Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EX10 
Mechanism of action

Midostaurin inhibits multiple receptor tyrosine kinases, including FLT3 and KIT kinase. Midostaurin inhibits FLT3 receptor signalling and induces cell cycle arrest and apoptosis in leukaemic cells expressing FLT3 ITD or TKD mutant receptors or over-expressing FLT3 wild type receptors. In vitro data indicate that midostaurin inhibits D816V mutant KIT receptors at exposure levels achieved in patients (average achieved exposure higher than IC50). In vitro data indicate that KIT wild type receptors are inhibited to a much lesser extent at these concentrations (average achieved exposure lower than IC50). Midostaurin interferes with aberrant KIT D816V-mediated signalling and inhibits mast cell proliferation, survival and histamine release.

In addition, midostaurin inhibits several other receptor tyrosine kinases such as PDGFR (platelet-derived growth factor receptor) or VEGFR2 (vascular endothelial growth factor receptor 2), as well as members of the serine/threonine kinase family PKC (protein kinase C). Midostaurin binds to the catalytic domain of these kinases and inhibits the mitogenic signalling of the respective growth factors in cells, resulting in growth arrest.

Midostaurin in combination with chemotherapeutic agents (cytarabine, doxorubicin, idarubicin and daunorubicin) resulted in synergistic growth inhibition in FLT3-ITD expressing AML cell lines.

Pharmacodynamic effects

Two major metabolites have been identified in murine models and humans, i.e. CGP62221 and CGP52421. In proliferation assays with FLT3-ITD expressing cells, CGP62221 showed similar potency compared to the parent compound, however CGP52421 was approximately 10-fold less potent.



Cardiac electrophysiology
A dedicated QT study in 192 healthy subjects with a dose of 75 mg twice daily did not reveal clinically significant prolongation of QT by midostaurin and CGP62221 but the study duration was not long enough to estimate the QTc prolongation effects of the long-acting metabolite CGP52421.
Therefore, the change from baseline in QTcF with the concentration of midostaurin and both metabolites was further explored in a phase II study in 116 patients with advanced SM. At the median peak Cmin concentrations attained at a dose of 100 mg twice daily, neither midostaurin, CGP62221 nor CGP52421 showed a potential to cause clinically significant QTcF prolongation, since the upper bounds of predicted change at these concentration levels were less than 10 msecs (5.8, 2.4, and 4.0 msecs, respectively). In the advanced SM population, 25.4% of patients had at least one ECG measurement with a QTcF greater than 450 ms and 4.7% greater than 480 ms.

Clinical efficacy and safety

AML
The efficacy and safety of midostaurin in combination with standard chemotherapy versus placebo plus standard chemotherapy and as single agent maintenance therapy was investigated in 717 patients (18 to 60 years of age) in a randomised, double-blind, phase III study. Patients with newly diagnosed FLT3-mutated AML as determined by a clinical study assay were randomised (1:1) to receive midostaurin 50 mg twice daily (n=360) or placebo (n=357) sequentially in combination with standard daunorubicin (60 mg/m2 daily on days 1-3) / cytarabine (200 mg/m2 daily on days 1-7) induction and high-dose cytarabine (3 g/m2 every 12 hours on days 1, 3, 5) consolidation, followed by continuous midostaurin or placebo treatment according to initial assignment for up to 12 additional cycles (28 days/cycle). While the study included patients with various AML-related cytogenetic abnormalities, patients with acute promyelocytic leukaemia (M3) or therapy-related AML were excluded. Patients were stratified by FLT3 mutation status: TKD, ITD with allelic ratio <0.7, and ITD with allelic ratio ≥0.7.

The two treatment groups were generally balanced with respect to the baseline demographics of disease characteristics. The median age of the patients was 47 years (range: 18 to 60 years), a majority of the patients had ECOG performance status of 0 or 1 (88.3%), and most patients had de novo AML (95%). Of the patients with race information reported, 88.1% were Caucasian. The majority of patients (77.4%) had FLT3-ITD mutations, most of them (47.6%) with a low allelic ratio (<0.7), and 22.6% of patients had FLT3-TKD mutations. Forty-eight per cent were male in the midostaurin arm and 41% in the placebo arm.

Patients who proceeded to haematopoietic stem cell transplant (SCT) stopped receiving study treatment prior to the start of the SCT conditioning regimen. The overall rate of SCT was 59.4% (214/360) of patients in the midostaurin plus standard chemotherapy arm versus 55.2% (197/357) in the placebo plus standard chemotherapy arm. All patients were followed for survival.

The primary endpoint of the study was overall survival (OS), measured from the date of randomisation until death by any cause. The primary analysis was conducted after a minimum follow-up of approximately 3.5 years after the randomisation of the last patient. The study demonstrated a statistically significant improvement in OS with a 23% risk reduction of death for midostaurin plus standard chemotherapy over placebo plus standard chemotherapy (see Table 6 and Figure 1).



Figure 1                                          Kaplan-Meier curve for overall survival, non-censored for SCT 
100
Midostaurin (n=360)
Median: 74.7 months
Placebo (n=357)
Overall survival probability, %



80
Median: 25.6 months
HR: 0.774 (95% CI, 0.629-0.953)
P = 0.0078
60


40



20



0
0       6     12    18    24      30     36    42    48    54    60   66    72     78        84 Months
Patients at risk
Months                                        0        6    12    18    24       30    36    42    48    54    60    66    72     78       84 Midostaurin                                   360     314   269   234   208      189   181   174   133   120   77    50    22     1        0 Placebo                                       357     284   221   179   163      152   148   141   110   95    71    45    20     1        0 


The key secondary endpoint was event-free survival (EFS; an EFS event is defined as a failure to obtain a complete remission (CR) within 60 days of initiation of protocol therapy, or relapse, or death from any cause). The EFS showed a statistically significant improvement for midostaurin plus standard chemotherapy over placebo plus standard chemotherapy (HR: 0.78 [95% CI, 0.66 to 0.93] p = 0.0024), and a median EFS of 8.2 months and 3.0 months, respectively; see Table 5.



   Table 5 Efficacy of midostaurin in AML

Efficacy parameter                         Midostaurin           Placebo              HR*           P-value¥ n=360                n=357            (95% CI)
Overall survival (OS)1
Median OS in months (95% CI)           74.7 (31.5, NE) 25.6 (18.6, 42.9) 0.77 (0.63, 0.95)        0.0078 Kaplan-Meier estimates at 5 years     0.51 (0.45, 0.56) 0.43 (0.38, 0.49) (95% CI)
Event free survival (EFS)2
Median EFS in months,                   8.2 (5.4, 10.7)       3.0 (1.9, 5.9)   0.78 (0.66, 0.93)  0.0024 considering CRs within 60 days of treatment start (95% CI)
Median EFS in months,                  10.2 (8.1, 13.9)       5.6 (2.9, 6.7)   0.73 (0.61, 0.87)  0.0001 considering CRs any time during induction (95% CI)
Disease free survival (DFS)
Median DFS in months (95% CI)          26.7 (19.4, NE) 15.5 (11.3, 23.5) 0.71 (0.55, 0.92)        0.0051 Complete remission (CR) within 60 days of treatment start         212 (58.9)           191 (53.5)             NE          0.073§ (%) any time during induction (%)             234 (65.0)           207 (58.0)             NE          0.027§ Cumulative incidence of relapse
(CIR)
Median (95% CI)                         NE (25.7, NE) 17.6 (12.7, 46.3) 0.68 (0.52, 0.89)         0.0023 1                    2 primary endpoint; key secondary endpoint; NE: Not Estimated
*
Hazard ratio (HR) estimated using Cox regression model stratified according to the randomisation FLT3 mutation factor.
¥
1-sided p-value calculated using log-rank test stratified according to the randomisation FLT3 mutation factor.
§
Not significant

There was a trend favouring midostaurin for CR rate by day 60 for the midostaurin arm (58.9% versus 53.5%; p = 0.073) that continued when considering all CRs during induction (65.0% versus 58.0%; p = 0.027). In addition, in patients who achieved complete remission during induction, the cumulative incidence of relapse at 12 months was 26% in the midostaurin arm versus 41% in the placebo arm.

Sensitivity analyses for both OS and EFS when censored at the time of SCT also supported the clinical benefit with midostaurin plus standard chemotherapy over placebo.

Results for OS by SCT status are shown in Figure 2. For EFS, considering complete remissions within 60 days of study treatment start, the HR was 0.602 (95% CI: 0.372, 0.974) for patients with SCT and 0.827 (95% CI: 0.689, 0.993) for patients without SCT, favouring midostaurin.



Figure 2                                                              Kaplan Meier curve for overall survival by SCT status in AML 
100%                                                                                                                               Median Survival
Subjects      Event    (months)      95% CI
MIDOSTAURIN – SCT              214        100         74.7      37.3 N.E.
PLACEBO – SCT              197        105         35.9      22.6 N.E.
80%                                                                           MIDOSTAURIN – no SCT             146         71         31.7      16.9 N.E.
Probability of Survival (%)



PLACEBO – no SCT             160         81         14.7      10.0 36.9 Probability of Survival (%)



60%



40%


1: 1:                                                                 HR (95% CI) – SCT         0.780 (0.593, 1.026) 20%                         MIDOSTAURIN
MIDOSTAURIN  - SCT – SCT
2: 2: PLACEBO
PLACEBO - SCT– SCT                                               HR (95% CI) – no SCT        0.798 (0.580, 1.098) 3: 3: MIDOSTAURIN
MIDOSTAURIN        – no SCT
- no SCT
4: 4: PLACEBO
PLACEBO       – no SCT
- no SCT
0%
Censored
Censored

0           6          12   18         24    30          36        42         48      54         60         66        72         78         84 Overall survival (months)
Overall survival (months)
No.
No.of ofpatients  stillatatrisk patients still        risk
1           214         207        178   154        137   122        117        112        84      76         50         33        12         1          0 2           197         184        151   118        105    97         93         90        67      58         42         28        12         1          0 3           146         107         91    80         71    67         64         62        49      44         27         17        10         0 4           160         100         70    61         58    55         55         51        43      37         29         17         8         0 


In a subgroup analysis, no apparent OS benefit was observed in females, however, a treatment benefit was observed in females in all secondary efficacy endpoints (see Table 6).

Table 6 Overview of OS, EFS, CR, DFS and CIR by gender in AML

Endpoint                         Overall                   Males                 Females 95% CI                   95% CI                 95% CI
OS (HR)                            0.774                    0.533                  1.007 (0.629, 0.953)           (0.392, 0.725)         (0.757, 1.338)
EFS (CR induction)                 0.728                    0.660                  0.825 (HR)                          (0.613, 0.866)           (0.506, 0.861)         (0.656, 1.037) CR induction (OR)                 0.743*                   0.675*                 0.824* (0.550, 1.005)           (0.425, 1.072)         (0.552, 1.230)
DFS (CR induction)                 0.663                    0.594                  0.778 (HR)                          (0.516, 0.853)           (0.408, 0.865)         (0.554, 1.093) CIR (CR induction)                 0.676                    0.662                  0.742 (HR)                          (0.515, 0.888)           (0.436, 1.006)         (0.516, 1.069) *Odds ratio calculated as (No complete remission in treatment/Complete remission in treatment) / (No complete remission in placebo/complete remission in placebo)
HR= Hazard ratio; OR=odds ratio

Efficacy and safety in patients > 60-70 years old were evaluated as part of a phase II, single- arm, investigator- initiated study of midostaurin in combination with intensive induction, consolidation including allogenic SCT and single-agent maintenance in patients with FLT3-ITD mutated AML.
Based on the final analysis, the EFS rate at 2 years (primary endpoint) was 34% (95% CI: 27, 44) and the median OS was 22.7 months in patients older than 60 years of age (128 out of 440 patients).

Advanced SM.
The efficacy of midostaurin in patients with ASM, SM-AHN and MCL, collectively referred to as advanced systemic mastocytosis (SM), was evaluated in two open-label, single-arm, multicentre studies (142 patients in total).


The pivotal study was a multicentre, single-arm phase II study in 116 patients with advanced SM (Study CPKC412D2201). Midostaurin was administered orally at 100 mg twice daily until disease progression or intolerable toxicity. Of the 116 patients enrolled, 89 were considered eligible for response assessment and constituted the primary efficacy population. Of these, 73 patients had ASM (57 with an AHN) and 16 patients had MCL (6 with an AHN). The median age in the primary efficacy population was 64 years with approximately half of the patients ≥65 years. Approximately one third (36%) received prior anti-neoplastic therapy for ASM, SM-AHN or MCL.At baseline in the primary efficacy population, 65% of the patients had >1 measurable C finding (thrombocytopenia, hypoalbuminaemia, anaemia, high total bilirubin, transfusion-dependent anaemia, weight loss, neutropenia, high ALT or high AST). The KIT D816V mutation was detected in 82% of patients.

The primary endpoint was overall response rate (ORR). Response rates were assessed based on the modified Valent and Cheson criteria and responses were adjudicated by a study steering committee.
Secondary endpoints included duration of response, time to response, and overall survival. Responses to midostaurin are shown in Table 7. Activity was observed regardless of number of prior therapies, and presence or absence of an AHN. Confirmed responses were observed in both KIT D816V mutation positive patients (ORR=63%) and KIT D816V wild type or unknown patients (ORR=43.8%). However, the median survival for KIT D816V positive patients was longer, i.e.
33.9 months (95% CI: 20.7, 42), than for KIT D816V wild type or unknown patients, i.e. 10 months (95% CI: 6.9, 17.4). Forty-six percent of patients had a decrease in bone marrow infiltration that exceeded 50% and 58% had a decrease in serum tryptase levels that exceeded 50%. Spleen volume decreased by ≥10% in 68.9% of patients with at least 1 post-baseline assessment (26.7% of patients had a reduction of ≥35%, which correlates with a 50% decrease by palpation).

The median time to response was 0.3 months (range: 0.1 to 3.7 months). The median duration of follow-up was 43 months.

Table 7     Efficacy of midostaurin in advanced SM: primary efficacy population 
All                ASM               SM-AHN                 MCL
N=89                N=16               N=57                  N=16
Primary endpoint
Overall response, n (%)        53 (59.6)            12 (75.0)          33 (57.9)            8 (50.0) (95% CI)                     (48.6, 69.8)          (47.6, 92.7)       (44.1, 70.9)        (24.7, 75.3) Major response, n         40 (44.9)            10 (62.5)          23 (40.4)            7 (43.8) (%)
Partial response, n       13 (14.6)             2 (12.5)          10 (17.5)             1 (6.3) (%)
Stable disease, n (%)          11 (12.4)              1 (6.3)           7 (12.3)            3 (18.8) Progressive disease, n         10 (11.2)              1 (6.3)           6 (10.5)            3 (18.8) (%)
Secondary endpoints
Median duration of          18.6 (9.9, 34.7)      36.8 (5.5, NE)    10.7 (7.4, 22.8)     NR (3.6, NE) response, months (95%
CI)
Median overall survival, 26.8 (17.6, 34.7)       51.1 (28.7, NE)   20.7 (16.3, 33.9)     9.4 (7.5, NE) months (95% CI)
Kaplan-Meier estimates     26.1 (14.6, 39.2)     34.8 (1.7, 76.2)   19.9 (8.6, 34.5)   33.7 (12.3, 56.8) at 5 years (95% CI)
NE: Not Estimated, NR: Not Reached
Patients who received non-study anti-neoplastic therapy were considered as having progressed at the time of the new therapy.

Although the study was designed to be assessed with the modified Valent and Cheson criteria, as a post-hoc exploratory analysis, efficacy was also assessed per the 2013 International Working 
Group - Myeloproliferative Neoplasms Research and Treatment - European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Response to Rydapt was determined using a computational algorithm applied without any adjudication. Out of 116 patients, 113 had a C-finding as defined by IWG response criteria (excluding ascites as a C-finding). All responses were considered and required a 12-week confirmation (see Table 8).

Table 8     Efficacy of midostaurin in advanced SM per IWG-MRT-ECNM consensus criteria using an algorithmic approach

All patients      ASM          SM-AHN          MCL             Subtype evaluated                                                    unknown
N=113          N=15           N=72           N=21             N=5
Overall response rate, n (%)      32 (28.3)      9 (60.0)      15 (20.8)       7 (33.3)        1 (20.0) (95% CI)                      (20.2, 37.6)   (32.3, 83.7)   (12.2, 32.0)   (14.6, 57.0)     (0.5, 71.6) Best overall response, n (%)
Complete remission              1 (0.9)           0               0         1 ( 4.8)            0 Partial remission              17 (15.0)       5 (33.3)       8 (11.1)      3 (14.3)         1 (20.0) Clinical improvement           14 (12.4)       4 (26.7)        7 (9.7)      3 (14.3)            0 Duration of response* n/N (%)                       11/32 (34.4)    4/9 (44.4)    4/15 (26.7)    3/7 (42.9)        0/1 (0.0) median (95% CI)                   NE             36.8           NE            NE                NE (27.0, NE)    (10.3, 36.8)   (17.3, NE)     (4.1, NE)
Overall survival n/N (%)                          65/113      4/15 (26.7)      49/72          12/21       0/5 (0.0) (57.5)                      (68.1)         (57.1) median (95% CI)                   29.9          51.1          22.1           22.6          NE (20.3, 42.0)    (34.7, NE) (16.8, 32.2)      (8.3, NE)
*Confirmation period for responses: 12 weeks
Analysis excludes ascites as a C-finding.
Patients who received non-study anti-neoplastic therapy were considered as having progressed at the time of the new therapy.

The supportive study was a single-arm, multicentre, open-label phase II study of 26 patients with advanced SM (CPKC412A2213). Midostaurin was administered orally at 100 mg twice daily in cycles of 28 days. Lack of a major response (MR) or partial response (PR) by the end of the second cycle required discontinuation from the study treatment. Twenty (76.9%) patients had ASM (17 [85%] with AHN) and 6 patients (23.1%) had MCL (2 [33.3%] with AHN). The median age was 64.5 years with half of the patients ≥65 years). At baseline, 88.5% had >1 C finding and 69.2% had received at least one prior anti-neoplastic regimen.

The primary endpoint was ORR evaluated by the Valent criteria during the first two cycles of treatment. Nineteen patients (73.1%; 95% CI = [52.2, 88.4]) achieved a response during the first two cycles of treatment (13 MR; 6 PR). The median duration of follow-up was 73 months, and the median duration of response has not been reached. Median overall survival was 40.0 months (patients were only followed up for one year after treatment discontinuation for survival).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Midostaurin is a compound with good absorption and poor solubility. Two of its metabolites demonstrated pharmacological activities (CGP52421 and CGP62221). Following multiple doses, the pharmacokinetics of midostaurin and CGP62221 were time-dependent, with an initial increase observed in the first week followed by a decline of concentrations until reaching steady state on day 28. CGP52421 concentrations do not appear to decline as significantly as for midostaurin and CGP62221.

Absorption

The absolute bioavailability of midostaurin following oral administration is not known.
In humans, the absorption of midostaurin was rapid after oral administration, with Tmax of total radioactivity observed at 1-3 hours post dose. The population pharmacokinetic analysis indicated that the absorption in patients was less than dose proportional at doses >50 mg twice daily.

In healthy subjects, after administration of a single dose of 50 mg midostaurin with food, AUC of midostaurin was increased to 20 800 ng*h/ml and Cmax was decreased to 963 ng/ml (see section 4.5).
Similarly, for CGP52421 and CGP62221 AUC increased to 19 000 and 29 200 ng*h/ml and Cmax decreased to 172 and 455 ng/ml, respectively. Time to peak concentration was also delayed in the presence of a high-fat meal. Tmax was delayed for all entities, midostaurin median Tmax was 3 h, and for CGP52421 and CGP62221 Tmax was delayed to 6 and 7 hours respectively.

In clinical studies, the efficacy and safety of Rydapt were investigated following administration with a light meal. After oral administration of a single 100 mg dose of midostaurin under fed conditions in advanced SM patients, AUCinf, Cmax and Tmax were 49 600 ng*h/ml, 2 940 ng/ml and 3 h, respectively, for midostaurin. For CGP52421, AUC0-12h and Cmax were 2 770 ng*h/ml and 299 ng/ml, respectively.
AUC0-12h and Cmax for CGP62221 were 8 700 ng*h/ml and 931 ng/ml, respectively. After 100 mg bid multiple oral doses of midostaurin the Cmin,ss plasma midostaurin in AML and advanced SM patients were 919 and 1 060 ng/ml, respectively. The CGP62221 Cmin, ss in the AML and the advanced SM population were 1 610 ng/ml and 2 020 ng/ml, respectively. The CGP52421, Cmin,ss in the AML and the advanced SM population were 8 630 ng/ml and 2 860 ng/ml, respectively.

Distribution

Midostaurin has a tissue distribution of geometric mean of 95.2 l (Vz/F). Midostaurin and its metabolites are distributed mainly in plasma rather than red blood cells. In vitro data showed midostaurin is more than 98% bound to plasma proteins, such as albumin, α1-acid glycoprotein (AGP) and lipoprotein.

Biotransformation

Midostaurin is metabolised by CYP3A4 mainly via oxidative pathways. The major plasma components included midostaurin and two major active metabolites, CGP62221 (via O-demethylation) and CGP52421 (via hydroxylation), accounting for 27.7±2.7% and 38.0±6.6%, respectively, of the total plasma exposure at 96 hours after a single 50 mg dose of midostaurin.



Elimination

The median terminal half-lives of midostaurin, CGP62221 and CGP52421 in plasma are approximately 20.9, 32.3 and 471 hours. The mean apparent plasma clearance (CL/F) was 2.4-3.1 l/h in healthy subjects. In AML and advanced SM patients, population pharmacokinetic estimates for clearance of midostaurin at steady state were 5.9 l/h and 4.4 l/h, respectively. The Human Mass Balance study results indicated that faecal excretion is the major route of excretion (78% of the dose), and mostly as metabolites (73% of the dose), while unchanged midostaurin accounts for 3% of the dose. Only 4% of the dose is recovered in urine.

Linearity/non-linearity

In general, midostaurin and its metabolites showed no major deviation from dose-proportionality after a single dose in the range of 25 mg to 100 mg. However, there was a less than dose-proportional increase in exposure after multiple doses within the dose range of 50 mg to 225 mg daily.

Following multiple oral doses, midostaurin displayed time-dependent pharmacokinetics with an initial increase in plasma concentrations during the first week (peak Cmin) followed by a decline with time to a steady-state after approximately 28 days (2.5-fold decrease). While the exact mechanism for the declining concentration of midostaurin is unclear, it is likely due to the auto-induction properties of midostaurin and its two active metabolite CGP52421 and CGP62221 on CYP3A4. The pharmacokinetics of the CGP62221 metabolite showed a similar trend. However, CGP52421 concentrations increased up to 2.5-fold for advanced SM and up to 9-fold for AML, compared to midostaurin after one month of treatment.

In vitro evaluation of drug-drug interaction potential

Based on in vitro data, midostaurin and its active metabolites, CGP52421 and CGP62221, are considered inhibitors of CYP1A2 and CYP2E1 and inducers of CYP2B6 (induction mediated by CAR) and CYP1A2 (induction mediated by AhR).

In vitro experiments demonstrated that midostaurin, CGP52421 and CPG62221 can potentially inhibit BCRP and BSEP. Simulations using physiologically-based pharmacokinetic (PBPK) models predicted that midostaurin given at a dose of 50 mg or 100 mg twice daily at steady state is unlikely to cause clinically relevant inhibition of OATP1B.

Special populations

Elderly patients
Based on population pharmacokinetic analyses no significant impact of age on the pharmacokinetics of midostaurin and its two active metabolites was identified for patients aged between 65 and 85 years. In adult patients with advanced SM or AML, no midostaurin dose adjustment is required based on age.

Gender
Based on population pharmacokinetic model analyses of the effect of gender on clearance of midostaurin and its active metabolites, there was no statistically significant finding and the anticipated changes in exposure (<20%) were not deemed to be clinically relevant. No midostaurin dose adjustment is required based on gender.



Race/ethnicity
There are no differences in the pharmacokinetic profile between Caucasian and Black subjects. Based on a phase I study in healthy Japanese volunteers, pharmacokinetic profiles of midostaurin and its metabolites (CGP62221 and CGP52421) are similar compared to those observed in other pharmacokinetic studies conducted in Caucasians and Blacks. No midostaurin dose adjustment is required based on ethnicity.

Hepatic impairment
A dedicated hepatic impairment study assessed the systemic exposure of midostaurin after oral administration of 50 mg twice daily for 6 days and a single 50 mg dose on day 7 in subjects with baseline mild or moderate (Child-Pugh Class A or B, respectively) and following a single dose administration of 50 mg in subjects with severe hepatic impairment (Child-Pugh Class C) in comparison to control subjects with normal hepatic function. The maximum concentration of midostaurin was reached between 2 and 3 hours after administration after single or repeated doses for all groups. On day 1, the AUC0-12 and Cmax were 8 130 ng*h/ml and 1 206 ng/ml, respectively, for healthy subjects. AUC0-12 was decreased by 39% and 36% in subjects with mild and moderate hepatic impairment, respectively. On day 7, AUCCtrough (exposure under the curve of Ctrough from day 1 to day 7) was 5 410 ng*h/ml in healthy subjects and was decreased by 35% and 20% in subjects with mild and moderate hepatic impairment, respectively. AUCtau was decreased by 28% and 20% on day 7, respectively.

The subjects with severe hepatic impairment had a lower geometric mean Cmax and AUCinf of midostaurin compared to the control group (Cmax: 1 360 ng/ml, AUCinf: 30 100 ng.h/ml). Cmax and AUCinf of midostaurin decreased on average by 78% and 59% respectively in subjects with severe hepatic impairment.


Finally, the long-term data from patients were analysed using a population pharmacokinetic approach.
No impact of hepatic impairment could be identified in patients with mild or moderate hepatic impairment in the advanced SM and AML populations.


Overall, there was no increase in exposure (AUC) to plasma midostaurin and its metabolites (CGP62221 and CGP52421) in subjects with mild,moderate or severe hepatic impairment compared to subjects with normal hepatic function. No dose adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Exposure to midostaurin and its active metabolite CGP62221 is substantially lower in patients with severe hepatic impairment than that in patients with normal hepatic function (see section 4.2). However, there are insufficient efficacy data in patients with severe hepatic impairment to suggest a dose adjustment is required.
Renal impairment
Renal elimination is a minor route of elimination for midostaurin. No dedicated renal impairment study was conducted for midostaurin. Population pharmacokinetic analyses were conducted using data from clinical studies in patients with AML (n=180) and advanced SM (n=141). Out of the 321 patients included, 177 patients showed pre-existing mild (n=113), moderate (n=60) or severe (n=4) renal impairment (15 ml/min ≤ creatinine clearance [CrCL] <90 ml/min). 144 patients showed normal renal function (CrCL >90 ml/min) at baseline. Based on the population pharmacokinetic analyses, midostaurin clearance was not significantly impacted by renal impairment and therefore no dose adjustment is necessary for patients with mild or moderate renal impairment.