BOSULIF (bosutinib) tablet Action And Clinical Pharmacology

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Mechanism of Action

BOSULIF belongs to a pharmacologic class of drugs known as tyrosine kinase inhibitors. BOSULIF inhibits the activity of the oncogenic Bcr-Abl kinase that promotes CML, and Src-family of kinases such as Src, Lyn and Hck, which participate in Bcr-Abl signaling. Modeling studies indicate that BOSULIF binds the kinase domain of Bcr-Abl. BOSULIF also inhibits other kinases such as EPH, TEC and STE20 kinases. BOSULIF minimally inhibits platelet-derived growth factor (PDGF) receptor and c-Kit (protein-tyrosine kinase Kit).

BOSULIF exhibits potent anti-leukemic activity in imatinib-sensitive and resistant BCR-ABL-dependent leukemia cells. In in vitro studies, BOSULIF inhibits proliferation and survival of established CML cell lines, Ph+ ALL cell lines, and patient-derived primary primitive CML cells. BOSULIF inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines, except T315I. Bosutinib treatment reduced the size of CML tumors growing in nude mice and inhibited growth of murine myeloid tumors expressing imatinib-resistant forms of Bcr-Abl. BOSULIF also inhibits receptor tyrosine kinases c-Fms, EphA and B receptors, Trk-family kinases, Axl-family kinases, Tec-family kinases, some members of the ErbB-family, the non-receptor tyrosine kinase Csk, serine/threonine kinases of the Ste20-family and two calmodulin-dependent protein kinases.

Pharmacodynamics

QT/QTc Prolongation

The effect of single dose BOSULIF 500 mg administration on corrected QT interval (QTcF=QT/RR0.33) was evaluated in a two part study (Part A & Part B).

Part A was a randomized, double-blind (with respect to bosutinib), 3 period crossover in which healthy male subjects (N=58) received single doses of bosutinib 500 mg, placebo, or moxifloxacin 400 mg in the fed state. The maximum observed QTcF difference from placebo during treatment with bosutinib 500 mg was 2.46 msec (90% CI: [0.54, 4.38]) at 8 h. The results for Part A cannot be extrapolated to steady-state use of bosutinib because the maximal plasma concentrations achieved after the single 500 mg dose (mean Cmax 114±39.8 ng/mL) were only 42-57% of the maximal plasma concentrations observed in the target patient population receiving bosutinib 500 mg at steady-state (mean Cmax 200-273 ng/mL).

Part B was a randomized, double-blind (with respect to bosutinib), 2 period crossover in which healthy male subjects (N=54) were administered a single dose of test article (bosutinib 500 mg or placebo) concomitantly with ketoconazole in the fed state. On day -1, ketoconazole was administered as a single oral 400 mg dose in each period. On day 1, the subjects received bosutinib 500 mg or placebo concomitantly with 400 mg ketoconazole in the fed state. On days 2 and 3, subjects received single oral doses of 400 mg ketoconazole. Part B did not have a placebo only treatment arm or a drug-free baseline. The maximal mean difference in QTcF interval between ketoconazole plus bosutinib and ketoconazole plus placebo was 7.36 msec (90% CI: [5.09, 9.63]) at 8 h on day 1. The mean Cmax achieved after a single 500 mg dose of bosutinib in the presence of ketoconazole was 326±77.2 ng/mL.

Patients with hepatic impairment may be at increased risk of developing QT/QTc prolongation. In a single-oral-dose (200 mg) study in non-CML patients, treatment-emergent QTc prolongation was observed in 50% of hepatically impaired patients (Child-Pugh class A, B or C), versus 11% of matching healthy volunteers; the frequency, magnitude and duration of QTc prolongation appeared to increase with severity of hepatic impairment: all 6 patients with Child-Pugh C at baseline had QTc prolongation following treatment, versus 1/6 and 2/6 of patients of Child-Pugh A and B, respectively. Except for one patient who recorded QTc of 450 msec at day 1 predose, all other Child-Pugh C patients (n=5) had QTc prolongation starting 3 hours post-dose lasted from Day 4 and beyond. The greatest relative QTc increase over baseline was 48 msec in one patient with Child-Pugh C hepatic impairment. However, no QTc > 500 msec was reported for any volunteer in the study.

Pharmacokinetics

Table 11. Summary of BOSULIF’s Pharmacokinetic Parameters in CML Fed Patients at Steady-state after 15 Consecutive Days of 400, 500 and 600 mg Oral Dose
Data are mean (standard deviation) values.
a: n = 7
b: n = 9

Dose

(mg)

N

Cmax

(ng/mL)

t½

(h)

AUC0-24

(ng*h/mL)

Clearance (CL/F)

(L/h)

400

3

146 (20)

46.0 (32.3)

2720 (442)

150 (23)

500

3

200 (12)

21.7 (4.6)

3650 (425)

138 (17)

600

10

208 (73)

25.9 (24.9)a

3630 (1270)b

185 (66)b

Absorption: Following administration of a single oral dose of BOSULIF (500 mg) with food in healthy subjects, the absolute bioavailability was 34%. Absorption was relatively slow, with a median time-to-peak concentration (tmax) reached after 6 hours. The mean (SD) Cmax value was 90 (24) ng/mL and the mean AUC was 2060 (448) ng•h/mL after a single dose of bosutinib (400 mg) with food; and the mean standard deviation (SD) Cmax value was 112 (29) ng/mL, and the mean (SD) AUC was 2740 (790) ng•h/mL after a single dose of bosutinib (500 mg) with food in healthy subjects, respectively.

Food increased bosutinib Cmax 1.8-fold and bosutinib AUC 1.7-fold compared to the fasting state. The mean (SD) Cmax value was 146 (20) ng/mL and the mean (SD) AUCtau was 2720 (442) ng•h/mL after 15 daily dosing of bosutinib tablet (400 mg) with food; and the mean (SD) Cmax value was 200 (12) ng/mL, and the mean (SD) AUCtau was 3650 (425) ng•h/mL after 15 daily dosing of bosutinib tablet (500 mg) with food in patients with CML.

Bosutinib displays pH-dependent aqueous solubility in vitro. Lansoprazole decreases bosutinib exposure (see Drug-Drug Interactions).

Distribution: After administration of a single intravenous (IV) dose of BOSULIF 120 mg to healthy subjects, bosutinib had a mean volume of distribution (standard deviation) of 2441 (796) L suggesting that bosutinib is extensively distributed to extra-vascular tissue and/or with low oral bioavailability. In an animal study with rat, bosutinib did not cross the blood-brain barrier.

Bosutinib was highly bound to human plasma proteins in vitro (94%) and ex vivo in healthy subjects (96%), and binding was not concentration-dependent.

Metabolism: In vitro studies with human liver microsomes indicated that the major CYP450 isozyme involved in the metabolism of bosutinib is CYP3A4. No metabolism of bosutinib was observed with CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A5. Flavin-containing monooxygenase enzymes (FMO1, FMO3, and FMO5) are capable of metabolizing bosutinib to its N-oxide metabolite. In vitro and in vivo studies indicated that bosutinib (parent compound) undergoes predominantly hepatic metabolism (by CYP3A4) in humans. Following administration of single or multiple doses of BOSULIF (400 mg or 500 mg) to humans, the major circulating metabolites appeared to be oxydechlorinated (M2) and N-desmethylated (M5) bosutinib, with bosutinib N-oxide (M6) as a minor circulating metabolite. The systemic exposure of N-desmethylated metabolite was 25% of the parent compound, while the oxydechlorinated metabolite was 19% of the parent compound. All three metabolites exhibited activity that was ≤ 5% that of bosutinib in a Src-transformed fibroblast anchorage-independent proliferation assay. In feces, bosutinib and N-desmethyl bosutinib were the major drug-related components.

Elimination: In 14 healthy subjects given a single IV dose (120 mg) of bosutinib, the mean (SD) terminal phase elimination half-life (t1/2) was 35.5 (8 .5) hours, and the mean (SD) clearance (Cl ) was 63.6 (14.1) L/h. In six healthy male subjects given a single oral dose of [14C] radiolabeled bosutinib, an average of 94.6% of the total administered radioactivity was recovered in 9 days; feces (91.3% of dose) was the major route of excretion, with 3.29% of the dose recovered in urine. Excretion was rapid, with 75% of the dose recovered within 96 hours. Excretion of unchanged bosutinib in urine was low, approximately 1% of the administered dose, in healthy subjects.

Linearity / Non-linearity: Both observed Cmax and AUC values of bosutinib increased with increasing dose in a linear fashion when single, ascending oral doses of 200- to 800 mg bosutinib were administered with food to healthy subjects. At steady state (reached in approximately 15 days), Cmax and AUC values of bosutinib increased in a less than dose proportional manner between 500 and 600 mg taken with food in CML patients in a dose escalation study (see Table 8). The interpretation of bosutinib dose proportionality finding at steady state may be limited by small number of subjects and high interindividual variability. Based on a population pharmacokinetic analysis in cancer patients, bosutinib is predicted to exhibit dose proportional increase over the dose range of 200 -600 mg with food.

OTHER CONSIDERATIONS:

Special Populations and Conditions

Pediatrics (<18 years of age): The safety and efficacy of BOSULIF in patients less than 18 years of age have not been evaluated. No data are available.

Geriatrics (≥ 65 years of age): No clinically relevant age-related pharmacokinetic differences have been observed in the elderly. No specific dose recommendation is necessary in the elderly.

Hepatic Impairment: Metabolism of bosutinib is mainly hepatic. Clinical studies have excluded patients with ALT and/or AST >2.5 (or >5, if related to disease) x ULN range and/or bilirubin >1.5 x ULN range.

In a single-oral-dose study, BOSULIF (200 mg) administered with food was evaluated in a cohort of 18 hepatically impaired subjects (Child-Pugh classes A, B, and C) and 9 matched healthy subjects. Cmax of bosutinib in plasma increased 2.4-fold, 2-fold, and 1.5-fold, respectively, in Child-Pugh classes A, B, and C; and bosutinib AUC in plasma increased 2.3-fold, 2-fold, and 1.9-fold, respectively. The t1/2 of bosutinib increased 1.6-fold, 2.0-fold and 2.0-fold and CL/F decreased to 45, 50 and 52% in hepatic impaired patients (subjects (Child-Pugh classes A, B, and C) as compared to the healthy subjects (see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS, Special Populations; DOSAGE AND ADMINISTRATION, Dosing Considerations; ADVERSE REACTIONS and ACTION AND CLINICAL PHARMACOLOGY).

Renal Impairment: In a dedicated renal impairment trial, a single dose of Bosulif 200 mg was administered with food to 26 non-CML subjects with mild, moderate or severe renal impairment and to 8 matching healthy volunteers. Renal impairment was based on CrCl (calculated by Cockcroft-Gault formula) of <30 mL/min (severe renal impairment), 30 ≤ CrCl ≤50 mL/min (moderate renal impairment), or 50 <CrCl ≤80 mL/min (mild renal impairment). Subjects with moderate and severe renal impairment had an increase in AUC over healthy volunteers of 35 % (90%CI: [-1.0, 85.0]) and 60% (90%CI: [16.0, 121.0]), respectively. Bosutinib exposure was not changed in subjects with mild renal impairment. Based on pharmacokinetic linearity, a daily dose of 400 mg in patients with moderate renal impairment and 300 mg in patients with severe renal impairment are predicted to result in an area under the concentration curve (AUC) that are 108% and 96%, respectively of the AUC seen in patients with normal renal function receiving 500 mg daily. The half-life (57, 55 and 57 hours) of bosutinib in subjects with mild, moderate and severe renal impairment was similar to its half-life (54 hours) in healthy subjects. CL/F values of bosutinib in healthy subjects and in subjects with mild, moderate and severe renal impairment were 3021, 2965, 2238 and 1892 mL/min.