Phase I trial to investigate the effect of renal impairment on isavuconazole pharmacokinetics.

Purpose: The purpose of the study is to evaluate the effect of renal impairment (RI) and end-stage renal disease (ESRD) on the pharmacokinetics (PK) of isavuconazole and the inactive cleavage product, BAL8728.

Methods: A single intravenous dose of the prodrug isavuconazonium sulfate (372 mg, equivalent to 200 mg isavuconazole and 75 mg of BAL8728 cleavage product) was administered to healthy controls (parts 1 and 2) and participants with mild, moderate, or severe RI (part 2) or ESRD (part 1); ESRD participants received two doses of 200 mg isavuconazole, 1 h post-dialysis (day 1) and prior to dialysis (day 15). Plasma PK parameters for isavuconazole included maximum concentration (C ), area under the concentration-time curve (AUC) from time of dose to 72 h (AUC), AUC extrapolated to infinity (AUC), AUC to last measurable concentration (AUC), half-life (t h), volume of distribution (V ), and total clearance (CL), for the healthy control group versus those with mild, moderate, or severe RI or ESRD.

Esomeprazole FDA Approval in Children With GERD: Exposure-Matching and Exposure-Response.

Objectives: Food and Drug Administration approval of proton-pump inhibitors for infantile gastroesophageal reflux disease has been limited by intrapatient variability in the clinical assessment of gastroesophageal reflux disease. For children 1 to 17 years old, extrapolating efficacy from adults for IV esomeprazole was accepted. The oral formulation was previously approved in children.

The variability in beta-cell function in placebo-treated subjects with type 2 diabetes: application of the weight-HbA1c-insulin-glucose (WHIG) model.

Aim: The weight-glycosylated haemoglobin (HbA1C)-insulin-glucose (WHIG) model describes the effects of changes in weight on insulin sensitivity (IS) in newly diagnosed, obese subjects receiving placebo treatment. This model was applied to a wider population of placebo-treated subjects, to investigate factors influencing the variability in IS and β-cell function.

Methods: The WHIG model was applied to the WHIG dataset (Study 1) and two other placebo datasets (Studies 2 and 3).

Reproducibility of QTc interval changes after meal intake.

Background: Detection of QTc decreases after meal intake was proposed as a possible proof of assay sensitivity in studies of drug-induced QTc changes. However, day-to-day reproducibility of QTc decreases after meal intake has not been established.

Methods: Holter recordings were available from 4 different baseline drug-free days of a thorough QT study in 157 females and 164 males.

QTc changes after meal intake: sex differences and correlates.

Background: Detection of food-induced QTc shortening has been proposed as an assay sensitivity in thorough QT/QTc (TQT) studies. Data of a large clinical study were used to investigate the food effects on QTc intervals.

Methods: Day-time drug-free 12-lead Holter recordings starting around 8:20AM were repeated 4 times in each of 176 female and 176 male healthy subjects aged 32.

Predicting the "First dose in children" of CYP3A-metabolized drugs: Evaluation of scaling approaches and insights into the CYP3A7-CYP3A4 switch at young ages.

First-dose-in-children relies on the prediction of clearance from adults for which little information is available on the accuracy of the scaling-approaches applied. For CYP3A-metabolized compounds, scaling of clearance is further challenged by different isoforms and by the CYP3A7 to CYP3A4 switch at young ages. This investigation aimed to evaluate the accuracy of two frequently used scaling approaches and to gain insights into the ontogeny of CYP3A.

The effect of mirabegron, a potent and selective β3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol.

Mirabegron is a potent and selective β3-adrenoceptor agonist developed for the treatment of overactive bladder. In vitro studies demonstrated that mirabegron partly acts as a (quasi-) irreversible, metabolism-dependent inhibitor of CYP2D6. The effect of steady-state mirabegron on single doses of the sensitive CYP2D6 substrates metoprolol (100 mg) and desipramine (50 mg) was assessed in two open-label, one-sequence crossover studies in healthy subjects (CYP2D6 extensive metabolizers).

Translational PK-PD modeling in pain.

The current gap between animal research and clinical development of analgesic drugs presents a challenge for the application of translational PK-PD modeling and simulation. First, animal pain models lack predictive and construct validity to accurately reflect human pain etiologies and, secondly, clinical pain is a multidimensional sensory experience that can't always be captured by objective and robust measures. These challenges complicate the use of translational PK-PD modeling to project PK-PD data generated in preclinical species to a plausible range of clinical doses.

Combination treatment with ipragliflozin and metformin: a randomized, double-blind, placebo-controlled study in patients with type 2 diabetes mellitus.

Background: Ipragliflozin (ASP1941) is a selective sodium glucose cotransporter 2 inhibitor in clinical development for the treatment of patients with type 2 diabetes mellitus (T2DM).

Objectives: The primary objective was to evaluate the safety profile and tolerability of ipragliflozin as a glucose-lowering agent in combination with stable metformin therapy in patients with T2DM. A secondary objective was to evaluate the effect of ipragliflozin on the pharmacokinetic (PK) properties of metformin.

The pharmacokinetics of darexaban are not affected to a clinically relevant degree by rifampicin, a strong inducer of P-glycoprotein and CYP3A4.

Aims: We investigated the effects of rifampicin on the pharmacokinetics (PK) of the direct clotting factor Xa inhibitor darexaban (YM150) and its main active metabolite, darexaban glucuronide (YM-222714), which almost entirely determines the antithrombotic effect.

Methods: In this open-label, single-sequence study, 26 healthy men received one dose of darexaban 60 mg on day 1 and oral rifampicin 600 mg once daily on days 4-14. On day 11, a second dose of darexaban 60 mg was given with rifampicin.

No pharmacokinetic interaction between ipragliflozin and sitagliptin, pioglitazone, or glimepiride in healthy subjects.

Aims: To investigate the effect of ipragliflozin on the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa in healthy subjects.

Methods: Three trials with an open-label, randomized, two-way crossover design were conducted in healthy subjects. Ipragliflozin 150 mg, sitagliptin 100 mg, pioglitazone 30 mg or glimepiride 1-2 mg were administered alone or in combination.

A semiphysiological population model for prediction of the pharmacokinetics of drugs under liver and renal disease conditions.

The application of model-based drug development in special populations becomes increasingly important for clinical trial optimization, mostly by providing a rationale for dose selection and thereby aiding risk-benefit assessment. In this article, a semiphysiological approach is presented, enabling the extrapolation of the pharmacokinetics from healthy subjects to patients with different disease conditions. This semiphysiological approach was applied to solifenacin, using clinical data on total and free plasma and urine concentrations in healthy subjects.