Pharmacokinetics of vaginal versus buccal misoprostol for labor induction at term.

The IMPROVE study (NCT02408315) compared the efficacy and safety of vaginal and buccal administration of misoprostol for full-term, uncomplicated labor induction. This report compares the pharmacokinetics of misoprostol between vaginal and buccal routes. Women greater than or equal to 14 years of age undergoing induction of labor greater than or equal to 37 weeks gestation without significant complications were randomized to vaginal or buccal misoprostol 25 μg followed by 50 μg doses every 4 h.

Pharmacokinetic modeling of R and S-Methadone and their metabolites to study the effects of various covariates in post-operative children.

Methadone is a synthetic opioid used as an analgesic and for the treatment of opioid abuse disorder. The analgesic dose in the pediatric population is not well-defined. The pharmacokinetics (PKs) of methadone is highly variable due to the variability in alpha-1 acid glycoprotein (AAG) and genotypic differences in drug-metabolizing enzymes.

Postprandial triglyceride reduction following acute treatment of a selective 5-hydroxytryptamine-2c agonist and characterization using a semi-physiological model.

Aim: To investigate the tolerability, pharmacokinetics (PK) and postprandial triglyceride (TG) response of single, escalating oral doses of a selective 5-hydroxytryptamine-2c (5-HT ) agonist in subjects with overweight/obesity and apply mechanistic population pharmacokinetic-pharmacodynamic modelling to identify a plausible drug mechanism of action.

Materials And Methods: This phase 1, single-centre, double-blind, randomized, placebo-controlled, four-period, two-alternating cohorts study evaluated single escalating oral doses ranging from 5 to 130 mg of LY2140112 (LY) in subjects with overweight/obesity (body mass index: 27-39 kg/m ). Postprandial TG response (total TG, chylomicrons and very low-density lipoprotein particles [VLDL]-V6) following a high-fat meal were assessed for 11 h postmeal for each dose level.

Exposure-Response Modeling to Characterize the Relationship Between Ixekizumab Serum Drug Concentrations and Efficacy Responses at Week 12 in Patients With Moderate to Severe Plaque Psoriasis.

Ixekizumab, a high-affinity monoclonal antibody, selectively targets interleukin-17A and has been shown to be efficacious in the treatment of moderate to severe psoriasis. The objective was to describe the relationship between ixekizumab concentrations and efficacy response (static Physician Global Assessment [sPGA] and the Psoriasis Activity and Severity Index [PASI) scores] after 12 weeks of ixekizumab treatment in psoriasis patients from 3 phase 3 studies. Data from 2888 psoriasis patients randomized to receive placebo or 80 mg ixekizumab every 2 weeks or every 4 weeks were analyzed.

Semi-physiological model of postprandial triglyceride response in lean, obese and very obese individuals after a high-fat meal.

Aims: To quantify the postprandial triglyceride (TG) response of chylomicrons and very-low-density lipoprotein-V6 (VLDL-V6) after a high-fat meal in lean, obese and very obese healthy individuals, using a mechanistic population lipokinetic modelling approach.

Methods: Healthy individuals from three body mass index population categories: lean (18.5-24.

Population pharmacokinetic meta-analysis of ramucirumab in cancer patients.

Aims: Ramucirumab is a human IgG1 monoclonal antibody that specifically binds vascular endothelial growth factor receptor-2 (VEGFR-2) and blocks binding of VEGF-A, VEGF-C and VEGF-D. The objective of the analysis was to characterize the clinical pharmacology profile of ramucirumab using a population pharmacokinetic approach.

Methods: A total of 1639 patients with 6427 serum concentrations from 11 Phase 1b, 2 and 3 clinical trials in patients with various cancer indications were included in the analysis.

Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer.

Ramucirumab is an IgG monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure-efficacy and exposure-safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials.

Population Pharmacokinetic Modeling of Olaratumab, an Anti-PDGFRα Human Monoclonal Antibody, in Patients with Advanced and/or Metastatic Cancer.

Background And Objectives: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population.

Clinical Pharmacokinetics of Dulaglutide in Patients with Type 2 Diabetes: Analyses of Data from Clinical Trials.

Background And Objective: Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist administered as once-weekly subcutaneous injections for the treatment of type 2 diabetes (T2D). The clinical pharmacokinetics of dulaglutide were characterized in patients with T2D and healthy subjects.

Methods: The pharmacokinetics of dulaglutide were assessed throughout clinical development, including conventional pharmacokinetic analysis in clinical pharmacology studies and population pharmacokinetic analyses of data from combined phase 2 and phase 3 studies in patients with T2D.

Dose selection using a semi-mechanistic integrated glucose-insulin-glucagon model: designing phase 2 trials for a novel oral glucokinase activator.

Selecting dosing regimens for phase 2 studies for a novel glucokinase activator LY2599506 is challenging due to the difficulty in modeling and assessing hypoglycemia risk. A semi-mechanistic integrated glucose-insulin-glucagon (GIG) model was developed in NONMEM based on pharmacokinetic, glucose, insulin, glucagon, and meal data obtained from a multiple ascending dose study in patients with Type 2 diabetes mellitus treated with LY2599506 for up to 26 days. The series of differential equations from the NONMEM model was translated into an R script to prospectively predict 24-h glucose profiles following LY2599506 treatment for 3 months for a variety of doses and dosing regimens.

Pharmacokinetics of teriparatide (rhPTH[1-34]) and calcium pharmacodynamics in postmenopausal women with osteoporosis.

Teriparatide (rhPTH[1-34]) affects calcium metabolism in a pattern consistent with the known actions of endogenous parathyroid hormone (PTH). This report describes the pharmacokinetics and resulting serum calcium response to teriparatide in postmenopausal women with osteoporosis. Pharmacokinetic samples for this analysis were obtained from 360 women who participated in the Fracture Prevention Trial.

Effects of varying degrees of renal impairment on the pharmacokinetics of duloxetine: analysis of a single-dose phase I study and pooled steady-state data from phase II/III trials.

Background: Duloxetine is indicated for patients with a variety of conditions, and some of these patients may have mild to moderate degrees of renal impairment. Renal impairment may affect the pharmacokinetics of a drug by causing changes in absorption, distribution, protein binding, renal excretion or nonrenal clearance. As duloxetine is highly bound to plasma proteins and its metabolites are renally excreted, it is prudent to evaluate the effect of renal insufficiency on exposure to duloxetine and its metabolites in the systemic circulation.

Prediction of prasugrel active metabolite concentrations from 2 downstream inactive metabolite concentrations using multilinear regression analysis.

Prasugrel is a thienopyridine prodrug that is metabolized to an active metabolite (Pras-AM), which inhibits adenosine diphosphate (ADP)-induced platelet aggregation. The study objective was to describe a multilinear regression correlation model that was used to quantitatively predict concentrations of Pras-AM from downstream inactive metabolites, R-119251 and R-106583, for the purpose of estimating Pras-AM exposure in patients in the TRITON-TIMI 38 substudies. The model development included 1462 Pras-AM, 1345 R-119251, and 1456 R-106583 concentration data points from 103 healthy participants with a prasugrel dose range of 15 to 80 mg.

Population pharmacokinetics of orally administered duloxetine in patients: implications for dosing recommendation.

Objectives: The objectives of this analysis were to characterize the pharmacokinetics of duloxetine at steady state in patients, estimate the variability, identify significant covariates that may influence duloxetine pharmacokinetics and provide appropriate dosing recommendations for patients on duloxetine treatment.

Methods: The pharmacokinetic meta-analysis dataset was created from one open-label clinical study and four double-blind, placebo-controlled clinical studies. Duloxetine concentrations (N = 2002) were obtained from 594 patients diagnosed with major depressive disorder (n = 223), diabetic peripheral neuropathic pain (n = 112), stress urinary incontinence (n = 128) and fibromyalgia (n = 131).

Pharmacokinetics/Pharmacodynamics and the stages of drug development: role of modeling and simulation.

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation (M&S) are well-recognized powerful tools that enable effective implementation of the learn-and-confirm paradigm in drug development. The impact of PK/PD M&S on decision making and drug development risk management is dependent on the question being asked and on the availability and quality of data accessible at a particular stage of drug development. For instance, M&S methodologies can be used to capture uncertainty and use the expected variability in PK/PD data generated in preclinical species for projection of the plausible range of clinical dose; clinical trial simulation can be used to forecast the probability of achieving a target response in patients based on information obtained in early phases of development.

Effect of age on the pharmacokinetics of duloxetine in women.

Aims: The effect of age on duloxetine pharmacokinetics was evaluated in healthy volunteers and in patients with urinary incontinence.

Methods: Twenty-four healthy subjects (12 women 65-77 years, and 12 women 32-50 years) were given a single 40-mg oral dose of duloxetine in Study 1. Plasma concentration-time data were analysed by noncompartmental pharmacokinetic methods.