Helen Tomkinson

Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies

BackgroundZibotentan (ZD4054) is a specific endothelin A (ETA) receptor antagonist being investigated for the treatment of prostate cancer. As zibotentan is eliminated by renal and metabolic routes, clearance may be reduced in patients with hepatic or renal impairment, leading to greater drug exposure.MethodsOpen-label studies investigated the PK and tolerability of zibotentan in subjects with hepatic or renal impairment, compared with those with normal organ function. In the hepatic and renal studies, respectively, subjects were divided into categories using Child-Pugh classification or 24-hour urine creatinine clearance (mild, moderate, or severe impairment and normal function). Each subject received a single oral dose of zibotentan 10 mg and PK sampling was undertaken. Within the hepatic study, AUC and Cmax were expressed as the ratio of geometric means and 90% CI for each impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure was considered if the upper 90% CI for the ratio exceeded 2. In the renal study, AUC, Cmax and t1/2 were analyzed using linear regression fitting effects for creatinine clearance and age.ResultsIn the hepatic and renal studies respectively, 32 subjects (eight per group) and 48 subjects received treatment (n = 18 normal, n = 12 mild, n = 9 moderate, n = 9 severe). Zibotentan Cmax was not significantly affected by hepatic or renal impairment. Compared with the normal function group, zibotentan AUC was 40% (1.40; 90% CI 0.91-2.17), 45% (1.45; 90% CI 0.94-2.24) and 190% (2.90; 90% CI 1.88-4.49) higher in subjects with mild, moderate and severe hepatic impairment, respectively, and 66% (1.66; 90% CI 1.38-1.99), 89% (1.89; 90% CI 1.50-2.39) and 117% (2.17; 90% CI 1.64-2.86) higher in subjects with mild, moderate and severe renal impairment, respectively. In both studies mean t1/2 increased and zibotentan clearance decreased with the degree of impairment. Headache was the most common AE in all groups.ConclusionsZibotentan absorption was unchanged, however, exposure was higher in subjects with hepatic or renal impairment due to slower clearance. This increased exposure did not result in differences in the range or severity of AEs observed.Trial RegistrationClinicalTrials.gov: NCT00672581 and AstraZeneca study number D4320C00016 (renal trial; conducted in Germany).

The metabolism of [14C]-zibotentan (ZD4054) in rat, dog and human, the loss of the radiolabel and the identification of an anomalous peak, derived from the animal feed

This paper presents an overview of a cross-species investigation of the metabolic fate of [(14)C]-zibotentan (ZD4054), with particular focus on the main analytical challenges encountered during the study. A combination of detection methods were used including HPLC coupled to UV, RAD and/or MS(MS), and (1)H NMR spectroscopy. The objective was to characterise and identify the major metabolites found in the circulation and excreta of rat and dog for comparison with those produced in human. Initial investigations in rat, using [(14)C]-labelled zibotentan positioned on the oxadiazole ring and HPLC-UV-RAD analysis, revealed seven labelled resolved metabolite peaks. Parallel analysis by HPLC-UV-MS (with in-source fragmentation) uncovered two additional metabolites, indicating loss of the radiolabel during biotransformation. Hence, in subsequent studies in rat, dog and human, dual-radiolabelled zibotentan was employed with the (14)C-label positioned on the pyridine ring, which was shown to be less prone to metabolism. A total of 12 metabolites were found in the excreta and plasma in all species. One of these metabolites was found in the circulation in humans, which warranted further investigations. Characterisation of the isolated human circulating metabolite by (1)H NMR was complicated by the co-extraction of a matrix component with a similar UV-chromophore to zibotentan, which was identified as daidzein, an isoflavone derived from the animal feed.

Harnessing Meta‐analysis to Refine an Oncology Patient Population for Physiology‐Based Pharmacokinetic Modeling of Drugs

Certain oncology compounds exhibit fundamental pharmacokinetic (PK) disparities between healthy and malignant conditions. Given the effects of tumor‐associated inflammation on enzyme and transporter expression, we performed a meta‐analysis of CYP‐ and transporter‐sensitive substrate clinical PK to quantitatively compare enzyme and transporter abundances between healthy volunteers (HV) and cancer patients (CP). Hepatic and intestinal CYP1A2, CYP2C19, and CYP3A4 abundance were subsequently adjusted via Simcyps sensitivity analysis tool. Of the 11 substrates we investigated, seven displayed marked exposure differences >1.25‐fold between CP and HV. Although CP studies are limited, meta‐analysis‐based reduction in CYP1A2, CYP2C19, and CYP3A4 enzyme abundances in a virtual oncology population effectively captures CP‐PK for caffeine, theophylline, midazolam, simvastatin, omeprazole, and a subset of oncology compounds. These changes allow extrapolation from HV to CP, enhancing predictive capability; therefore, conducting simulations in this CYP‐modified oncology (MOD‐CP) population provides a more relevant characterization of CP‐PK.

An open-label, randomized, single-center, two-period, phase I, crossover study of the effect of zibotentan (ZD4054) on the pharmacokinetics of midazolam in healthy male volunteers.

BACKGROUND Zibotentan (ZD4054) is an oral, specific endothelin A receptor antagonist presently under investigation for the treatment of hormone-resistant prostate cancer. Preclinical in vitro studies suggest that zibotentan has the potential to act as a time-dependent inhibitor of the cytochrome P450 isozyme 3A4 (CYP3A4) metabolic pathway. In clinical practice, it is likely that zibotentan will be coadministered with drugs metabolized by this pathway; the potential exists, therefore, that zibotentan-induced drug interactions could occur. OBJECTIVES The primary objective of this study was to evaluate the effect of zibotentan on the pharmaco-kinetics of a clinically relevant dose of midazolam in healthy volunteers. Secondary objectives were to evaluate exposure to zibotentan, ensure the safety of the healthy volunteers dosed, and investigate the effect of zibotentan on the pharmacokinetics of the midazolam metabolites 1-hydroxy midazolam and 4-hydroxy midazolam. The potency of zibotentan as a CYP3A4 inhibitor was also assessed. METHODS This was an open-label, randomized, singlecenter, 2-period, Phase I, crossover study. Volunteers were randomized in a 1:1 ratio to 1 of 2 cohorts. In cohort 1, volunteers received a single dose of midazolam 7.5 mg on day 1 (treatment A) of a 2-day study period. After a minimum 7-day washout period, volunteers received zibotentan 10 mg once daily on days 1 through 7, plus a single dose of midazolam 7.5 mg on day 6 (treatment B) of a 7-day study period. In cohort 2, volunteers received treatment B followed by treatment A, with a minimum 7-day washout period between treatments. AUC(0-infinity) and C(max) data were expressed as geometric least squares mean ratios and 90% CIs for midazolam + zibotentan:midazolam. A moderate interaction between midazolam and zibotentan was predefined to have occurred if the upper 90% CI of the ratio was >1.5. Adverse events (AEs) were assessed according to the National Cancer Institutes Common Terminology Criteria for Adverse Events version 3. AE data were assessed based on information provided by the volunteer, through open-ended and nonleading verbal questions to the volunteer at each visit, and through observation by the investigational team, other care providers, or relatives. RESULTS Six volunteers (all white) were included in each cohort (cohort 1, mean [SD] age, 48 [7] years; mean weight, 74 [6] kg; cohort 2, mean age, 51 [11] years; mean weight, 75 [13] kg). Steady-state levels of zibotentan, achieved over 7 days, increased the midazolam AUC(0-infinity) by 1.2-fold compared with midazolam alone. The upper limits of the 90% CIs for the AUC(0-infinity) and C(max) ratios were below the predefined level of 1.5 (1.37 and 1.32, respectively). Zibotentan had no apparent effect on the pharmacokinetics of 1-hydroxy midazolam and 4-hydroxy midazolam. Fatigue was reported in 11 volunteers (92%) receiving midazolam monotherapy and 10 (83%) receiving midazolam combined with zibotentan. Headache was reported in all 12 volunteers after zibotentan monotherapy. CONCLUSIONS In this population of healthy male volunteers, once-daily zibotentan 10 mg increased the AUC(0-infinity) of midazolam 1.2-fold; however, the treatment ratio was below the predefined limit for clinical significance. Zibotentan was well tolerated when given alone or in combination with midazolam. The results indicate that once-daily zibotentan 10 mg acted as a weak inhibitor of the CYP3A4 pathway. ClinicalTrials. gov identifier: NCT00709553.

Radiation and PD-(L)1 treatment combinations: immune response and dose optimization via a predictive systems model

BackgroundNumerous oncology combination therapies involving modulators of the cancer immune cycle are being developed, yet quantitative simulation models predictive of outcome are lacking. We here present a model-based analysis of tumor size dynamics and immune markers, which integrates experimental data from multiple studies and provides a validated simulation framework predictive of biomarkers and anti-tumor response rates, for untested dosing sequences and schedules of combined radiation (RT) and anti PD-(L)1 therapies.MethodsA quantitative systems pharmacology model, which includes key elements of the cancer immunity cycle and the tumor microenvironment, tumor growth, as well as dose-exposure-target modulation features, was developed to reproduce experimental data of CT26 tumor size dynamics upon administration of RT and/or a pharmacological IO treatment such as an anti-PD-L1 agent. Variability in individual tumor size dynamics was taken into account using a mixed-effects model at the level of tumor-infiltrating T cell influx.ResultsThe model allowed for a detailed quantitative understanding of the synergistic kinetic effects underlying immune cell interactions as linked to tumor size modulation, under these treatments. The model showed that the ability of T cells to infiltrate tumor tissue is a primary determinant of variability in individual tumor size dynamics and tumor response. The model was further used as an in silico evaluation tool to quantitatively predict, prospectively, untested treatment combination schedules and sequences. We demonstrate that anti-PD-L1 administration prior to, or concurrently with RT reveal further synergistic effects, which, according to the model, may materialize due to more favorable dynamics between RT-induced immuno-modulation and reduced immuno-suppression of T cells through anti-PD-L1.ConclusionsThis study provides quantitative mechanistic explanations of the links between RT and anti-tumor immune responses, and describes how optimized combinations and schedules of immunomodulation and radiation may tip the immune balance in favor of the host, sufficiently to lead to tumor shrinkage or rejection.

The disposition and metabolism of zibotentan (ZD4054): an oral-specific endothelin A receptor antagonist in mice, rats and dogs

Zibotentan (ZD4054) is an oral-specific endothelin A receptor antagonist in development for the treatment of castration-resistant prostate cancer. In a number of preclinical studies, the disposition and metabolism of zibotentan were investigated in mice, rats and dogs. Following oral and intravenous administration, zibotentan was slowly absorbed (maximal concentration at approximately 4 h) and rapidly excreted, with the majority being eliminated by 48 h. The main route of elimination was via the urine in dogs and female rats, but via the faeces in male rats and mice of both sexes. Zibotentan was moderately bound to plasma proteins of all species examined (55–95%), and widely distributed throughout all tissues with the highest concentrations seen in the organs of excretion. Zibotentan was moderately metabolised. Zibotentan was well absorbed, moderately bound to plasma proteins, widely distributed and excreted predominantly via the urine.

Population Pharmacokinetic and Exposure‐Response Analysis of Selumetinib and Its N‐desmethyl Metabolite in Patients With Non‐Small Cell Lung Cancer

Selumetinib (AZD6244, ARRAY‐142886) is a mitogen‐activated protein kinase kinase inhibitor that has been tested for treatment of non‐small cell lung cancer (NSCLC). Selumetinib (75 mg twice daily) plus docetaxel in patients with advanced NSCLC has been assessed in phase 2 (SELECT‐2) and phase 3 (SELECT‐1) clinical trials. The objective of the current analysis was to investigate the exposure‐response relationship of selumetinib in these 2 clinical trials, based on the development of a population pharmacokinetic (PopPK) model for selumetinib and its active metabolite, N‐desmethyl selumetinib, in patients with NSCLC. A PopPK model using data from seven phase 1 studies was first developed and served as prior information for the development of the patient PopPK model. The pharmacokinetics (PK) of selumetinib and N‐desmethyl selumetinib were modeled simultaneously. A two‐compartment model with zero‐first order absorption and first‐order elimination reasonably described the selumetinib PK. The N‐desmethyl metabolite of selumetinib was described by a one‐compartment model with first‐order elimination. The final PK parameter estimates were similar between patients with NSCLC and patients in the phase 1 population. Selumetinib apparent clearance and central volume of distribution were 11.9 L/h and 32.1 L, respectively, in patients. Individual selumetinib exposure metrics were estimated to investigate the correlation between exposure and efficacy/safety endpoints observed in NSCLC studies. There was no significant difference in progression‐free survival (the primary endpoint) among the different quartiles of exposure. Similarly, no significant correlation was observed between selumetinib exposure and other secondary efficacy or safety endpoints. The conclusions are in accordance with the reported clinical findings.

Erratum to: A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors

The article A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors, written by Jeffrey R. Infante, Roger B. Cohen, Kevin B. Kim, Howard A. Burris III, Gregory Curt, Ugochi Emeribe, Delyth Clemett, Helen K. Tomkinson, and Patricia M. LoRusso, was originally published electronically on the publisher’s internet portal (currently SpringerLink) on April 19, 2017 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on July 03, 2017 to

Comparison of the Pharmacokinetics of the Phase II and Phase III Capsule Formulations of Selumetinib and the Effects of Food on Exposure: Results From Two Randomized Crossover Trials in Healthy Male Subjects

PURPOSE Selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective mitogen-activated protein kinase 1/2 inhibitor with a short half-life, has shown activity across various tumor types. Before initiation of Phase III trials, the site, scale, and color (hypromellose shell from white [Phase II] to blue [Phase III]) of the selumetinib 25mg capsule manufacture was changed. We present 2 crossover trials evaluating Phase III capsules in healthy subjects. METHODS The relative bioavailability trial was a Phase I, open-label, randomized, 3-treatment, 4-period, 6-sequence crossover trial in healthy male subjects (aged 18-55 years). Subjects received selumetinib 75mg (3 × 25 mg) Phase II or Phase III capsules, or a 35mg oral solution, during 4 dosing periods in 1 of 6 randomized treatment sequences. The food effect trial was a Phase I, open-label, randomized, 2-period crossover trial in healthy male subjects (aged 18-45 years). Subjects were randomized to 1 of 2 sequences to receive selumetinib 75mg (3 × 25 mg) Phase III capsules. In sequence 1, subjects received selumetinib after 10 hours of fasting. Following a washout period, selumetinib was administered after a high-fat meal. In sequence 2, subjects received selumetinib in the fed state, before the fasted state. Pharmacokinetic parameters were determined from serial blood sampling. FINDINGS Twenty-seven subjects were randomized to the relative bioavailability trial; 26 completed all dosing periods. Mean selumetinib AUC was unchanged (geometric least squares mean ratio [GLSMR], 90.01% [90% CI, 81.74-99.11]). Cmax was 18% lower with the Phase III capsules (GLSMR, 81.97% [90% CI, 69.01-97.36]). A post hoc exploratory statistical analysis excluding outlying observations with later Tmax showed that Phase II and III capsules produced similar exposure in terms of Cmax and AUC. High intrasubject variability for Cmax attributed to the pharmacokinetic sampling schedule was judged to have impacted on the estimated GLSMR. In the food effect trial, 34 subjects completed both study periods. A high-fat meal reduced selumetinib Cmax compared with the fasted state (GLSMR, 49.76% [90% CI, 43.82-56.51]); AUC was minimally changed (GLSMR, 84.08% [90% CI, 80.72-87.59]). Median Tmax was prolonged by 1.49 hours. No deaths or serious adverse events were reported. IMPLICATIONS Selumetinib 75mg (3 × 25 mg) Phase III capsules are being used in ongoing pivotal Phase III trials and should be administered in the fasted state. Based on findings from the relative bioavailability trial, pharmacokinetic sampling frequency was increased for healthy subject trials, including the food effect trial. ClinicalTrials.gov identifiers: NCT01635023 (relative bioavailability) and NCT01974349 (food effect).

Abstract 2770: An open-label comparative study of the pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with mild, moderate, or severe hepatic impairment, or normal hepatic function

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Zibotentan (ZD4054) is a small-molecule, specific endothelin A (ETA) receptor antagonist being investigated for the treatment of hormone-resistant prostate cancer. Zibotentan is eliminated by both renal (58%) and metabolic clearance. The current study investigated whether hepatic impairment has a clinically relevant effect on exposure to zibotentan. This open-label, two-centre study investigated the PK and tolerability of zibotentan in subjects with hepatic impairment, compared with subjects with normal hepatic function. Subjects were divided into four categories using the Child-Pugh (CP) classification: mild hepatic impairment (CP A), moderate hepatic impairment (CP B), severe hepatic impairment (CP C) and normal hepatic function. Each subject received a single oral dose of zibotentan 10 mg. AUC and Cmax are expressed as the ratio (R) of geometric means and 90% confidence intervals (CI) for each hepatic impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure of zibotentan was considered if the upper 90% CI for the ratio exceeded two. Thirty-seven subjects were enrolled and 32 subjects (eight per group) received zibotentan and completed the study. Compared with the normal function group, zibotentan Cmax was 7% (R 0.93; 90% CI 0.75-1.15), 11% (R 0.89; 90% CI 0.72-1.1) and 5% (R 0.95; 90% CI 0.77-1.17) lower in subjects with CP A, CP B and CP C hepatic impairment, respectively. Zibotentan AUC was 40% (R 1.40; 90% CI 0.91-2.17), 45% (R 1.45; 90% CI 0.94-2.24) and 190% (R 2.90; 90% CI 1.88-4.49) higher in subjects with CP A, CP B and CP C hepatic impairment, respectively, compared with those with normal function. Mean t½ was 9.28 h, 13.0 h, 14.6 h and 24.8 h for the normal function, CP A, CP B and CP C hepatic impairment groups, respectively. Compared with the normal function group, CL/F was approximately 25%, 29% and 64% lower, respectively, in the CP A, CP B and CP C hepatic impairment groups. Zibotentan was well tolerated by all subjects, with headache (CTC Grade 1-2) being the most common adverse event in each group. Despite increased exposure to zibotentan with increased hepatic impairment, there were no differences in the type or severity of adverse events. In conclusion, following a single oral dose of zibotentan 10 mg, there was no significant difference in Cmax with degree of hepatic impairment, indicating that hepatic impairment did not affect the absorption of zibotentan. AUC was higher and t½ longer in subjects with hepatic impairment than in those with normal function due to the slower clearance of zibotentan, with the extent of the difference being related to the degree of impairment. Trial sponsored by AstraZeneca ([NCT00672581][1]; AZ code D4320C00025). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2770. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00672581&atom=%2Fcanres%2F70%2F8_Supplement%2F2770.atom