolize macimorelin.
Macimorelin was eliminated with a mean terminal half-life (T1/2) of 4.1 hours.

PK/PD relationship
Macimorelin showed a dose-dependent release of GH after oral dosing. A dose of 0.5 mg/kg macimorelin was shown to induce maximal GH release. Maximal GH release has been observed at macimorelin plasma concentrations of ≥ 7 ng/mL.

Special populations

No studies have been conducted to evaluate the pharmacokinetics of macimorelin in paediatric patients or in patients with renal or hepatic impairment. Only limited pharmacokinetic data are available in the elderly.