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Background: 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). Methods: 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). Results: RT234 was generally safe and well tolerated at single doses of 0.2–2.4 mg and after repeated dose administration of up to 2.4 mg q4h for four doses daily for 9 days. The most common treatment-emergent adverse events were mild-to-moderate headaches. There was no evidence of pulmonary irritation or inflammation. Vardenafil was absorbed very rapidly after inhalation as RT234, independent of dose level and number of doses administered. The tmax occurred at the time that the first blood sample following completion of dosing. After Cmax was achieved, plasma vardenafil concentrations declined rapidly in an exponential fashion that appeared to be parallel among dose levels. Vardenafil plasma concentrations and PK parameters increased in a dose-proportional manner. Vardenafil systemic exposure was notably greater after oral administration of 20 mg vardenafil tablets (Levitra®) than after administration of any dose level of RT234. During repeated dose administration of RT234, Cmax was attained rapidly following each dose and in a pattern similar to that observed after single-dose administration. Minor accumulation, characterized by very low mean morning predose vardenafil concentrations (

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. The model was developed in two stages: (1) concentration–time data were analyzed with a 3-analyte model for EP, irinotecan, and SN38; and (2) a 5-analyte model developed based on expansion of 3-analyte model to include concentration–time data for SN38 glucuronide and APC with parameter values from 3-analyte model fixed. Covariate relationships with parameters were selected based on Wald’s test within the Wald’s Approximation Method approach, first for the 3-analyte model then the 5-analyte model. Results The final integrated popPK model for the five analytes was a two-compartment per analyte model that followed the metabolic cascade of EP to irinotecan, followed by metabolism of irinotecan to the previously known metabolites, but with altered exposures as compared to administration of irinotecan. With the model developed based on total dose of EP, the population estimates of EP clearance and central volume were 0.237 L/h and 5.5 L, respectively. Patient age, body surface area (BSA), and estimated glomerular filtration rate were found to correlate with EP clearance and BSA with EP central volume. Individuals who were homozygous for UGT1A1*28 genotype had modestly reduced elimination capacity of SN38 compared to heterozygous and wild-type genotypes. Simulations evaluating the clinical importance of significant covariates indicated minimal change in areas under the curve and peak concentrations of EP and SN38. Conclusions The pharmacokinetics of EP and four metabolites including the active metabolite SN38 were described by an integrated popPK model. Other than BSA, which was already accounted by a BSA-based dosing scheme, no other covariates were deemed to have clinical implications. No EP starting dose adjustment based on patient demographics and other covariates was deemed necessary. Electronic supplementary material The online version of this article (10.1007/s00280-018-3562-3) contains supplementary material, which is available to authorized users.

Opioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind to µ-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 µ-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. At the human µ-opioid receptor in vitro, naloxegol was a potent inhibitor of binding (Ki = 7.42 nM) and a neutral competitive antagonist (pA2 - 7.95); agonist effects were

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. Subjects Forty-two randomized subjects (73.8% male, 81% white, mean age = 25 years). Methods The primary objective was to evaluate single orally administered 100, 200, and 400 mg NKTR-181 doses in solution compared with 40 mg oxycodone and placebo solutions using the Drug Liking visual analog scale. Secondary measures included the Drug Effects Questionnaire, Addiction Research Center Inventory/Morphine Benzedrine Group Subscale, Price Value Assessment Questionnaire, Global Assessment of Overall Drug Liking, and Take Drug Again Assessment. Central nervous system mu-opioid effects were assessed using pupillometry. The study included qualifying and treatment phases. Subjects received each of the five treatments using a crossover design. Results NKTR-181 at all dose levels had significantly lower Drug Liking Emax than oxycodone (P

ObjectiveTo 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.DesignThis double-blind, randomized, single-dose, crossover human abuse potential study was conducted in healthy, adult, non–physically dependent recreational opioid users.SettingInpatient clinical research site.SubjectsSeventy-one subjects randomized (95.7% male, 65.2% African American, mean age = 31.7 years).MethodsThe primary objective was to compare two therapeutic doses of NKTR-181 (400 and 600 mg) with 40 and 60 mg of oxycodone and a supratherapeutic dose (1200 mg) of NKTR-181 with 60 mg of oxycodone using visual analog scale (VAS) ratings for Drug Liking “at this moment” (Drug Liking). Secondary objectives included VAS ratings for other subjective measures, and central nervous system (CNS) mu-opioid effects were assessed using pupillometry. Each subject received single oral doses of five treatments and matching placebo.ResultsCompared with 40 and 60 mg of oxycodone, the maximum mean Drug Liking score at 400 and 600 mg NKTR-181 was significantly lower, and the rate of onset and extent of Drug Liking for all NKTR-181 doses in the first two hours postdose were also significantly lower. Delayed attenuated Drug Liking and pupillary miosis response following administration of NKTR-181 vs oxycodone were consistent with slower NKTR-181 CNS entry kinetics and mu-opioid receptor binding. No adverse events were rated as severe, and somnolence and dizziness occurred more frequently when subjects received oxycodone.ConclusionsNKTR-181 at oral doses of 400 and 600 mg showed significantly fewer and less severe subjective effects accepted as representative of opioid abuse potential, such as lower peak Drug Liking in recreational opioid users, than 40 and 60 mg of oxycodone.

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. Two separate models were created describing SN38 concentration time profiles after either irinotecan or EP administrations to project the AUC0–168h after Day 1 and Day 22 doses. The relationship between incidence of neutropenia and SN38 exposure was explored using logistic regression. Results The incidence of neutropenia in dogs receiving weekly doses of irinotecan or EP was strongly correlated with maximum plasma SN38 concentration (C max), but not SN38 area under the concentration–time curve (AUC). Neutropenia occurred in approximately 80% of dogs receiving irinotecan (mean SN38 C max of 13.5 and 26.3 ng/mL for 20 and 25 mg/kg, respectively). No neutropenia occurred in dogs receiving EP at doses up to and including 25 mg/kg (mean SN38 C max of 3.4 and 4.9 ng/mL for 20 and 25 mg/kg, respectively), despite 2.5–3.6 times greater SN38 AUC after EP compared to irinotecan at equivalent doses. Conclusions EP administration avoids both high SN38 C max values and development of dose-limiting neutropenia observed after irinotecan, while maintaining greater and sustained SN38 exposure between doses. Electronic supplementary material The online version of this article (doi:10.1007/s00280-016-3192-6) contains supplementary material, which is available to authorized users.

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. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.

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. Activity was assessed by tumor growth delay (TGD) and regression. Mice bearing established colorectal and lung tumors were treated with etirinotecan pegol or irinotecan, and serial blood and tumor samples were collected at planned times between 0 and 60 days post-treatment for quantitation of etirinotecan pegol and SN38. For PK analysis, analyte concentration–time data were fit with compartmental models; PK/PD analysis was based on an inhibitory Emax response model. Results Etirinotecan pegol was active in all tumor models. TGD was sustained for 2–10 weeks after last dose, while conventional irinotecan resulted in little suppression of tumor growth. Etirinotecan pegol was eliminated very slowly from the tumor (t1/2 = 17 days), achieving higher and more sustained tumor exposure when compared with conventional irinotecan. The increased tumor exposure following etirinotecan pegol correlated with strong and prolonged suppression of tumor growth. Sustained plasma exposure to active SN38 was consistently observed across nonclinical species (including mouse, rat, and dog) and translated to cancer patients. Conclusions Etirinotecan pegol is the first long-acting topoisomerase 1 inhibitor that provides sustained exposure, which results in prolonged anti-tumor activity in a wide variety of cancer models. Electronic supplementary material The online version of this article (doi:10.1007/s00280-014-2577-7) contains supplementary material, which is available to authorized users.

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. Results: Seventy-six patients were entered onto 3 dosing schedules (58–245 mg/m2). The MTD was 115 mg/m2 for the w × 3q4w schedule and 145 mg/m2 for both the q14d and q21d schedules. Most adverse events related to study drug were gastrointestinal disorders and were more frequent at higher doses of etirinotecan pegol. Late onset diarrhea was observed in some patients, the frequency of which generally correlated with dose density. Cholinergic diarrhea commonly seen with irinotecan treatment did not occur in patients treated with etirinotecan pegol. Etirinotecan pegol administration resulted in sustained and controlled systemic exposure to SN-38, which had a mean half-life of approximately 50 days. Overall, the pharmacokinetics of etirinotecan pegol are predictable and do not require complex dosing adjustments. Confirmed partial responses were observed in 8 patients with breast, colon, lung (small and squamous cell), bladder, cervical, and neuroendocrine cancer. Conclusion: Etirinotecan pegol showed substantial antitumor activity in patients with various solid tumors and a somewhat different safety profile compared with the irinotecan historical profile. The MTD recommended for phase II clinical trials is 145 mg/m2 q14d or q21d. Clin Cancer Res; 19(1); 268–78. ©2012 AACR.

Background: Etirinotecan pegol (NKTR-102) is a unique topoisomerase 1 inhibitor that provides continuous exposure to SN38. In a Phase 2 study in pts with mBC whose disease had failed prior taxane-based treatment (Tx) etirinotecan pegol given q14d or q21d demonstrated a 29% overall response rate (J Clin Oncol 29: 2011 (suppl; abstr 1034)). Here we present the relationship between the dynamics of serum tumor marker CA27.29, etirinotecan pegol pharmacokinetics, and tumor response. Methods: Data from 45 pts with at least two CA27.29 measurements (pre- & post-first dose), were fitted with a PK/PD model developed to correlate CA27.29 dynamics with SN38 exposure predicted from individual pt dosing history: d[CA27.29]/dt = Kin*exp(beta*t)*(1−[SN38]/(IC50+[SN38]))-Kout*[CA27.29]. Correlation of CA27.29 and RECIST response was investigated; % change of CA27.29 from baseline was also correlated with progression-free survival (PFS). Results: CA27.29 vs time profiles were well described by the model, with a population mean plasma SN38 IC50 of 1.6 ng/mL. Typical minimum/maximum SN38 concentrations during Tx were 1.5/ 3 ng/mL for q14d and 0.9/ 2.4 ng/mL for q21d, indicating that both schedules resulted in SN38 exposure near the IC50. The half-life of CA27.29 decline was 15 days. 41 pts had pre- and post-Tx tumor measurements for correlation of CA27.29 response with tumor size. Of the 15 pts with RECIST CR or PR, 14 (93%) exhibited at least 10% declines in CA27.29 during Tx; all 5 pts with RECIST SD ≥ 6 months (mths) also manifested ≥10% declines, whereas only 45% (5/11) of pts with SD < 6 mths showed ≥10% decline in CA27.29. Among the 10 pts with RECIST progressive disease (PD), 80% showed ≥10% CA27.29 elevations during Tx. The median maximum % reduction in observed CA27.29 from baseline during the course of Tx ranged from −55% to +30% and correlated with responder status as tabulated below. To investigate whether response in CA27.29 can serve as early indicator of Tx outcome, we assessed the impact of a reduction of ≥25% after 6 weeks (wks) of Tx (2 or 3 Tx cycles for q21d and q14d schedules, respectively) on PFS. Among the 26 pts who had not had tumor progression or discontinued Tx by wk 6, median PFS for pts with ≥ 25% reduction in CA27.29 (n = 9) was 12 mths. Pts with Conclusions: The PK/PD model described CA27.29 dynamics well and provides a tool to predict response based on etirinotecan pegol pharmacokinetic data. 25% reduction in CA27.29 at wk 6, may constitute an early marker for Tx response to etirinotecan pegol. A Phase 3 global pivotal study (BEACON) utilizing the q21 day dosing schedule is underway in pts with advanced breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-31.

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. Methods Female nude mice were intracranially or intracardially implanted with human brain seeking breast cancer cells (MDA-MB-231Br) and dosed with irinotecan or NKTR-102 to determine plasma and tumor pharmacokinetics of irinotecan and SN38. Tumor burden and survival were evaluated in mice treated with vehicle, irinotecan (50 mg/kg), or NKTR-102 low and high doses (10 mg/kg, 50 mg/kg respectively). Results NKTR-102 penetrates the blood-tumor barrier and distributes to brain metastases. NKTR-102 increased and prolonged SN38 exposure (>20 ng/g for 168 h) versus conventional irinotecan (>1 ng/g for 4 h). Treatment with NKTR-102 extended survival time (from 35 days to 74 days) and increased overall survival for NKTR-102 low dose (30 % mice) and NKTR-102 high dose (50 % mice). Tumor burden decreased (37 % with 10 mg/kg NKTR-102 and 96 % with 50 mg/kg) and lesion sizes decreased (33 % with 10 mg/kg NKTR-102 and 83 % with 50 mg/kg NKTR-102) compared to conventional irinotecan treated animals. Conclusions Elevated and prolonged tumor SN38 exposure after NKTR-102 administration appears responsible for increased survival in this model of breast cancer brain metastasis. Further, SN38 concentrations observed in this study are clinically achieved with 145 mg/m2 NKTR-102, such as those used in the BEACON trial, underlining translational relevance of these results. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1672-4) contains supplementary material, which is available to authorized users.

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. The pulmonary route has received the most attention, helped by advances in inhaler devices and insulin formulation technology. As a result, several insulin inhalation systems are at varying stages of development, with one already filed for marketing approval in Europe. Knowledge of the pharmacokinetic and pharmacodynamic characteristics of the various inhaled insulin formulations will help to determine their positioning in current and evolving diabetes treatment strategies. For instance, a rapid onset and short duration of action would be desirable for use in postprandial glucose control. Pharmacokinetic studies with inhaled insulin reveal that serum insulin concentrations peak earlier and decay more rapidly following inhalation compared with subcutaneously administered regular insulin, and pharmacodynamic studies measuring glucose infusion rate under euglycaemic glucose clamp show corresponding rapid changes in glucose control. Furthermore, intrapatient variability in the pharmacokinetics and pharmacodynamics of inhaled insulin is low; variability is similar to (or perhaps less than) that seen when insulin is administered subcutaneously. Estimates of the bioavailability and bioefficacy achievable with the current inhalation systems are typically in the region of 10% of that experienced with subcutaneously administered insulin. Most of the losses are in the device, mouth and throat, with approximately 30-50% of the insulin deposited in the lungs being absorbed. Clinical experience to date indicates that inhaled insulin has the potential to be an effective treatment in patients with diabetes, and that it may have particular utility in the treatment of postprandial hyperglycaemia.

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. Individual plasma ethinyl estradiol and norethindrone pharmacokinetic parameters were calculated by noncompartmental methods for each treatment and analyzed by ANOVA to obtain differences between least squares treatment mean values and associated 90% confidence intervals. Rates of ethinyl estradiol and norethindrone availability from tablets administered with food were slower than availability rates from tablets administered while fasting. Systemic exposure to ethinyl estradiol was unaffected by administration of tablets with food, whereas exposure to norethindrone increased by 27%. Because administration of norethindrone acetate/ethinyl estradiol 1/10 tablets with a high-fat meal did not decrease systemic exposure to norethindrone and ethinyl estradiol, this formulation can be taken without regard to meals.

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.

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 μg budesonide PulmoSphere inhaled from Eclipse® DPI at target PIF of 25 L·min-1 (PSbud25), and 50 L·min-1 (PSbud50), and 800 μg of pelletized budesonide from Pulmicort® Turbuhaler® at 60 L·min-1(THbud60). PSbud powder was radiolabeled with 99mTc and lung deposition determined scintigraphically. Plasma budesonide concentrations were measured for 12 h after inhalation. Results. Pulmonary deposition (mean ± sd) of PSbud was 57 ± 7% and 58 ± 8% of the nominal dose at 25 and 50 L·min-1, respectively. Mean peak plasma budesonide levels were 4.7 (PSbud25), 4.0 (PSbud50), and 2.2 ng·ml-1 (THbud60). Median tmax was 5 min after both PSbud inhalations compared to 20 min for Turbuhaler (P < 0.05). Mean AUCs were comparable after all inhalations, 5.1 (PSbud25), 5.9 (PSbud50), and 6.0 (THbud60) ng·h·ml-1. The engineered PSbud powder delivered at both flow rates from the Eclipse® DPI was twice as efficiently deposited as pelletized budesonide delivered at 60 L·min-1 from the Turbuhaler. Intersubject variability was also dramatically decreased for PSbud relative to THbud. Conclusion. Delivery of an engineered PulmoSphere formulation is more efficient and reproducible than delivery of micronized drug from passive DPIs.

Introduction: NKTR-214 is a biologic prodrug currently in a Phase 1 / 2 clinical trial in patients with solid tumors, as a single agent and in combination with anti-PD1. It is a CD122-biased cytokine agonist conjugated with multiple releasable chains of polyethylene glycol and designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand effector CD8+ T and NK cells over Tregs. Here we describe a mechanistic mathematical model that quantifies conjugated aldesleukin (IL-2) species that are generated from NKTR-214, their sustained exposure, and biased receptor pharmacology in rodent models. Methods: A mechanistic mathematical model, using ordinary differential equations (ODE), was developed using Matlab® programming language to describe the dynamics of NKTR-214 PEG release, clearance, distribution, and receptor occupancy in vivo. The model was conditioned using experimental data for in vitro binding of unconjugated IL-2 and active conjugated IL-2 derived from NKTR-214 to IL-2 receptors using surface plasmon resonance, in vitro PEG release data, and mouse pharmacokinetics data. Simulations were performed to 1) quantify the concentration-time profiles of the various conjugated IL-2 species derived from NKTR-214 and contribution of each of them to the NKTR-214 mechanism of action, and 2) compare occupancy at IL-2Rβγ and IL-2Rαβγ receptors after administration of therapeutic doses of NKTR-214 and aldesleukin. Results: After NKTR-214 administration, PEG chains are released slowly from the prodrug and active conjugated IL-2 species gradually increase and reach maximum concentrations about one day post-dose, followed by sustained exposure for up to a week. Compared to an equivalent dose of aldesleukin, the active conjugated IL-2 species derived from NKTR-214 achieve a 26-fold higher area under the curve (AUC) of IL-2Rβγ occupancy, and a 0.34-fold lower AUC of IL-2Rαβγ occupancy. The significant difference is due to the combined effects of slow release of active conjugated IL-2 species from NKTR-214 and their favorable binding kinetics towards IL-2Rβγ. Aldesleukin, even when simulated at repeated daily doses or constant infusion, is incapable of increasing the receptor occupancy at IL-2Rβγ without simultaneously increasing the receptor occupancy at IL-2Rαβγ in this model. Conclusions: The mechanistic model demonstrated how NKTR-214’s intrinsic design enables both biased receptor pharmacology and sustained exposure in vivo. Such biased receptor binding could not be achieved by a sustained delivery of aldesleukin. Citation Format: Samira Khalili, Aleksandrs Odinecs, Deborah H. Charych, Vidula Dixit, Peter Kirk, Thomas Chang, John Langowski, Werner Rubas, Steve Doberstein, Jonathan Zalevsky, Michael A. Eldon, Ute Hoch. Mechanistic modeling of a new kinetically-controlled CD122 agonist for cancer immunotherapy: NKTR-214 pharmacokinetics, pharmacodynamics, and receptor pharmacology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1617. doi:10.1158/1538-7445.AM2017-1617

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. Four cohorts, each with 4 male and 4 female volunteers, were randomized 3:1 to a twice-daily naloxegol solution (25, 60, 125, and 250 mg) or matching placebo solution. Doses were given every 12 hours for 7 days, with a single final dose on the morning of day 8. All 32 subjects completed the study. The incidence of most AEs was similar in the naloxegol and placebo groups; no AE led to study discontinuation. Naloxegol was rapidly absorbed. Plasma naloxegol pharmacokinetics showed dose proportionality, negligible accumulation at steady state, and no sex differences. Naloxegol in doses up to 250 mg every 12 hours was generally safe and well tolerated in this healthy volunteer population.

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. Assessments included safety, tolerability, orocecal transit time (OCTT), pupillary miosis, and pharmacokinetics. The study was completed by 46 subjects. The most common adverse events were somnolence, dizziness, headache, and nausea. Greater reversal of morphine-induced delay in OCTT occurred with increasing naloxegol dose, demonstrating dose-ordered antagonism of morphine's peripheral gastrointestinal effects. Forty-four subjects showed no reversal of pupillary miosis; 2 showed potential partial reversal at 250 and 1000 mg, indicating negligible antagonism of morphine's CNS effects at doses ≤ 125 mg. Rapid absorption, linear pharmacokinetics up to 1000 mg, and low to moderate between-subject pharmacokinetic variability was observed. The pharmacokinetics of morphine or its glucuronide metabolites were unaltered by concurrent naloxegol administration. Naloxegol was generally safe and well tolerated at single doses up to 1000 mg.

To assess the delivery characteristics of a new 7 day 17 beta-estradiol transdermal delivery system (TDS), estradiol and estrone pharmacokinetics were evaluated following a single 7 d application of one TDS or two TDSs in 24 healthy, postmenopausal women in a nonblind, randomized, two-period crossover study. Serial blood samples and total urine output were collected before (baseline measurement of endogenous hormone) and during TDS application, and for 24 h (urine) or 72 h (blood) following TDS removal. Serum was assayed for estradiol and estrone by a validated radioimmunoassay (RIA) method. The combined amounts of estradiol and its conjugates, and estrone and its conjugates in urine were determined by validated RIA methods. Overall, one or two estradiol TDSs were well tolerated by healthy, postmenopausal female volunteers. Estradiol absorption from the TDS was characterized by a zero-order process and was dose proportional, resulting in average steady-state serum estradiol concentrations of 16 and 33 pg mL-1 above baseline during the 7 d application of one and two TDSs, respectively. Parallel but smaller increases in serum estrone concentrations were observed, resulting in an increase in the serum estradiol/estrone concentration ratio from approximately 0.2 at baseline to median values of 0.64 and 0.88 during application of one and two TDSs, respectively. The 7 day 17 beta-estradiol TDS delivered a nominal estradiol dose of 0.02 mg/24 h during the intended wear period.

Fosphenytoin sodium, a phosphate ester prodrug of phenytoin, was developed as a replacement for parenteral phenytoin sodium. Unlike phenytoin, fosphenytoin is freely soluble in aqueous solutions, including standard i.v. solutions, and is rapidly absorbed by the i.m. route. Fosphenytoin is metabolized (conversion half-life of 8 to 15 min) to phenytoin by endogenous phosphatases. Therapeutic free (unbound) and total plasma phenytoin concentrations are consistently attained after i.m. or i.v. administration of fosphenytoin loading doses. Fosphenytoin has fewer local adverse effects (e.g., pain, burning, and itching at the injection site) after i.m. or i.v. administration than parenteral phenytoin. Systemic effects related to the CNS are similar for both preparations, but transient paresthesias are more common with fosphenytoin.

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

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).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). Seven subjects with end-stage renal disease (ESRD; Group 3) received single doses of BAY41-6551 on days 1 and 9, with hemodialysis (HD) scheduled 24 h postdose on day 1 and 3 h postdose on day 9. PK analysis was performed on serum, urine, and dialysate samples (Group 3).Individual serum amikacin concentrations in Groups 1 and 2 were below 6 mg/L at all times [mean maximum serum drug concentration (C(max)) 0.94 mg/L and 2.46 mg/L, respectively). In Group 3, serum amikacin concentrations decreased after each HD session, and amikacin area under the serum concentration-time curve from zero to 72 h (AUC(72)) and C(max) values were lower on day 9 than on day 1 (mean AUC(72) 71.5 mg · h/L vs. 151.5 mg · h/L; mean C(max) 2.09 mg/L vs. 6.16 mg/L). The amounts of amikacin removed by HD and the dialysate clearance rates were similar on days 1 and 9. No serious adverse events were reported.Single doses of BAY41-6551 were well tolerated in subjects with CKD. HD effectively removed amikacin from serum in subjects with ESRD, and the timing relative to BAY41-6551 administration was an important determinant of systemic amikacin exposure. Nevertheless, standard precautionary measures for intravenous amikacin should apply for patients receiving BAY41-6551, and dose adjustments and/or dialysis should be considered for subjects with severe renal impairment.

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.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.v.) antimicrobial therapy]. CVVHDF parameters were recorded and a PK analysis was performed using serum, urine, and bronchoalveolar lavage fluid samples.Maximum serum amikacin concentration [median 1.93 (range: 0.63-3.99) mg/L] and area under the concentration-time curve from zero to 12 h on day 3 [median 19.32 (range 6.32-36.87) mg · h/L] were elevated compared with mechanically ventilated patients with normal renal function; however, serum amikacin trough concentrations were within accepted safety limits. The median amikacin concentration in epithelial lining fluid [887 (range: 406-12,819) mg/L] was similar to that reported previously in mechanically ventilated patients with normal renal function. BAY41-6551 demonstrated acceptable safety and tolerability with most adverse events (AEs) as expected for the patient population. One serious AE of bronchospasm was attributed to the study medication; no reported AEs were related to the PDDS Clinical device.CVVHDF appears to provide adequate clearance of systemically absorbed amikacin in mechanically ventilated patients with ARF, suggesting that dose adjustments for BAY41-6551 are probably not necessary for this patient population. Nonetheless, the standard precautionary measures for critically ill patients receiving i.v. amikacin should be followed for patients with ARF who are treated with BAY41-6551.

T Cell Modulatory Peptide (TCMP-80), L-lysine-L-serine, is a synthetic dipeptide structurally related to a selected amino acid sequence in human immunoglobulin G. Based on in vitro and preclinical in vivo testing, TCMP-80 has immunomodulatory properties. This report describes the first administration of TCMP-80 to man in a randomized, double-blind, placebo-controlled, single rising-dose tolerability trial. Healthy male volunteers received TCMP-80 or placebo as a 10-minute intravenous infusion. At weekly intervals, two of four subjects were given TCMP-80; the remaining two received placebo. Each subject could receive only one dose during the study. Dosing started at 0.01 mg/kg and was increased to 0.03, 0.1, 0.3, 1, 3, 6.5, and 10 mg/kg. CBCs, blood chemistries, urinalyses, and lymphocyte subset populations were monitored predose and postdose on Days 1, 5, and 14. Three placebo and three TCMP-80 subjects reported adverse events. Adverse events reported after TCMP-80 administration were mild in nature (headache, dizziness, hematoma at injection site), appeared to be independent of dose, and resolved without medical intervention. No clinically significant alterations in vital signs, physical examination parameters, or clinical laboratory values were observed. Based on the results of this study, TCMP-80 is safe and well-tolerated within the dose range studied when administered as single intravenous infusions. Additionally, this study design represents an approach to assess the safety of an investigational immunomodulatory drug.

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.Cyclosporine (CsA) was administered intravenously (1.0 mg/kg) to eight LTx patients, and multiple blood samples were collected over 24 h. At least 24 h later, aCsA (300 mg in propylene glycol) was administered to the same patients using nebulization and multiple blood samples were obtained again. Five patients had an additional inhalational gamma scintigraphy study with aCsA and 99MTc-labeled albumin to measure drug deposition.Peak blood concentrations of CsA after aerosol administration ranged from 119-402 ng/ml, and concentrations at 24 h ranged from 9-48 ng/ml. The rate of decline in drug concentration in blood in the apparent elimination phase was notably slower after administration of aCsA than after IV infusion. Terminal disposition half life (t 1/2 lambda(z)) values ranged from 4.1-9.9 h (mean 6.5 h) following IV administration and from 23.1 to 65.2 h (mean 40.7 h) following pulmonary administration, suggesting that drug absorption occurred throughout the 24-h sampling period following pulmonary administration. Deconvolution analysis indicated biphasic absorption of CsA from the lung in all patients, characterized by rapid initial absorption (absorption half-life 0.73 +/- 0.38 h) over the first 4 to 6 h followed by slower, sustained absorption throughout the remainder of the sampling period (absorption half-life 16.2 +/- 13.2 h). The absolute bioavailability of CsA after aerosol administration ranged from 5.4-11.2% (mean 8.2%) of the dose placed in the nebulizer. The total dose delivered to the lung estimated from scintigraphy ranged from 17.8-39.3 mg, and was in approximate agreement with the amount of drug absorbed, estimated using deconvolution. Essentially all drug deposited in the lungs was systemically absorbed.This study documents that cyclosporine can be effectively delivered by aerosolization to the lung of transplant patients in the early postoperative period. Part of the cyclosporine deposited in the lung is absorbed rapidly into systemic circulation and a portion is absorbed slowly but completely over a prolonged period.

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).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). PSbud powder was radiolabeled with 99mTc and lung deposition determined scintigraphically. Plasma budesonide concentrations were measured for 12 h after inhalation.Pulmonary deposition (mean +/- sd) of PSbud was 57+/-7% and 58+/-8% of the nominal dose at 25 and 50 L x min(-1), respectively. Mean peak plasma budesonide levels were 4.7 (PSbud25), 4.0 (PSbud50), and 2.2 ng x ml(-1) (THbud60). Median t(max) was 5 min after both PSbud inhalations compared to 20 min for Turbuhaler (P0.05). Mean AUCs were comparable after all inhalations, 5.1 (PSbud25), 5.9 (PSbud50), and 6.0 (THbud60) ng x h x ml(-1). The engineered PSbud powder delivered at both flow rates from the Eclipse DPI was twice as efficiently deposited as pelletized budesonide delivered at 60 L x min(-1) from the Turbuhaler. Intersubject variability was also dramatically decreased for PSbud relative to THbud.Delivery of an engineered PulmoSphere formulation is more efficient and reproducible than delivery of micronized drug from passive DPIs.

The pharmacokinetics and relative oral bioavailability of procaterol, an orally active beta 2-adrenergic agonist bronchodilator were evaluated in healthy volunteers. Procaterol was rapidly absorbed after oral administration. Mean plasma procaterol concentration-time profiles and pharmacokinetic parameters for both formulations were essentially superimposable. Following tablet administration, the mean Cmax was 358 pg/mL and the corresponding mean tmax was 1.6 hr. Mean renal clearance was 163 mL/min and accounted for approximately one-sixth of the mean apparent oral plasma clearance (988 mL/min). The mean apparent elimination half-life of procaterol was 4.2 hr. Hepatic metabolism appears to be the primary mechanism for elimination of procaterol from the body, and first-pass metabolism may limit systemic bioavailability.

s / Drug and Alcohol Dependence 140 (2014) e169–e251 e239 therefore be an appropriate and potentially effective cognitive rehabilitation tool in this population. Financial support: NIDA, NIMH. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.660 Abuse potential assessment of novel opioid analgesic NKTR-181: Implications for labeling and scheduling Lynn R. Webster1, S. Smith2, J. Silowsky2, K. Gogas2, A. Odinecs2, M. Eldon2, N. Abrouk2, R. Medve2, J. Henningfield3, A. Buchhalter3, E. Cone3, R. Fant3, S. Schnoll3 1 CRI Lifetree, Salt Lake City, UT, United States 2 Nektar, San Francisco, CA, United States 3 PinneyAssociates, Bethesda, MD, United States Aims: Discuss challenges to opioid development when early data suggest the possibility of less restrictive scheduling than CII. Thiswill be illustratedby initial findings forNKTR-181.NKTR-181 is a newmolecule intended to provide analgesic efficacy of prototypic mu-opioids but with reduced respiratory depression, sedation and abuse potential. Mu-opioid activity of NKTR-181 is retained in a morphinan core to which polymers are covalently bound resulting in slower and lower brain penetration upon oral or parenteral administration to animals than prototypic opioids. Morphinans are placed inSchedule II duringdevelopmentandcanonlybe rescheduled if the abuse potential assessment by FDA (during review of the New Drug Application) warrants less restrictive scheduling. This regulatorychallenge isnotunique toNKTR-181butdata concerning NKTR-181 will be included to support the commentary. Although oralNKTR-181 is readily absorbed, time course of pupil constriction lags drug plasma appearance 2–3h, consistent with a reduced rate of CNS uptake. These effects are maintained after repeat administration with no evidence of tolerance. Nonclinical studies suggest mu-opioid CNS effects are of substantially lower potency for NKTR181 compared to other opioids with mixed findings across models, e.g., NKTR-181 produced dose-related generalization similar to prototypic opioids at doses many times analgesic doses but with significantly reduced reinforcing effects. Opioid-like side-effects linked with abuse potential (e.g., “dreamy”, “sleepy”, “high”) were not reported in healthy volunteers at expected therapeutic doses with central effects no different than placebo. Conclusions: A preliminary 8-factor analysis of NKTR-181 suggests lower abuse potential than prototypic Schedule II opioids. How FDA addresses this challenge to drug development and scheduling will have implications for other drugs in development. Financial support: Nektar. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.661 Brief screening for alcohol and drug problems among prisoners Matthew Webster, Carl Leukefeld, Michele Staton-Tindall, Jamieson L. Duvall, Carrie B. Oser, Jennifer R. Havens Center on Drug & Alcohol Research, University of Kentucky, Lexington, KY, United States Aims: Although drug and alcohol abuse rates are high among prisoners, these problems often go undetected, which represent lost treatment opportunities. Brief, no-cost screening instruments can be used to efficiently identify individuals who could be further assessed and who may benefit from treatment. The purpose of this study is to examine the feasibility of using the Alcohol Use Disorders Identification Test (AUDIT) as a brief screener for alcohol use among prisoners and whether it can identify other drug problems. Methods: The AUDIT and the NIDA-modified Alcohol, Smoking, Substance Involvement Screening Test (NM-ASSIST) were administered to 382 prisoners in four Kentucky state prisons who were approaching release and consented to participate in NIDA Criminal Justice Drug Abuse Treatment Studies (CJDATS 2) cooperative agreement protocols. Participants were divided into two groups based on whether they screened positive (n=189) or negative (n=193) on the AUDIT. NM-ASSIST Substance Involvement (SI) scores were calculated for each of the nine drugs measured by the NM-ASSIST and compared between AUDIT groups. Results: No significant differences in age, race, or rurality for AUDIT groups were found, but the AUDIT positive group had a significantly higher percentage of males (73.0% vs. 61.5%). ANCOVAs, controlling for gender, found significantly higher SI scores (p< .05) for the AUDIT positive group for cannabis (15.0 vs. 10.3), cocaine (15.3 vs. 8.0), prescription stimulants (5.0 vs. 1.9), inhalants (0.6 vs. 0.2), sedatives (10.7 vs. 5.7), hallucinogens (1.1 vs. 0.5), and prescription opiates (15.6 vs. 11.1). No differences were found for SI scores for methamphetamine or street opioids. Conclusions: Findings suggest that prisoners who screen positive on the AUDIT have higher drug risk than those who screen negative, which suggests that the AUDIT may be an indirect screening for other substance problems. The majority of SI scores fell in the moderate risk range (4–26), suggesting that prisoners have drug risk for multiple drugs. Financial support: CJDATS 2 is funded by NIDA in collaboration with SAMSHA and DOJ. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.662 Association of the A335G polymorphism with striatal dopamine D2/3 receptor availability in healthy men and women Elise Weerts, M. McCaul, H. Kuwabara, M. Stephens, X. Xu, D. Wong, G.S. Wand Johns Hopkins University, Baltimore, MD, United

To determine whether variation in the level of expression of p16 and p21WAF1 (p21) is associated with critical stages in cutaneous melanoma development or progression, the expression of these antigens was analyzed by immunohistochemistry in 110 benign and malignant melanocytic lesions. Differential expression of p16 protein has been reported in cutaneous melanocytic lesions, with loss of expression associated with the invasive stage of tumor development. Expression of p16 was seen in 31 of 35 benign melanocytic tumors (89%), 11 of 12 in situ melanomas (92%), 19 of 38 invasive primary melanomas (50%), and 16 of 25 metastatic melanomas (64%). There was a significant difference in the expression level of p16 observed in in situ versus invasive primary melanomas (p = 0.006), which is consistent with loss of normal p16 activity occurring in association with malignant tumor invasion. Overall, p21 levels were found to be low or undetectable in the majority of benign lesions, with greater p21 expression seen in malignant tumors. p21 was expressed in 28% of nevi, 60% of in situ melanomas, 61% of invasive melanomas, and 48% of metastatic melanomas. Among primary invasive tumors, the frequency of p21 expression increased with level of invasion (p < 0.01) and with increasing thickness (p < 0.01). However, differences in p21 expression were not clearly related to a particular stage of melanoma development.

Anticonvulsants that induce hepatic metabolism increase clearance of oral contraceptive hormones and thereby cause contraceptive failure. Gabapentin is not metabolized in humans and has little liability for causing metabolic-based drug-drug interactions. In healthy women receiving 2.5 mg norethindrone acetate and 50 microg ethinyl estradiol daily for three consecutive menstrual cycles, concurrent gabapentin administration did not alter the steady-state pharmacokinetics of either hormone. Thus, gabapentin is unlikely to cause contraceptive failure.Anticonvulsants that induce hepatic metabolism increase the clearance of synthetic estrogens and progestogens used in oral contraceptives (OCs), thereby potentiating contraceptive failure. In contrast, the anticonvulsant drug gabapentin is not metabolized in humans and has little liability for metabolic-based drug interactions. The present study sought to confirm whether concurrent administration of gabapentin would alter the pharmacokinetics of norethindrone acetate (2.5 mg) and ethinyl estradiol (50 mcg) in healthy US women. A total of 13 women were enrolled for three menstrual cycles each. Pharmacokinetic values did not change appreciably as a result of the addition of gabapentin. The rate and extent of absorption of both hormones were unaffected by the anticonvulsant. Gabapentin plasma concentration time profiles and pharmacokinetic values from this study were similar to historical values after administration of gabapentin alone. The observed lack of interaction between gabapentin and norethindrone acetate or ethinyl estradiol is consistent with the fact that gabapentin is not metabolized, is not an inducer or inhibitor of hepatic drug metabolizing enzymes, is absorbed via a specific transport system for amino acids, and is not bound to plasma proteins. Anticonvulsant drugs that do not interact with OCs should be considered for the treatment of epileptic women of childbearing age who are using this method of fertility control.

Gabapentin is an anticonvulsant drug, which in man is cleared solely by renal excretion and is not bound to plasma proteins. Because the clearance of gabapentin is dependent on renal function, the pharmacokinetics of gabapentin were investigated in anuric subjects maintained on hemodialysis. Plasma samples were obtained over an 8-day period after administration of single oral 400-mg doses of gabapentin. Pre- and post-dialyzer plasma samples and dialysate samples from quantitative collection of dialyzer effluent were obtained during hemodialysis sessions performed 2, 4, and 7 days after dosing. A mean (SD) maximum gabapentin plasma concentration of 6.0 (2.4) micrograms/mL was achieved at 4.7 (2.1) hours post-dose. The elimination half-life of gabapentin on non-hemodialysis days averaged 132 hours. Approximately 35% of the gabapentin dose was recovered in dialysate, and mean hemodialysis clearance of gabapentin was 142 (26) mL/min; approximately 93% of the dialyzer creatinine clearance. Gabapentin elimination half-life during hemodialysis was approximately 4 hours. Systemic plasma gabapentin concentrations increased approximately 30% during the first 2 hours after hemodialysis as a result of drug redistribution in the body. It is recommended that patients with end-stage renal disease maintained on hemodialysis receive an initial 300-mg to 400-mg gabapentin loading dose. Plasma gabapentin concentrations can be maintained by giving 200 to 300 mg of gabapentin after every 4 hours of hemodialysis.

5048 Background: NKTR-102 is a unique topoisomerase 1 inhibitor that provides continuous exposure to SN38. In heavily pretreated pts with PROC (median of 3 prior therapies; 27 pts were platinum refractory), 145 mg/m2 NKTR-102 given q14d or q21d demonstrated significant anti-tumor activity (JCO 28:7s, 5013). We present a PK/PD model for CA125 kinetics that can be used to project GCIG response as an aide to selecting dose and schedule. Methods: Data from 55 pts with PROC and elevated CA125 (median baseline = 515 U/mL) were fit with a PK/PD model developed to correlate CA125 dynamics with SN38 conc-time profiles predicted from individual pt dosing history: d[CA125]/dt = Kin*exp(beta*t)*(1-[SN38]/(IC50+[SN38]))-Kout*[CA125]. Results: CA125 profiles were well described by the model, with a population mean SN38 IC50 of 1.1 ng/mL. Typical min and max SN38 conc during treatment were 1.5 and 3 ng/mL for q14d and 0.9 and 2.4 ng/mL for q21d, indicating that both schedules resulted in SN38 exposure near the IC50. The half-life of CA125 decline was 6.4 days, similar to literature values. 46 of 55 pts had pre- and post-treatment tumor measurements for correlation of CA125 response and tumor size. Overall best response by GCIG and RECIST correlated in 57% of pts. 33% of pts with GCIG response showed declines in tumor size, albeit insufficient to classify as RECIST response. 72% of pts with GCIG SD showed at least SD by RECIST. CA125 vs time was simulated for 1000 pts receiving 145 mg/m2 NKTR-102 q14d or q21d, to allow comparison of CA125 and GCIG response between schedules (see table). The % pts per GCIG response was comparable between schedules, supporting use of the better-tolerated q21d regimen. Conclusions: The PK/PD model described CA125 profiles well, providing a tool to predict drug response from SN38 PK data. Close correlation of CA125 with tumor size is consistent with historical use of CA125 as a surrogate marker. Predicted CA125 profiles for NKTR-102 q14d or q21d were similar, suggesting that the better-tolerated q21d schedule will produce results consistent with those from Ph 2. [Table: see text]

Purpose: NKTR-102, a next generation topoisomerase I inhibitor, has been demonstrated to be superior to cisplatin, carboplatin and irinotecan in a mouse model of platinum-resistant A2780 Human Ovarian Cancer (Abstract 8015, ECCO 15-ESMO 34, 22 SEP 09). NKTR-102 as a single agent in women with platinum resistant/refractory ovarian cancer who have failed pegylated liposomal doxorubicin (PLD) therapy has demonstrated a confirmed ORR of 20% (RECIST, n = 30) to 36% (CGIC, n = 33) (JCO Vol 29, No 15_suppl, 2011: 5047). As a single agent, NKTR-102 appears highly active in the defined population; however, we hypothesize that the combination of NKTR-102 and PLD could result in synergistic activity through concurrent, long lasting inhibition of Topo I by NKTR-102 and Topo II by PLD, resulting in greater efficacy than observed as sequential single agents. This report is a presentation of the results of a study of NKTR-102 as a single agent, PLD as a single agent, and a combination of NKTR-102 and PLD in mice bearing A2780 Human Ovarian tumors that are minimally responsive to cisplatin. Methods: The MTD of PLD in mice was determined to be 10 mg/kg q7d×2 in a pilot study. NKTR-102 doses were limited to 150 mg/kg due to viscosity and dose volume limitations rather than tolerability. Mice bearing A2780 ovarian tumors (∼ 100 mm3) received either vehicle, PLD, NKTR-102, or a combination of NKTR-102 and PLD as follows: 5 or 10 mg/kg PLD on days 1 and 8; 100 or 150 mg/kg NKTR-102 on day 1; or 5/100, 10/100, 5/150, or 10/150 mg/kg PLD on days 1 and 8/NKTR-102 on day 1 (n = 10/treatment). Anti-tumor efficacy was evaluated based on tumor growth delay (TGD) and response rate. Results: Control tumors grew rapidly and uniformly to the 2000 mm3 endpoint in a median of 12 days. PLD administered at 5 and 10 mg/kg q7d×2 resulted in TGD of 7 and 24 days, respectively, with one partial response at the highest dose. Tumor growth was slower following PLD, but was continuous in all animals. NKTR-102 at single doses of 100 and 150 mg/kg resulted in TGDs of 32 and 38 days, respectively, with 100% (10 of 10) complete responses in each group. Following complete tumor regression in all animals, growth resumed after approximately 25 and 35 days in the 100 and 150 mg/kg treatment groups, respectively. TGD was 57 days (maximum possible value; 474% TGD) following any combination of NKTR-102 and PLD and all mice achieved complete response. There was no tumor regrowth within the 69-day observation period in 37 of 40 animals (93%). There was no accentuated weight loss in any dose group, indicating that the combination treatments were tolerated as well as single agent PLD. Conclusions: NKTR-102 as a single agent shows superior activity compared to PLD as a single agent in the A2780 ovarian tumor model, with a 100% complete response rate at all doses. NKTR-102 and PLD in combination showed marked synergism demonstrated by complete response in all animals with no tumor regrowth in 93%. Nektar intends to conduct a Phase I study of NKTR-102 with PLD in patients with advanced/metastatic refractory solid tumors, including those with platinum-resistant ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C209.

Enoxacin is a quinolone antibacterial agent currently being developed for oral and intravenous treatment of bacterial infections. Ten healthy subjects received a single 400-mg intravenous dose of enoxacin alone, with 300 mg (four times daily) oral cimetidine and with 150 mg (twice daily) oral ranitidine. Serial blood and urine samples were collected over a 48-hour period. Plasma and urine enoxacin concentrations were determined using a validated high-performance liquid chromatographic method. Mean enoxacin plasma concentrations were higher after administration of enoxacin with cimetidine than those measured after enoxacin alone or enoxacin with ranitidine. Cimetidine coadministration reduced enoxacin renal clearance by 26% and systemic clearance by 20%, and resulted in a 30% increase in elimination half-life. In contrast, concurrent ranitidine therapy did not significantly alter the pharmacokinetics of intravenous enoxacin.

e13503 Background: NKTR-102 is an advanced polymer conjugate of irinotecan with broad single agent activity and a unique pharmacokinetic (pk) profile. The apparent half-life of the active metabolite SN-38 in patients (pts) administered NKTR-102 is approximately 50 days. NKTR-102 in combination with cetuximab was evaluated in pts with refractory solid tumors to define the maximum tolerated dose (MTD). Methods: NKTR-102 was infused over 90 minutes every 3 weeks per cycle. Cetuximab was infused over 2 hours at 400mg/m2 on day 1 followed by a weekly 1 hour infusion at 250mg/m2. Cohorts of 3 -12 pts were treated with escalating doses of NKTR- 102. MTD was established based on the dose limiting toxicities observed in cycle 1 and safety data from subsequent cycles. Serial plasma samples were collected throughout the study for PK analysis. Results: Eighteen pts were enrolled: main tumor types include colon (5), pancreas (4), rectal (2), breast (2), gastric (1), other (4). Pts received 100 mg/m2 (12) or 125 mg/m2 (6) of NKTR-102 for a median of 2.5 cycles (range 1 to 11+). At 125 mg/m2, 3 pts had G3 diarrhea, 1 in cycle 1; 2 in cycle 2. At 100mg/m2, 1 pt had G3 diarrhea in cycle 1 and a further pt had G4 fatigue in cycle 2. Other G3 toxicities for all patients in both dose groups include nausea (3), vomiting (3) and neutropenia (2). No G3 rash was reported. Partial responses (PR) were observed in 3 pts at 100 mg/m2: confirmed (rectal, colorectal) and unconfirmed (gastric). Another pt with pancreatic cancer had a decrease in CA19–9 from 2000 at baseline to 157 U/ml with associated symptomatic benefit. NKTR-102 resulted in sustained exposure to SN-38 with no evidence of PK drug interactions between NKTR-102 and cetuximab. Conclusions: NKTR-102 shows evidence of clinical antitumor activity in combination with cetuximab. Toxicity is manageable; diarrhea and neutropenia are dose limiting. The recommended dose of NKTR-102 with cetuximab is 100mg/m2 every three weeks. Data support further evaluation of this combination in appropriate tumor types. [Table: see text]

13518 Background: NKTR-102 is a novel PEGylated form of irinotecan with superior efficacy against a range of xenografts compared with irinotecan. Sustained tumor inhibition is associated with incre...

Nektar is developing Amphotericin B Inhalation Powder (ABIP; NKTR-024) to prevent invasive pulmonary fungal infections in immunocompromised patients. NKTR-024 is a proprietary dry-powder amphotericin B (AmB) formulation that is delivered to the patient’s respiratory tract with a proprietary breath-actuated inhalation device (T-326). This study assessed 1) the safety and tolerability and 2) the pharmacokinetics (PK) of AmB in epithelial lining fluid (ELF) and plasma after a loading dose (LD) and 4 weekly maintenance doses (MD) of NKTR-024 in healthy subjects. Thirty-six (36) subjects enrolled in a single center in the US into 2 cohorts 2:1 to receive either NKTR-024 (n=12) or a matching (powder load) placebo inhalation powder (n=6), respectively. Subjects in Cohort 1 (Coh1) received a 25-mg LD and 4 weekly 5-mg MD (25/5) and subjects in Cohort 2 (Coh2) received a 50-mg LD and 4 weekly 10-mg MD (50/10) of NKTR-024 or placebo, respectively. PK assessments used blood [plasma] and bronchoalveolar lavage (BAL) [ELF] samples. Concomitant medications, adverse events (AEs) and other safety parameters were monitored for 17 wk (screening period of up to 28 d, a 4-wk treatment period, and a 9-wk post-treatment period). All 36 subjects received 1 LD and 4 MDs. Subjects were mostly male (n=24, 66.7%) and Caucasian (n=27, 75%). Mean age=28.1 yr, median height=175.3 cm and median weight=77.4 kg. PK data have been previously presented and will not serve as the focus of this abstract. Maximal plasma AmB concentrations occurred at ∼8–12 hr postdose following a ∼1 hr postdose lag. Plasma AmB concentrations (20% temporally related to bronchoscopy. Repeated administration of NKTR-024 resulted in high pulmonary and low systemic AmB exposure. Plasma AmB concentrations were well below those associated with renal toxicity; this observation supports an important potential benefit of the NKTR-024 investigational product. Constitutional symptoms and electrolyte abnormalities traditionally seen with systemic administration of AmB were essentially spared.

Two multiple dose crossover pharmacokinetic studies were carried out to determine the steady-state bioavailability of newly formulated generic propranolol HCl tablets relative to Inderal tablets. In Study I, 24 healthy volunteers were dosed with 4 x 10 mg test tablets, 1 x 40 mg test tablet, 4 x 10 mg Inderal tablets, and 40 mg of propranolol HCl in solution. In Study II, 24 healthy volunteers were dosed with 1 x 80 mg test tablet, 1 x 80 mg Inderal tablet, and 80 mg of propranolol HCl in solution. Both studies were of randomized design with each formulation administered every 8 h for 15 doses. Serial plasma samples were obtained for 8 h after morning doses on Days 4 and 5 of each treatment period and assayed for propranolol using a validated HPLC method. Mean plasma concentration-time data for test tablets and reference tablets were superimposable in both studies. Pharmacokinetic parameters from Days 4 and 5 were combined for statistical analysis since subjects were determined to have reached steady-state. Mean AUC, Cmax, tmax, and Cmin values were not statistically different between test tablets and Inderal tablets in either study. Based on these findings, the test tablets demonstrated the same rate and extent of propranolol absorption as did corresponding Inderal tablets. Therefore, the test tablets and Inderal tablets were determined to be bioequivalent.

Pentigetide is a synthetic pentapeptide derived from the Fc region of human IgE reported to inhibit IgE-mediated allergic responses. A randomized, double-blind, placebo-controlled trial was conducted to evaluate the safety and efficacy of subcutaneously administered pentigetide in the treatment of allergic rhinitis. After a 3-day baseline period, 55 patients received 5 injections of either 20 mg of pentigetide for injection (n = 31) or placebo solution (n = 24), one injection every 3 to 4 days for 14 days. Physician assessment of frequency and severity of sneezing, rhinorrhea, congestion, nasal itching, and 3 non-nasal symptoms obtained at baseline, after 1 week, and study completion were compared between pentigetide and placebo treatment groups. The physician's assessment of therapeutic response made at study completion showed that 71% of patients receiving pentigetide were improved, whereas 37% of patients receiving placebo had improved, a difference which was statistically (chi square, p = 0.013) as well as clinically significant. Mean symptom scores indicated that the frequency and severity of sneezing, rhinorrhea, and nasal itching decreased after 1 week of pentigetide treatment and remained decreased until study completion, whereas congestion was unchanged or slightly increased. In contrast, the frequency and severity of sneezing, rhinorrhea, and nasal itching increased after placebo treatment, with congestion essentially unchanged. No clinical or statistical differences in safety parameters between pentigetide and placebo treatments were observed. The results of this pilot trial suggested that subcutaneous pentigetide is safe and effective in the treatment of allergic rhinitis and justified expanded safety and efficacy studies in a greater number of patients treated for a longer period of time.

A sensitive and selective HPLC assay has been developed for the analysis of a new antihypertensive agent in human plasma. The drug and internal standard were isolated from plasma by liquid-liquid extraction. Separation was accomplished on unmodified silica gel with a mobile phase of 60:40 acetonitrile:10 mM dibasic ammonium phosphate. Detection was by UV absorbance at 291 nm. The method is linear over a range of 20 to 4000 ng/ml. Relative error of calibration and control standards ranged from −1.5 to 5.0% and precision, as indicated by relative standard deviation, ranged from 0.8 to 5.2%. The method has been successfully used for analysis of plasma samples from human volunteers following oral administration of PD 78,799.

As part of a multiple dose bioavailability study, 80-mg verapamil hydrochloride tablets were administered to healthy subjects every 8 hours for 15 doses. Statistically significant successive decreases in verapamil maximum plasma concentrations (Cmax) and area under the concentration-time curve (AUC) values were observed corresponding to dosing at 8 AM, 4 PM, and 12 AM. Mean Cmax and AUC values from the 12 AM dose were decreased 36% and 30%, respectively, relative to those from the 8 AM dose. Similar effects on norverapamil pharmacokinetics were observed. Decreased Cmax and AUC values show that verapamil absorption is influenced by the time of day when doses are administered. Pharmacokinetic simulation results suggest that the rate of absorption is reduced approximately by one half and two thirds during the 4 PM and 12 AM dosing intervals, respectively, relative to the 8 AM dosing interval. The reductions in verapamil absorption as a function of time of administration observed in this study may in part explain previous reports of reduced antihypertensive effect during evening and night hours as compared to daytime hours.