Gleevec (Imatinib Mesylate) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism of Action

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the bcr-abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). It inhibits proliferation and induces apoptosis in bcr-abl positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. In colony formation assays using ex vivo peripheral blood and bone marrow samples, imatinib shows inhibition of bcr-abl positive colonies from CML patients.

      In vivo, it inhibits tumor growth of bcr-abl transfected murine myeloid cells as well as bcr-abl positive leukemia lines derived from CML patients in blast crisis.

      Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating c-kit mutation.

Pharmacokinetics

The pharmacokinetics of Gleevec^® (imatinib mesylate) have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients. Imatinib is well absorbed after oral administration with C_max achieved within 2-4 hours post-dose. Mean absolute bioavailability is 98%. Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-desmethyl derivative, are approximately 18 and 40 hours, respectively. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg-1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at steady state when Gleevec is dosed once daily. At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and α₁-acid glycoprotein.

      The pharmacokinetics of Gleevec are similar in CML and GIST patients.

Metabolism and Elimination

CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite CGP71588 is similar to that of the parent compound.

      Elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral ¹⁴C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites.

      Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. However, the inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicity.

Special Populations

Pediatric: As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a C_max of 2-4 hours. Apparent oral clearance was similar to adult values (11.0 L/hr/m² in children vs. 10.0 L/hr/m² in adults), as was the half-life (14.8 hours in children vs. 17.1 hours in adults). Dosing in children at both 260 mg/m² and 340 mg/m² achieved an AUC similar to the 400-mg dose in adults. The comparison of AUC_(0-24) on Day 8 vs. Day 1 at 260 mg/m² and 340 mg/m² dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose.

Hepatic Insufficiency:   The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment (Table 1) at imatinib doses ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. However, patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC24/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC24/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Table 1:      Liver Function Classification

Liver Function Test	Normal (n=14)	Mild (n=30)	Moderate (n=20)	Severe (n=20)
	≤ ULN	1.5 ULN	>1.5-3x ULN	>3-10x ULN
	≤ ULN	> ULN (can be normal if Total Bilirubin is >ULN)	Any	Any

ULN=upper limit of normal for the institution

Renal Insufficiency: No clinical studies were conducted with Gleevec in patients with decreased renal function (studies excluded patients with serum creatinine concentration more than 2 times the upper limit of the normal range). Imatinib and its metabolites are not significantly excreted via the kidney.

Drug -Drug Interactions

CYP3A4 Inhibitors: There was a significant increase in exposure to imatinib (mean C_max and AUC increased by 26% and 40%, respectively) in healthy subjects when Gleevec was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). (See PRECAUTIONS.)

CYP3A4 Substrates: Gleevec increased the mean C_max and AUC of simvastatin (CYP3A4 substrate) by 2- and 3.5-fold, respectively, indicating an inhibition of CYP3A4 by Gleevec. (See PRECAUTIONS.)

CYP3A4 Inducers: Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 8 days, followed by a single 400-mg dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold (90% confidence interval = 3.5- to 4.3-fold), which represents mean decreases in C_max, AUC_(0-24) and AUC_(0-∞) by 54%, 68% and 74%, of the respective values without rifampin treatment. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

In Vitro Studies of CYP Enzyme Inhibition: Human liver microsome studies demonstrated that Gleevec is a potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5 with K_i values of 27, 7.5 and 8 µM, respectively. Gleevec is likely to increase the blood level of drugs that are substrates of CYP2C9, CYP2D6 and CYP3A4/5. (See PRECAUTIONS.)

CLINICAL STUDIES

Chronic Myeloid Leukemia

Chronic Phase, Newly Diagnosed: An open-label, multicenter, international randomized Phase 3 study has been conducted in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. This study compared treatment with either single-agent Gleevec^® (imatinib mesylate) or a combination of interferon-alfa (IFN) plus cytarabine (Ara-C). Patients were allowed to cross over to the alternative treatment arm if they failed to show a complete hematologic response (CHR) at 6 months, a major cytogenetic response (MCyR) at 12 months, or if they lost a CHR or MCyR. Patients with increasing WBC or severe intolerance to treatment were also allowed to cross over to the alternative treatment arm with the permission of the study monitoring committee (SMC). In the Gleevec arm, patients were treated initially with 400 mg daily. Dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily to 800 mg daily. In the IFN arm, patients were treated with a target dose of IFN of 5 MIU/m²/day subcutaneously in combination with subcutaneous Ara-C 20 mg/m²/day for 10 days/month.

      A total of 1,106 patients were randomized from 177 centers in 16 countries, 553 to each arm. Baseline characteristics were well balanced between the two arms. Median age was 51 years (range 18-70 years), with 21.9% of patients ≥60 years of age. There were 59% males and 41% females; 89.9% Caucasian and 4.7% Black patients. With a median follow-up of 31 and 30 months for Gleevec and IFN, respectively, 79% of patients randomized to Gleevec were still receiving first-line treatment. Due to discontinuations and cross-overs, only 7% of patients randomized to IFN were still on first-line treatment. In the IFN arm, withdrawal of consent (13.6%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the Gleevec arm was severe intolerance to treatment (25.1%).

      The primary efficacy endpoint of the study was progression-free survival (PFS). Progression was defined as any of the following events: progression to accelerated phase or blast crisis, death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management. The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive Gleevec were compared with patients randomized to receive interferon. Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment. The estimated rate of progression-free survival at 30 months in the ITT population was 87.8% in the Gleevec arm and 68.3% in the IFN arm (p<0.0001), (Figure 1). The estimated rate of patients free of progression to accelerated phase (AP) or blast crisis (BC) at 30 months was 94.8% in the Gleevec arm compared to the 89.6%, (p=0.0016) in the IFN arm, (Figure 2). There were 33 and 46 deaths reported in the Gleevec and IFN arm, respectively, with an estimated 30-month survival rate of 94.6% and 91.6%, respectively (differences not significant). The probability of remaining progression-free at 30 months was 100% for patients who were in complete cytogenetic response with major molecular response (≥3-log reduction in bcr-abl transcripts as measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, compared to 93% for patients in complete cytogenetic response but without a major molecular response, and 82% in patients who were not in complete cytogenetic response at this time point (p<0.001).

Figure 1      Time to Progression (ITT)

Figure 2      Time to Progression to AP or BC (ITT)

      Major cytogenetic response, hematologic response, evaluation of minimal residual disease (molecular response), time to accelerated phase or blast crisis and survival were main secondary endpoints. Response data are shown in Table 2. Complete hematologic response, major cytogenetic response and complete cytogenetic response were also statistically significantly higher in the Gleevec arm compared to the IFN + Ara-C arm.

Table 2      Response in Newly Diagnosed CML Study (30-Month Data)

(Best Response Rate)	Gleevec ®   n=553	IFN+Ara−C n=553
Hematologic Response 1
CHR Rate n (%)	527 (95.3%)*	308 (55.7%)*
[95% CI]	[93.2%, 96.9%]	[51.4%, 59.9%]
Cytogenetic Response 2
Major Cytogenetic Response n (%)	461 (83.4%)*	90 (16.3%)*
[95% CI]	[80.0%, 86.4%]	[13.3%, 19.6%]
Unconfirmed3	87.2%*	23.0%*
Complete Cytogenetic Response n (%)	378 (68.4%)*	30 (5.4%)*
Unconfirmed3	78.8%*	10.7%*
Molecular Response 4
Major Response at 12 Months (%)	40%*	2%*
Major Response at 24 Months (%)	54%*	NA5

*      p<0.001, Fischer’s exact test

¹       Hematologic response criteria (all responses to be confirmed after ≥4 weeks):
      WBC<10 x 10⁹/L, platelet <450 x 10⁹/L, myelocyte + metamyelocyte <5% in blood, no blasts and promyelocytes in blood, basophils <20%, no extramedullary involvement.

²       Cytogenetic response criteria (confirmed after ≥4 weeks): complete (0% Ph+ metaphases) or partial (1%-35%). A major response (0%-35%) combines both complete and partial responses.

³      Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic responses might have had a lesser cytogenetic response on a subsequent bone marrow evaluation.

⁴      Major molecular response criteria: in the peripheral blood, after 12 months of therapy, reduction of ≥3 logarithms in the amount of bcr-abl transcripts (measured by real-time quantitative reverse transcriptase PCR assay) over a standardized baseline.

⁵      Not Applicable: insufficient data, only two patients available with samples

      Physical, functional, and treatment-specific biologic response modifier scales from the FACT-BRM (Functional Assessment of Cancer Therapy - Biologic Response Modifier) instrument were used to assess patient-reported general effects of interferon toxicity in 1,067 patients with CML in chronic phase. After one month of therapy to six months of therapy, there was a 13%-21% decrease in median index from baseline in patients treated with interferon, consistent with increased symptoms of interferon toxicity. There was no apparent change from baseline in median index for patients treated with Gleevec.

Late Chronic Phase CML and Advanced Stage CML: Three international, open-label, single-arm Phase 2 studies were conducted to determine the safety and efficacy of Gleevec in patients with Ph+ CML: 1) in the chronic phase after failure of IFN therapy, 2) in accelerated phase disease, or 3) in myeloid blast crisis. About 45% of patients were women and 6% were Black. In clinical studies 38%-40% of patients were ≥60 years of age and 10%-12% of patients were ≥70 years of age.

Chronic Phase, Prior Interferon -Alpha Treatment: 532 patients were treated at a starting dose of 400 mg; dose escalation to 600 mg was allowed. The patients were distributed in three main categories according to their response to prior interferon: failure to achieve (within 6 months), or loss of a complete hematologic response (29%), failure to achieve (within 1 year) or loss of a major cytogenetic response (35%), or intolerance to interferon (36%). Patients had received a median of 14 months of prior IFN therapy at doses ≥25 x 10⁶ IU/week and were all in late chronic phase, with a median time from diagnosis of 32 months. Effectiveness was evaluated on the basis of the rate of hematologic response and by bone marrow exams to assess the rate of major cytogenetic response (up to 35% Ph+ metaphases) or complete cytogenetic response (0% Ph+ metaphases). Median duration of treatment was 29 months with 81% of patients treated for ≥24 months (maximum = 31.5 months). Efficacy results are reported in Table 3. Confirmed major cytogenetic response rates were higher in patients with IFN intolerance (66%) and cytogenetic failure (64%), than in patients with hematologic failure (47%). Hematologic response was achieved in 98% of patients with cytogenetic failure, 94% of patients with hematologic failure, and 92% of IFN-intolerant patients.

Accelerated Phase: 235 patients with accelerated phase disease were enrolled. These patients met one or more of the following criteria: ≥15%-<30% blasts in PB or BM; ≥30% blasts + promyelocytes in PB or BM; ≥20% basophils in PB; and <100 x 10⁹/L platelets. The first 77 patients were started at 400 mg, with the remaining 158 patients starting at 600 mg.

      Effectiveness was evaluated primarily on the basis of the rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia (i.e., clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. Cytogenetic responses were also evaluated. Median duration of treatment was 18 months with 45% of patients treated for ≥24 months (maximum=35 months). Efficacy results are reported in Table 3. Response rates in accelerated phase CML were higher for the 600-mg dose group than for the 400-mg group: hematologic response (75% vs. 64%), confirmed and unconfirmed major cytogenetic response (31% vs. 19%).

Myeloid Blast Crisis: 260 patients with myeloid blast crisis were enrolled. These patients had ≥30% blasts in PB or BM and/or extramedullary involvement other than spleen or liver; 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg; the remaining 223 patients were started at 600 mg.

      Effectiveness was evaluated primarily on the basis of rate of hematologic response, reported as either complete hematologic response, no evidence of leukemia, or return to chronic phase CML using the same criteria as for the study in accelerated phase. Cytogenetic responses were also assessed. Median duration of treatment was 4 months with 21% of patients treated for ≥12 months and 10% for ≥24 months (maximum=35 months). Efficacy results are reported in Table 3. The hematologic response rate was higher in untreated patients than in treated patients (36% vs. 22%, respectively) and in the group receiving an initial dose of 600 mg rather than 400 mg (33% vs. 16%). The confirmed and unconfirmed major cytogenetic response rate was also higher for the 600-mg dose group than for the 400-mg dose group (17% vs. 8%).

Table 3      Response in CML Studies

	Chronic Phase	Accelerated	Myeloid Blast
	IFN Failure	Phase	Crisis
	(n=532)	(n=235)	(n=260)
		600 mg n=158	600 mg n=223
	400 mg	400 mg n=77	400 mg n=37
	% of patients [CI 95% ]
Hematologic Response 1	95% [92.3−96.3]	71%[64.8-76.8]	31% [25.2−36.8]
Complete Hematologic            Response (CHR)	95%	38%	7%
No Evidence of Leukemia (NEL)	Not applicable	13%	5%
Return to Chronic            Phase (RTC)	Not applicable	20%	18%
Major Cytogenetic Response 2	60% [55.3−63.8]	21% [16.2−27.1]	7% [4.5−11.2]
(Unconfirmed3)	(65%)	(27%)	(15%)
Complete4 (Unconfirmed3)	39% (47%)	16% (20%)	2% (7%)

¹ Hematologic response criteria (all responses to be confirmed after ≥4 weeks):

CHR:      Chronic phase study [WBC <10 x 10⁹/L, platelet <450 x 10⁹/L, myelocytes + metamyelocytes <5% in blood, no blasts and promyelocytes in blood, basophils <20%, no extramedullary involvement] and in the accelerated and blast crisis studies [ANC ≥1.5 x 10⁹/L, platelets ≥100 x 10⁹/L, no blood blasts, BM blasts <5% and no extramedullary disease]

NEL:      Same criteria as for CHR but ANC ≥1 x 10⁹/L and platelets ≥20 x 10⁹/L (accelerated and blast crisis studies)

RTC:     <15% blasts BM and PB, <30% blasts + promyelocytes in BM and PB, <20% basophils in PB, no extramedullary disease other than spleen and liver (accelerated and blast crisis studies).

BM=bone marrow, PB=peripheral blood

²       Cytogenetic response criteria (confirmed after ≥4 weeks): complete (0% Ph+ metaphases) or partial (1%-35%). A major response (0%-35%) combines both complete and partial responses.

³      Unconfirmed cytogenetic response is based on a single bone marrow cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic responses might have had a lesser cytogenetic response on a subsequent bone marrow evaluation.

⁴       Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least 1 month after the initial bone marrow study.

      The median time to hematologic response was 1 month. In late chronic phase CML, with a median time from diagnosis of 32 months, an estimated 87.8% of patients who achieved MCyR maintained their response 2 years after achieving their initial response. After 2 years of treatment, an estimated 85.4% of patients were free of progression to AP or BC, and estimated overall survival was 90.8% [88.3, 93.2]. In accelerated phase, median duration of hematologic response was 28.8 months for patients with an initial dose of 600 mg (16.5 months for 400 mg, p=0.0035). An estimated 63.8% of patients who achieved MCyR were still in response 2 years after achieving initial response. The median survival was 20.9 [13.1, 34.4] months for the 400-mg group and was not yet reached for the 600-mg group (p=0.0097). An estimated 46.2% [34.7, 57.7] vs. 65.8% [58.4, 73.3] of patients were still alive after 2 years of treatment in the 400-mg vs. 600-mg dose groups, respectively (p=0.0088). In blast crisis, the estimated median duration of hematologic response is 10 months. An estimated 27.2% [16.8, 37.7] of hematologic responders maintained their response 2 years after achieving their initial response. Median survival was 6.9 [5.8, 8.6] months, and an estimated 18.3% [13.4, 23.3] of all patients with blast crisis were alive 2 years after start of study.

      Efficacy results were similar in men and women and in patients younger and older than age 65. Responses were seen in Black patients, but there were too few Black patients to allow a quantitative comparison.

Pediatric CML:   One open-label, single-arm study enrolled 14 pediatric patients with Ph+ chronic phase CML recurrent after stem cell transplant or resistant to interferon-alpha therapy. Patients ranged in age from 3-20 years old; 3 were 3-11 years old, 9 were 12-18 years old, and 2 were >18 years old. Patients were treated at doses of 260 mg/m²/day (n=3), 340 mg/m²/day (n=4), 440 mg/m²/day (n=5) and 570 mg/m²/day (n=2). In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a complete cytogenetic response, and 2 had a minimal cytogenetic response. At the recommended dose of 260 mg/m²/day, 2 of 3 patients achieved a complete cytogenetic response. Cytogenetic response rate was similar at all dose levels.

      In a second study, 2 of 3 patients with Ph+ chronic phase CML resistant to interferon-alpha therapy achieved a complete cytogenetic response at doses of 242 and 257 mg/m²/day.

Gastrointestinal Stromal Tumors

One open-label, multinational study was conducted in patients with unresectable or metastatic malignant gastrointestinal stromal tumors (GIST). In this study, 147 patients were enrolled and randomized to receive either 400 mg or 600 mg orally q.d. for up to 36 months. The study was not powered to show a statistically significant difference in response rates between the 2 dose groups. Patients ranged in age from 18 to 83 years old and had a pathologic diagnosis of Kit (CD117) positive unresectable and/or metastatic malignant GIST. Immunohistochemistry was routinely performed with Kit antibody (A-4502, rabbit polyclonal antiserum, 1:100; DAKO Corporation, Carpinteria, CA) according to analysis by an avidin-biotin-peroxidase complex method after antigen retrieval.

      The primary outcome of the study was objective response rate. Tumors were required to be measurable at entry in at least one site of disease, and response characterization was based on Southwestern Oncology Group (SWOG) criteria.  Results are shown in Table 4.

Table 4 Tumor Response in GIST Trial

	(N=147)
	400 mg n= 73 600 mg n=74
	n (%)
Complete Response	1(0.7)
Partial Response	98 (66.7%)
Total (CR + PR)	99 (67.3% with 95% C.I. 59.1, 74.8)

      There were no differences in response rates between the 2 dose groups. For the 99 responders to imatinib observed in the GIST study, the Kaplan-Meier estimate of median duration of response is 118 weeks (95% CI: 96, not reached) The median time to response was 12 weeks (range was 3-98 weeks).