Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects

Cancer Chemotherapy and Pharmacology - Zanubrutinib (BGB-3111) is a potent Bruton’s tyrosine kinase inhibitor with promising clinical activity in B-cell malignancies. Zanubrutinib was shown...     

Single-dose pharmacokinetics of aztreonam in healthy volunteers and renal failure patients

The pharmacokinetics of aztreonam were studied in 6 healthy male volunteers and 12 male patients with various degrees of chronic renal failure after intravenous bolus injection of 1g of the drug. Serum pharmacokinetics of aztreonam were described by an open, two-compartment kinetic model. The serum levels of aztreonam exceeded the reported minimum inhibitory concentration (MIC)90 for Enterobacteriaceae for 8 hours and up to 24 hours, in healthy volunteers and renal failure patients, respectively. However, the serum levels of the drug exceeded the MIC50 for Pseudomonas aeruginosa for only 4 hours and 12 hours in healthy volunteers and patients, respectively. The half-life of elimination (t 1/2/beta) increased significantly (P less than 0.001) from 1.8 +/- 0.14 h in healthy volunteers and to 4.9 +/- 1.1 h in patients with renal failure. The total serum clearance of aztreonam decreased significantly (P less than 0.001) from 84.2 +/- 7.8 ml/h/kg in healthy volunteers to 30.2 + 9.2 ml/h/kg in patients with renal failure. A linear correlation (r = 0.971, P less than 0.001) was found between creatinine clearance and the total serum clearance of aztreonam. The AUC0-infinity increased significantly (P less than 0.001) from 137.5 +/- 12.2 micrograms/h/ml in healthy volunteers to 464 +/- 114.5 micrograms/h/ml in patients with renal failure.     

Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers

Purpose

To evaluate the effect of food on axitinib pharmacokinetics in healthy volunteers with two different crystal polymorphs.

Methods

Two separate open-label, randomized, single-dose, three-period, crossover trials were conducted. Study I, conducted first using 5-mg axitinib Form IV film-coated immediate-release (FCIR) tablets, enrolled 18 subjects to compare fed versus fasted states and 24 subjects to evaluate the effect of timing of food consumption on axitinib pharmacokinetics. Study II enrolled 30 subjects to assess the effect of food using 5-mg axitinib Form XLI FCIR tablets. Subjects received axitinib after overnight fasting, with limited fasting or, depending on the study design, after consuming high-fat, high-calorie or moderate-fat, standard-calorie meals.

Results

For Form IV FCIR, compared with overnight fasting, axitinib plasma exposure [area under the concentration curve (AUC)] was decreased 23?% when administered with food. For Form XLI FCIR, mean axitinib plasma AUC and maximum plasma concentration (C _max) were 19 and 11?% higher, respectively, with a high-fat, high-calorie meal compared with overnight fasting. When Form XLI FCIR was administered with moderate-fat, standard-calorie meal, AUC and C _max were 10 and 16?% lower compared with overnight fasting. Both formulations were well tolerated. Adverse events, mostly gastrointestinal (7?% with Form IV FCIR and 13?% with Form XLI FCIR), were mild to moderate in both studies.

Conclusions

While axitinib Form IV FCIR was associated with higher plasma exposure after overnight fasting, axitinib Form XLI FCIR can be administered with or without food as differences in axitinib pharmacokinetics under the two conditions were not clinically meaningful.     

Effects of famotidine or an antacid preparation on the pharmacokinetics of nilotinib in healthy volunteers

Purpose

This study evaluated the effects of either famotidine or antacid on the pharmacokinetics of nilotinib in healthy subjects, with the specific focus to explore different dosing separation schemes leading to a minimized drug–drug interaction.

Methods

Fifty-two subjects were randomized to receive the following treatments in a crossover manner: (A) single oral nilotinib 400 mg alone; (B) famotidine 20 mg twice a day for 3 days, followed by a single administration of nilotinib 400 mg and famotidine 20 mg on Day 4, where famotidine was given 2 h after nilotinib; (C) single oral nilotinib 400 mg and antacid suspension 20 mL, where antacid was given 2 h before nilotinib; (D) single oral nilotinib 400 mg and antacid suspension 20 mL, where antacid was given 2 h after nilotinib.

Results

Comparing Treatment B to Treatment A, the geometric mean ratios of nilotinib C _max, AUC_0-tlast, and AUC_0-inf were 0.966, 0.984, and 0.911, respectively (90 % confidence intervals (CIs), 0.875–1.066, 0.905–1.069, and 0.798–1.039, respectively). Nilotinib pharmacokinetic parameters following Treatment C or Treatment D were similar to those after Treatment A; the corresponding 90 % CIs of the geometric mean ratios of C _max, AUC_0-tlast, and AUC_0-inf all fell within the bioequivalence range of 0.8–1.25.

Conclusions

Neither famotidine nor antacid significantly affected nilotinib pharmacokinetics. When concurrent use of an H2 blocker or an antacid is necessary, the H2 blocker may be administered 10 h before and 2 h after nilotinib dose, or the antacid may be administered 2 h before or 2 h after nilotinib dose.     

Effects of demographic variables on vorozole pharmacokinetics in healthy volunteers and in breast cancer patients

Purpose: Vorozole (VOR) is a selective nonsteroidal inhibitor of the cytochrome P450-dependent aromatase that catalyzes the conversion of androgens to estrogens. It is currently being developed as a therapeutic agent in the endocrine treatment of postmenopausal women with breast cancer. This work was aimed to explore the effects of demographic and other variables on VOR pharmacokinetics. Methods: VOR plasma concentration-time data were obtained in healthy volunteers and in breast cancer patients after the oral administration of 2.5 mg of VOR as a single dose or once daily. The data obtained in 6 formal pharmacokinetics (PK) studies with frequent plasma sampling were included in the data base (84 healthy male and female volunteers and 13 breast cancer patients). Also included were data from 2 clinical efficacy trials involving 286 breast cancer patients who were treated for several months (1 sample per visit, up to 14 samples/patient). The nonlinear mixed-effect modeling (NONMEM) approach was applied. The two-compartment linear PK model with first-order absorption parameterized in terms of apparent clearance (CL), apparent central and peripheral volumes of distribution (Vc and Vp, respectively), apparent distributional flow (Q), and absorption constant (k _a ) was used. A population model was developed using data from formal PK studies. The final estimates of fixed and random effect parameters were obtained using both formal study data and clinical-efficacy trial data. Results: The typical CL value obtained after a single dose was lower in patients (4.8 l/h) as compared with healthy volunteers (8.6 l/h) and did not depend on gender. The multiple- to single-dose ratio was 0.76. CL was constant over ages of up to 50 years and then decreased slightly (0.047 l/h per year). The typical CL value did not depend on any demographic variable related to body size (total body weight, WT; body surface area; lean body mass). Q and Vc were proportional to WT (0.17 l h⁻¹ kg⁻¹ and 0.43 l/kg, respectively). Vp was also proportional to WT and was higher in women as compared with men (0.64 and 0.40 l/kg, respectively). The same was true for the apparent steady-state volume of distribution. No effect of race or the duration of therapy (0.5–28 months) was seen. The unexplained variability in CL and the residual variability in VOR plasma concentrations were 39% and 28% (coefficient of variation), respectively. Conclusions: Healthy volunteer/patient, single/multiple dosing differences, and age were identified as the fixed effects influencing the CL of VOR. WT was the main determinant of distributional PK parameters. The peripheral and steady-state volumes of distribution were gender-dependent. In view of the relatively high degree of residual interpatient variability in CL, the slight effect of age on it is unlikely to be clinically significant. Received: 20 April 1997 / Accepted: 9 January 1998     

The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

AG-013736 is an oral anti-angiogenesis agent with activity against a variety of receptor tyrosine kinases, including VEGFR-1, VEGFR-2, VEGFR-3, c-kit, and PDGFR-beta. A phase 2 study was conducted in patients with poor prognosis AML or MDS. Twelve patients (six AML; six MDS) were treated with AG-013736 at a dose of 10mg orally daily for a median of 56 days (range, 1-248 days). Median age was 80 years (range, 58-88 years). Grade 3 or 4 drug-related toxicities included hypertension (42%), mucositis (8%) and deep venous thrombosis (8%). No objective responses occurred; two patients with MDS had stable disease for 8.3 and 6.2 months, respectively. Bone marrow expression of VEGFR-1 and VEGFR-2 was observed in 11% and 0% of patients, respectively. Sustained decreases in soluble VEGFR-2 plasma levels with concomitant elevation in plasma VEGF and placental growth factor levels were obtained during the course of therapy with AG-013736. AG-01736 had minimal biologic or clinical activity in this elderly patient population.     

Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec,STI571) in healthy subjects

Objective This study was carried out to investigate the influence of CYP3A induction with rifampicin on imatinib (Gleevec) exposure.Methods The study employed a single center, single-sequence design. A group of 14 healthy male and female subjects received imatinib as a single 400 mg oral dose on two occasions: on study day 1 and on study day 15. Rifampicin treatment (600 mg once daily) for CYP4503A induction was initiated on study day 8 and maintained until day 18. Imatinib pharmacokinetics were determined up to 96 h after dosing on day 1 (no induction) and on days 15–18 (during concomitant rifampicin). Plasma concentrations of imatinib and its main metabolite CGP74588 were determined using a LC/MS/MS method. The ratio of 6-hydroxycortisol to cortisol excreted in the urine was measured to monitor the induction of CYP3A.Results During concomitant rifampicin administration, the mean imatinib C_max, AUC_0–24 and AUC_0– decreased by 54% (90% CI: 48–60%), 68% (64–70%) and 74% (71–76%), respectively. The increase in clearance (Cl/f) was 385% (348–426%) during rifampicin treatment. The mean C_max and AUC_0–24 of the metabolite CGP74588 increased by 88.6% (68.3%–111.4%) and 23.9% (13.5%–35.2%) after rifampicin pretreatment. However, the AUC_0– decreased by 11.7% (3.3–19.4%). All subjects demonstrated a marked induction of hepatic microsomal CYP3A analyzed by the excretion ratio of 6-hydroxycortisol to cortisol from a mean baseline concentration of 5.6 U to 50.5 U.Conclusion Concomitant use of imatinib and rifampicin or other potent inducers of CYP4503A may result in subtherapeutic plasma concentrations of imatinib. In patients in whom rifampicin or other CYP3A inducers are prescribed, alternative therapeutic agents with less potential for enzyme induction should be selected.This work was submitted as an abstract to the 44th Annual Meeting of The American Society of Hematology (ASH), Philadelphia, USA. Abstract published in Blood, vol 100, no. 11, abstract no. 4364, November 2002.A.E.B., B.P., M.H., A.K.-B. and R.C. are employees of Novartis U.K. and M.S. received grant support from Novartis Pharma AG for the conduct of the study.     

Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results.

PURPOSE: We studied the safety, clinical activity, and pharmacokinetics (PK) of AG-013736, an oral receptor tyrosine kinase inhibitor of vascular endothelial cell growth factor, platelet-derived growth factor, and c-Kit, in patients with advanced cancer. PATIENTS AND METHODS: Patients received fixed doses of AG-013736 orally in 28-day cycles. In the first cohort, patients initially received two single test doses of AG-013736 (10 and 30 mg); subsequent dosing was determined by individual PK parameters. Doses in subsequent cohorts were assigned by using a traditional dose-escalation/de-escalation rule based on observed toxicities in the current and previous cohorts. PK analysis included evaluation of the effect of food and antacid. RESULTS: Thirty-six patients received AG-013736 at doses ranging from 5 to 30 mg by mouth twice daily. The dose-limiting toxicities observed included hypertension, hemoptysis, and stomatitis and were seen primarily at the higher dose levels. The observed hypertension was manageable with medication. Stomatitis was generally tolerable and managed by dose reduction or drug holidays. AG-013736 was absorbed rapidly, with peak plasma concentrations observed within 2 to 6 hours after dosing. The maximum-tolerated dose and recommended phase II dose of AG-013736 is 5 mg, twice daily, administered in the fasted state. No significant drug interaction with antacid was seen. There were three confirmed partial responses and other evidence of clinical activity. CONCLUSION: In this study, we have demonstrated clinical activity and safety of AG-013736 in patients with advanced solid tumors and identified the dose for phase II testing. The unique phase I study design allowed early identification of important absorption and metabolic issues critical to phase II testing of this agent.     

Evaluation of the effect of food and ketoconazole on the pharmacokinetics of the smoothened inhibitor PF-04449913 in healthy volunteers

Purpose

To evaluate the effect of a potent cytochrome P450 3A4 (CYP3A4) inhibitor, ketoconazole, and separately the effect of food on PF-04449913 pharmacokinetics in healthy volunteers.

Methods

This was an open-label, two-sequence, three-period, three-treatment, single-dose, crossover study. Subjects were randomized to receive single doses of 200 mg PF-04449913 after an overnight fast or after consuming a high-fat meal during Period 1 or 2, with a washout period of at least 8 days. In Period 3, all subjects received ketoconazole (400 mg/day) (days 1–7) and a co-administered single 200-mg PF-04449913 dose (day 4).

Results

Geometric mean ratio of PF-04449913 in the presence of ketoconazole versus PF-04449913 alone was 2.40 [90 % confidence interval (CI) 2.15, 2.68] for area under the plasma concentration–time curve from time zero to infinity (AUC_0–inf) and 1.40 (90 % CI 1.24, 1.58) for peak plasma concentration (C _max). The geometric mean ratio for fed state compared with fasted state for AUC_0–inf was 0.87 (90 % CI 0.78, 0.97) and for C _max was 0.66 (90 % CI 0.56, 0.78). PF-04449913 was well tolerated, and all adverse events were mild to moderate.

Conclusions

PF-04449913 plasma exposures and peak concentrations were increased following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for expected PF-04449913 exposures after co-administration of a strong CYP3A4 inhibitor in patients with cancer who routinely receive antifungal azoles. While a high-fat meal decreased PF-04449913 exposure, the differences in plasma exposure under the two conditions were not considered clinically meaningful.     

Effect of axitinib (AG‐013736) on fatigue,thyroid‐stimulating hormone,and biomarkers: A phase I study in Japanese patients

Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, antitumor activity, and recommended starting dose of axitinib in patients with advanced solid tumors. Twelve patients received single‐dose axitinib 5 mg and were monitored for ≥48 h. Continuous 5 mg twice‐daily dosing was then initiated. One patient had dose‐limiting toxicity (grade 3 proteinuria and fatigue). Common treatment‐related adverse events were anorexia, fatigue, and diarrhea. Grade 3 treatment‐related adverse events were fatigue and hypertension. Maximum axitinib plasma concentration occurred 1–4 h after steady‐state dosing. Eleven patients experienced thyroid‐stimulating hormone elevation; time‐course change and fatigue onset appeared to be related in some patients. Significant correlation was observed between thyroid‐stimulating hormone change and area under the plasma concentration–time curve (AUC; r = 0.80, P = 0.005). Axitinib decreased plasma soluble vascular endothelial growth factor receptor 2 (s‐VEGFR2), with significant correlation between change in s‐VEGFR2 and AUC (r = ?0.92, P < 0.0001). Fluorodeoxyglucose positron emission tomography revealed a substantial decrease in tumor metabolic activity associated with axitinib. Tumor size decreased in nine patients. The time‐course of thyroid‐stimulating hormone change appeared correlated with fatigue. There were significant correlations between thyroid‐stimulating hormone or s‐VEGFR2 and axitinib exposure. Axitinib 5 mg twice‐daily is the recommended starting dose for Japanese patients. This trial is registered with ClinicalTrials.gov, identifier NCT00447005. (Cancer Sci 2010) (Cancer Sci 2010; 101: 963–968)     

A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors

BackgroundAxitinib and bevacizumab are targeted therapies against the vascular endothelial growth factor pathway.MethodsPatients with previously treated solid tumors received axitinib (starting dose 5 mg twice daily) combined with FOLFOX plus bevacizumab (1, 2, or 5 mg/kg, cohorts 1–3, respectively), FOLFIRI (cohort 4), or FOLFOX (cohort 5). Safety and pharmacokinetics were assessed.ResultsThirty patients were enrolled (n = 16, 8, and 6 for cohorts 1–3, 4, and 5, respectively). Plasma concentrations and pharmacokinetic (PK) parameters were similar when drugs were administered alone and in various combinations. Most treatment-emergent adverse events (AEs) were mild to moderate and clinically manageable (most common: nausea, fatigue, diarrhea, anorexia, hypertension). Two of the four patients receiving axitinib with FOLFOX plus 5 mg/kg bevacizumab experienced dose-limiting toxicity (DLT) of inability to resume treatment for 14 days following treatment interruption (associated AE: hypertension); the maximum tolerated dose of bevacizumab in this combination was 2 mg/kg. No DLTs occurred with axitinib plus FOLFIRI or FOLFOX. Ten patients had RECIST-confirmed partial tumor responses (objective response rate: 33.3%).ConclusionAxitinib is well tolerated in combination with FOLFOX, FOLFIRI, or FOLFOX plus 2 mg/kg bevacizumab. PK interactions appear to be absent.     

Effect of lenvatinib (E7080) on the QTc interval: results from a thorough QT study in healthy volunteers

Purpose

QT assessment of oncology drugs is generally challenging because they are genotoxic and, of necessity, they require multisite evaluation in cancer patients. Lenvatinib is not genotoxic, therefore, this thorough QT (TQT) study with lenvatinib, a multityrosine kinase inhibitor, was undertaken utilizing healthy volunteers and concentration-effect modeling to project the TQT effect at high plasma levels.

Methods

Fifty-two healthy subjects randomly received single doses of lenvatinib 32 mg, placebo, or moxifloxacin 400 mg in a three-way crossover study. Serial electrocardiograms were recorded, and the effect on placebo-corrected change-from-baseline QTcF (??QTcF) was evaluated. The relationship between lenvatinib plasma concentrations and QTcF was analyzed with linear mixed-effects modeling.

Results

Lenvatinib mildly lowered the heart rate by 5–8 bpm during the first 12 h after dosing. ??QTcF was shortened with a peak effect of ?5.72 ms (90 % confidence interval (90 % CI) ?7.76 to ?3.69 ms) at 6 h postdosing. The upper bound of mean ??QTcF did not exceed 2 ms at any time point postdosing. A concentration-dependent effect of lenvatinib on ??QTcF was identified with an estimated population intercept of ?2.96 ms (90 % CI ?4.49 to ?1.43 ms; P = 0.0016) and a negative slope of ?0.0045 (90 % CI ?4.49 to ?1.43) ms per ng/mL, respectively. The safety profile after a single dose of lenvatinib was acceptable, with adverse events (AEs) of mild-to-moderate severity and no serious AEs.

Conclusions

Lenvatinib had no clinically relevant effect on the QTc interval. Concentration-effect modeling supports the lack of QTc prolongation at high plasma concentrations.     

Effect of Renal Impairment on the Pharmacokinetics and Safety of Axitinib

Background

Axitinib, an inhibitor of vascular endothelial growth factor (VEGF) receptors, is approved as second-line treatment for advanced renal cell carcinoma (RCC). Agents targeting the VEGF pathway may induce renal toxicities, which may be influenced by pre-existing renal dysfunction.

Objective

The objective was to characterize axitinib pharmacokinetics and safety in patients with renal impairment.

Patients and Methods

Effect of renal function (baseline creatinine clearance [CrCL]) on axitinib clearance was evaluated in a population pharmacokinetic model in 207 patients with advanced solid tumors who received a standard axitinib starting dose, and in 383 healthy volunteers. Axitinib safety according to baseline CrCL was assessed in previously treated patients with RCC (n?=?350) who received axitinib in the phase 3 AXIS study.

Results

Median axitinib clearance was 14.0, 10.7, 12.3, 7.81, and 12.6 L/h, respectively, in individuals with normal renal function (≥90 ml/min; n?=?381), mild renal impairment (60–89 ml/min; n?=?139), moderate renal impairment (30–59 ml/min; n?=?64), severe renal impairment (15–29 ml/min; n?=?5), and end-stage renal disease (<15 ml/min; n?=?1). The population pharmacokinetic model adequately predicted axitinib clearance in individuals with severe renal impairment or end-stage renal disease. Grade ≥3 adverse events (AEs) were reported in 63 % of patients with normal renal function or mild impairment, 77 % with moderate impairment, and 50 % with severe impairment; study discontinuations due to AEs were 10 %, 11 %, and 0 %, respectively.

Conclusions

Axitinib pharmacokinetics and safety were similar regardless of baseline renal function; no starting-dose adjustment is needed for patients with pre-existing mild to severe renal impairment.

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Urinary excretion of 5-(hydroxymethyl)uracil in healthy volunteers: Effect of active and passive tobacco smoke

The urinary excretion of 5-(hydroxymethyl)uracil (5-HMUra), one of the major oxidative modifications of thymine, was investigated in 134 healthy volunteers living in North Italy. Overnight urine was collected, and a questionnaire was completed on smoking habits and exposure to environmental tobacco smoke (ETS). 5-HMUra was analyzed by GC/MS, following urine purification by HPLC. 5-HMUra excretion showed an approximately normal distribution, ranging from 0.08 to 0.84 (mean 0.44) nmoles/kg/8 hr and from 3.2 to 18.7 (mean 8.5) nmoles/mmoles creatinine. 5-HMUra excretion was significantly higher in women than in men and in smokers than in non-smokers when results were expressed as the ratio to creatinine. Slightly higher levels of 5-HMUra excretion, expressed as nmoles/mmoles creatinine, were also found in subjects highly exposed to ETS, monitored either as the number of hours of exposure or as the number of smokers in the workplace and at home. Our results show that the urinary excretion of 5-HMUra is higher than that of other oxidized nucleobases, including 8-oxo-7,8-dihydroguanine, and can be slightly modified by environmental factors such as tobacco smoke. These findings suggest that measurement of urinary excretion of 5-HMUra could be useful as a biomarker of oxidative DNA damage and repair, though further research is needed to support these data. Int. J. Cancer 77:40–46, 1998.© 1998 Wiley-Liss, Inc.