Mobocertinib Dose Rationale in Patients with Metastatic NSCLC with EGFR Exon 20 Insertions: Exposure-Response Analyses of a Pivotal Phase I/II Study.

Mobocertinib is an oral tyrosine kinase inhibitor approved for treatment of patients with locally advanced or metastatic non-small cell lung cancer (mNSCLC) with epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20ins) mutations previously treated with platinum-based chemotherapy. These exposure-response analyses assessed potential relationships between exposure and efficacy or safety outcomes in platinum-pretreated patients with EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily (q.d.

Forward and reverse translational approaches to predict efficacy of neutralizing respiratory syncytial virus (RSV) antibody prophylaxis.

Background: Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.

Magnesium sulfate pharmacokinetics after intramuscular dosing in women with preeclampsia.

Background: Current intramuscular magnesium dosing regimens in low and middle-income countries are based on indirect absorption parameters to inform pharmacokinetic and pharmacodynamic response.

Objective: To determine if therapeutic serum magnesium levels are obtained in women with severe preeclampsia receiving intramuscular administration of magnesium sulfate using the Pritchard regimen and to compare the key pharmacokinetic variables to those previously published.

Study Design: Serum magnesium levels were obtained at multiple time points at baseline and after magnesium sulfate administration from women with severe preeclampsia receiving the standard Pritchard regimen for seizure prophylaxis at Bayero University, Kano, Nigeria.

Meta-Analyses of Clinical Efficacy of Risankizumab and Adalimumab in Chronic Plaque Psoriasis: Supporting Evidence of Risankizumab Superiority.

Risankizumab, an anti-interleukin-23 monoclonal antibody, achieved significantly (P < 0.001) greater Psoriasis Area and Severity Index (PASI) and static Physician Global Assessment (sPGA) clear or almost clear (0/1) responses than adalimumab in a phase III trial in patients with moderate-to-severe psoriasis. Meta-analyses of the PASI 50, PASI 75, PASI 90, PASI 100, and sPGA0/1 responses after 16 weeks of treatment from eight (three for risankizumab and five for adalimumab) randomized, placebo-controlled trials were conducted to estimate the efficacy difference between risankizumab and adalimumab.

Maternal-Neonatal Raltegravir Population Pharmacokinetics Modeling: Implications for Initial Neonatal Dosing.

Raltegravir readily crosses the placenta to the fetus with maternal use during pregnancy. After birth, neonatal raltegravir elimination is highly variable and often extremely prolonged, with some neonates demonstrating rising profiles after birth despite removal from the source of extrinsic raltegravir. To establish an appropriate dosing regimen, an integrated maternal-neonatal pharmacokinetics model was built to predict raltegravir plasma concentrations in neonates with in utero raltegravir exposure.

Alternative Magnesium Sulfate Dosing Regimens for Women With Preeclampsia: A Population Pharmacokinetic Exposure-Response Modeling and Simulation Study.

Magnesium sulfate is the anticonvulsant of choice for eclampsia prophylaxis and treatment; however, the recommended dosing regimens are costly and cumbersome and can be administered only by skilled health professionals. The objectives of this study were to develop a robust exposure-response model for the relationship between serum magnesium exposure and eclampsia using data from large studies of women with preeclampsia who received magnesium sulfate, and to predict eclampsia probabilities for standard and alternative (shorter treatment duration and/or fewer intramuscular injections) regimens. Exposure-response modeling and simulation were applied to existing data.

Operating characteristics of stepwise covariate selection in pharmacometric modeling.

Stepwise covariate modeling (SCM) is a widely used tool in pharmacometric analyses to identify covariates that explain between-subject variability (BSV) in exposure and exposure-response relationships. However, this approach has several potential weaknesses, including over-estimated covariate effect and incorrect selection of covariates due to collinearity. In this work, we investigated the operating characteristics (i.

Population Pharmacokinetic Modeling to Evaluate Standard Magnesium Sulfate Treatments and Alternative Dosing Regimens for Women With Preeclampsia.

Magnesium sulfate is the standard therapy for prevention and treatment of eclampsia. Two standard dosing regimens require either continuous intravenous infusion or frequent, large-volume intramuscular injections, which may preclude patients from receiving optimal care. This project sought to identify alternative, potentially more convenient, but similarly effective dosing regimens that could be used in restrictive clinical settings.

Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer.

Aims: To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters.

Methods: PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK.

Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization.

Objective: To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF.

Design: Phase 3 randomized, double-blind, noninferiority trial.

Setting: Multicenter trial.

Comparative analysis of the effects of nomegestrol acetate/17 β-estradiol and drospirenone/ethinylestradiol on premenstrual and menstrual symptoms and dysmenorrhea.

Objectives: To compare premenstrual and menstrual symptoms in healthy women using nomegestrol acetate/17β-estradiol (NOMAC/E2) and drospirenone/ethinylestradiol (DRSP/EE) via the Moos Menstrual Distress Questionnaire Form C (MDQ-C).

Methods: Women completed the MDQ-C at baseline and after completion of cycles 1, 3, 6 and 13, for the premenstrual (four days before most recent flow) and menstrual (most recent flow) phases in two randomized controlled trials. Treatment effects of NOMAC/E2 and DRSP/EE on the t-scores of eight MDQ-C symptom domains from 3522 women were examined, and the effects of both treatments on the score for cramps from 1779 women with moderate to severe cramps at baseline.

Prognostic models for high and low ovarian responses in controlled ovarian stimulation using a GnRH antagonist protocol.

Study Question: Can predictors of low and high ovarian responses be identified in patients undergoing controlled ovarian stimulation (COS) in a GnRH antagonist protocol?

Summary Answer: Common prognostic factors for high and low ovarian responses were female age, antral follicle count (AFC) and basal serum FSH and LH.

What Is Known Already: Predictors of ovarian response have been identified in GnRH agonist protocols. With the introduction of GnRH antagonists to prevent premature LH rises during COS, and the gradual shift in use of long GnRH agonist to short GnRH antagonist protocols, there is a need for data on the predictability of ovarian response in GnRH antagonist cycles.

Short follicular phase of stimulation following corifollitropin alfa or daily recombinant FSH treatment does not compromise clinical outcome: a retrospective analysis of the Engage trial.

To evaluate whether a short follicular phase of ovarian stimulation compromises the chance of pregnancy, subjects from a double-blind, randomized trial treated with a single dose of corifollitropin alfa (n=756) or daily recombinant FSH (n=750) were categorized as early responders if three follicles ≥17 mm were reached and human chorionic gonadotrophin (HCG) was administered prior to or on stimulation day 8, and as normal responders if three follicles ≥17 mm were reached and HCG was administered after stimulation day 8. In the corifollitropin alfa and recombinant FSH groups, 23.2% and 29.

Progesterone elevation does not compromise pregnancy rates in high responders: a pooled analysis of in vitro fertilization patients treated with recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in six trials.

Objective: To compare the impact of elevated P during the late follicular phase on the chance of pregnancy in low, normal, and high responders.

Design: Retrospective combined analysis from six clinical trials.

Setting: IVF centers.

Clinical impact of LH rises prior to and during ganirelix treatment started on day 5 or on day 6 of ovarian stimulation.

Background: We sought to evaluate the incidence and clinical impact of luteinizing hormone (LH) rises prior to and during gonadotropin-releasing hormone (GnRH) antagonist treatment started on day 5 or 6 of ovarian stimulation with recombinant follicle-stimulating hormone (rFSH).

Methods: Pooled data from three trials with the GnRH antagonist ganirelix started on day 5 (n = 961) and from five trials with ganirelix started on day 6 (n = 1135) of ovarian stimulation with rFSH were retrospectively analyzed.

Results: The incidence of LH rises (LH ≥ 10.

Corifollitropin alfa or rFSH treatment flexibility options for controlled ovarian stimulation: a post hoc analysis of the Engage trial.

Background: We sought to determine the impact of treatment flexibility on clinical outcomes in either a corifollitropin alfa or recombinant follicle-stimulating hormone (rFSH) protocol.

Methods: Post hoc analysis of a prospective, multicenter, randomized, double-blind, double-dummy non-inferiority clinical trial (Engage). Efficacy outcomes were assessed on patients from the Engage trial who started treatment on menstrual cycle day 2 versus menstrual cycle day 3, patients who received rFSH step-down or fixed-dose rFSH, patients who received rFSH on the day of human chorionic gonadotropin (hCG) compared with those who did not, and patients who received hCG when the criterion was reached versus those with a 1-day delay.

High ovarian response does not jeopardize ongoing pregnancy rates and increases cumulative pregnancy rates in a GnRH-antagonist protocol.

Study Question: Is the ovarian response to controlled ovarian stimulation (COS) related to the ongoing pregnancy rate when taking into account the main covariates affecting the probabilities of pregnancy following fresh embryo transfer?

Summary Answer: In patients treated with corifollitropin alfa or daily recombinant FSH (rFSH) in a GnRH-antagonist protocol, a high ovarian response did not compromise ongoing pregnancy rates and increased cumulative pregnancy rates following fresh and frozen-thawed embryo transfer.

What Is Known And What This Paper Adds: A strong association between the number of oocytes and pregnancy rates has been described but this is the first comprehensive analysis assessing important confounders that might affect pregnancy rates.

Study Design: In a large, prospective, double-blind, randomized trial (Engage; n = 1506), patients were treated with either a single dose of 150 μg corifollitropin alfa or daily 200 IU rFSH for the first 7 days of COS in a GnRH-antagonist (ganirelix) protocol.

A comparison of live birth rates and cumulative ongoing pregnancy rates between Europe and North America after ovarian stimulation with corifollitropin alfa or recombinant follicle-stimulating hormone.

Objective: To compare live birth rates after fresh embryo transfer (ET) and cumulative ongoing pregnancy rates after fresh ET and frozen-thawed (ET) between continents and overall after one treatment cycle with corifollitropin alfa or recombinant FSH.

Design: Double-blind, multicenter, randomized controlled trial.

Setting: Fourteen centers in North America (NA); 20 in Europe (EU).

A randomized controlled trial of the GnRH antagonist ganirelix in Chinese normal responders: high efficacy and pregnancy rates.

Gonadotropin-releasing hormone (GnRH) antagonists for controlled ovarian stimulation (COS) were only recently introduced into China. The efficacy and safety of the GnRH antagonist ganirelix was assessed in a multicenter, controlled, open-label study, in which Chinese women were randomized to either ganirelix (n = 113) or a long GnRH agonist protocol of triptorelin (n = 120). The primary end point was the amount of recombinant follicle-stimulating hormone (rFSH) required to meet the human chorionic gonadotropin criterion (three follicles ≥17 mm).

No association between endogenous LH and pregnancy in a GnRH antagonist protocol: part I, corifollitropin alfa.

The relationship between endogenous LH concentrations and ongoing pregnancy rates among normogonadotrophic patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol were examined. In the Engage trial, 1506 patients received corifollitropin alfa (150 μg) or daily recombinant FSH (rFSH) (200 IU) for the first 7 days of stimulation with 0.25mg ganirelix from stimulation day 5.

Corifollitropin alfa in a long GnRH agonist protocol: proof of concept trial.

Fifty healthy women, aged 18-39 years with no known risk of ovarian hyperstimulation were treated with 100 or 150 μg corifollitropin alfa (dependent on body weight) in a long GnRH agonist protocol. At these doses, corifollitropin alfa initiated and supported growth of a large cohort of follicles during the first week of ovarian stimulation.

LH concentrations do not correlate with pregnancy in rFSH/GnRH antagonist cycles.

The possible relationship between endogenous LH concentrations and clinical outcome was evaluated in 750 patients treated with a standardized gonadotrophin-releasing hormone (GnRH) antagonist and recombinant FSH (rFSH)-only protocol. Serum LH concentrations were measured during stimulation by a central laboratory and patients were stratified into quantiles of P75. The P25 values were 3.