Stable isotope-intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults (original) (raw)
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Cancer Chemotherapy and Pharmacology, 2015
% of exposure compared with drug intake either 30 min before, 30 min after (fed), or 2 h after a high-fat meal. Similar food effect was observed (study 3) when ibrutinib was given 30 min before meal. In CLL patients (study 2), the C max and AUC under fasting conditions were 43 and 61 %, respectively, relative to fed conditions. When administered once-daily in uncontrolled food-intake conditions (≥30 min before or 2 h after), exposures were slightly (≈30 %) lower than in fed condition. When corrected for repeated dosing, pharmacokinetic parameters in healthy participants and patients were comparable. Ibrutinib was generally well tolerated in all settings studied. Conclusions Ibrutinib administered in fasted condition reduces exposure to approximately 60 % as compared with dosing in proximity to food-intake, regardless of timing/ type of meal. Because repeated drug intake in fasted condition is unlikely, no food restrictions may be needed to administer ibrutinib. Keywords Chronic lymphocytic leukemia • Food effect • Ibrutinib • Pharmacokinetics • Tyrosine kinase inhibitor Western world is CLL and has a mean onset between 65 and 75 years of age. It is characterized by an accumulation of mature B cells in the blood, lymph nodes, and bone marrow [3]. There were an estimated 15,680 new cases of CLL among the 69,740 newly diagnosed non-Hodgkin's
Effect of Food on the Pharmacokinetics of Quizartinib
Clinical Pharmacology in Drug Development
Quizartinib is an oral, highly potent, and selective type II FMS-like tyrosine kinase 3 inhibitor in development for acute myeloid leukemia. This parallel-group study evaluated potential food effects on quizartinib absorption in healthy subjects who received a single 30-mg dose after overnight fasting (n = 34) or a high-fat, high-calorie meal (n = 30). Blood samples were collected through 504 hours after dosing, and pharmacokinetic parameters calculated were maximum observed concentration (C max) and area under plasma concentration-time curve from time 0 to last quantifiable concentration (AUC last) and from time 0 to infinity (AUC inf). Mean quizartinib pharmacokinetic profiles were similar under fasted and fed conditions. The geometric least squares means ratios (%) for fed/fasted and associated 90% confidence intervals (CIs) for C max , AUC last , and AUC inf were 91.58 (82.15-102.08), 105.39 (90.79-122.35), and 108.39 (91.54-128.34), respectively. The 90%CI for the ratio fell within the 80% to 125% limits for C max and AUC last , with 90%CI for AUC inf slightly outside the limits (ie, 128%). Food delayed quizartinib time to C max by 2 hours. All adverse events were either mild or moderate; no discontinuations due to adverse events occurred. Based on these results, quizartinib can be administered without regard to food.
Cancer Chemotherapy and Pharmacology, 2014
Different compartmental PK models were explored using nonlinear mixed effects modeling. Results A two-compartment PK model with sequential zero-first-order absorption and first-order elimination was able to characterize the PK of ibrutinib. The compound was rapidly absorbed, had a high oral plasma clearance (approximately 1,000 L/h) and a high apparent volume of distribution at steady state (approximately 10,000 L). PK parameters were not dependent on dose, study, or clinical indication. The fasting state was characterized by a 67 % relative bioavailability compared with the meal conditions used in the trials and administration after a high-fat meal. Body weight and coadministration of antacids marginally increased volume of distribution and duration of absorption, respectively. Conclusions The proposed population PK model was able to describe the plasma concentration-time profiles of ibrutinib across various trials. The linear model indicated that the compound's PK was dose independent and time independent.
Drug Metabolism and Disposition, 2014
Downloaded from DMD #60061 P a g e 3 o f 3 2 Abbreviations: AE, adverse events; AUC 24 , area under the concentration-time curve from time 0 to 24 h; AUC∞, AUC from time 0 to infinite time; AUC last, AUC from time 0 to time of the last quantifiable concentration; Abstract: The absorption, metabolism, and excretion of ibrutinib were investigated in healthy men after administration of a single oral dose of 140 mg of 14 C-labeled ibrutinib. The mean (SD) cumulative excretion of radioactivity of the dose was 7.8 (1.4) % in urine and 80.6 (3.1) % in feces with <1% excreted as parent ibrutinib. Only oxidative metabolites and very limited parent compound were detected in feces, and this indicated that ibrutinib was completely absorbed from the GI tract. Metabolism occurred via three major pathways (hydroxylation of the phenyl (M35), opening of the piperidine (M25 and M34), and epoxidation of the ethylene on the acryloyl moiety with further hydrolysis to dihydrodiol (PCI-45227, M37). Additional metabolites were formed by combinations of the primary metabolic pathways or by further metabolism. In blood and plasma, a rapid initial decline in radioactivity was observed along with long terminal t1/2 for total radioactivity. Cmax and AUC for total radioactivity were higher in plasma compared with blood. The main circulating entities in blood and plasma were M21 (sulphate conjugate of a mono-oxidized metabolite on phenoxyphenyl), M25, M34, M37 (PCI-45227) and ibrutinib. At
Journal of Chromatography B
Green tea (GT) is one of the most consumed beverages worldwide. Tyrosine kinase inhibitors (TKIs) belong to the oral targeted therapy that gained much interest in oncology practice, among which are erlotinib (ERL) and lapatinib (LAP). Since green tea polyphenols (GTP) are known to be inhibitors of receptor tyrosine kinases, GTE could likely potentiate the anticancer effect of TKIs, but with a possibility of pharmacokinetic (PK) interaction with co-administered TKIs. In this study, the effect of GTE on the PK of ERL/LAP in rats was studied. UPLC-ESI-MS/MS method has been developed and validated for the quantification of ERL and LAP in rat plasma, using gefitinib (GEF) as the internal standard. Plasma samples were treated extensively by protein precipitation (PPT) followed by solid phase extraction (SPE) using octadecyl C 18/14% cartridges. Chromatographic analysis was carried out on Acquity UPLC BEH TM C18 column with a mobile phase consisting of water: acetonitrile (20: 80, v/v), each with 0.15% formic acid. Quantification was performed in the positive electrospray ionization (ESI +) mode with multiple reaction monitoring (MRM) of the transitions m/z 394.29 → 278.19 (ERL), m/z 581.07 → 365.13 (LAP), and m/z 447.08 → 128.21 (GEF). The method was fully validated as per the FDA guidelines showing linearity over the range of 0.4-1000 (ERL) and 0.6-1000 (LAP) ng/mL with very low lower limit of quantification (LLOQ) of 0.4 and 0.6 ng/mL for ERL and LAP, respectively. The applicability of the method was extended to perform a comparative study of the PK of ERL/LAP following short-term and long-term administration of GTE, compared with their single oral administration. The results revealed that a significant reduction in the oral bioavailability was recorded with both ERL and LAP following the ingestion of GTE particularly for short-term administration. A reduction in C max (AUC) by 67.60% (69.50%) and 70.20% (73.96%), was recorded with short-term administration of GTE, compared with only 16.03% (21.09%) and 13.53% (22.12%) reduction for ERL and LAP, respectively, with long-term administration. Thus patients taking TKIs should preferably avoid drinking GT or ingesting GTE capsules during the period of treatment with TKIs.
European Journal of Clinical Nutrition, 2004
More than a decade has passed since it was unintentionally discovered that grapefruit juice interacts with certain drugs. The coadministration of these drugs with grapefruit juice can markedly elevate drug bioavailability, and can alter pharmacokinetic and pharmacodynamic parameters of the drug. The predominant mechanism for this interaction is the inhibition of cytochrome P-450 3A4 in the small intestine, resulting in a significant reduction of drug presystemic metabolism. An additional mechanism is, presumably, the inhibition of P-glycoprotein, a transporter that carries drug from the enterocyte back to the gut lumen, resulting in a further increase in the fraction of drug absorbed. Some calcium channel antagonists, benzodiazepines, HMG-CoA reductase inhibitors and cyclosporine are the most affected drugs. A single exposure to one glass of the juice can usually produce the maximal magnitude of the interaction. The data available so far, concerning this interaction and its clinical implications, are reviewed in this article. It is likely that more information regarding this interaction will accumulate in the future, and awareness of such is necessary for achieving optimal drug therapy.
PeerJ
Background Erlotinib (ERL) and Gefitinib (GEF) are considered first line therapy for the management of non-small cell lung carcinoma (NSCLC). Like other tyrosine kinase inhibitors (TKIs), ERL and GEF are mainly metabolized by the cytochrome P450 (CYP450) CYP3A4 isoform and are substrates for transporter proteins with marked inter-/intra-individual pharmacokinetic (PK) variability. Therefore, ERL and GEF are candidates for drug-drug and food-drug interactions with a consequent effect on drug exposure and/or drug-related toxicities. In recent years, the consumption of flavoured water (FW) has gained in popularity. Among multiple ingredients, fruit extracts, which might constitute bioactive flavonoids, can possess an inhibitory effect on the CYP450 enzymes or transporter proteins. Therefore, in this study we investigated the effects of different types of FW on the PK parameters of ERL and GEF in Wistar rats. Methods ERL and GEF PK parameters in different groups of rats after four weeks...
2010
The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of 14 C-labeled brivanib alaninate and the safety and tolerability of brivanib after multiple doses in patients with advanced or metastatic solid tumors. This was a two-part, single-center, open-label, single oral-dose (part A) followed by multiple-dose (part B) study in patients with advanced or metastatic solid tumors. In part A, patients received a single dose of [ 14 C]brivanib alaninate and in part B patients received 800 mg of nonradiolabeled brivanib alaninate every day. Four patients (two white, two black: two with non-small-cell lung cancer, one with ovarian cancer, and one with renal cell carcinoma) were treated in both parts. The median time to reach the maximal plasma concentration of brivanib was 1 h, geometric mean maximal plasma con-centration was 6146 ng/ml, mean terminal half-life was 13.8 h, and geometric mean apparent oral clearance was 14.7 l/h. After a single oral dose of [ 14 C]brivanib alaninate, 12.2 and 81.5% of administered radioactivity was recovered in urine and feces, respectively. Brivanib alaninate was completely converted to the active moiety, brivanib, and the predominant route of elimination was fecal. Renal excretion of unchanged brivanib was minimal. Brivanib was well tolerated; fatigue was the most frequent adverse event occurring in all patients and the most frequent treatment-related adverse event in three (75%). The best clinical response in one patient was stable disease; the other three had progressive disease. Brivanib alaninate was rapidly absorbed and extensively metabolized after a single 800-mg oral dose; the majority of drugrelated radioactivity was excreted in feces. (2009) Mass balance, pharmacokinetics and metabolism of 14 C of brivanib in subjects with advanced or metastatic solid tumors. to reach maximum observed plasma concentration; AUC 0-inf , area under the concentration-time curve from time 0 extrapolated to infinity; AUC 0-T , AUC from time 0 to the last quantifiable concentration; t 1/2 , terminal elimination half-life; CLR, renal clearance; CL/F, apparent total body clearance.
Effect of grapefruit juice on bioavailability of montelukast
The Laryngoscope, 2012
The aim of this study was to investigate possible interactions between grapefruit juice and montelukast for up to 4 hours. Study Design: A prospective, crossover study with 23 healthy volunteers was performed in two sessions. Methods: In the first session, volunteers were treated with oral montelukast 10 mg once daily with 250 ml water. After a 10-day washout period, the same volunteers were treated with 10 mg montelukast with 250 ml grapefruit juice. Blood samples were collected 2, 3, and 4 hours after drug administration and kept at À80 C after both applications. Plasma samples were analyzed for montelukast concentration. Results: The mean plasma concentration of montelukast across all time intervals was significantly greater (P ¼ 0.0001) for those given grapefruit juice (517, 484, and 440) versus those treated with water (366, 356, and 292). Moreover, with respect to the time the sample was collected, there was no significant difference (P ¼ 0.13) in the mean total plasma concentration up to 4 hours after montelukast ingestion for either group. There was a significant difference between the groups according to the area under curve with regard to marginal and cumulative values for all different time intervals (P < 0.05). Conclusions: Plasma concentration of montelukast was higher when administered with grapefruit juice, as compared to with water. This may have been due to the effect of grapefruit on liver metabolism of montelukast and the cytochrome P450 system.