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Relugolix, the first orally active, nonpeptide gonadotropin‐releasing hormone receptor antagonist, is approved in the United States and the European Union for the treatment of adult patients with advanced prostate cancer. The recommended dosing regimen is a 360‐mg loading dose followed by a 120‐mg daily dose. Relugolix and testosterone concentration data and clinical information from two phase I studies, two phase II studies, and the phase III safety and efficacy study (HERO) were used to develop a population pharmacokinetic (PopPK) model and a semimechanistic population pharmacokinetic/pharmacodynamic (PopPK/PD) model that characterized relugolix exposure and its relationship to testosterone concentrations. Age, body weight, and Black/African American race had at most minimal effects on relugolix exposure or testosterone concentrations with no clinical relevance. Simulations using the PopPK/PD model confirmed the recommended dosing regimen of relugolix, with the median simulated testosterone concentrations predicted to achieve castration levels (< 50 ng/dL) and profound castration levels (< 20 ng/dL) by day 2 and day 9, respectively, and demonstrated that 97.3% and 85.5% of the patients remained at castration levels (< 50 ng/dL) upon temporary interruption of treatment for 7 days and 14 days, respectively. Collectively, simulations based on the PopPK and PopPK/PD models were consistent with actual data from clinical studies, reflecting the high predictiveness of the models and supporting the reliability of model‐based simulations. These models can be used to provide guidance regarding dosing recommendations under various circumstances (e.g., temporary interruption of treatment, if needed) for relugolix. [ABSTRACT FROM AUTHOR]

We have detected deletions of portions of the Y chromosome long arm in 12 of 89 men with azoospermia (no spermatozoa in their semen). No Y deletions were detected in their male relatives or in 90 other fertile males. The 12 deletions overlap, defining a region likely to contain one or more genes required for spermatogenesis (the azoospermia factor, AZF). Deletion of the AZF region is associated with highly variable testicular defects, ranging from the complete absence of germ cells to spermatogenic arrest with the occasional production of condensed spermatids. We found no evidence of YRRM genes, recently proposed as AZF candidates hi the AZF region. The region contains a single-copy gene, DAZ (deleted in azoospermia), which is transcribed in the adult testis and appears to encode an RNA-binding protein. The possibility that DAZ is AZF should now be explored. [ABSTRACT FROM PUBLISHER]