{'fraction_non_alphanumeric': 0.0575973669775096, 'fraction_numerical': 0.04278661546900713, 'mean_word_length': 4.5105740181268885, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Atrasentan (ABT-627, ATN) pharmacokinetics (PK) and endothelin-1 (ET-1) pharmacodynamics (PD) in a phase 2 study of patients with asymptomatic hormone-refractory prostate cancer (HRPC).

4721 Background: ATN, an oral ET antagonist with high selectivity for ETA receptor, is in phase 3 clinical development for the treatment of HRPC. ETA receptors are primarily responsible for ET-1 mediated vasoconstriction and cell proliferation. ET-1 is the main ET isoform in mammalian tissues and fluids.


METHODS
ATN PK and ET-1 PD were assessed in a phase 2, randomized, double-blind, placebo-controlled, multicenter study (M96-594). 288 HRPC patients (mean±SD 71±8 yrs, 81±13 kg) were assigned to receive PO QD: ATN 2.5 mg, ATN 10 mg, or placebo, along with continued hormone ablation therapy. Predose blood samples were collected starting Day 14, every 2 weeks for 6 months, and monthly thereafter. For a PK subset (N=9), blood samples for ATN and ET-1 assay were collected over 24 h on Day 28. ATN and ET-1 plasma concentrations were determined using validated methods. Mixed model statistical analysis of ATN and ET-1 predose data included effects for day, dose, age, race, body weight and day*dose.


RESULTS
Predose ATN (N=1214 from 173 subjects) and ET-1 (N=1876 from 257 subjects) concentrations did not vary with time, body weight or race, but were positively correlated with age. Only 3% of variability in ATN concentration was explained by age. ATN modestly increased average predose ET-1 levels: 2.8, 3.8 and 4.5 pg/mL for 0, 2.5 and 10 mg dose groups, respectively. ATN and ET-1 results for the PK subset (Day 28): [Figure: see text] Conclusions: ATN PK were approximately linear and time-independent. No dose adjustment for age or body weight is warranted. ATN modestly increased plasma ET-1 levels. [Table: see text].