The Importance of Assessing Drug Pharmacokinetics and Pharmacodynamics in the Obese Population During Drug Development.

Obesity remains a US national health crisis and a growing concern worldwide. Concerningly, individuals who are obese are at an increased risk for comorbid diseases that include, but are not limited to, hypertension, diabetes, cardiovascular disease, and cancer. Beyond the risk for developing these conditions, obesity may also impact the pharmacological activity of the therapies being used to treat them and other disease states.

JNJ-10450232 (NTM-006), A novel non-opioid with structural similarities to acetaminophen, produces relatively long-lasting analgesia after a single dose in patients undergoing 3rd molar extraction.

JNJ-10450232 (NTM-006) is a non-opioid, non-NSAID analgesic and antipyretic compound with structural similarity to acetaminophen. Preclinical models show comparable analgesia relative to acetaminophen and no evidence of hepatotoxicity associated with overdose. Moreover, it was safe and generally well tolerated in a First-in-Human Study.

Model-informed bridging of rivaroxaban doses for thromboprophylaxis in pediatric patients aged 9 years and older with congenital heart disease.

Rivaroxaban is approved in various regions for the treatment of acute venous thromboembolism (VTE) in children aged between 0 and 18 years and was recently investigated for thromboprophylaxis in children aged between 2 and 8 years (with body weights <30 kg) with congenital heart disease who had undergone the Fontan procedure. In the absence of clinical data, rivaroxaban doses for thromboprophylaxis in post-Fontan children aged 9 years and older or ≥30 kg were derived by a bridging approach that used physiologically-based pharmacokinetic (PBPK) and population pharmacokinetic (popPK) models based on pharmacokinetic (PK) data from 588 pediatric patients and from adult patients who received 10 mg once daily for thromboprophylaxis after major orthopedic surgeries as a reference. Both models showed a tendency toward underestimating rivaroxaban exposure in post-Fontan patients aged between 2 and 5 years but accurately described rivaroxaban PK in post-Fontan patients aged between 5 and 8 years.

Prediction of Drug-Drug Interactions After Esketamine Intranasal Administration Using a Physiologically Based Pharmacokinetic Model.

Background And Objective: A physiologically based pharmacokinetic (PBPK) modeling approach for esketamine and its metabolite noresketamine after esketamine intranasal administration was developed to aid the prediction of drug-drug interactions (DDIs) during the clinical development of esketamine nasal spray (SPRAVATO). This article describes the development of the PBPK model to predict esketamine and noresketamine kinetics after intranasal administration of esketamine and its verification and application in the prediction of prospective DDIs with esketamine using models of index perpetrator and victim drugs.

Methods: The intranasal PBPK (IN-PBPK) models for esketamine/noresketamine were constructed in Simcyp v14.

The effects of intranasal esketamine on on-road driving performance in patients with major depressive disorder or persistent depressive disorder.

Background: Intranasal esketamine demonstrates rapid improvement of depressive symptoms. However, transient adverse effects (dissociation, sedation and dizziness) may occur, which could impact driving performance.

Aims: To evaluate the effects of 84 mg intranasal esketamine on driving performance in unipolar major depressive disorder (MDD) or persistent depressive disorder (PDD) patients.

Dosing Regimen Prediction and Confirmation With Rivaroxaban for Thromboprophylaxis in Children After the Fontan Procedure: Insights From the Phase III UNIVERSE Study.

Thrombosis remains an important complication for children with single-ventricle physiology following the Fontan procedure, and effective thromboprophylaxis is an important unmet medical need. To obviate conventional dose-finding studies and expedite clinical development, a rivaroxaban dose regimen for this indication was determined using a model-informed drug development approach. A physiologically based pharmacokinetic rivaroxaban model was used to predict a pediatric dosing regimen that would produce drug exposures similar to that of 10 mg once daily in adults.

Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression.

Background: Esketamine nasal spray is approved for treatment-resistant depression.

Objective: The objective of this study was to characterize the pharmacokinetics of esketamine and noresketamine in healthy subjects and patients with treatment-resistant depression.

Methods: Esketamine and noresketamine were measured in > 9000 plasma samples collected from 820 individuals who received esketamine by the intranasal, intravenous, and oral routes.

First evaluation of tapentadol oral solution for the treatment of moderate to severe acute pain in children aged 6 to <18.

Background: This is the first clinical trial in the global pediatric clinical development program for the use of the analgesic tapentadol in children and adolescents.

Patients And Methods: This multicenter, open-label clinical trial investigated pharmacokinetics, safety and tolerability, and efficacy of tapentadol and its major metabolite tapentadol-O-glucuronide after administration of a single dose of tapentadol oral solution (OS) in pediatric patients aged 6 to <18 years experiencing moderate to severe acute pain after surgery. Efficacy (change in pain intensity after tapentadol intake) was assessed in an exploratory manner using the McGrath Color Analog Scale and Faces Pain Scale-Revised.

Fatty Acid Amide Hydrolase Inhibition by JNJ-42165279: A Multiple-Ascending Dose and a Positron Emission Tomography Study in Healthy Volunteers.

Inhibition of fatty acid amide hydrolase (FAAH) potentiates endocannabinoid activity and is hypothesized to have therapeutic potential for mood and anxiety disorders and pain. The clinical profile of JNJ-42165279, an oral selective FAAH inhibitor, was assessed by investigating the pharmacokinetics, pharmacodynamics, safety, and binding to FAAH in the brain of healthy human volunteers. Concentrations of JNJ-42165279 (plasma, cerebrospinal fluid (CSF), urine) and fatty acid amides (FAA; plasma, CSF), and FAAH activity in leukocytes was determined in a phase I multiple ascending dose study.

Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study.

Background: The effect of intranasal esketamine on cognitive functioning in healthy participants is assessed in this study.

Methods: Twenty-four participants (19-49 years) were randomized to one of two treatment sequences in which either esketamine 84 mg or placebo was intranasally administered in a double-blind, two-period crossover design. Primary measures included five tests of Cogstate computerized test battery assessed at 1 h predose and 40 min, 2, 4, and 6 h postdose.

Quantifying the Exposure of Tapentadol Extended Release in Japanese Patients with Cancer Pain and Bridging Tapentadol Pharmacokinetics Across Populations Using a Modeling Approach.

Background And Objectives: Tapentadol extended release (ER) is approved for the management of chronic and acute pain in adults. There has been no report of tapentadol ER pharmacokinetics in subjects with cancer pain. This analysis investigated tapentadol ER pharmacokinetics in Japanese patients with cancer pain and bridged it with the pharmacokinetics in Japanese healthy subjects and Caucasian patients with cancer pain.

Pharmacokinetic evaluation of tapentadol extended-release tablets in healthy subjects.

Objective: To evaluate serum pharmacokinetics of tapentadol administered to healthy subjects as extended-release (ER) tablets.

Design: Seven single-dose studies (five randomized, crossover, bioequivalence studies; a study in Japanese men; and a randomized, crossover, effects-of-food study) and one repeated-dose study.

Setting: Clinical research settings in the United States and The Netherlands.

A phase I trial and pharmacokinetic study of a 24-hour infusion of trabectedin (Yondelis®, ET-743) in children and adolescents with relapsed or refractory solid tumors.

Background: The objectives of this phase I study were to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of a 24-hour continuous intravenous infusion of trabectedin administered to children and adolescents with refractory or relapsed solid tumors.

Procedure: Patients between the ages of 4 and 16 years old with refractory solid tumors received trabectedin as a 24-hour infusion every 21 days. Dexamethasone and prophylactic growth factor support were administered with each cycle.

Effect of carisbamate on the pharmacokinetics and pharmacodynamics of warfarin in healthy participants.

Carisbamate's effect (200 mg twice-daily [study 1], 600 mg twice-daily [study 2]) on warfarin's (25 mg single dose) pharmacokinetics and pharmacodynamics (international normalized ratio) was assessed during 2 open-label studies in healthy participants. Coadministration of either carisbamate regimen produced small changes on the mean maximum plasma concentration (C(max)) and mean area under the plasma concentration-time curve to the last measurable time point (AUC(last)) of (S)- and (R)-warfarin, which are unlikely to be clinically significant. For (S)-warfarin, the ratios (with carisbamate/without carisbamate) of geometric means for C(max) were 105.

Cognitive effects of carisbamate in randomized, placebo-controlled, healthy-volunteer, multidose studies.

Adverse cognitive effects are an important concern for drugs that influence the central nervous system. Carisbamate is a novel drug in development for treatment of seizures and neuropathic pain. Information on its cognitive effects is limited.

Effect of mild and moderate hepatic impairment on the pharmacokinetics and safety of carisbamate.

This open-label, parallel-group study was designed to characterize the pharmacokinetics (PK) of carisbamate in participants with mild or moderate hepatic impairment versus those with normal hepatic function. Healthy (n = 10) and hepatic-impaired (n = 20) participants received a single 200-mg oral dose of carisbamate. Serial PK blood samples were collected up to 120 hours postdose.

Pharmacokinetics and tolerability of rabeprazole in children 1 to 11 years old with gastroesophageal reflux disease.

Background: The pharmacokinetics of rabeprazole after a single oral dose and once-daily administration for 5 consecutive days was characterized in children 1 to 11 years old with gastroesophageal reflux disease (GERD).

Patients And Methods: The initial 8 patients received rabeprazole sodium (hereafter referred to as rabeprazole) 0.14 mg/kg (part 1); the next 20 patients were randomized to receive 0.

Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report from the Children's Oncology Group.

Background: The objectives of this trial were to define the toxicity profile, dose, pharmacokinetics, and pharmacodynamics of the farnesyl transferase (FTase) inhibitor, tipifarnib, in children and adolescents with hematological malignancies.

Procedure: Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at a dose of 300 mg/m(2) /dose. Pharmacokinetic sampling was performed for 36 hr after the first dose and leukemic blasts were collected pre-treatment and at steady state for determination of FTase activity.

Validation and application of an LC-MS/MS method for quantitation of three fatty acid ethanolamides as biomarkers for fatty acid hydrolase inhibition in human plasma.

Endogenous ethanolamides (fatty acid amides), including arachidonyl ethanolamide (anandamide, AEA), oleoyl ethanolamide (OEA), and palmitoyl ethanolamide (PEA), are substrates of fatty acid amide hydrolase (FAAH). FAAH may play an important role for pain, anxiety/depression, and metabolic disorders. Ethanolamides are considered to be potential pharmacodynamic biomarkers to determine target engagement for FAAH inhibition by novel pharmaceutical agents.

Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma.

Purpose: Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses.

Methods: Forty-two patients were randomized to receive bortezomib 1.0 or 1.

Pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western subjects.

Purpose: To compare the pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations.

Methods: An open-label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3-day washout period; twice-daily dosing of 250 mg carisbamate on days 5-8; subsequently, 500 mg on days 9-12 and a single dose of 500 mg on day 13.

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors.

Purpose: To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors.

Methods: Patients with ECOG performance status 0-1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m(2)) followed by trabectedin (starting dose, 0.

Pharmacokinetics, safety, and tolerability of the new antiepileptic carisbamate in the elderly.

Purpose: To evaluate the effect of age on the disposition of two different oral formulations of carisbamate (RWJ-333369), a novel neuromodulator under investigation.

Methods: The disposition of carisbamate was studied in eight men and eight women in each of the three age groups: 18-55, 65-74, and >or= 75 years (N=48). Subjects received single (100mg immediate-release [IR] tablets or 250 mg controlled-release [CR] tablets) or repeated administration (up to 500 mg IR BID or 1250 mg CR QD) of carisbamate in a randomized, double-blind, placebo-controlled, parallel-group, single-center study.