Comparative bioavailability of inhaled treprostinil administered as LIQ861 and Tyvaso® in healthy subjects.

Introduction: Treprostinil is a synthetic prostacyclin analogue approved for inhalation administration to patients with pulmonary arterial hypertension (PAH) via nebulized Tyvaso® inhalation solution. LIQ861 is an inhaled, dry-powder formulation of treprostinil produced using Print® (Particle Replication in Nonwetting Templates) technology, a proprietary process for designing and producing highly uniform drug particles.

Methods: We conducted comparative bioavailability analyses of treprostinil exposure from LIQ861 (79.

Safety, Tolerability, and Pharmacokinetics of RT234 (Vardenafil Inhalation Powder): A First-in-Human, Ascending Single- and Multiple-Dose Study in Healthy Subjects.

RT234 (vardenafil inhalation powder) is being developed for pulmonary administration "as needed", to acutely improve exercise tolerance and symptoms in patients with pulmonary arterial hypertension (PAH). This single-center, open-label, randomized study in 32 healthy adult subjects evaluated single and multiple inhalation doses of RT234, for safety, tolerability, and pharmacokinetics (PKs). RT234 was generally safe and well tolerated at single doses of 0.

Human Abuse Potential of Oral NKTR-181 in Recreational Opioid Users: A Randomized, Double-Blind, Crossover Study.

Objective: To evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of oral NKTR-181 (oxycodegol), a novel full mu-opioid receptor agonist, relative to oral oxycodone.

Design: This double-blind, randomized, single-dose, crossover human abuse potential study was conducted in healthy, adult, non-physically dependent recreational opioid users.

Setting: Inpatient clinical research site.

Integrated population pharmacokinetics of etirinotecan pegol and its four metabolites in cancer patients with solid tumors.

Purpose: Etirinotecan pegol (EP), a long-acting topoisomerase-1 inhibitor, is a polyethylene glycol conjugate of irinotecan, with an intended indication for treatment of breast cancer with brain metastases. The objective of this study was to develop a population pharmacokinetic (popPK) model of EP and four of its metabolites (irinotecan, SN38, SN38-glucuronide, and APC) and determine covariates affecting their pharmacokinetics.

Methods: Data from 83 cancer patients enrolled in phase 1 studies were used.

Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy.

Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug.

Human Abuse Potential of the New Opioid Analgesic Molecule NKTR-181 Compared with Oxycodone.

Objective: Evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone.

Design: This randomized, single-center, double-blind, active- and placebo-controlled five-period crossover study enrolled healthy, adult, non-physically dependent recreational opioid users.

Setting: Inpatient clinical research site.

Pharmacologic Profile of Naloxegol, a Peripherally Acting -Opioid Receptor Antagonist, for the Treatment of Opioid-Induced Constipation.

Opioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind to -opioid receptors in the enteric nervous system (ENS). Naloxegol, a polyethylene glycol derivative of naloxol, which is a derivative of naloxone and a peripherally acting -opioid receptor antagonist, targets the physiologic mechanisms that cause OIC. Pharmacologic measures of opioid activity and pharmacokinetic measures of central nervous system (CNS) penetration were employed to characterize the mechanism of action of naloxegol.

Etirinotecan pegol administration is associated with lower incidences of neutropenia compared to irinotecan administration.

Purpose: The relationship between incidences of neutropenia and 10-hydroxy-7-ethyl camptothecin (SN38) exposure was explored using SN38 pharmacokinetic and neutrophil count data from toxicology studies of etirinotecan pegol (EP) and irinotecan in beagle dogs.

Methods: Dogs received four weekly intravenous infusions of either vehicle control (n = 22), EP (6, 15, 20, 25, 40/25 mg/kg; n = 3-9 dogs/dose group/sex; n = 48), or irinotecan (20 or 25 mg/kg n = 3-4 dogs/dose group/sex; n = 14). Blood samples were collected up to 50 days post-dose for characterization of SN38 pharmacokinetics.

Safety, tolerability, and pharmacokinetics of multiple ascending doses of naloxegol.

Opioid-induced constipation (OIC) is the most common and often a treatment-limiting adverse event (AE) of opioid therapy for chronic pain. Naloxegol (previously NKTR-118), a PEGylated derivative of naloxone that has minimal penetration of the central nervous system, has received regulatory approval as an oral therapy for OIC. This randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed to assess safety, tolerability, and pharmacokinetics of multiple doses of naloxegol in healthy volunteers.

Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of naloxegol at peripheral and central nervous system receptors in healthy male subjects: A single ascending-dose study.

This randomized, double-blind, placebo-controlled, ascending-dose, crossover study evaluated single oral doses of naloxegol (NKTR-118; 8, 15, 30, 60, 125, 250, 500, and 1000 mg), a PEGylated derivative of naloxone, for safety and tolerability, antagonism of peripheral and central nervous system (CNS) effects of intravenous morphine, and pharmacokinetics. Healthy men were randomized 1:1 to naloxegol or naloxegol-matching placebo administered with morphine and lactulose in a 2-period crossover design. Periods were separated by a 5- to 7-day washout.

NKTR-102 Efficacy versus irinotecan in a mouse model of brain metastases of breast cancer.

Background: Brain metastases are an increasing problem in women with invasive breast cancer. Strategies designed to treat brain metastases of breast cancer, particularly chemotherapeutics such as irinotecan, demonstrate limited efficacy. Conventional irinotecan distributes poorly to brain metastases; therefore, NKTR-102, a PEGylated irinotecan conjugate should enhance irinotecan and its active metabolite SN38 exposure in brain metastases leading to brain tumor cytotoxicity.

Nonclinical pharmacokinetics and activity of etirinotecan pegol (NKTR-102), a long-acting topoisomerase 1 inhibitor, in multiple cancer models.

Purpose: The aim of the study was to demonstrate the activity of etirinotecan pegol, a polymer conjugate of irinotecan, in multiple human tumor models and to establish both the pharmacokinetic/pharmacodynamics (PK/PD) relationship and clinical relevance of the findings.

Experimental Design: Anti-tumor activity was evaluated in mouse models of human lung, colorectal, breast, ovarian, and gastric cancers. Etirinotecan pegol was administered intravenously (once or every 3-7 days) to animals with established tumors.

A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation.

Naloxegol (previously known as NKTR-118) is a peripherally acting μ-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n=207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30-1000 mg/day morphine equivalents for ≥ 2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.

A multicenter, phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of etirinotecan pegol in patients with refractory solid tumors.

Purpose: This study was designed to establish the maximum tolerated dose (MTD) and to evaluate tolerability, pharmacokinetics, and antitumor activity of etirinotecan pegol.

Experimental Design: Patients with refractory solid malignancies were enrolled and assigned to escalating-dose cohorts. Patients received 1 infusion of etirinotecan pegol weekly 3 times every 4 weeks (w × 3q4w), or every 14 days (q14d), or every 21 days (q21d), with MTD as the primary end point using a standard 3 + 3 design.

Pharmacokinetics and tolerability of BAY41-6551 in subjects with chronic kidney disease.

Unlabelled: Abstract Background: BAY41-6551, a drug-device combination in development for adjunctive treatment of Gram-negative pneumonia in mechanically ventilated patients, consists of amikacin formulated for inhalation coupled with the Pulmonary Drug Delivery System (PDDS) Clinical aerosol delivery platform. This study evaluated safety, tolerability, and pharmacokinetics (PK) of BAY41-6551 in subjects with chronic kidney disease (CKD).

Methods: Single doses of BAY41-6551 (400 mg amikacin) were administered using the PDDS Clinical handheld device to six subjects with mild-to-moderate (Group 1) and six subjects with severe renal impairment (Group 2).

Pharmacokinetics and tolerability of amikacin administered as BAY41-6551 aerosol in mechanically ventilated patients with gram-negative pneumonia and acute renal failure.

Background: BAY41-6551, a drug-device combination in development for adjunctive treatment of Gram-negative pneumonia in intubated and mechanically ventilated patients, consists of amikacin formulated for inhalation coupled with the Pulmonary Drug Delivery System (PDDS) Clinical aerosol delivery platform. Given the predominantly renal clearance of aminoglycosides, understanding systemic amikacin exposure and safety during administration of BAY41-6551 to patients with acute renal failure (ARF) is clinically important.

Methods: Seven mechanically ventilated patients with Gram-negative pneumonia and ARF receiving continuous veno-venous hemodiafiltration (CVVHDF) were treated with multiple administrations of BAY41-6551 400 mg amikacin twice daily using the PDDS Clinical on-ventilator device [in addition to standard intravenous (i.

Clinical pharmacokinetics and pharmacodynamics of inhaled insulin.

The benefits of intensive insulin therapy in the prevention of complications in patients with diabetes mellitus are now well established. However, the current methods of insulin administration fall well short of the ideal. Consequently, alternative routes of insulin administration have been investigated.

Lung deposition and pharmacokinetics of cyclosporine after aerosolization in lung transplant patients.

Purpose: Aerosolized cyclosporine (aCsA) has proven to be an effective therapy for refractory acute and chronic rejection in lung transplant (LTx) patients. The objective of this study is to evaluate the lung deposition and systemic absorption of aCsA after aerosolized cyclosporine administration in LTx patients in the immediate postoperative period.

Method: Cyclosporine (CsA) was administered intravenously (1.

The effect of food on the bioavailability of norethindrone and ethinyl estradiol from norethindrone acetate/ethinyl estradiol tablets intended for continuous hormone replacement therapy.

As part of the development of a combination product containing norethindrone acetate and low-dose ethinyl estradiol for continuous hormone replacement therapy in postmenopausal women, a study was conducted to determine the effect of a high-fat meal on the bioavailability of norethindrone and ethinyl estradiol from tablets containing 1 mg norethindrone acetate/10 micrograms ethinyl estradiol. Eighteen healthy postmenopausal women participated in an open-label, single-dose, randomized, three-way crossover study in which 2 x 1/10 norethindrone acetate/ethinyl estradiol tablets were administered fasting and with a high-fat breakfast, and the same dose was administered in solution. Following each treatment, serial blood samples were collected for 48 hours, and plasma ethinyl estradiol and norethindrone concentrations were determined by a validated gas chromatography/mass spectrometry (GC/MS) method.

Improved lung delivery from a passive dry powder inhaler using an Engineered PulmoSphere powder.

Purpose: To assess the pulmonary deposition and pharmacokinetics of an engineered PulmoSphere powder relative to standard micronized drug when delivered from passive dry powder inhalers (DPIs).

Methods: Budesonide PulmoSphere (PSbud) powder was manufactured using an emulsion-based spray-drying process. Eight healthy subjects completed 3 treatments in crossover fashion: 370 microg budesonide PulmoSphere inhaled from Eclipse DPI at target PIF of 25 L x min(-1) (PSbud25), and 50 L x min(-1) (PSbud50), and 800 microg of pelletized budesonide from Pulmicort Turbuhaler at 60 L x min(-1)(THbud60).