Ophelia Q. P. Yin

Clinical Pharmacokinetics of the BCR–ABL Tyrosine Kinase Inhibitor Nilotinib

This article describes studies that investigated the pharmacokinetics of nilotinib, a highly specific, oral, second‐generation BCR–ABL tyrosine kinase inhibitor. After a once‐ or twice‐daily regimen at doses ranging from 50 to 1,200 mg/day in 119 patients with chronic myeloid leukemia (CML), the area under the serum concentration–time curve (AUC) and peak serum concentration (Cmax) of nilotinib were found to be nearly dose proportional up to a dose of 400 mg once daily. Solubility‐limited absorption at higher doses was observed, but this was partially overcome by dividing the daily dose into two. For instance, the administration of 400 mg nilotinib twice daily resulted in a 35% increase in AUC as compared to a once‐daily dose of 800 mg. Exploratory pharmacodynamic assessment showed a general trend of greater reduction in white blood cell (WBC) levels with increase in nilotinib concentrations. This finding was consistent with the observation of an 82% reduction in WBC levels in patients after a regimen of 400 mg nilotinib twice daily for 15 days. The type and quantity of food intake variably affected nilotinib absorption. When administered after a high‐fat meal, the AUC of nilotinib increased by 50% in CML patients (n = 10) and by 82% in healthy volunteers (n = 44).

Effect of the Proton Pump Inhibitor Esomeprazole on the Oral Absorption and Pharmacokinetics of Nilotinib

Nilotinib (Tasigna), a highly selective and potent BCR‐ABL tyrosine kinase inhibitor (TkI), is administered orally and has pH‐dependent aqueous solubility, with lower dissolution at higher pH. This study evaluated the effect of esomeprazole on the pharmacokinetics of nilotinib in healthy participants. Twenty‐two participants (6 women, 16 men, mean age of 44.9 ± 12.9 years) were enrolled to receive nilotinib as a single oral 400‐mg dose on days 1 and 13 and esomeprazole as 40 mg once daily on days 8 to 13. Serial blood samples were collected up to 72 hours after nilotinib dosing, and nilotinib serum concentrations were determined by a validated liquid chromatography/ tandem mass spectrometry assay. Gastric pH was also monitored in all participants. When coadministered with esomeprazole, nilotinib Cmax was decreased by 27% and AUC0‐∞ decreased by 34%. Nilotinib tmax was prolonged from 4.0 to 6.0 hours, but t1/2 was not altered. Mean gastric pH was 1.0 ± 0.5 at baseline and increased to 2.79 ± 2.50, 3.98 ± 2.27, 5.30 ± 1.70, 5.38 ± 1.26, and 5.31 ± 1.42 at predose and 1, 2, 3, and 4 hours after the fifth esomeprazole dose, respectively. These results suggested a modest reduction in the rate and extent of nilotinib absorption by esomeprazole. Nilotinib is a TKI that may be used concurrently with esomeprazole or other proton pump inhibitors.

Effect of Grapefruit Juice on the Pharmacokinetics of Nilotinib in Healthy Participants

Nilotinib (Tasigna; Novartis Pharmaceuticals) is a second‐generation BCR‐ABL tyrosine kinase inhibitor newly approved for the treatment of imatinib‐resistant or imatinib‐intolerant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia in chronic phase or accelerated phase. This study evaluated the effect of grapefruit juice on the pharmacokinetics of nilotinib in 21 healthy male participants. All participants underwent 2 study periods during which they received a single oral dose of 400 mg nilotinib with 240 mL double‐strength grapefruit juice or 240 mL water in a crossover fashion. Serial blood samples were collected for the determination of serum nilotinib concentrations by a validated liquid chromatography/tandem mass spectrometry assay. Concurrent intake of grapefruit juice increased the nilotinib peak concentration (Cmax) by 60% and the area under the serum concentration‐time curve (AUC>0–∞) by 29% but did not affect the time to reach Cmax or the elimination half‐life of nilotinib. The most common adverse events were headache and vomiting, which were mild or moderate in severity, and their frequency appeared to be similar between 2 treatments. Based on the currently available information about nilotinib and the observed extent of increase in nilotinib exposure, concurrent administration of nilotinib with grapefruit juice is not recommended.

Effects of imatinib (Glivec) on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in Chinese patients with chronic myelogenous leukaemia.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Imatinib, a tyrosine kinase inhibitor, exhibits a competitive inhibition on the CYP450 2D6 isozyme with a K(i) value of 7.5 microm. However, the clinical significance of the inhibition and its relevance to 2D6 polymorphisms have not been evaluated. The pharmacokinetics of imatinib have been well studied in Caucasians, but not in a Chinese population. Metoprolol, a CYP2D6 substrate, has different clearances among patients with different CYP2D6 genotypes. It is often used as a CYP2D6 probe substrate for clinical drug-drug interaction studies. WHAT THIS STUDY ADDS Co-administration of imatinib at 400 mg twice daily increased the plasma AUC of metoprolol by approximately 23% in 20 Chinese patients with chronic myeloid leukaemia (CML), about 17% increase in CYP2D6 intermediate metabolizers (IMs) (n = 6), 24% in extensive metabolizers (EMs) (n = 13), and 28% for the subject with unknown 2D6 status (n = 1) suggesting that imatinib has a weak to moderate inhibition on CYP2D6 in vivo. * The clearance of imatinib in Chinese patients with CML showed no difference between CYP2D6 IMs and EMs, and no major difference from Caucasian patients with CML based on data reported in the literature. AIMS To investigate the effect of imatinib on the pharmacokinetics of a CYP2D6 substrate, metoprolol, in patients with chronic myeloid leukaemia (CML). The pharmacokinetics of imatinib were also studied in these patients. METHODS Patients (n = 20) received a single oral dose of metoprolol 100 mg on day 1 after an overnight fast. On days 2-10, imatinib 400 mg was administered twice daily. On day 8, another 100 mg dose of metoprolol was administered 1 h after the morning dose of imatinib 400 mg. Blood samples for metoprolol and alpha-hydroxymetoprolol measurement were taken on study days 1 and 8, and on day 8 for imatinib. RESULTS Of the 20 patients enrolled, six patients (30%) were CYP2D6 intermediate metabolizers (IMs), 13 (65%) extensive metabolizers (EMs), and the CYP2D6 status in one patient was unknown. In the presence of 400 mg twice daily imatinib, the mean metoprolol AUC was increased by 17% in IMs (from 1190 to 1390 ng ml(-1) h), and 24% in EMs (from 660 to 818 ng ml(-1) h). Patients classified as CYP2D6 IMs had an approximately 1.8-fold higher plasma metoprolol exposure than those classified as EMs. The oral clearance of imatinib was 11.0 +/- 2.0 l h(-1) and 11.8 +/- 4.1 l h(-1) for CYP2D6 IMs and EMs, respectively. CONCLUSIONS Co-administration of a high dose of imatinib resulted in a small or moderate increase in metoprolol plasma exposure in all patients regardless of CYP2D6 status. The clearance of imatinib showed no difference between CYP2D6 IMs and EMs.

Effects of rifampin and ketoconazole on the pharmacokinetics of nilotinib in healthy participants.

Nilotinib (Tasigna), an orally bioavailable second‐generation BCR‐ABL tyrosine kinase inhibitor, is approved for use in patients with chronic myeloid leukemia in chronic phase and accelerated phase who are resistant or intolerant to prior therapy, including imatinib. Previous in vitro studies indicated that nilotinib metabolism is primarily mediated by CYP3A4. To investigate the effect of CYP3A4 induction and inhibition on nilotinib pharmacokinetics, 2 studies were conducted in healthy volunteers prior to and following treatment with a strong inducer (rifampin) or inhibitor (ketoconazole). In the induction study, administration of rifampin 600 mg once daily for 8 days significantly increased urinary 6β‐hydroxycortisol/cortisol ratio, from a preinduction baseline of 5.8 ± 2.7 to 18.0 ± 10.2 after 8 days of rifampin treatment, confirming an inductive effect on CYP3A4. Nilotinib oral clearance was increased by 4.8‐fold, and the maximum serum concentration (Cmax) and area under the serum concentration‐time curve (AUC) were decreased by 64% and 80%, respectively, in the induced state compared with baseline. In the inhibition study, ketoconazole 400 mg once daily for 6 days increased the Cmax and AUC of nilotinib by 1.8‐ and 3‐fold, respectively, compared with nilotinib alone. These results indicate that concurrent use of strong CYP3A4 inducers or inhibitors may necessitate dosage adjustments of nilotinib and should be avoided when possible.

Dose- and Time-Dependent Pharmacokinetics of Midostaurin in Patients With Diabetes Mellitus

Midostaurin is a novel potent inhibitor of both protein kinase C and the major receptor for vascular endothelial growth factor involved in angiogenesis, presenting a rationale for its use in diabetic retinopathy. This study evaluated the safety and pharmacokinetics of midostaurin following multiple oral doses of midostaurin for 28 days at 4 dose levels (25 mg bid, 50 mg bid, 75 mg bid, 75 mg tid), as well as a single oral 100‐mg dose in patients with diabetes mellitus (n = 9–13 per dose cohort). Pharmacokinetic parameters were determined on days 1 and 28 based on the plasma concentrations of midostaurin and its metabolites, CGP62221 and CGP52421. The plasma exposures (Cmax and AUC0‐ẗ) of midostaurin and metabolites increased less than proportionally over the dose range of 25 to 100 mg, showing a 2.2‐fold increase after the first dose. Midostaurin concentrations increased during the first 3 to 6 days of dosing, then declined with time (by 30%‐50%) until a steady state was achieved, representing an average accumulation factor (R) of 1.7. CGP62221 showed a similar concentration‐time pattern as midostaurin (R = 2.5), but CGP52421 accumulated significantly (R = 18.8). A high‐fat meal was found to significantly increase the Cmax and AUC0–12 h of midostaurin by 1.5‐fold (P = .04) and 1.8‐fold (P = .01), respectively, compared with taking the drug after an overnight fast. Midostaurin administered at 50 to 225 mg/day appeared to be generally safe in this group of patients. The most common treatment‐related adverse events (eg, loose stools, nausea, vomiting, and headache) were found to be dose related, and the frequency increased markedly above the 150‐mg/day dose level.

Effects of hepatic impairment on the pharmacokinetics of nilotinib: An open-label, single-dose, parallel-group study

BACKGROUND Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor approved for the treatment of patients who have imatinib-resistant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic or accelerated phase or who are unable to tolerate imatinib. Nilotinib is metabolized in the liver via oxidation and hydroxylation pathways, mediated primarily by the cytochrome P450 3A4 isozyme. Interpatient variability in systemic exposure to nilotinib has been reported to range from 32% to 64%. OBJECTIVE This study compared the pharmacokinetics of nilotinib in subjects with hepatic impairment and subjects with normal hepatic function. METHODS Hepatic impairment was classified as mild (Child-Pugh grade A), moderate (Child-Pugh grade B), or severe (Child-Pugh grade C). Healthy control subjects were matched with hepatically impaired subjects by age (+/-10 years) and body weight (+/-20%). All subjects received a single oral dose of nilotinib 200 mg under fasted conditions, and serial blood samples were collected at specific times up to 120 hours after dosing. Serum nilotinib concentrations were measured using a validated LC-MS/MS assay with a lower limit of quantification of 2.5 ng/mL. The pharmacokinetic parameters analyzed were C(max), T(max), AUC(0-last), AUC(0-infinity), t(1/2), CL/F, and Vz/F. Tolerability assessments included adverse events (AEs), regular monitoring of clinical laboratory measures (eg, hematology, blood chemistry, urinalysis), physical examinations, vital signs, and ECGs. Each AE was evaluated in terms of its clinical significance, severity, duration, relation to study drug, and action taken. RESULTS The study enrolled 18 subjects with hepatic impairment (all male; age range, 47-67 years; weight range, 73.9-103.9 kg) and 9 healthy controls (all male; age range, 36-62 years; weight range, 73.3-109.5 kg). Among subjects with hepatic impairment, 6 had mild impairment, 6 moderate impairment, and 6 severe impairment. The nilotinib AUC(0-infinity) was a mean of 35%, 35%, and 19% higher in subjects with mild, moderate, and severe impairment, respectively, compared with healthy controls. The nilotinib CL/F was lower in all hepatic-impairment groups compared with healthy controls. The mean (SD) t(1/2) was 15.1 (4.97) and 16.0 (9.13) hours in the mild-impairment and control groups, respectively, but was 21.6 (7.77) and 32.4 (10.7) hours in the moderate- and severe-impairment groups, respectively, reflecting the decrease in CL/F and/or increase in Vz/F in the latter 2 groups. All AEs were mild or moderate, and the frequency of AEs was not associated with the degree of hepatic impairment. AEs included abdominal pain (1 subject with mild impairment), dyspepsia (2 with mild impairment), flatulence (1 with severe impairment), nausea (1 with mild impairment), urinary tract infection (1 with mild impairment), back pain (1 each with mild impairment and severe impairment, 1 control subject), and headache (1 each with mild impairment and severe impairment). CONCLUSIONS After a single 200-mg dose, nilotinib pharmacokinetics were modestly affected by hepatic impairment. The extent of change in nilotinib exposure in subjects with hepatic impairment was generally within the range of variability that has been observed clinically. The results of this study suggest that dose adjustment may not be necessary in patients with hepatic impairment. Nilotinib should be used with caution, and careful clinical monitoring is recommended in this population. ClinicalTrials.gov identifier: NCT00418626.

Nilotinib for imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase, accelerated phase, or blast crisis: A single- and multiple-dose, open-label pharmacokinetic study in Chinese patients

BACKGROUND Nilotinib, an oral second-generation Bcr-Abi tyrosine kinase inhibitor, is approved in the United States and European Union for the treatment of Philadelphia chromosome-positive (Ph+), chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) resistant to or intolerant of prior therapy, including imatinib. Information on the pharmacokinetics of nilotinib in Chinese patients with CML is lacking, and regulatory requirements for registration of this drug are needed in China. OBJECTIVES This study assessed the pharmacokinet-ics of single and multiple oral doses of nilotinib in Chinese patients with CML and compared the pharmacokinetic profiles of nilotinib between the Chinese patients and a subgroup of white patients with CML. METHODS Chinese patients aged > or =18 years with Ph+ CML-CP, CML-AP, or CML-BC (blast crisis) resistant to or intolerant of imatinib were eligible. Patients were administered oral nilotinib 400 mg BID for 15 days. Serial blood samples were collected before and at 1, 2, 3, 5, 8, and 12 hours after the administration of a single dose (day 1) and multiple doses (day 15, steady state). Serum nilotinib concentrations were determined using a validated liquid chromatography-tandem mass spectrometry assay, and pharmacokinetic parameters of nilotinib were calculated using a noncompartmental method. Tolerability was assessed using cardiac assessments; laboratory analysis (hematology, blood chemistry, and urinalysis); and physical examination, including vital signs. RESULTS Twenty-three patients were enrolled (18 men, 5 women; mean age, 40.0 years; mean weight, 68.3 kg; CML-CP, 22 patients; CML-AP, 1). All 23 patients were included in the tolerability analysis. Two patients withdrew consent and discontinued after administration of the first dose; thus, 21 patients were included in the pharmacokinetic analysis. Median T(max) was ~2 hours after administration of single and multiple doses. At steady state, C(min) was 1025.4 ng/mL and C(max) was 2160.7 ng/mL. Mean AUCs from time 0 to the end of the dosing interval tau (AUC(0-tau)) were 5076.3 and 17,751.3 ng . h/mL at days 1 and 15, respectively, representing an accumulation factor of 3.92. Apparent oral clearance (CL/F) was 0.39 L/h/kg (range, 0.12-0.74 L/h/ kg) at steady state. The study found a 42% intersubject variability in nilotinib pharmacokinetics. Steady-state C(max), C(min), AUC(0-tau), and CL/F were not significantly different from those previously reported in a subgroup of white patients with CML who received the same 400-mg BID dose. Rash (11/23 patients [47.8%]) and elevated bilirubin, headache, and muscle pain (4 patients each [17.4%]) were the most frequently reported nonhematologic adverse events. CONCLUSIONS In this pharmacokinetic study in Chinese patients with CML resistant to or intolerant of imatinib, nilotinib 400 mg BID was rapidly absorbed after a single dose and multiple doses. The steady-state pharmacokinetic properties in this population were consistent with those reported previously in white patients with CML.

A mechanism-based population pharmacokinetic model for characterizing time-dependent pharmacokinetics of midostaurin and its metabolites in human subjects.

AbstractBackground and objective: Midostaurin, a novel potent inhibitor of protein kinase C enzyme and class III receptor tyrosine kinases, including Fms-like tyrosine kinase-3 (FLT3) and c-KIT, shows time-dependent pharmacokinetics in human subjects, presumably due to enzyme auto-induction. The purpose of this study was to develop a mechanism-based population pharmacokinetic model to describe the plasma concentration profiles of midostaurin and its metabolites and to characterize the time course of auto-induction. Subjects and methods: Data from 37 diabetic patients who received oral doses of midostaurin (25 mg twice daily, 50 mg twice daily or 75 mg twice daily) for 28 days were analysed using nonlinear mixed-effects modelling. The structural model included a gut compartment for drug input and central and peripheral compartments for midostaurin, with drug output from the central compartment to either of two compartments for the midostaurin metabolites CGP62221 and CGP52421. Different enzyme induction sub-models were evaluated to account for the observed time-dependent decrease in midostaurin concentrations. Results: An enzyme turnover model, with CGP62221 formation (CL1) being a linear process but CGP52421 formation (CL2) being inducible, was found to be most appropriate. In the pre-induced state, CL1 and CL2 of midostaurin were determined to be 1.47 L/h and 0.501 L/h, respectively. At the end of 28 days of dosing, CL2 was increased by 5.2-, 6.6- and 6.9-fold in the 25 mg, 50 mg and 75 mg groups, respectively, resulting in a 2.1- to 2.5-fold increase in total clearance of midostaurin. The final model estimated a mean maximum fold of induction (Emax) of 8.61 and a concentration producing 50% of the Emax (EC50) of 1700 ng/mL (∼2.9 μmol/L) for CGP52421-mediated enzyme induction. Conclusions: The population pharmacokinetic model that was developed was able to describe the time-dependent pharmacokinetic profiles of midostaurin and its auto-induction mechanism. Thus it may be useful for designing an appropriate dosage regimen for midostaurin. The unique feature of this model included a precursor compartment that was able to capture the time delays of auto-induction. The use of such precursor extension in the model may be applicable to other drugs showing long time delays in enzyme auto-induction.

Effects of Nilotinib on Single-Dose Warfarin Pharmacokinetics and Pharmacodynamics

AbstractBackground and Objective: Nilotinib (Tasigna®), a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukaemia in the chronic phase (CML-CP) and the accelerated phase (CML-AP) in patients resistant or intolerant to prior therapy, including imatinib. Nilotinib has shown competitive inhibition of cytochrome P450 enzyme (CYP) 2C9 in vitro, but its effect on CYP2C9 activity in humans is unknown. This study evaluated the effects of nilotinib on the pharmacokinetics and pharmacodynamics of warfarin, a sensitive CYP2C9 substrate, in healthy subjects. Methods: Twenty-four subjects (six female, 18 male, aged 21–65 years) were enrolled to receive a single oral dose of warfarin 25 mg with either a single oral dose of nilotinib 800 mg or matching placebo (all administered 30 minutes after consumption of a high-fat meal) in a crossover design. Serial blood samples were collected post-dose for determining serum concentrations of nilotinib and plasma concentrations of S- and R-warfarin. Prothrombin time (PT) and international normalized ratio (INR) values were determined as pharmacodynamic measures of warfarin activity. CYP2C9 genotyping was performed in all subjects using TaqMan® assay. Results: Sixteen subjects were identified as CYP2C9 extensive metabolizers (EMs) and eight as intermediate metabolizers (IMs). There were no CYP2C9 poor metabolizers. Pharmacokinetic parameters of S- and R-warfarin were similar between the two treatments (warfarin + nilotinib vs warfarin alone) in both the EM and the IM groups. The geometric mean ratios (90% CIs) for the maximum concentration in plasma (Cmax) and area under the concentration-time curve from time zero to infinity (AUC∞) of S-warfarin in plasma in all subjects were 0.98 (0.95, 1.02) and 1.03 (0.99, 1.07), respectively, and for R-warfarin 1.00 (0.96, 1.04) and 1.02 (0.99, 1.04), respectively. Mean ratios for the maximum observed value and AUC from time zero to the last sampling time for PT were 1.00(0.96,1.04) and 1.00(0.98,1.02), respectively, and for the maximum observed value for INR and the AUC from time zero to the last sampling time for INR were 1.00(0.97,1.03) and 1.00(0.99, 1.01), respectively. Mean ± SD serum nilotinib Cmax was 1872 ±560 ng/mL, which is comparable to steady-state Cmax in CML and gastrointestinal stromal tumour patients receiving twice-daily 400 mg doses. Adverse events observed following either treatment were generally consistent with the known safety profiles of both drugs, and no new safety issues were observed. Conclusion: The study results demonstrate that nilotinib has no effect on single-dose warfarin pharmacokinetics and pharmacodynamics. This implies that nilotinib is unlikely to inhibit CYP2C9 activity in human subjects. These findings suggest that warfarin and nilotinib may be used concurrently as needed.