Once-Weekly Somapacitan vs Daily GH in Children With GH Deficiency: Results From a Randomized Phase 2 Trial.

Context: Daily growth hormone (GH) injections can be burdensome for patients and carers. Somapacitan is a long-acting, reversible albumin-binding GH derivative in development for once-weekly administration in patients with growth hormone deficiency (GHD).

Objective: The objective of this study is to evaluate the efficacy, safety, and tolerability of once-weekly somapacitan vs once-daily GH.

Rotational thromboelastometry can predict the probability of bleeding events in a translational rat model of haemophilia A following gene-based FVIIa prophylaxis.

Introduction: Monitoring of clinical effectiveness of bypassing agents in haemophilia patients is hampered by the lack of validated laboratory assays. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) have been evaluated for predicting clinical effectiveness of bypassing agents, however, with limited success.

Aim: Application of a longitudinal model-based approach may allow for a quantitative characterization of the link between ROTEM parameters and the probability of bleeding events.

Impact of trial design on the estimation of drug potency and power in clinical trials of haemophilia with inhibitors.

Historically, clinical trials of haemophilia with inhibitors (HwI) have been challenged by the small patient population. New approaches to clinical trial methodology and statistical modelling could potentially be used for study optimization. The aim of this work was to evaluate the impact of different trial designs and study conditions on the estimated drug potency and power, and compare traditional statistical methods with repeated time-to-event (RTTE) modelling in terms of power.

Pharmacokinetics and Pharmacodynamics of Once-Weekly Somapacitan in Children and Adults: Supporting Dosing Rationales with a Model-Based Analysis of Three Phase I Trials.

Background: Somapacitan, a long-acting growth hormone (GH) derivative, has been well-tolerated in children with GH deficiency (GHD) and adults (healthy and adult GHD), in phase I, single- and multiple-dose trials, respectively, and has pharmacokinetic and pharmacodynamic properties supporting a once-weekly dosing regimen.

Objective: In the absence of a multiple-dose phase I trial in children with GHD, the aim was to develop a pharmacokinetic/pharmacodynamic model to predict somapacitan exposure and insulin-like growth factor-I (IGF-I) response after once-weekly multiple doses in both children and adults with GHD.

Methods: Pharmacokinetic/pharmacodynamic models were developed from pharmacokinetic and IGF-I profiles in three phase I trials of somapacitan (doses: healthy adults, 0.

Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia.

Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and rFVIII in mice, rats, monkeys, and dogs using nonlinear mixed-effects modelling, accounting for inter-individual variability, nonlinear kinetics and covariate effects.

Quantification of the Pharmacodynamic Interaction of Morphine and Gabapentin Using a Response Surface Approach.

The combination of morphine and gabapentin has shown to be promising for managing postoperative pain but finding the right dose for the combination has proven to be a challenge. The purpose of this study was to quantitatively characterize the pharmacodynamic interaction between the two drugs and to identify the optimal concentration-effect relationship of the combination. Information regarding plasma concentrations and von Frey withdrawal thresholds following incisional surgery on Sprague Dawley rats, after administration of morphine, gabapentin, or their combination was available from published studies.

Analysis of opioid consumption in clinical trials: a simulation based analysis of power of four approaches.

Inconsistent trial design and analysis is a key reason that few advances in postoperative pain management have been made from clinical trials analyzing opioid consumption data. This study aimed to compare four different approaches to analyze opioid consumption data. A repeated time-to-event (RTTE) model in NONMEM was used to simulate clinical trials of morphine consumption with and without a hypothetical adjuvant analgesic in doses equivalent to 15-62% reduction in morphine consumption.

Population Pharmacokinetic Modelling of Morphine, Gabapentin and their Combination in the Rat.

Purpose: The combination of morphine and gabapentin seems promising for the treatment of postoperative and neuropathic pain. Despite the well characterised pharmacodynamic interaction, little is known about possible pharmacokinetic interactions. The aim of this study was to evaluate whether co-administration of the two drugs leads to modifications of their pharmacokinetic profiles.

A Pharmacokinetic-Pharmacodynamic Model of Morphine Exposure and Subsequent Morphine Consumption in Postoperative Pain.

Purpose: To characterize the pharmacokinetic-pharmacodynamic (PK-PD) relationship between exposure of morphine and subsequent morphine consumption and to develop simulation tools for model validation.

Methods: Dose, formulation and time of morphine administration was available from a published study in 63 patients receiving intravenous, oral immediate release or oral controlled release morphine on request after hip surgery. The PK-PD relationship between predicted exposure of morphine and morphine consumption was modeled using repeated time to event (RTTE) modeling in NONMEM.

Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain.

Despite much evidence that combination of morphine and gabapentin can be beneficial for managing postoperative pain, the nature of the pharmacological interaction of the two drugs remains unclear. The aim of this study was to assess the interaction of morphine and gabapentin in range of different dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7mg/kg), gabapentin (10, 30 and 100mg/kg) or their combination (9 combinations in total) were evaluated in the rat plantar incision model using an electronic von Frey device.

Repeated Time-to-event Analysis of Consecutive Analgesic Events in Postoperative Pain.

Background: Reduction in consumption of opioid rescue medication is often used as an endpoint when investigating analgesic efficacy of drugs by adjunct treatment, but appropriate methods are needed to analyze analgesic consumption in time. Repeated time-to-event (RTTE) modeling is proposed as a way to describe analgesic consumption by analyzing the timing of consecutive analgesic events.

Methods: Retrospective data were obtained from 63 patients receiving standard analgesic treatment including morphine on request after surgery following hip fracture.

Population pharmacokinetics of piperacillin in the early phase of septic shock: does standard dosing result in therapeutic plasma concentrations?

Antibiotic dosing in septic shock patients poses a challenge for clinicians due to the pharmacokinetic (PK) variability seen in this patient population. Piperacillin-tazobactam is often used for empirical treatment, and initial appropriate dosing is crucial for reducing mortality. Accordingly, we determined the pharmacokinetic profile of piperacillin (4 g) every 8 h, during the third consecutive dosing interval, in 15 patients treated empirically for septic shock.