Jagadeesh Aluri

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.

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.

Concentration-Response Modeling of ECG Data From Early-Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk - Experience From the Development Program of Lemborexant.

Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration–response (CR) modeling applied to data from 2 multiple ascending‐dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to “bridge” pharmacokinetic and safety data between Japanese and non‐Japanese subjects (J‐MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high‐precision measurement technique and evaluated using a linear mixed‐effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was –0.00002 milliseconds per ng/mL (90%CI, –0.01019 to 0.01014 milliseconds). The highest observed Cmax was 400 ng/mL, representing a margin 8‐fold above exposures expected for the highest planned clinical dose. The model‐predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, –3.49 to 5.78 milliseconds). In neither the J‐MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early‐phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies.

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.

Bioavailability of three rufinamide oral suspensions compared with the marketed 400-mg tablet formulation: results from a randomized-sequence, open-label, four-period, four-sequence crossover study in healthy subjects.

BACKGROUND Rufinamide is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in patients aged ≥4 years. OBJECTIVES The primary purpose of this study was to compare the relative bioavailability and other pharmacokinetics of rufinamide administered as a 400-mg tablet formulation (reference) with 10 mL of a newly developed 40-mg/mL suspension (test) manufactured using 3 different homogenization speeds in healthy subjects under fed conditions. The study also explored whether homogenization speed had any effect on rufinamide pharmacokinetics when administered as a suspension formulation. METHODS This was a randomized, open-label, crossover, single-dose study in healthy, fed subjects aged 18 to 55 years (inclusive), conducted at a single center in the United Kingdom. Subjects were randomized to 1 of 4 treatment sequences, with each sequence consisting of 4 treatment periods. In each treatment period, subjects received a single dose of either the reference product (400-mg rufinamide tablet) or the test product (10 mL of rufinamide suspension [40 mg/mL] manufactured using 3 different homogenization speeds [1800, 2100, and 3000 revolutions per minute (rpm)]). Serial blood samples were collected for 72 hours after dosing for the measurement of rufinamide in plasma. Primary comparisons between test (suspension) and reference (tablet) formulations focused on AUC from 0 to 72 hours (AUC(0-72 h)) and C(max). The formulations were considered bioequivalent if the ratios of geometric least squares means and associated 90% CIs of AUC(0-72 h) and C(max) were within the predetermined range of 80%-125%, according to the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) requirements. Tolerability was assessed by subject interviews, physical examinations, and laboratory tests. RESULTS Twenty-four healthy subjects were randomized: 8 were male and 16 were female; 22 white, 1 black, and 1 Asian subjects were enrolled. Mean (SD) age was 29.8 (10.0) years. Mean weight was 68.2 (11.0) kg, and mean body mass index was 23.6 (3.0) kg/m(2). Twenty-one subjects completed the study; 2 subjects discontinued because of adverse events (both urinary tract infections considered unrelated to treatment) and 1 because of protocol deviation. The 72-hour pharmacokinetic data for the last complete treatment period before discontinuation were included in group means. The geometric least squares mean C(max) value for the reference tablet formulation was 4840.24 ng/mL; and 4254.87, 4204.29, and 4418.44 ng/mL for the 1800-, 2100-, and 3000-rpm test suspensions, respectively. The ratios of the geometric least squares mean values (test/reference) for C(max) were 0.88 (90% CI, 0.84-0.92), 0.87 (0.83-0.91) and 0.91 (0.88-0.95) for the 1800-, 2100-, and 3000-rpm suspensions, respectively, compared with the tablet formulation. The geometric least squares mean AUC(0-72 h) values were 75,960.48 ng · h/mL for the tablet formulation and 74,279.02, 73,746.03, and 73,701.17 ng · h/mL for the 1800-, 2100-, and 3000-rpm suspensions, respectively. The ratios of the geometric least squares mean values (test/reference) for AUC(0-72 h) were 0.98 (90% CI, 0.95-1.00), 0.97 (0.95-1.00) and 0.97 (0.95-0.99) for the 1800-, 2100-, and 3000-rpm suspensions, respectively, compared with the tablet formulation. The ratios and associated 90% CI limits (for test suspensions to the reference tablet) for AUC(0-72 h) and C(max) were within the FDA and EMA criteria for assuming bioequivalence to the 400 mg tablet. Comparisons among the 3 rufinamide test suspensions also met the regulatory criteria for assuming bioequivalence to one another. Treatment-emergent adverse events (TEAEs) were experienced by 18.2% (4/22) of subjects treated with the 400-mg tablet, 21.7% (5/23) of subjects treated with the 1800-rpm suspension, 26.1% (6/23) of subjects treated with the 2100-rpm suspension, and 8.7% (2/23) of subjects treated with the 3000-rpm suspension. Overall, 54.2% (13/24) of subjects experienced a TEAE; all TEAEs were mild or moderate in severity, with headache being the most frequently reported (37.5% [9/24]). There were no serious adverse events or deaths. CONCLUSION This single-dose study in a small population of fed, healthy subjects found no statistically significant differences in relative bioavailability among each of the 3 test suspensions and the currently marketed 400-mg tablet formulation of rufinamide, meeting FDA and EMA regulatory requirements for assuming bioequivalence.

Pharmacokinetics, Pharmacodynamics, Pharmacogenomics, Safety, and Tolerability of Avatrombopag in Healthy Japanese and White Subjects

Avatrombopag, an orally administered, small‐molecule thrombopoietin receptor (c‐Mpl) agonist, is currently in clinical development for the potential treatment of severe thrombocytopenia in patients with chronic liver disease undergoing an elective procedure. The objectives of this study were to characterize and compare the pharmacokinetics (including the food effect) and pharmacodynamics (platelet count) of avatrombopag following single doses in Japanese and white subjects. Following single dosing under fasted and fed conditions, mean peak concentrations occurred at 5 to 8 hours and subsequently declined with a half‐life of 16 to 18 hours in Japanese and white subjects. Administration with food did not alter the rate or extent of avatrombopag absorption but substantially reduced pharmacokinetic variability relative to the fasted state. CYP2C9 polymorphism (*2, *3) was associated with higher pharmacokinetic variability but not with any clinically important effect on variability in platelet response. Plasma exposures of avatrombopag increased in a dose‐proportional manner over the dose range tested. After a single dose, platelet count increased in a dose‐related manner, reaching a maximum by day 11 and returning to baseline levels by day 27. No clinically important differences were found when avatrombopag pharmacokinetics and pharmacodynamics were compared between Japanese and white subjects. Administration of avatrombopag was generally well tolerated.

E2027, A NOVEL PHOSPHODIESTERASE-9 (PDE9) INHIBITOR IN DEVELOPMENT FOR TREATMENT OF DEMENTIA WITH LEWY BODIES (DLB), SHOWED NO CLINICALLY SIGNIFICANT DRUG INTERACTION WITH DILTIAZEM

effect of short vs long forms of Ab on glutamate and nicotinic neurotransmission. Results: Both the 5-HTTLPR and COMT genotype substantially affect the cognitive trajectory in placebo patients. The beneficial effect of 5HT-6 antagonism is reduced by donepezil or other AChE-I; other negative pharmacodynamic interactions are observed with some antipsychotics and anti-depressants. Aweak 5HT4 agonist while ineffective in mild-to-moderate AD patients shows benefit in the more severe AD case. The cognitive effect of both 5-HT4 and 5-HT6 modulators is heavily dependent upon the baseline state of b-amyloid. Conclusions: Quantitative Systems Pharmacology, when applied to clinical trial design has the capacity to identify and mitigate negative pharmacodynamic interactions that otherwise could reduce the clinical signal of a novel drug, resulting in a negative trial. This would suggest that many trials have failed due to imbalance of comedications, genotypes and b-amyloid status over the different treatment arms.

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

POPULATION PHARMACOKINETIC-PHARMACODYNAMIC (PK/PD) MODELING OF E2027, A SELECTIVE PHOSPHODIESTERASE-9 (PDE9) INHIBITOR, FOLLOWING SINGLE ASCENDING ORAL DOSES IN HEALTHY VOLUNTEERS

months. Patients with Alzheimer’s disease had a transient improvement in cognitive function with conventional therapy (CT), but declined to a level similar to no treatment after 18 months. CT supplemented with herbal medicine provided additional benefit. The effect from herbal medicines became more pronounced over time. Expected decline of MMSE were calculated by formula produced from previous data. CT+H denotes conventional therapy with herbal medicine; CT denotes conventional therapy alone; MMSE, mini-mental state examination. * P<0.05.

Abstract A5: Effects of rifampin on the pharmacokinetics (PK) of lenvatinib (L) in healthy participants.

Background: L is an orally administered multitargeted tyrosine kinase inhibitor of VEGF receptors 1, 2, 3; FGF receptors 1, 2, 3, 4; PDGFR-β; RET; and KIT under clinical investigation in solid tumors at doses of 24 mg/d. This study in volunteers assessed the influence of P-glycoprotein (Pgp) inhibition (single-dose R) and simultaneous CYP3A4 and Pgp induction (multiple-dose R) on L PK parameters. Methods: This was a single-center, single-dose, open-label, sequential, 3-period study. Subjects were administered 3 regimens with a 14-day washout between each treatment. Subjects received a single oral dose of L 24 mg on Day 1 (Period 1), Day 15 (Period 2), and Day 43 (Period 3). In Period 2 on Day 15, subjects received a single oral dose of rifampin 600 mg coadministered with L. In Period 3, subjects received oral rifampin 600 mg/d for 21 days (Days 29 to 49). Results: 15 subjects were enrolled and completed the study. Single-dose rifampin increased free (unbound) L AUC0-∞ (32%) and Cmax (30%). Multidose rifampin decreased free L AUC0-∞ (9%) without a corresponding decrease in Cmax; mean t1/2(free L) decreased by ∼2.5 h (to ∼17 h) following single-dose rifampin and by ∼5 h following multidose R. The 90% confidence intervals (CIs) of the geometric least squares (GLS) mean ratios for Cmax and AUCs were above the upper CI boundary of the prespecified bioequivalence interval of 80%-125% following a single rifampin dose but within the prespecified bioequivalence interval following multidose R. Headache (n=3, 20%) was the most frequently reported treatment-emergent adverse event (TEAE); 5 subjects reported mild or moderate treatment-related TEAEs (n=5, 33%) most frequently nausea (n=3, 20%) and diarrhea (n=2, 13%). Conclusions: L exposure was increased by single-dose rifampin but decreased by multiple rifampin doses. The magnitude of these changes was relatively small and likely not clinically meaningful. ![Figure][1] Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A5. Citation Format: Robert Shumaker, Jagadeesh Aluri, Jean Fan, Gresel Martinez, Gary A. Thompson, Min Ren. Effects of rifampin on the pharmacokinetics (PK) of lenvatinib (L) in healthy participants. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A5. [1]: pending:yes