Afatinib, an oral irreversible ErbB family blocker, undergoes minimal metabolism by non-enzyme-catalysed adduct formation with proteins or nucleophilic small molecules and is predominantly non-renally excreted via the entero-hepatic system. This trial assessed whether mild or moderate hepatic impairment influences the pharmacokinetics of afatinib.

We report population pharmacokinetic (popPK) and exposure-response (E-R) analyses for efficacy (induced amenorrhoea [IA]) and safety (unbound oestradiol [E2] concentrations) of the selective progesterone receptor modulator vilaprisan. Results were used to inform the dose for the Phase 3 programme in patients with uterine fibroids.

Afatinib is an oral irreversible ErbB-Family Blocker indicated for treatment of patients with EGFR mutation positive advanced non-small cell lung cancer. This trial assessed whether renal impairment influences the pharmacokinetics and safety of afatinib.

Selatogrel is a potent and selective reversible P2Y12 receptor antagonist in development for early treatment of acute myocardial infarction via subcutaneous (s.c.) self-injection. Selatogrel is almost exclusively eliminated via the hepatobiliary route. Hepatic impairment is associated with reduced drug clearance and primary hemostasis. This single-center, open-label study investigated the effect of mild and moderate hepatic impairment on pharmacokinetics (PK) and pharmacodynamics (PD) of a single s.c. dose of selatogrel (16 mg). The study included groups of eight subjects with mild and moderate hepatic impairment, and matched healthy control subjects. Compared to healthy subjects, exposure to selatogrel in subjects with mild and moderate hepatic impairment was 30% and 108% (maximum plasma concentration [Cmax ]) and 47% and 212% (area under the concentration-time curve from zero to infinity [AUC0-∞ ]) higher, respectively. Hepatic impairment was associated with lower clearance and volume of distribution, whereas plasma protein binding was not affected. Marked inhibition of platelet aggregation (IPA > 80%) was attained within 30 min in all subjects and hepatic impairment prolonged IPA duration. Area under the effect curve was 60% and 160% higher in subjects with mild and moderate hepatic impairment, respectively. PK/PD modeling identified a change in the relationship between exposure and IPA, with a steeper concentration-effect relationship in healthy subjects compared to subjects with hepatic impairment. The combination of higher exposure and lower half-maximum inhibitory concentration resulted in longer lasting effect. In conclusion, hepatic impairment alters the PK/PD relationship leading to prolonged effects. Therefore, dose adjustments may be warranted in subjects with moderate hepatic impairment.

Serelaxin, a recombinant human relaxin-2 hormone, is in clinical development for treating acute heart failure. This open-label, parallel-group study investigated serelaxin pharmacokinetics (PK) after a single 4-hour intravenous infusion (10 µg/kg) in patients with severe renal impairment (n = 6) or end-stage renal disease (ESRD) requiring hemodialysis (PK on the day of dialysis [n = 6] or during dialysis-free interval [n = 6]), compared with matched healthy subjects (n = 18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with mean terminal elimination half-life of 6.5-8.8 hours. Compared with healthy subjects, a moderate decrease in serelaxin systemic clearance (37%-52%) and increase in its exposure (30%-115%) were observed in all patients. During the 4-hour hemodialysis in ESRD patients, 30% serelaxin was removed, with hemodialysis clearance constituting approximately 52% of total systemic clearance. Serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. Antiserelaxin antibodies were not detected in any participant. Given the shallow dose-response relationship observed with serelaxin in clinical studies and its wide therapeutic window, the observed PK differences in patients with severe renal impairment compared with healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients.

The primary objective was to explore whether the suppression of ovarian activity induced by a combined oral contraceptive (COC) is influenced by the simultaneous intake of the selective progesterone receptor modulator (SPRM) vilaprisan (VPR).

Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone-dependent. Steroidal and non-steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the treatment of such diseases. Steroidal SPRMs, including mifepristone and ulipristal acetate, have proven effective in clinical trials. However, several steroidal SPRMs containing a dimethylamino substituent have been associated with elevated liver enzymes in patients. An earlier drug discovery program identified lonaprisan as a highly selective SPRM that did not show drug-related change in liver enzyme activity. Building on data obtained from that work, here we describe the research program that culminated in the discovery of a novel steroidal SPRM, vilaprisan, which combines an extremely high potency with very favorable drug metabolism and pharmacokinetic properties. Vilaprisan has entered clinical development and is currently undergoing phase 3 clinical trials.

The study objective was to evaluate the pharmacokinetics of the selective progesterone receptor modulator vilaprisan in participants with hepatic impairment. Additionally, the safety and tolerability of vilaprisan were investigated.