Brivaracetam exposure-response predictions in pediatric patients from age 1 month: Extrapolation of levetiracetam adult-pediatric scaling to brivaracetam.

Background: An adult population pharmacokinetic/pharmacodynamic (PK/PD) model for the antiseizure medication (ASM) brivaracetam (BRV) was previously extended to children aged 4-16 years by using a pediatric BRV population PK model. Effects were scaled using information from a combined adult-pediatric PK/PD model of a related ASM, levetiracetam (LEV).

Objective: To scale an existing adult population PK/PD model for BRV to children aged 1 month to < 4 years using information from a combined adult-pediatric PK/PD model for LEV, and to predict the effective dose of BRV in children aged 1 month to < 4 years using the adult BRV PK/PD model modified for the basal seizure rate in children.

Pharmacokinetics and safety of brivaracetam in neonates with repeated electroencephalographic seizures: A multicenter, open-label, single-arm study.

Objective: To evaluate the pharmacokinetics (PK), safety, and tolerability of brivaracetam (BRV) in neonates with repeated electroencephalographic seizures not controlled with previous antiseizure medications (ASMs).

Methods: Phase 2/3, multicenter, open-label, single-arm study (N01349/NCT03325439) in neonates with repeated electroencephalographic seizures (lasting ≥10 s) confirmed by video-electroencephalography, and inadequate seizure control with at least one ASM. A screening period (up to 36 h) was followed by a 48-h evaluation period during which patients received 0.

Pharmacokinetics, Safety, and Tolerability of Brivaracetam in Healthy Elderly Participants.

The pharmacokinetics, metabolism, safety, and tolerability of the antiseizure medication brivaracetam (BRV) were characterized in 16 healthy elderly participants (8 men/8 women) aged 65-78 years who received a single 200-mg oral dose of BRV on day 1, followed by 200 mg twice daily from day 3 until day 12. BRV and three metabolites were determined in plasma and urine. Adverse events, vital signs, electrocardiograms, laboratory tests, general and neurological examinations, and psychometric rating scales were recorded at regular intervals.

Pharmacokinetics, safety, and tolerability of intravenous brivaracetam in pediatric patients with epilepsy: An open-label trial.

Objective: To evaluate the pharmacokinetics, safety, and tolerability of brivaracetam (BRV) as 15-min intravenous (IV) infusion and bolus (≤2-min injection).

Methods: EP0065 (ClinicalTrials.gov: NCT03405714) was a Phase 2, multicenter, open-label trial in patients ≥1 month to <16 years of age with epilepsy.

Pharmacokinetics of solifenacin in pediatric populations with overactive bladder or neurogenic detrusor overactivity.

The aim of this investigation was to characterize and compare the pharmacokinetics (PK) of the antimuscarinic drug solifenacin in pediatric patients with overactive bladder (OAB) or neurogenic detrusor overactivity (NDO) utilizing data from three phase III trials. LION was a placebo-controlled, 12-week trial in children (5-<12 years) and adolescents (12-<18 years) with OAB. MONKEY and MARMOSET were open-label, 52-week trials in children and adolescents or younger children (6 months-<5 years), respectively, with NDO.

Validation of LC-MS/MS methods for the determination of mirabegron and eight metabolites in human plasma in a paediatric population.

Mirabegron is the first registered β3-adrenoceptor agonist for treatment of overactive bladder as an alternative to antimuscarinics. Previously four liquid chromatography-tandem mass spectrometry assays were published to determine mirabegron and eight metabolites (M5, M8, M11-M16) in human plasma. In order to support paediatric development, the assays were further optimized to reduce the required blood volume and increase the sensitivity.

Safety, Pharmacokinetics, and Pharmacodynamics of ASP3662, a Novel 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor, in Healthy Young and Elderly Subjects.

Inhibition of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) represents a potential mechanism for improving pain conditions. ASP3662 is a potent and selective inhibitor of 11β-HSD1. Two phase I clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses of ASP3662 in healthy young and elderly non-Japanese and young Japanese subjects.

Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach.

Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human, and to predict drug concentration-time profiles in multiple CNS compartments on available human data of four drugs (acetaminophen, oxycodone, morphine and phenytoin). Values of the system-specific parameters in the rat CNS PBPK model were replaced by corresponding human values.

Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.

Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions.

A Generic Multi-Compartmental CNS Distribution Model Structure for 9 Drugs Allows Prediction of Human Brain Target Site Concentrations.

Purpose: Predicting target site drug concentration in the brain is of key importance for the successful development of drugs acting on the central nervous system. We propose a generic mathematical model to describe the pharmacokinetics in brain compartments, and apply this model to predict human brain disposition.

Methods: A mathematical model consisting of several physiological brain compartments in the rat was developed using rich concentration-time profiles from nine structurally diverse drugs in plasma, brain extracellular fluid, and two cerebrospinal fluid compartments.

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).

Pharmacokinetic Interactions Between Mirabegron and Metformin, Warfarin, Digoxin or Combined Oral Contraceptives.

Background And Objectives: Mirabeg ron is a selective β3-adrenoceptor agonist approved for the treatment of overactive bladder (OAB). Four phase 1 studies were conducted in healthy subjects to evaluate the potential for pharmacokinetic interactions between mirabegron and metformin, warfarin, digoxin, or a combination oral contraceptive (COC).

Methods: Thirty-two male subjects received metformin (500 mg twice daily) or mirabegron (160 mg once daily) alone, in combination or with placebo.

Pharmacokinetic Drug Interaction Studies with Enzalutamide.

Background And Objectives: Two phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

Methods: A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg).

Clinical Pharmacokinetic Studies of Enzalutamide.

Background And Objectives: Oral enzalutamide (160 mg once daily) is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This article describes the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide.

Methods: Results are reported from five clinical studies.

Clinical pharmacokinetics and pharmacodynamics of the novel SGLT2 inhibitor ipragliflozin.

Ipragliflozin (Suglat(®)) is a potent and selective inhibitor of sodium-glucose cotransporter-2 that was recently launched in Japan. Its mechanism of action involves the suppression of glucose re-absorption in the kidney proximal tubules, causing excretion of glucose in the urine. The aim of this review is to provide a comprehensive overview of currently available pharmacokinetic and pharmacodynamic data on ipragliflozin, including studies in healthy subjects, patients with type 2 diabetes mellitus and special populations.

Absence of clinically relevant cardiovascular interaction upon add-on of mirabegron or tamsulosin to an established tamsulosin or mirabegron treatment in healthy middle-aged to elderly men.

Objective: Tamsulosin and mirabegron may be used concomitantly in patients with lower urinary tract symptoms. Since alpha1-adrenoceptor antagonists are associated with cardiovascular side effects, potential pharmacokinetic and cardiovascular interactions were evaluated.

Materials And Methods: This was an open-label, randomized, 2-arm, 2-sequence study in 48 healthy men (24/arm) aged 44 - 72 years.

Ipragliflozin does not prolong QTc interval in healthy male and female subjects: a phase I study.

Background: Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. The International Conference on Harmonisation recommends that the safety investigation of new drugs include characterization of each agent's effects on the QT/QTc interval.

Objective: The goal of this study was to assess the effect on cardiac repolarization (QTc interval) of repeated oral dosing of ipragliflozin at therapeutic (100 mg/d) and supratherapeutic (600 mg/d) levels in healthy subjects.

Evaluation of the Pharmacokinetic Interaction Between the β3 -Adrenoceptor Agonist Mirabegron and the Muscarinic Receptor Antagonist Solifenacin In Healthy Subjects.

Mirabegron, a selective β3 -adrenoceptor agonist, is approved for the treatment of overactive bladder (OAB). Solifenacin is a muscarinic receptor antagonist widely used in the treatment of OAB. This open-label, 1-sequence, 2-arm study investigated whether any pharmacokinetic interaction exists between mirabegron and solifenacin.

The effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin, a novel sodium glucose co-transporter 2 (SGLT2) inhibitor.

Background: Ipragliflozin (ASP1941), a potent selective sodium glucose co-transporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. Ipragliflozin is primarily eliminated via conjugation by the liver as five pharmacologically inactive metabolites (M1, M2, M3, M4 and M6). This study evaluated the effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin and its metabolites.

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).

Role of cytochrome p450 isoenzymes 3A and 2D6 in the in vivo metabolism of mirabegron, a β3-adrenoceptor agonist.

Background: Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6.

Objective: To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism.

Effect of renal or hepatic impairment on the pharmacokinetics of mirabegron.

Background And Objectives: Mirabegron, a selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is eliminated by renal and metabolic routes. The potential influence of renal or hepatic impairment on the pharmacokinetics of mirabegron was evaluated.

Methods: Two separate open-label, single-dose, parallel-group studies were conducted.

Pharmacokinetic properties of mirabegron, a β3-adrenoceptor agonist: results from two phase I, randomized, multiple-dose studies in healthy young and elderly men and women.

Background: Mirabegron (YM178) is a β(3)-adrenoceptor agonist for the treatment of overactive bladder (OAB). As part of the clinical development program for mirabegron, 2 human volunteer studies were performed to derive detailed data on the multiple-dose pharmacokinetic (PK) properties of mirabegron.

Objective: Two randomized Phase I studies were conducted to evaluate the PK properties of mirabegron, including metabolic profile and effects of age and sex, following multiple oral doses in healthy subjects.

Absorption, metabolism and excretion of [(14)C]mirabegron (YM178), a potent and selective β(3)-adrenoceptor agonist, after oral administration to healthy male volunteers.

The mass balance and metabolite profiles of 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)[U-(14)C]phenyl]acetamide ([(14)C]mirabegron, YM178), a β(3)-adrenoceptor agonist for the treatment of overactive bladder, were characterized in four young, healthy, fasted male subjects after a single oral dose of [(14)C]mirabegron (160 mg, 1.85 MBq) in a solution. [(14)C]Mirabegron was rapidly absorbed with a plasma t(max) for mirabegron and total radioactivity of 1.

Effect of Ipragliflozin (ASP1941), a novel selective sodium-dependent glucose co-transporter 2 inhibitor, on urinary glucose excretion in healthy subjects.

Background: Hyperglycaemia is associated with serious complications, significant morbidity and death. Despite the availability of a wide range of therapeutic options, many patients with diabetes mellitus fail to achieve or maintain recommended glycaemic goals. Ipragliflozin (ASP1941) is a novel, selective inhibitor of the sodium-dependent glucose co-transporter 2, which is highly expressed in the proximal tubules of the kidneys.