Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EJ01 
Mechanism of action

Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC50 values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively). These mediate the signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function.

MF and PV are myeloproliferative neoplasms known to be associated with dysregulated JAK1 and JAK2 signalling. The basis for the dysregulation is believed to include high levels of circulating cytokines that activate the JAK-STAT pathway, gain-of-function mutations such as JAK2V617F, and silencing of negative regulatory mechanisms. MF patients exhibit dysregulated JAK signalling regardless of JAK2V617F mutation status. Activating mutations in JAK2 (V617F or exon 12) are found in >95% of PV patients.
Ruxolitinib inhibits JAK-STAT signalling and cell proliferation of cytokine-dependent cellular models of haematological malignancies, as well as of Ba/F3 cells rendered cytokine-independent by expressing the JAK2V617F mutated protein, with IC50 ranging from 80-320 nM.
JAK-STAT signalling pathways play a role in regulating the development, proliferation, and activation of several immune cell types important for GvHD pathogenesis.

Pharmacodynamic effects

Ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy subjects, MF patients and PV patients. Ruxolitinib resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 8 hours in both healthy subjects and MF patients, indicating no accumulation of either parent or active metabolites.

Baseline elevations in inflammatory markers associated with constitutional symptoms such as TNFα, IL-6 and CRP in subjects with MF were decreased following treatment with ruxolitinib. MF patients did not become refractory to the pharmacodynamic effects of ruxolitinib treatment over time.
Similarly, patients with PV also presented with baseline elevations in inflammatory markers and these JAK API May24 V7                                                              EU SmPC April 2024 markers were decreased following treatment with ruxolitinib.

In a thorough QT study in healthy subjects, there was no indication of a QT/QTc prolonging effect of ruxolitinib in single doses up to a supratherapeutic dose of 200 mg, indicating that ruxolitinib has no effect on cardiac repolarisation.

Clinical efficacy and safety

Myelofibrosis
Two randomised phase 3 studies (COMFORT-I and COMFORT-II) were conducted in patients with MF (primary MF, post-polycythaemia vera MF or post-essential thrombocythaemia MF). In both studies, patients had palpable splenomegaly at least 5 cm below the costal margin and risk category of intermediate-2 or high risk based on the International Working Group (IWG) Consensus Criteria. The starting dose of Jakavi was based on platelet count. Patients with platelet counts ≤100,000/mm3 were not eligible for enrolment in COMFORT studies but 69 patients were enrolled in the EXPAND study, a Phase Ib, open label, dose-finding study in patients with MF (primary MF, post-polycythaemia vera MF or post-essential thrombocythaemia MF) and baseline platelet counts ≥50,000 and <100,000/mm3.

COMFORT-I was a double-blind, randomised, placebo-controlled study in 309 patients who were refractory to or were not candidates for available therapy. The primary efficacy endpoint was proportion of subjects achieving ≥35% reduction from baseline in spleen volume at week 24 as measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT).

Secondary endpoints included duration of maintenance of a ≥35% reduction from baseline in spleen volume, proportion of patients who had ≥50% reduction in total symptom score, changes in total symptom scores from baseline to week 24, as measured by the modified MF Symptom Assessment Form (MFSAF) v2.0 diary, and overall survival.

COMFORT-II was an open-label, randomised study in 219 patients. Patients were randomised 2:1 to ruxolitinib versus best available therapy. In the best available therapy arm, 47% of patients received hydroxyurea and 16% of patients received glucocorticoids. The primary efficacy endpoint was proportion of patients achieving ≥35% reduction from baseline in spleen volume at week 48 as measured by MRI or CT.

Secondary endpoints included proportion of patients achieving a ≥35% reduction of spleen volume from baseline at week 24 and duration of maintenance of a ≥35% reduction from baseline spleen volume.

In COMFORT-I and COMFORT-II, patient baseline demographics and disease characteristics were comparable between the treatment arms.

Table 6      Percentage of patients with ≥35% reduction from baseline in spleen volume at week 24 in COMFORT-I and at week 48 in COMFORT-II(ITT)

COMFORT-I                            COMFORT-II
Jakavi      Placebo                  Jakavi         Best
(N=155)      (N=153)                 (N=144)         available therapy
(N=72)
Time points                                  Week 24                             Week 48 Number (%) of subjects          65 (41.9)             1 (0.7)         41 (28.5)             0 with spleen volume reduced by ≥35%
95% confidence intervals         34.1, 50.1            0, 3.6         21.3, 36.6             0.0, 5.0 p-value                                      <0.0001                               <0.0001 
JAK API May24 V7                                                              EU SmPC April 2024 A significantly higher proportion of patients in the Jakavi group achieved ≥35% reduction from baseline in spleen volume (Table 6) regardless of the presence or absence of the JAK2V617F mutation (Table 7) or the disease subtype (primary MF, post-polycythaemia vera MF, post-essential thrombocythaemia MF).

Table 7      Percentage of patients with ≥35% reduction from baseline in spleen volume by JAK mutation status (safety set)

COMFORT-I                               COMFORT-II
Jakavi               Placebo               Jakavi          Best available therapy
JAK           Positive     Negative   Positive   Negativ   Positive Negative Positiv Negativ mutation       (N=113)      (N=40)     (N=121)       e      (N=110) (N=35)        e          e status          n (%)        n (%)      n (%)     (N=27)     n (%)       n (%) (N=49) (N=20) n (%)                        n (%)      n (%)
Number              5         1          1          0         3            5     0          0 (%)                 4         1        (0.8)                  6        (14.3) of                (47.8)    (27.5)                          (32.7) subjec ts with spleen volume reduced by
≥35%
Time point     After 24 weeks                               After 48 weeks 

The probability of maintaining spleen response (≥35% reduction) to Jakavi for at least 24 weeks was 89% in COMFORT-I and 87% in COMFORT-II; 52% maintained spleen responses for at least 48 weeks in COMFORT-II.

In COMFORT-I, 45.9% subjects in the Jakavi group achieved a ≥50% improvement from baseline in the week 24 total symptom score (measured using MFSAF diary v2.0), as compared to 5.3% in the placebo group (p<0.0001 using chi-square test). The mean change in the global health status at week 24, as measured by EORTC QLQ C30 was +12.3 for Jakavi and -3.4 for placebo (p<0.0001).

In COMFORT-I, after a median follow-up of 34.3 months, the death rate in patients randomised to the ruxolitinib arm was 27.1% versus 35.1% in patients randomised to placebo; HR 0.687; 95% CI 0.459- 1.029; p=0.0668.

In COMFORT-I, after a median follow–up of 61.7 months, the death rate in patients randomised to the ruxolitinib arm was 44.5% (69 of 155 patients) versus 53.2% (82 of 154) in patients randomised to placebo. There was a 31% reduction in the risk of death in the ruxolitinib arm as compared to placebo (HR 0.69; 95% CI 0.50-0.96; p=0.025).

In COMFORT-II, after a median follow-up of 34.7 months, the death rate in patients randomised to ruxolitinib was 19.9% versus 30.1% in patients randomised to best available treatment (BAT); HR 0.48; 95% CI 0.28-0.85; p=0.009. In both studies, the lower death rates noted in the ruxolitinib arm were predominantly driven by the results obtained in the post polycythaemia vera and post essential thrombocythaemia subgroups.

In COMFORT-II, after a median follow-up of 55.9 months, the death rate in patients randomised to 
JAK API May24 V7                                                             EU SmPC April 2024 the ruxolitinib arm was 40.4% (59 of 146 patients) versus 47.9% (35 of 73 patients) in patients randomized to best available therapy (BAT). There was a 33% reduction in risk of death in the ruxolitinib arm compared to the BAT arm (HR 0.67; 95% CI 0.44-1.02; p=0.062).

Polycythaemia vera

A randomised, open-label, active-controlled phase 3 study (RESPONSE) was conducted in 222 patients with PV who were resistant to or intolerant of hydroxyurea defined based on the
European LeukemiaNet (ELN) international working group published criteria. 110 patients were randomised to the ruxolitinib arm and 112 patients to the BAT arm. The starting dose of Jakavi was 10 mg twice daily. Doses were then adjusted in individual patients based on tolerability and efficacy with a maximum dose of 25 mg twice daily. BAT was selected by the investigator on a patient-by- patient basis and included hydroxyurea (59.5%), interferon/pegylated interferon (11.7%), anagrelide (7.2%), pipobroman (1.8%) and observation (15.3%).

Baseline demographics and disease characteristics were comparable between the two treatments arms.
The median age was 60 years (range 33 to 90 years). Patients in the ruxolitinib arm had PV diagnosis for a median of 8.2 years and had previously received hydroxyurea for a median of approximately 3 years. Most patients (>80%) had received at least two phlebotomies in the last 24 weeks prior to screening. Comparative data regarding long-term survival and incidence of disease complications is missing.

The primary composite endpoint was the proportion of patients achieving both an absence of phlebotomy eligibility (HCT control) and a ≥35% reduction in spleen volume from baseline at week 32. Phlebotomy eligibility was defined as a confirmed HCT of >45%, i.e. at least 3 percentage points higher than the HCT obtained at baseline or a confirmed HCT of >48%, depending on which was lower. Key secondary endpoints included the proportion of patients who achieved the primary endpoint and remained free from progression at week 48, as well as the proportion of patients achieving complete haematological remission at week 32.

The study met its primary objective and a higher proportion of patients in the Jakavi group achieved the primary composite endpoint and each of its individual components. Significantly more patients treated with Jakavi (23%) achieved a primary response (p<0.0001) compared to BAT (0.9%).
Haematocrit control was achieved in 60% of patients in the Jakavi arm compared to 18.8% in the BAT arm and a ≥35% reduction in spleen volume was achieved in 40% of patients in the Jakavi arm compared to 0.9% in the BAT arm (Figure 1).

Both key secondary endpoints were also met. The proportion of patients achieving a complete haematological remission was 23.6% on Jakavi compared to 8.0% on BAT (p=0.0013) and the proportion of patients achieving a durable primary response at week 48 was 20% on Jakavi and 0.9% on BAT (p<0.0001).



JAK API May24 V7                                                             EU SmPC April 2024 Figure 1     Patients achieving the primary endpoint and components of the primary endpoint at week 32



Symptom burden was assessed using the MPN-SAF total symptom score (TSS) electronic patient diary, which consisted of 14 questions. At week 32, 49% and 64% of patients treated with ruxolitinib achieved a ≥50% reduction in TSS-14 and TSS-5, respectively, compared to only 5% and 11% of patients on BAT.

Treatment benefit perception was measured by the Patient Global Impression of Change (PGIC) questionnaire. 66% of patients treated with ruxolitinib compared to 19% treated with BAT reported an improvement as early as four weeks after beginning treatment. Improvement in perception of treatment benefit was also higher in patients treated with ruxolitinib at week 32 (78% versus 33%).

Additional analyses from the RESPONSE study to assess durability of response were conducted at week 80 and week 256 following randomisation. Out of 25 patients who had achieved primary response at week 32, 3 patients had progressed by week 80 and 6 patients by week 256. The probability to have maintained a response from week 32 up to week 80 and week 256 was 92% and 74%, respectively (see Table 8).

Table 8      Durability of primary response in the RESPONSE study

Week 32            Week 80             Week 256
Primary response         25/110 (23%)            n/a                  n/a achieved at week 32* n/N (%)
Patients maintaining          n/a              22/25                 19/25 primary response
Probability of                n/a               92%                  74% maintaining primary response
* According to the primary response composite endpoint criteria: absence of phlebotomy eligibility (HCT control) and a ≥35% reduction in spleen volume from baseline.
n/a: not applicable

A second randomised, open label, active-controlled phase 3b study (RESPONSE 2) was conducted in 149 PV patients who were resistant to, or intolerant of, hydroxyurea but without palpable splenomegaly. The primary endpoint defined as the proportion of patients achieving HCT control (absence of phlebotomy eligibility) at week 28 was met (62.2% in the Jakavi arm versus 18.7% in the BAT arm). The key secondary endpoint defined as the proportion of patients achieving complete haematological remission at week 28 was also met (23.0% in the Jakavi arm versus 5.3% in the BAT arm).
JAK API May24 V7                                                            EU SmPC April 2024 Graft-versus-host disease
Two randomised phase 3, open-label, multi-centre studies investigated Jakavi in patients 12 years of age and older with acute GvHD (REACH2) and chronic GvHD (REACH3) after allogeneic haematopoietic stem cell transplantation (alloSCT) and insufficient response to corticosteroids and/or other systemic therapies. The starting dose of Jakavi was 10 mg twice daily.

Acute graft-versus-host disease
In REACH2, 309 patients with grade II to IV corticosteroid-refractory, acute GvHD were randomised 1:1 to Jakavi or BAT. Patients were stratified by severity of acute GvHD at the time of randomisation.
Corticosteroid refractoriness was determined when patients had progression after at least 3 days, failed to achieve a response after 7 days or failed corticosteroid taper.

BAT was selected by the investigator on a patient-by-patient basis and included anti-thymocyte globulin (ATG), extracorporeal photopheresis (ECP), mesenchymal stromal cells (MSC), low dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, or infliximab.

In addition to Jakavi or BAT, patients could have received standard allogeneic stem cell transplantation supportive care including anti-infective medicinal products and transfusion support.
Ruxolitinib was added to continued use of corticosteroids and/or calcineurin inhibitors (CNIs) such as cyclosporine or tacrolimus and/or topical or inhaled corticosteroid therapies per institutional guidelines.

Patients who received one prior systemic treatment other than corticosteroids and CNI for acute GvHD were eligible for inclusion in the study. In addition to corticosteroids and CNI, prior systemic medicinal product for acute GvHD was allowed to continue only if used for acute GvHD prophylaxis (i.e. started before the acute GvHD diagnosis) as per common medical practice.

Patients on BAT could cross over to ruxolitinib after day 28 if they met the following criteria:
•     Failed to meet the primary endpoint response definition (complete response [CR] or partial response [PR]) at day 28; OR
•     Lost the response thereafter and met criteria for progression, mixed response, or no response, necessitating new additional systemic immunosuppressive treatment for acute GvHD, AND
•     Did not have signs/symptoms of chronic GvHD.

Tapering of Jakavi was allowed after the day 56 visit for patients with treatment response.

Baseline demographics and disease characteristics were balanced between the two treatment arms. The median age was 54 years (range 12 to 73 years). The study included 2.9% adolescent, 59.2% male and 68.9% white patients. The majority of enrolled patients had malignant underlying disease.

The severity of acute GvHD was grade II in 34% and 34%, grade III in 46% and 47%, and grade IV in 20% and 19% of the Jakavi and BAT arms, respectively.

The reasons for patients’ insufficient response to corticosteroids in the Jakavi and BAT arms were i) failure in achieving a response after 7 days of corticosteroid treatment (46.8% and 40.6%, respectively), ii) failure of corticosteroid taper (30.5% and 31.6%, respectively) or iii) disease progression after 3 days of treatment (22.7% and 27.7%, respectively).

Among all patients, the most common organs involved in acute GvHD were skin (54.0%) and lower gastrointestinal tract (68.3%). More patients in the Jakavi arm had acute GvHD involving skin (60.4%) and liver (23.4%), compared to the BAT arm (skin: 47.7% and liver: 16.1%).


JAK API May24 V7                                                              EU SmPC April 2024 The most frequently used prior systemic acute GvHD therapies were corticosteroids+CNIs (49.4% in the Jakavi arm and 49.0% in the BAT arm).

The primary endpoint was the overall response rate (ORR) on day 28, defined as the proportion of patients in each arm with a complete response (CR) or a partial response (PR) without the requirement of additional systemic therapies for an earlier progression, mixed response or non-response based on investigator assessment following the criteria by Harris et al. (2016).

The key secondary endpoint was the proportion of patients who achieved a CR or PR at day 28 and maintained a CR or PR at day 56.

REACH2 met its primary objective. ORR at day 28 of treatment was higher in the Jakavi arm (62.3%) compared to the BAT arm (39.4%). There was a statistically significant difference between the treatment arms (stratified Cochrane-Mantel-Haenszel test p<0.0001, two-sided, OR: 2.64; 95% CI: 1.65, 4.22).

There was also a higher proportion of complete responders in the Jakavi arm (34.4%) compared to BAT arm (19.4%).

Day-28 ORR was 76% for grade II GvHD, 56% for grade III GvHD, and 53% for grade IV GvHD in the Jakavi arm, and 51% for grade II GvHD, 38% for grade III GvHD, and 23% for grade IV GvHD in the BAT arm.

Among the non-responders at day 28 in the Jakavi and BAT arms, 2.6% and 8.4% had disease progression, respectively.

Overall results are presented in Table 9.

Table 9      Overall response rate at day 28 in REACH2
Jakavi                                 BAT
N=154                                 N=155 n (%)             95% CI              n (%)               95% CI
Overall response            96 (62.3)        54.2, 70.0           61 (39.4)           31.6, 47.5 OR (95% CI)                                            2.64 (1.65,4.22) p-value (2-sided)                                         p <0.0001
Complete response                    53 (34.4)                              30 (19.4) Partial response                     43 (27.9)                              31 (20.0) 
The study met its key secondary endpoint based on the primary data analysis (data cut-off date: 25-Jul- 2019). Durable ORR at day 56 was 39.6% (95% CI: 31.8, 47.8) in the Jakavi arm and 21.9% (95% CI:
15.7, 29.3) in the BAT arm. There was a statistically significant difference between the two treatment arms (OR: 2.38; 95% CI: 1.43, 3.94; p=0.0007). The proportion of patients with a CR was 26.6% in the Jakavi arm versus 16.1% in the BAT arm. Overall, 49 patients (31.6%) originally randomised to the BAT arm crossed over to the Jakavi arm.

Chronic graft-versus-host disease
In REACH3, 329 patients with moderate or severe corticosteroid-refractory, chronic GvHD were randomised 1:1 to Jakavi or BAT. Patients were stratified by severity of chronic GvHD at the time of randomisation. Corticosteroid refractoriness was determined when patients had lack of response or disease progression after 7 days, or had disease persistence for 4 weeks or failed corticosteroid taper twice.



JAK API May24 V7                                                              EU SmPC April 2024 BAT was selected by the investigator on a patient-by-patient basis and included extracorporeal photopheresis (ECP), low dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, or ibrutinib.

In addition to Jakavi or BAT, patients could have received standard allogeneic stem cell transplantation supportive care including anti-infective medicinal products and transfusion support.
Continued use of corticosteroids and CNIs such as cyclosporine or tacrolimus and topical or inhaled corticosteroid therapies were allowed per institutional guidelines.

Patients who received one prior systemic treatment other than corticosteroids and/or CNI for chronic GvHD were eligible for inclusion in the study. In addition to corticosteroids and CNI, prior systemic medicinal product for chronic GvHD was allowed to continue only if used for chronic GvHD prophylaxis (i.e. started before the chronic GvHD diagnosis) as per common medical practice.

Patients on BAT could cross over to ruxolitinib on cycle 7 day 1 and thereafter due to disease progression, mixed response, or unchanged response, due to toxicity to BAT, or due to chronic GvHD flare.

Efficacy in patients that transition from active acute GvHD to chronic GvHD without tapering off corticosteroids and any systemic treatment is unknown. Efficacy in acute or chronic GvHD after donor lymphocyte infusion (DLI) and in patients who did not tolerate steroid treatment is unknown.

Tapering of Jakavi was allowed after the cycle 7 day 1 visit.

Baseline demographics and disease characteristics were balanced between the two treatment arms. The median age was 49 years (range 12 to 76 years). The study included 3.6% adolescent, 61.1% male and 75.4% white patients. The majority of enrolled patients had malignant underlying disease.

The severity at diagnosis of corticosteroid-refractory chronic GvHD was balanced between the two treatment arms, with 41% and 45% moderate, and 59% and 55% severe, in the Jakavi and the BAT arms, respectively.

Patients’ insufficient response to corticosteroids in the Jakavi and BAT arm were characterised by i) a lack of response or disease progression after corticosteroid treatment for at least 7 days at 1 mg/kg/day of prednisone equivalents (37.6% and 44.5%, respectively), ii) disease persistence after 4 weeks at 0.5 mg/kg/day (35.2% and 25.6%), or iii) corticosteroid dependency (27.3% and 29.9%, respectively).

Among all patients, 73% and 45% had skin and lung involvement in the Jakavi arm, compared to 69% and 41% in the BAT arm.

The most frequently used prior systemic chronic GvHD therapies were corticosteroids only (43% in the Jakavi arm and 49% in the BAT arm) and corticosteroids+CNIs (41% patients in the Jakavi arm and 42% in the BAT arm).

The primary endpoint was the ORR on day 1 of cycle 7, defined as the proportion of patients in each arm with a CR or a PR without the requirement of additional systemic therapies for an earlier progression, mixed response or non-response based on investigator assessment per National Institutes of Health (NIH) criteria.

A key secondary endpoint was failure free survival (FFS), a composite time to event endpoint, incorporating the earliest of the following events: i) relapse or recurrence of underlying disease or death due to underlying disease, ii) non-relapse mortality, or iii) addition or initiation of another systemic therapy for chronic GvHD.

REACH3 met its primary objective. At the time of primary analysis (data cut-off date: 08-May-2020), the ORR at week 24 was higher in the Jakavi arm (49.7%) compared to the BAT arm (25.6%). There JAK API May24 V7                                                               EU SmPC April 2024 was a statistically significant difference between the treatment arms (stratified Cochrane-Mantel- Haenszel test p<0.0001, two-sided, OR: 2.99; 95% CI: 1.86, 4.80). Results are presented in Table 10.

Among the non-responders at cycle 7 day 1 in the Jakavi and BAT arms, 2.4% and 12.8% had disease progression, respectively.

Table 10       Overall response rate at cycle 7 day 1 in REACH3

Jakavi                                 BAT
N=165                                 N=164 n (%)             95% CI               n (%)              95% CI
Overall response            82 (49.7)        41.8, 57.6           42 (25.6)           19.1, 33.0 OR (95% CI)                                            2.99 (1.86, 4.80) p-value (2-sided)                                         p<0.0001
Complete response                    11 (6.7)                                5 (3.0) Partial response                     71 (43.0)                              37 (22.6) 
The key secondary endpoint, FFS, demonstrated a statistically significant 63% risk reduction of Jakavi versus BAT (HR: 0.370; 95% CI: 0.268, 0.510, p<0.0001). At 6-months, the majority of FFS events were “addition or initiation of another systemic therapy for cGvHD” (probability of that event was 13.4% vs 48.5% for the Jakavi and the BAT arms, respectively). Results for “relapse of underlying disease” and non-relapse mortality (NRM) were 2.46% vs 2.57% and 9.19% vs 4.46%, in the Jakavi and the BAT arms, respectively. No difference of cumulative incidences between treatment arms was observed when focusing on NRM only.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Jakavi in all subsets of the paediatric population for the treatment of MF and PV. In GvHD paediatric patients (12 years of age and older), the safety and efficacy of Jakavi are supported by evidence from the randomised phase 3 studies REACH2 and REACH3 (see section 4.2 for information on paediatric use). In REACH2, responses were observed at day 28 in 4/5 adolescent patients with acute GvHD (3 had CR and 1 had PR) in the ruxolitinib arm and in 3/4 adolescent patients (3 had CR) in the BAT arm. In REACH3, responses were observed at cycle 7 day 1 in 3/4 adolescent patients with chronic GvHD (all had PR) in the ruxolitinib arm and in 2/8 adolescent patients (both had PR) in the BAT arm.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Ruxolitinib is a Biopharmaceutical Classification System (BCS) class 1 compound, with high permeability, high solubility and rapid dissolution characteristics. In clinical studies, ruxolitinib is rapidly absorbed after oral administration with maximal plasma concentration (Cmax) achieved approximately 1 hour post-dose. Based on a human mass balance study, oral absorption of ruxolitinib, as ruxolitinib or metabolites formed under first-pass, is 95% or greater. Mean ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single dose range of 5-200 mg. There was no clinically relevant change in the pharmacokinetics of ruxolitinib upon administration with a high-fat meal. The mean Cmax was moderately decreased (24%) while the mean AUC was nearly unchanged (4% increase) on dosing with a high-fat meal.

Distribution

The mean volume of distribution at steady state is approximately 75 litres in MF and PV patients. At clinically relevant concentrations of ruxolitinib, binding to plasma proteins in vitro is approximately 
JAK API May24 V7                                                               EU SmPC April 2024 97%, mostly to albumin. A whole body autoradiography study in rats has shown that ruxolitinib does not penetrate the blood-brain barrier.

Biotransformation

Ruxolitinib is mainly metabolised by CYP3A4 (>50%), with additional contribution from CYP2C9.
Parent compound is the predominant entity in human plasma, representing approximately 60% of the drug-related material in circulation. Two major and active metabolites are present in plasma representing 25% and 11% of parent AUC. These metabolites have one half to one fifth of the parent JAK-related pharmacological activity. The sum total of all active metabolites contributes to 18% of the overall pharmacodynamics of ruxolitinib. At clinically relevant concentrations, ruxolitinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and is not a potent inducer of CYP1A2, CYP2B6 or CYP3A4 based on in vitro studies. In vitro data indicate that ruxolitinib may inhibit P-gp and BCRP.

Elimination

Ruxolitinib is mainly eliminated through metabolism. The mean elimination half-life of ruxolitinib is approximately 3 hours. Following a single oral dose of [14C]-labelled ruxolitinib in healthy adult subjects, elimination was predominately through metabolism, with 74% of radioactivity excreted in urine and 22% via faeces. Unchanged parent substance accounted for less than 1% of the excreted total radioactivity.

Linearity/non-linearity

Dose proportionality was demonstrated in the single and multiple dose studies.
Special populations

Effects of body surface area, age, gender or race
Based on studies in healthy subjects, no relevant differences in ruxolitinib pharmacokinetics were observed with regard to gender and race. In a population pharmacokinetic evaluation in MF patients, no relationship was apparent between oral clearance and patient age or race. The predicted oral clearance was 17.7 l/h in women and 22.1 l/h in men, with 39% inter-subject variability in MF patients. Clearance was 12.7 l/h in PV patients, with a 42% inter-subject variability and no relationship was apparent between oral clearance and gender, patient age or race, based on a population pharmacokinetic evaluation in PV patients. Clearance was 10.4 l/h in patients with acute GvHD and 7.8 l/h in patients with chronic GvHD, with a 49% inter-subject variability. No relationship was apparent between oral clearance and gender, patient age or race, based on a population pharmacokinetic evaluation in GvHD patients. Exposure was increased in GvHD patients with a low body surface area (BSA). In subjects with a BSA of 1 m2, 1.25 m2 and 1.5 m2, the predicted mean exposure (AUC) was respectively 31%, 22% and 12% higher than the typical adult (1.79 m2).

Paediatric population
The pharmacokinetics of Jakavi in paediatric patients <18 years old with MF and PV have not been established. The pharmacokinetics profile observed in adolescent patients with acute or chronic GvHD was comparable to the overall patient population (see section 5.1, “Paediatric population”).
Ruxolitinib has not yet been evaluated in paediatric patients with acute or chronic GvHD below the age of 12.

Renal impairment
Renal function was determined using both Modification of Diet in Renal Disease (MDRD) and urinary creatinine. Following a single ruxolitinib dose of 25 mg, the exposure of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites tended to increase with increasing severity of renal 
JAK API May24 V7                                                              EU SmPC April 2024 impairment, and were most markedly increased in the subjects with severe renal impairment. It is unknown whether the increased metabolite exposure is of safety concern. A dose modification is recommended in patients with severe renal impairment and end-stage renal disease (see section 4.2).
Dosing only on dialysis days reduces the metabolite exposure, but also the pharmacodynamic effect, especially on the days between dialysis.

Hepatic impairment
Following a single ruxolitinib dose of 25 mg in patients with varying degrees of hepatic impairment, the mean AUC for ruxolitinib was increased in patients with mild, moderate and severe hepatic impairment by 87%, 28% and 65%, respectively, compared to patients with normal hepatic function.
There was no clear relationship between AUC and the degree of hepatic impairment based on Child-Pugh scores. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). A dose reduction of approximately 50% is recommended for MF and PV patients with hepatic impairment (see section 4.2).

In GvHD patients with hepatic impairment not related to GvHD, the starting dose of ruxolitinib should be reduced by 50%.