Erik Mannaert

Ibrutinib Dosing Strategies Based on Interaction Potential of CYP3A4 Perpetrators Using Physiologically Based Pharmacokinetic Modeling

Based on ibrutinib pharmacokinetics and potential sensitivity towards CYP3A4‐mediated drug–drug interactions (DDIs), a physiologically based pharmacokinetic approach was developed to mechanistically describe DDI with various CYP3A4 perpetrators in healthy men under fasting conditions. These models were verified using clinical data for ketoconazole (strong CYP3A4 inhibitor) and used to prospectively predict and confirm the inducing effect of rifampin (strong CYP3A4 inducer); DDIs with mild (fluvoxamine, azithromycin) and moderate inhibitors (diltiazem, voriconazole, clarithromycin, itraconazole, erythromycin), and moderate (efavirenz) and strong CYP3A4 inducers (carbamazepine), were also predicted. Ketoconazole increased ibrutinib area under the curve (AUC) by 24‐fold, while rifampin decreased ibrutinib AUC by 10‐fold; coadministration of ibrutinib with strong inhibitors or inducers should be avoided. The ibrutinib dose should be reduced to 140 mg (quarter of maximal prescribed dose) when coadministered with moderate CYP3A4 inhibitors so that exposures remain within observed ranges at therapeutic doses. Thus, dose recommendations for CYP3A4 perpetrator use during ibrutinib treatment were developed and approved for labeling.

Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants

Ibrutinib (PCI‐32765), a potent covalent inhibitor of Brutons tyrosine kinase, has shown efficacy against a variety of B‐cell malignancies. Given the prominent role of CYP3A in ibrutinib metabolism, effect of coadministration of CYP3A perpetrators with ibrutinib was evaluated in healthy adults. Ibrutinib (120 mg [Study 1, fasted], 560 mg [studies 2 (fasted), and 3 (nonfasted)]) was given alone and with ketoconazole [Study 1; 400 mg q.d.], rifampin [Study 2; 600 mg q.d.], and grapefruit juice [GFJ, Study 3]. Lower doses of ibrutinib were used together with CYP3A inhibitors [Study 1: 40 mg; Study 3: 140 mg], as safety precaution. Under fasted condition, ketoconazole increased ibrutinib dose‐normalized (DN) exposure [DN‐AUClast: 24‐fold; DN‐Cmax: 29‐fold], rifampin decreased ibrutinib exposure [Cmax: 13‐fold; AUClast: 10‐fold]. Under nonfasted condition, GFJ caused a moderate increase [DN‐Cmax: 3.5‐fold; DN‐AUC: 2.2‐fold], most likely through inhibition of intestinal CYP3A. Half‐life was not affected by CYP perpetrators indicating the interaction was mainly on first‐pass extraction. All treatments were well‐tolerated.

Helicobacter pylori treatment in children: defining a dose for rabeprazole as a part of a triple therapy regimen.

The proton pump inhibitor, rabeprazole, has been studied in children for the treatment of gastroesophageal reflux disease (GERD). In adults, rabeprazole is indicated for Helicobacter pylori eradication in combination with amoxicillin and clarithromycin. Nonlinear mixed effects modeling was conducted to estimate pharmacokinetic (PK) parameters for rabeprazole and its thioether metabolite from 336 subjects, 35% of whom were children 1–11 years with GERD from phase I and III studies. A 2‐compartment disposition model with a transit absorption model provided the best fit for rabeprazole PK. The steady‐state area under the concentration‐time curves given several candidate doses were simulated to identify a dose per each body weight group that is comparable to a 20 mg twice‐daily dose in adults, which is the recommended dose for treatment of H. pylori in adults. Simulations provided the following recommended twice‐daily weight‐based doses for children ≥1 year and <16 years: 10 mg for 6–10 kg, 15 mg for 10–30 kg, and 20 mg for ≥30 kg.

Single-dose pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment*

Abstract This open-label, single-dose study was designed to characterize pharmacokinetics and safety profile of ibrutinib in hepatically impaired subjects. Each subject received single oral dose of ibrutinib (140 mg) following an overnight fast (hepatic impairment-mild [n = 6], moderate [n = 10], and severe [n = 8]; healthy control [n = 6]). Subjects with hepatic impairment showed significant increase in ibrutinib plasma exposures and fraction unbound ibrutinib. Compared to control group, mean exposure (AUClast; unbound) in mild, moderate, and severe cohorts was 4.1-, 9.8-, 13.4-fold higher, respectively. Terminal half-life trended slightly longer in moderately and severely impaired subjects, but risk of accumulation on repeated dosing appears negligible as half-life did not exceed 10 h. Based on observed effects on exposure, reduced doses are recommended for patients with mild and moderate liver impairment (Child–Pugh Class A and B), whereas 140 mg is considered too high for severely impaired patients (Class-C). A single dose of 140 mg was well tolerated in this study (NCT01767948).

Abstract 4637: Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy treated with chemoimmunotherapy. Such treatment results in high response rates but patients may eventually relapse and require alternate therapies. Ibrutinib (PCI-32765), a recently developed novel treatment, is unique in its mechanism as it inhibits Bruton9s tyrosine kinase, a key kinase in the B-cell receptor signaling pathway. It9s a Biopharmaceutics Classification Systems (BCS) class 2 compound and is metabolized rapidly by CYP3A. Three studies were conducted. The primary objectives were to assess the pharmacokinetics (PK) of ibrutinib under fed and fasted conditions and to assess the impact of food intake timing. Additionally, the safety and tolerability of ibrutinib were assessed. Study 1 was a randomized, open-label, single-center, single-dose, 4-way crossover study in 44 healthy subjects. Study 2 was a multicenter, randomized, repeated-dose crossover study in 16 patients with relapsed or refractory CLL. The ibrutinib dose was 420 mg in both. Study 3 was an open-label, single-center, sequential study to assess absolute bioavailability of ibrutinib 560 mg in 8 healthy subjects. Ibrutinib was well tolerated in these studies. There were no serious adverse events (AEs) or discontinuations due to an AE. There were no clinically significant changes in laboratory safety parameters, electrocardiograms, or vital signs. Administration of ibrutinib to healthy subjects under fasting conditions resulted in approximately 60% of exposure compared to drug intake either 30 min before or 2 h after a high-fat meal. When ibrutinib was taken 30 min after a meal, drug exposure was comparable to the dosing conditions of either 30 min before or 2 h after the meal. Study 2 revealed that under fed conditions, the maximum concentration was 2.24 times greater and the area under the curve was 1.65 times greater compared to the fasted conditions, but similar to uncontrolled food intake conditions. A similar food effect was observed in study 3, in which a standard meal was consumed starting 30 min after dosing. When corrected for repeated dosing in patients, the PK parameters in healthy subjects and patients were comparable. The observed food effect is most likely the result of a decreased (intestinal and hepatic) first-pass effect, rather than an effect on solubilization. Since ibrutinib is a highly permeable compound, residence time in the gut and liver cells could be reduced when mesenteric and portal vein blood flow is increased under fed conditions, making ibrutinib less available to CYP3A clearance. The effect on bioavailability may outweigh the higher clearance due to liver blood flow. In conclusion, food causes no more than a doubling in ibrutinib systemic exposure. Considering the favorable safety profile, ibrutinib can be administered with or without food. Citation Format: Jan de Jong, Juthamas Sukbuntherng, Donna Skee, Joe Murphy, Susan O9Brien, John C. Byrd, Danelle James, Peter Hellemans, Juhui James Jiao, Vijay Chauhan, Italo Poggesi, Erik Mannaert. Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4637. doi:10.1158/1538-7445.AM2014-4637

Abstract B20: Pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment: Results from an open-label, multicenter study.

Background: Ibrutinib is a first-in-class, once-daily, oral covalent inhibitor of Bruton9s tyrosine kinase, and is extensively metabolized by CYP3A. No subjects with clinically significant hepatic impairment have been enrolled in the clinical efficacy and safety studies performed to date and more data are needed to understand the safety of ibrutinib in this patient population. Methods: This was an open-label, multi-center, single-dose study in 30 subjects with pharmacokinetic (PK) sampling up to 96 h postdose. Ibrutinib was administered orally at 140 mg following an overnight fast to non-cancer subjects with mild (n=6), moderate (n=10), and severe (n=8) hepatic impairment according to Child-Pugh, and to age- and weight-matched control subjects (n=6). Results: Subjects with mild, moderate, and severe hepatic impairment, but who were otherwise healthy, showed a significant increase in ibrutinib plasma exposures, as well as fraction unbound ibrutinib, with increasing impairment. Regardless of the severity of hepatic impairment, ibrutinib plasma concentration versus time profiles showed an elimination profile with an initial rapid decline which became gradual towards the terminal phase. Compared to control subjects, mean unbound exposure (AUC last,unbound ) in the mild, moderate, and severe cohorts was 4.4-, 9.6-, and 13-fold higher. Compared with normal hepatic function, C max of unbound ibrutinib increased 5.7- to 9.9- fold with increasing hepatic impairment. Terminal half-life trended slightly higher in moderately and severely impaired subjects, but the risk for accumulation on repeated dosing appears negligible as half-life did not exceed 10 hours. Urinary excretion of unchanged ibrutinib, although increasing with severity of hepatic impairment, remained negligible at Conclusion: Based on the observed effect on plasma exposure, the recommended doses for patients with mild and moderate liver impairment are 280 mg/day and 140 mg/day (Child-Pugh Class A and B), respectively. Since no lower capsule strengths are currently available, it is not recommended to administer ibrutinib to patients with severe liver impairment (Child-Pugh Class C). Citation Format: Donna Skee, Jan De Jong, Peter Hellemans, Dominique Swerts, Deborah Conover, Christopher Jones, Eric Lawitz, Thomas Marbury, William Smith, Vijay Chauhan, Juhui James Jiao, Juthamas Sukbuntherng, Erik Mannaert. Pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment: Results from an open-label, multicenter study. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B20.

Pharmacokinetics of rabeprazole granules versus tablets, and the effect of food on the pharmacokinetics of rabeprazole granules in healthy adults-cross-study comparison.

The primary objective was to compare the pharmacokinetics (PK) of rabeprazole granules versus rabeprazole tablets, and assess the effect of food on the PK of rabeprazole granules. Data from three phase 1, open‐label, single‐dose, randomized, crossover studies in healthy adult participants are presented separately and as a cross‐study comparison; study 1: PK of phase 1 rabeprazole granules versus rabeprazole tablets under fasting conditions; study 2: PK of phase 3 rabeprazole granules versus phase 1 rabeprazole granules; study 3: bioequivalence of to‐be‐marketed rabeprazole granules (sprinkle capsules) versus phase 3 rabeprazole granules; and assessment of the food effect for the to‐be‐marketed rabeprazole granules. Overall, 123 of 130 participants enrolled completed the studies. The overall plasma exposure as measured by area under the plasma concentration–time curve (AUC) was comparable between rabeprazole granules and tablets; mean peak plasma concentration (Cmax) was lower for the granules compared with tablets. The plasma elimination half‐life was short and independent of formulation. Food intake prior to administration of the to‐be‐marketed granules delayed the absorption and reduced the estimated parameters for bioavailability by 55% (Cmax) and 28% (AUCinf). Rabeprazole was well‐tolerated.