Robert Shumaker

Influence of hepatic impairment on lenvatinib pharmacokinetics following single‐dose oral administration

This open‐label, single‐dose study assessed lenvatinib pharmacokinetics (PK) in subjects with normal hepatic function (n = 8) and mild, moderate, or severe hepatic impairment (n = 6 each). Subjects received 10 mg oral lenvatinib, except those with severe hepatic impairment (5 mg). Plasma and urine samples were collected over 14 days; free and total lenvatinib and its metabolites were analyzed using validated chromatography/spectrometry. PK parameters were estimated using noncompartmental analysis. There were no clinically meaningful effects of mild or moderate hepatic impairment on lenvatinib PK. Dose‐normalized Cmax for free lenvatinib was 7.0, 3.7, 5.7, and 5.6 ng/mL in subjects with normal hepatic function, mild, moderate, and severe hepatic impairment, respectively. There was no consistent trend, although dose‐normalized Cmax was lower for all subjects with hepatic impairment. AUCs increased 170% and t1/2 increased (37 versus 23 hours) in subjects with severe hepatic impairment. Changes in exposure based on total plasma concentrations were generally less than those based on free concentrations, suggesting changes in plasma protein binding in subjects with severe hepatic impairment. Lenvatinib was generally well tolerated. Subjects with severe hepatic impairment should begin lenvatinib treatment at a reduced dose of 14 mg versus 24 mg for subjects with normal liver function and subjects with mild or moderate hepatic impairment.

Phase I dose-escalation study of the multikinase inhibitor lenvatinib in patients with advanced solid tumors and in an expanded cohort of patients with melanoma

Purpose: This “3+3” phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors. Experimental Design: Ascending doses of lenvatinib were administered per os twice daily in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort. Results: Seventy-seven patients were treated in 3 cohorts: 18 with intermittent twice-daily dosing (7 days on, 7 days off) of 0.1–3.2 mg; 33 with twice-daily dosing of 3.2–12 mg; and 26 with twice-daily dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg per os twice daily. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n = 9) or unconfirmed PR (uPR, n = 3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD ≥23 weeks was 40.3% (n = 31). Responses (PR/uPR) by disease were as follows: melanoma, 5 of 29 patients (includes 1 patient with NRAS mutation); thyroid, 3 of 6 patients; pancreatic, 1 of 2 patients; lung, 1 of 1 patients; renal, 1 of 1 patients; endometrial, 1 of 4 patients; and ovarian, 1 of 5 patients. AUC0–24 and Cmax increased dose proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P = 0.041 and P = 0.03, respectively). Conclusions: The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients. Clin Cancer Res; 21(21); 4801–10. ©2015 AACR.

Evaluation of the effects of formulation and food on the pharmacokinetics of lenvatinib (E7080) in healthy volunteers.

OBJECTIVE To evaluate the effect of formulation and a high-fat meal on the pharmacokinetics of orally administered lenvatinib (E7080). MATERIALS Lenvatinib 10-mg capsule and tablet. METHODS Pharmacokinetics and safety of a single 10-mg lenvatinib dose were evaluated in healthy subjects in two randomized, two-period, crossover, phase 1, bioavailability trials. The first compared a new capsule formulation with an older tablet formulation (n = 20 subjects); the second evaluated the influence of a standard high-fat meal on the relative bioavailability of the capsule formulation (n = 16 subjects). Geometric least squares mean ratios of AUC0-∞, maximum observed concentration (Cmax), and AUC0-t were determined. tmax, tlag (food effect only), and t1/2,z were also calculated, and descriptive statistics were provided. RESULTS A total of 36 healthy volunteers were enrolled in the two studies (mean ages 29 and 33 years). In the formulation study, AUC0-∞ and AUC0-t of the capsule formulation were ~ 10% less than the tablet formulation, and Cmax for the capsule formulation was ~ 14% lower. 90% Confidence intervals (CIs) for both AUCs were within the 80 - 125% CI, which is generally considered to denote bioequivalence, while the lower bound of the interval for Cmax was 79.8%. tmax and t1/2,z were comparable. For the capsule formulation, the mean (%CV) t1/2,z was 27.6 hours (27.3) and the median (range) tmax was 2.0 hours (2 - 4). In the food effect study, lenvatinibs AUC0-∞ and AUC0-t increased ~ 6% and 4% with the high-fat meal. Cmax following a high-fat meal was 5% lower than following administration in the fasted state. Administration with food delayed lenvatinibs tmax (2 vs. 4 hours). 90% CIs for AUCs were within the 80 - 125% CI, while the CI for Cmax was 72.1 - 126.4%. The single 10-mg dose demonstrated an acceptable tolerability profile; treatment-emergent adverse events occurred in 9 subjects (25%) overall and were typically mild in severity. CONCLUSIONS These studies show that a new capsule formulation produces slightly lower exposure (~10 - 14%) to lenvatinib compared with the original tablet formulation, and that oral administration with a high-fat meal does not significantly affect exposure, although absorption is delayed. Thus, lenvatinib can be administered without regard to the timing of meals.

Model-based treatment optimization of a novel VEGFR inhibitor

AIM To evaluate dosing and intervention strategies for the phase II programme of a VEGF receptor inhibitor using PK-PD modelling and simulation, with the aim of maximizing (i) the number of patients on treatment and (ii) the average dose level during treatment. METHODS A previously developed PK-PD model for lenvatinib (E7080) was updated and parameters were re-estimated (141 patients, once daily and twice daily regimens). Treatment of lenvatinib was simulated for 16 weeks, initiated at 25 mg once daily. Outcome measures included the number of patients on treatment and overall drug exposure. A hypertension intervention design proposed for phase II studies was evaluated, including antihypertensive treatment and dose de-escalation. Additionally, a within-patient dose escalation was investigated, titrating up to 50 mg once daily unless unacceptable toxicity occurred. RESULTS Using the proposed antihypertension intervention design, 82% of patients could remain on treatment, and the mean dose administered was 21.5 mg day⁻¹. The adverse event (AE) guided dose titration increased the average dose by 4.6 mg day⁻¹, while only marginally increasing the percentage of patients dropping out due to toxicity (from 18% to 20.8%). CONCLUSIONS The proposed hypertension intervention design is expected to be effective in maintaining patients on treatment with lenvatinib. The AE-guided dose titration with blood pressure as a biomarker yielded a higher overall dose level, without relevant increases in toxicity. Since increased exposure to lenvatinib seems correlated with increased treatment efficacy, the adaptive treatment design may thus be a valid approach to improve treatment outcome.

Effects of ketoconazole on the pharmacokinetics of lenvatinib (E7080) in healthy participants

Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor under clinical investigation in solid tumors. In vitro evidence indicates that lenvatinib metabolism may be modulated by ketoconazole, an inhibitor of CYP3A4 and p‐glycoprotein.

Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer

AIMS Lenvatinib was recently approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Here, we characterized the pharmacokinetic (PK) profile of lenvatinib and identified intrinsic and extrinsic factors that explain interindividual PK variability in humans. METHODS This population PK analysis used pooled data from 15 clinical studies, including eight phase 1 studies in healthy subjects, four phase 1 studies in patients with solid tumours, two phase 2 studies in patients with thyroid cancer and one phase 3 study in patients with RR-DTC. RESULTS The final pooled dataset included data from 779 subjects receiving 3.2-32 mg oral lenvatinib, mainly once daily as tablets or capsules. Lenvatinib PK was best described by a three-compartment model with linear elimination. Lenvatinib absorption was best described by simultaneous first- and zero-order absorption. The population mean value for lenvatinib apparent clearance (CL/F) was 6.56 l h(-1) [percent coefficient of variation (%CV) 25.5], and was independent of dose and time. The relative bioavailability of lenvatinib in capsule form was 90% vs. tablets (%CV 30.2). The final PK model included significant but marginal effects of body weight (2.8% of CL/F variation), liver-function markers [alkaline phosphatase (-11.7%) and albumin (-6.3%)] and concomitant cytochrome P450 3A4 inducers (+30%) and inhibitors (-7.8%) on lenvatinib CL/F. Lenvatinib PK was unaffected by pH-elevating agents, dose, age, sex, race, alanine aminotransferase, aspartate aminotransferase or bilirubin levels, or renal function. CONCLUSIONS The significant effects of several covariates on lenvatinib PK variability were small in magnitude, and therefore were not considered clinically relevant, or to warrant any dose adjustment.

Development and validation of LC–MS/MS assays for the quantification of E7080 and metabolites in various human biological matrices

To support clinical pharmacokinetic studies with the anticancer agent E7080 (lenvatinib), liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were developed for the quantification of E7080 and four of its metabolites in human plasma, urine and faeces and of E7080 in whole blood. Cross-analyte interferences between metabolites and parent compound were expected and therefore accounted for early in the method development. Plasma, urine and faeces samples were extracted with acetonitrile. Chromatographic separation was achieved on a 50 mm × 2.1 mm I.D. XTerra MS C18 column, with a 0.2 mL/min flow and gradient elution starting with 100% formic acid in water, followed by an increasing percentage of acetonitrile. Whole blood samples were extracted with diethyl ether and extracts were injected on a 150 mm × 2.1mm I.D. Symmetry Shield RP8 column. Detection was performed using an API3000 triple quadrupole mass spectrometer, with a turbo ion spray interface, operating in positive ion mode. Using 250 μL of plasma, E7080 and its metabolites could be quantified between 0.25 and 50.0ng/mL. The quantifiable ranges of E7080 in whole blood, urine and faeces were 0.25-500 ng/mL, 1.00-500 ng/mL and 0.1-25μg/g, using sample volumes of 250 μL, 200 μL and 250 mg, respectively. Calibration curves in all matrices were linear with a correlation coefficient (r(2)) of 0.994 or better. At the lower limit of quantification, accuracies were within ±20% of the nominal concentration with CV values less than 20%. At the other concentrations the accuracies were within ±15% of the nominal concentration with CV values below 15%. The developed methods have successfully been applied in a mass balance study of E7080.

Mltidose: A Multiple-Dose Simulation Program for Linear Systems Characterized by Exponential Functions

MLTIDOSE is a multiple-dose simulation program for use on IBM PC (and compatible) computers. It assumes dose-independent disposition and absorption (i.e., a linear system) and simulates blood concentration-time profiles (over a range of times or at specific times) upon administration of any combination of intravascular (i.v.) (bolus and/or intermittent constant rate infusions) and extravascular (e.v.) doses of fixed or variable size, administered at fixed or variable intervals. Input requirements include pharmacokinetic parameters obtained following single-dose administration (entered from the keyboard or from a data file). Options for printing data to files (e.g., ASCII and DIF) for further use are also provided.

Abstract C116: Lenvatinib (E7080) does not prolong the QTc interval: Results from a thorough QT study in healthy volunteers.

Lenvatinib is an orally administered, tyrosine kinase inhibitor targeting VEGFR1–3, FGFR1–4, PDGFRβ, RET, and KIT, which is currently being studied in patients with solid tumors in doses of 24 mg daily. A previous study in patients with solid tumors treated continuously with 25 mg QD, suggested that Lenvatinib had little or no effect on the QTc interval (mean change-from-baseline QTcF [ΔQTcF] of 2.4 ms). This thorough QT study was conducted to exclude a QTc effect of concern in preparation for phase 3 development. Methods: The effect of Lenvatinib on the QTc interval and on other ECG parameters was studied in 52 healthy male and female volunteers in a randomized, partially double-blinded, 3-way crossover study. The effect of a single dose of 32 mg Lenvatinib on ECG parameters was assessed and the study9s ability to detect a small QTc effect was tested by the inclusion of a positive control, moxifloxacin. Using 12-lead continuous ECG recordings, up to 10 ECGs were collected at each predefined time point before and after dosing. Measurements were performed with the High Precision QT (HAQT) measurement technique. Results: The mean placebo-corrected change from baseline QTcF (ΔΔQTcF) was negative at most timepoints post-dosing and the upper bound of the 90% confidence interval did not exceed 10 ms at any timepoint. Concentration effect modeling (CEM) demonstrated a negative slope of −0.0045 ms/ng/mL with an intercept of −2.96 ms. At the observed geometric mean peak Lenvatinib plasma concentration (370 ng/mL; 90% CI 332 to 412), the predicted ΔΔQTcF was −4.62 ms (90% CI: −5.86 to −3.38), which is consistent with the time matched analysis. Based on CEM, it can also be shown that the ΔΔQTcF effect at plasma concentration up to levels observed in patients with impaired clearance of the drug will not exceed 10 ms. Moxifloxacin prolonged ΔΔQTcF with a peak effect of 12.6 ms and the lower bound of the 90% confidence interval (CI) exceeded 5 ms at all 4 pre-specified timepoints, thereby demonstrating the study9s ability to detect a small QT effect. The precision of the QTc measurement using High Precision QT was very high with a standard deviation of ΔQTcF across treatments of 5.85 ms. No effect of Lenvatinib on the PR and QRS intervals or on T-wave morphology was observed. Lenvatinib seemed to exert a mild heart rate lowering effect of 3 to 8 beats per minute, without correlation to the peak plasma levels. The incidence of treatment emergent AEs (TEAEs) in subjects who received Lenvatinib was similar to that observed in subjects who received moxifloxacin or placebo. Most TEAEs were mild in severity. No severe AEs were observed in this study. Conclusion: In this Phase I thorough QTc study in healthy subjects, at clinically relevant plasma concentrations, Lenvatinib did not prolong the QTc interval and had no other clinically relevant ECG effects. A single dose of 32 mg Lenvatinib was safe and well tolerated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C116.

Abstract 5050: Pharmacodynamic and pharmacokinetic relationship of single agent E7449 in patients with advanced solid tumors or B-cell malignancies

E7449 is a small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP). Preclinical studies reported antitumor activity of single-agent E7449 in BRCA-deficient in vivo models. An open-label, multicenter, phase 1 study was completed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of single-agent E7449. The MTD was determined to be 600 mg/day (n = 8). Treatment-emergent adverse events led to drug withdrawal in 1 patient and dose interruption in 2 patients at this dose level. E7449 treatment at the MTD was associated with substantial and sustained dose-dependent PARP inhibition. The overall response rate was 7.1% (2 confirmed partial responses [PR]) and durable stable disease (≥23 weeks) was observed in 21.4% of patients. Here we report additional PD and PK results from this trial. Patients in this study (N=28) were ≥ 18 years and had measurable, confirmed, advanced solid tumors or B-cell lymphoma that had progressed after approved treatment. Patients received E7449 at 50, 100, 200, 600, or 800 mg/day. Food effect was examined in an MTD expansion cohort. PD assessments included measurement of PARP activity and comet assay to determine the extent of DNA damage. In the food-effect cohort (n=13), PARP inhibition (up to 90%) was sustained during treatment with the MTD of E7449 600 mg/day up to 24 hours post-dose. Peak E7449 plasma concentrations were delayed by 2 hours in fed patients compared with fasted patients. In the PK/PD analysis set, peak plasma concentrations of E7449 were observed at 2 hours following a single dose, and coincided with the lowest levels of poly (ADP-ribose) (PAR; up to 90% inhibition). Of note, while E7449 exposure was highest at the 800 mg dose, the lowest PAR levels were observed at the 600 mg dose. At the time of observed responses, the 2 patients with confirmed PR demonstrated greater than 90% PAR inhibition from baseline. E7449 did not cause a change in the level of DNA damage that could be detected by the comet assay. DNA damage levels remained similar to the damage seen in healthy donors. No significant changes in percent DNA in the electrophoresis comet tail by dose or E7449 plasma concentration were observed. In conclusion, continuous E7449 dosing at 600 mg/day was associated with sustained PARP inhibition. Dose-dependent PARP inhibition was observed and the greatest PARP inhibition occurred at the 600 mg dose. Peak E7449 plasma concentration appeared to coincide with maximal PARP inhibition. These results support E7449 dosing at 600 mg/day. Citation Format: Pallavi Sachdev, Shannon McGrath, Robert Shumaker, Jagadeesh Aluri, Claudio Savulsky. Pharmacodynamic and pharmacokinetic relationship of single agent E7449 in patients with advanced solid tumors or B-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5050. doi:10.1158/1538-7445.AM2017-5050