Robert A. Carr

Atrasentan, an Endothelin-Receptor Antagonist for Refractory Adenocarcinomas: Safety and Pharmacokinetics

PURPOSE Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION Adverse events were consistent with atrasentans pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

Organic anion transporting polypeptide 1B1 activity classified by SLCO1B1 genotype influences atrasentan pharmacokinetics

Our objective was to learn whether genetic polymorphisms of metabolic enzymes or transport proteins provide a mechanistic understanding of the in vivo disposition of atrasentan, a selective endothelin A receptor antagonist.

Dose-Ranging Study of the Safety and Pharmacokinetics of Atrasentan in Patients with Refractory Malignancies

Purpose: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ETA. Due to the potential activity of this agent against prostate cancer, the majority of subjects enrolled in prior studies had been male. This Phase I study sought to determine the toxicity and pharmacokinetics of daily atrasentan in a population of both female and male subjects with advanced malignancies. Experimental Design: Patients with refractory malignancies received atrasentan once daily at doses ranging from 5 mg to 75 mg. At least 3 subjects were treated at each dose level before enrollment began at the next higher dose level. Enrollment for specific dose levels was expanded if any subject experienced serious drug-related toxicity. Plasma concentration profiles for atrasentan were determined after dosing on days 1 and 28. Results: Thirty-five patients received atrasentan at doses from 5 mg to 75 mg. The most frequent drug-related adverse events were headache (60%), rhinitis (49%), and peripheral edema (31%). These toxicities were mild to moderate in severity and reversible on cessation of treatment. Dose escalation was stopped at the 75-mg dose level due to the occurrence of three severe adverse events (2 hyponatremia and 1 hypotension). Atrasentan was rapidly absorbed after oral administration; mean time to maximum observed concentration ranged from 0.3 to 1.7 h. Terminal elimination half-life averaged 26 h. No significant difference between sexes was found in any atrasentan pharmacokinetic parameter tested, including maximum observed plasma concentration, time to maximum observed concentration, minimum observed plasma concentration, area under the plasma concentration-time curve, and elimination rate constant. Conclusions: Atrasentan is well tolerated in both female and male cancer patients at doses of up to 60 mg/day with dose-limiting toxicity observed at 75 mg/day. The most frequently observed toxicities were headache, rhinitis, and edema. There was no statistically significant difference in atrasentan pharmacokinetics between sexes.

Phase 0 Trials: An Industry Perspective

Worldwide, cancer is a leading cause of morbidity and mortality. An increased understanding of the disease and its process has resulted in a multitude of new targeted therapies. The costs as well as time from drug discovery to market, however, remain staggeringly high and protracted, with the majority of compounds never reaching phase III. The concept of an exploratory or phase 0 trial was introduced as a mechanism to enhance and accelerate the overall process of new oncologic drug development. Performance of a phase 0 study allows researchers to better understand the pharmacokinetic and pharmacodynamic properties of compounds in human subjects before initiation of phase I trials. Data gleaned from a phase 0 trial are beneficial not only in prioritizing promising compounds but also in allowing the modification of phase I study design before initiation. To date, few researchers have taken advantage of the potential benefits of phase 0 trials. This review focuses on the purpose as well as the potential merits of phase 0 trials from the perspective of a pharmaceutical company. The review summarizes the experience of a team of researchers with ABT-888, a novel poly (ADP-ribose) polymerase agent that inhibits an enzyme critical for repairing damage to DNA, which is one of the first compounds to be investigated using the phase 0 clinical trial design.

Dual Effects of Rifampin on the Pharmacokinetics of Atrasentan

The effect of rifampin, a cytochrome P450 3A4 inducer, on the pharmacokinetics of atrasentan was assessed in 12 healthy male subjects in an open‐label study. Single doses of atrasentan 10 mg were administered orally on days 1 and 12. Rifampin 600 mg was given once daily from days 4 through 14. On day 12, atrasentan and rifampin were administered simultaneously. Blood samples were collected before and during 72 hours after each atrasentan dose. On average, rifampin increased atrasentan peak plasma concentrations by 150% and reduced its terminal half‐life by 77% (P < .05), without affecting the AUC or peak time of atrasentan. Rifampin may affect atrasentan pharmacokinetics by acting as both an inhibitor of organic anion transporting polypeptide‐mediated hepatic uptake of atrasentan and an inducer of atrasentan metabolism. The effect of rifampin on atrasentan pharmacokinetics may depend on the time of rifampin administration relative to that of atrasentan.

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751

Objective ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751. Methods UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes. Results UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (>2) was associated with an average 34% increase in ABT-751 clearance (P=0.044), an 18% reduction in ABT-751 AUC (P=0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P=0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 C trough (P=0.009). Conclusion These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability.

Pharmacogenetic meta‐analysis suggests that atrasentan is an organic anion transport protein C substrate

To assess whether genetic polymorphisms of drug metabolizing enzymes or drug transporters correlate with atrasentan pharmacokinetics.

The effect of hepatic insufficiency on the safety and pharmacokinetics of paricalcitol (Zemplar

Background/Aims: Paricalcitol is highly protein bound, extensively metabolized and eliminated primarily by hepatobiliary excretion. This study was designed to determine if hepatic disease alters the pharmacokinetics or affects the safety of paricalcitol. Methods: Subjects with mild (n = 5) or moderate (n = 5) hepatic impairment, and subjects with normal hepatic function (n = 10) enrolled in and completed the study. Each subject was administered a single 0.24 µg/kg intravenous dose of paricalcitol, injected within 1 min. Results: For both total and unbound paricalcitol, there were no statistically significant differences in the pairwise comparisons between hepatic function groups in paricalcitol concentration at 5 min postdose (C5) or area under the plasma concentration-time curve from time zero to infinity (AUC0–∞), except C5 of total paricalcitol between mild and moderate impairment groups (p = 0.02). Paricalcitol binding to plasma proteins was extensive in all hepatic function groups (mean values >99.7%); unbound fraction was greater in subjects with moderate impairment than either healthy subjects or subjects with mild impairment (p < 0.01). Paricalcitol appeared to be well tolerated both by healthy subjects and subjects with mild to moderate hepatic insufficiency. Conclusion: No adjustment of paricalcitol dose is required for subjects with mild to moderate hepatic impairment. However, caution should be exercised in extrapolating the results from this study to subjects with severe hepatic impairment.

Abstract B62: Potent single agent in vivo activity of the PARP inhibitor veliparib (ABT-888) in BRCA-deficient xenografts (MX-1 and Capan-1).

PARP9s role in DNA damage recognition/repair makes PARP inhibition an attractive cancer therapeutic target. Veliparib (ABT-888) is a potent PARP inhibitor with excellent oral bioavailability that readily crosses the blood-brain barrier and is currently in Phase 2 clinical trials. Veliparib has shown significant ability to potentiate multiple DNA damaging agents (cisplatin, carboplatin, cyclophosphamide, irinotecan, radiation and temozolomide) in a spectrum of tumors from multiple histological types. In studies using cytotoxic combinations with veliparib (cisplatin, cyclophosphamide, TMZ) there was a marked increase in efficacy over cytotoxic monotherapies, especially in the MX-1 breast model. Since DNA repair deficiencies ( e.g. HR-defective) are known to render cells very sensitive to PARP inhibition, we genotyped the MX-1 breast line and found it to be HR-deficient. Subsequent studies with both the MX-1 ( BRCA1 -deleted and BRCA2 -mutated breast line) and the Capan-1 ( BRCA2 -deficient pancreatic cancer cell line), showed that veliparib (25 mg/kg/day, p.o., b.i.d.×5) demonstrated enhancement of TMZ (50 mg/kg/day, p.o., q.d.×5) activity, with regressions compared to TMZ alone (81–97% TGI, tumor growth inhibition). Continuous dosing at 4×-8× higher doses (100 and 200 mg/kg/day, p.o., b.i.d.×21) demonstrated a significant single agent, dose-responsive activity (26–87% TGI). Similar results were observed with single agent veliparib treatment of BRCA isogenic cell lines in vitro. Further, the combination treatment of veliparib (100 and 200 mg/kg/day, p.o., b.i.d.×21) with carboplatin, carbotaxol, radiation, gemcar, cyclophosphamide, topotecan and TMZ also demonstrated a measurable advantage over either veliparib or cytotoxic agent alone. Both high dose single agent veliparib and the cytotoxic combination therapy were well tolerated and there were no observable animal health concerns; this indicated the feasibility of using the single agent and cytotoxic combination regimen in the clinic. Analysis of tumors for the reduction of PAR after veliparib treatment demonstrated a correlative and significant reduction by western blot indicating the ability of veliparib to inhibit PARP activity in vivo. Altogether, our studies show the strong activity of veliparib as a single agent in BRCA -deficient xenografts as well as the enhanced activity and tolerability of veliparib in combination with various cytotoxic agents. These results warrant investigation of single agent therapy and cytotoxic combination regimens in BRCA -deficient patients to further the clinical development of veliparib. 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 B62.