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Mycophenolic acid (MPA) is commonly used for organ rejection prophylaxis via oral administration in the clinic. Recent studies have shown that MPA also has anticancer activities. To explore new therapeutic options for oral precancerous/cancerous lesions, MPA was designed to release topically on the dorsal tongue surface via a mucoadhesive patch. The objective of this study was to establish the pharmacokinetic (PK) and tongue tissue distribution of mucoadhesive MPA patch formulation after supralingual administration in rats and also compare the PK differences between oral, intravenous, and supralingual administration of MPA. Blood samples were collected from Sprague Dawley rats before and after a single intravenous bolus injection, a single oral dose, or a mucoadhesive patch administration on the dorsal tongue surface for 4 h, all with a dose of 0.5 mg/kg of MPA. Plots of MPA plasma concentration versus time were obtained. As multiple peaks were found in all three curves, the enterohepatic recycling (EHR) model in the Phoenix software was adapted to describe their PK parameters with an individual PK analysis method. The mean half-lives of intravenous and oral administrations were 10.5 h and 7.4 h, respectively. The estimated bioavailability after oral and supralingual administration was 72.4% and 7.6%, respectively. There was a 0.5 h lag-time presented after supralingual administration. The results suggest that the systemic plasma MPA concentrations were much lower in rats receiving supralingual administration compared to those receiving doses from the other two routes, and the amount of MPA accumulated in the tongue after patch application showed a sustained drug release pattern. Studies on the dynamic of drug retention in the tongue after supralingual administration showed that ~3.8% of the dose was accumulated inside of tongue right after the patch removal, ~0.11% of the dose remained after 20 h, and ~20.6% of MPA was not released from the patches 4 h after application. The data demonstrate that supralingual application of an MPA patch can deliver a high amount of drug at the site of administration with little systemic circulation exposure, hence lowering the potential gastrointestinal side effects associated with oral administration. Thus, supralingual administration is a potential alternative route for treating oral lesions.

Riluzole, a benzothiazole sodium channel blocker that received FDA approval to attenuate neurodegeneration in amyotrophic lateral sclerosis (ALS) in 1995, was found to be safe and potentially efficacious in a spinal cord injury (SCI) population as evident in a Phase I clinical trial. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes can alter the pharmacokinetics of therapeutics. A one-compartment with first-order elimination population pharmacokinetic model for riluzole incorporating time-dependent clearance and volume of distribution was developed from combined data of the Phase I and the ongoing Phase II/III trials. This change in therapeutic exposure may lead to a biased estimate of the exposure-response relationship when evaluating therapeutic effects. With the developed model, a rational, optimal dosing scheme can be designed with time-dependent modification that preserves the required therapeutic exposure of riluzole. This article is protected by copyright. All rights reserved.

Background Doxorubicin-loaded hollow gold nanospheres (Dox@HAuNS) are a promising technology for simultaneous trans-arterial tumor-targeted chemotherapy delivery and thermal ablation. We evaluated the efficacy of intra-arterial delivery of Dox@HAuNS followed by photothermal ablation (PTA) in a rabbit model of liver cancer. Adult New Zealand white rabbits (N = 25) were inoculated with VX2 tumors into the left lobe of the liver. The animals were then randomized to sham surgery (N = 5), PTA only (N = 3), Dox@HAuNS only (N = 5), HAuNS + PTA (N = 5), and Dox@HAuNS + PTA (N = 7). Nanoparticles were delivered as an emulsion with Lipiodol (Guerbet, France) via a trans-arterial approach. Following nanoparticle delivery, PTA was performed using an 808-nm fibered laser at 1.5 W for 3 min. Thermography during PTA demonstrated a sustained elevation in tumoral temperature in both HAuNS + laser and Dox@HAuNS + laser treatment groups relative to animals that underwent laser treatment without prior nanoparticle delivery. Results There was a significant decrease in tumor volumes in all three treatment arms relative to control arms (P = 0.004). Concentrations of intratumoral doxorubicin were significantly greater in animals treated with laser compared to those that were not treated with laser (P Conclusions Doxorubicin-loaded HAuNS is a promising therapeutic agent for dual ablation/chemoembolization treatment of liver cancer.

PURPOSE: Undergoing Roux-en Y gastric bypass (RYGB) is expected to affect orally administered drug absorption. Statins are commonly prescribed to patients with obesity for the prevention of atherosclerotic cardiovascular diseases by lowering cholesterol. This is the first longitudinal prospective study on impacts of RYGB on weight loss, pharmacodynamics and pharmacokinetics of atorvastatin, rosuvastatin, and simvastatin, and their active metabolites, up to one-year post-surgery. METHODS: Forty-six patients were recruited, five patients on atorvastatin, twelve on rosuvastatin, nine on simvastatin, and twenty on no statin. The concentrations of atorvastatin rosuvastatin, and simvastatin with their active metabolites were monitored. RESULTS: Mean plasma concentrations of atorvastatin and metabolites, and rosuvastatin normalized by the unit dose [(nM)/(mg/kg)] decreased by 3 to 6 months post-surgery. Conversely, simvastatin and its metabolite concentrations increased up to 6 months post-surgery, then declined to pre-operative levels by one-year post-surgery. The metabolisms of atorvastatin to hydroxyl-metabolites and simvastatin to simvastatin acid were decreased after RYGB. The weight loss and PD outcomes were comparable between statin and non-statin groups suggesting the key impacts were from RYGB. The discontinuation or reduction of dose of atorvastatin or rosuvastatin post-RYGB exhibited rebounds of LDL levels in some subjects, but the rebound was not apparent with patients on simvastatin pre-surgery. CONCLUSION: Discontinuations of statin dosing post-RYGB require LDL monitoring and reducing the dose to half seems to have better results. Patients on statin treatment post-RYGB should be followed-up closely based on our pharmacokinetic findings, to ensure therapeutic effects of the treatment with minimal adverse effects.

Purpose Irinotecan is a potent and widely used anticancer drug for the treatment of metastatic colorectal cancer and elevated concentrations of its active metabolite, SN-38, causes severe diarrhea,...

The aim of this study was to evaluate the pharmacokinetic variations of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), in both pediatric and adult patients following hematopoietic stem cell transplantation (HSCT). Twenty pediatric patients with a median age of 3 years (range 0.2-12 years) and 13 adult patients with a median age of 54 years (range 18-63 years) were enrolled. Blood samples were collected on days 0, 7, 14, 21, and 30 after allogeneic HSCT. Total and free (unbound) MPA as well as MPA 7-O-glucuronide (MPAG) were quantified using a validated LC-MS/MS assay. The plasma protein binding of MPA and MPAG did not change significantly in pediatric patients over the 1-month sampling period post-HSCT. However, it increased in adult patients from day 7 to day 30 post-HSCT, from 97.3 ± 0.8% to 98.3 ± 0.6% for MPA (P < .05), and 74.6 ± 9.4% to 82.9 ± 8.1% for MPAG (P < .05). The plasma protein binding of MPA was significantly higher in males compared to females in both pediatric (98.3 ± 1.1% vs 97.4 ± 1.1%) and adult (98.1 ± 0.7% vs 97.4 ± 1.2%) patients (P < .05). The MPAG/MPA ratios on a milligram-per-kilogram dose basis in adult patients were significantly higher than those in pediatric patients (4.3 ± 3.4 vs 2.4 ± 2.6; P < .05). Time-dependent plasma protein binding and age-related differences in MPA metabolism at least in part impact the reported large intra- and interindividual variability in MPA pharmacokinetics. These patient and pharmacologic factors, if incorporated into MMF regimen design and modification, may contribute to the rational dose selection of MMF in HSCT patients.

Purpose: Pharmacokinetic (PK) dispositions of vincristine (VCR) and its M1 metabolite were characterized through PK co-modeling for Kenyan pediatric cancer patients with acute lymphoblastic leukemia or nephroblastoma. VCR dosing strategies are largely empirical regardless of its extensive use in pediatric oncology. Little information is known about its disposition and optimal therapeutic dosing. Renbarger and associates reported that CYP3A5 enzyme metabolizes VCR to M1 more efficiently than CYP3A4 enzyme. This may be clinically significant as CYP3A5 expression varies among Kenyans (90%), African Americans (AA, 70%) and Caucasians (10-20%). Therefore, it is essential to characterize the disposition of M1 in humans to provide an insight into the inter-ethnic variability in VCR metabolism and clearance, which will be helpful for future dosing regimen optimization. Methods: Pharmacokinetic Study: Dried blood spot (DBS) samples were collected, via finger stick at various time points depending on the feasibility, from 25 Kenyan pediatric cancer patients (13 males/12 females, 1-14 years, BSA of 0.36 - 1.3 m2) after an IV dose of VCR (1.6 – 3.1 mg/m2). Concentrations of VCR and M1 from DBS were quantified using a validated LC-MS-MS assay. Pharmacokinetic Modeling: A population PK (pop PK) co-model was developed using Phoenix® NLMETM software to simultaneously capture and predict the PK of VCR and M1 concentrations. A correlation between the observed and predicted concentrations of VCR and M1 PK was established by pop PK fitting. Model discrimination was performed on data by visual inspection, the goodness of fit plots and AIC values. Results: The best fit pop PK co-model for VCR and its M1 metabolite was established. PK parameter estimates were derived for both analytes. Volumes of distribution for VCR and M1 were 0.12 L (33.55 %CV) and 249.07 L (33.42 %CV), respectively. The elimination rate constants for VCR and M1 were 5.6 hr-1 (22.81 %CV) and 0.00015 hr-1 (66.85 %CV), respectively. The conversion rate constant of VCR to M1 was 9.66 hr-1 (32.49 %CV). Finally, clearance values were 0.67 L/hr for VCR and 0.04 L/hr for M1. In conclusion, VCR and its M1 metabolite exhibit distinct PK characteristics, in that M1 distribution is substantially larger than that of VCR (249 vs 0.12 L), and clearance is slower than that of VCR (0.04 vs 0.67 L/hr). The conversion kinetics of VCR to M1 is characterized for the first time, which may potentially offer a rationale for ethnic disparity in VCR therapy. In addition, a large inter-patient variability is documented even within the same ethnic Kenyan population. After model refinement and validation, our model could potentially serve as a tool for rational VCR dosing regimen modification for Kenyan/AA pediatric cancer patients. Citation Format: Lorita Agu, Lei Wu, Jamie Renbarger, Jodi Skiles, Andi Masters, Diana S-L. Chow. Population pharmacokinetics of vincristine and its metabolite in Kenyan pediatric cancer patients [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-117.

Introduction: The 5-year survival rate for Pancreatic Ductal Adenocarcinoma (PDAC) remains 7%. An emerging treatment strategy involves the combination of vitamin D receptor (VDR) ligands with chemotherapeutic agents to re-program the activated cancer-associated fibroblast (CAFs). Calcipotriol (CAP), a synthetic analogue of vitamin D can reprogram CAFs, but is toxic with side effects including cachexia and edema. Due to the abundance of the VDR in the body, diminished plasma exposure and elimination of calcipotriol together with enhanced accumulation in the tumor are desirable to reduce toxicity and increase efficacy. We propose to achieve this with a slow-releasing micellar nanoformulation with a well-controlled size to take advantage of the leaky tumor fenestrations and enhance delivery. Method: 8-week old male C57BL/6 mice were administered with either formulated or non-formulated single IV bolus dose of CAP and paclitaxel (PTX). Drugs from blood samples were extracted, and simultaneously quantified using validated LC-MS/MS assay. Pharmacokinetic modeling was performed with Phoenix® WinNonlin (8.0) using 2-compartment model. Results: Our co-formulation of CAP and PTX resulted in >2-fold decrease in plasma exposure (AUC) and 5-fold reduction of peak concentration (Cmax) of CAP. Similarly, PTX AUC and Cmax were halved in mice administered with the formulated drugs. The PTX total clearance (CL) was similar between both groups, but CAP CL was 5-fold lower in formulation-administered mice. Further, CAP elimination (k10) from central compartment and from central to peripheral compartments (k12) were 2 and >3-fold slower, respectively, in the formulation group. The reverse elimination (k21) are similar. Similarly, the k10 of PTX was almost halved, while the k12 was 44-fold slower in mice receiving formulated drugs. The reverse elimination from the peripheral to the central compartment (k21) for formulated PTX is almost 10 times slower than in the mice receiving non-formulated PTX. Conclusion: Our micellar co-formulation of CAP and PTX is able to reduce total clearance of these agents from the systemic circulation. Further, rate constants derived show that PTX elimination from the systemic circulation to tissues is very slow and we expect this to correlate with an extended duration of action of this drug. Finally, our formulation halved the systemic exposure and peak concentrations of CAP that should lead to a more favorable safety profile of this agent. Ongoing work will focus on studying the pharmacokinetics of co-formulated CAP and PTX in a larger cohort of animals and we eventually hope to demonstrate the therapeutic merits of our nanoformulation strategy in pancreatic tumor-bearing mice. Citation Format: Victor R Lincha, Jun Zhao, Chun Li, Diana S-L Chow. Pharmacokinetic analysis of co-formulation of calcipotriol and paclitaxel for pancreatic ductal adenocarcinoma shows reduced systemic exposures and eliminations: Implications for safety and efficacy [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D052.

Objectives: The aim of this study was to develop a pharmacokinetic (PK) model that can determine the PK of vincristine (VCR) and its M1 metabolite using concentration data from Kenyan pediatric cancer patients. VCR is one of the most widely used anticancer agents in treating a variety of malignancies in pediatric oncology. Regardless of its extensive pediatric use, dosing strategies for VCR are largely empirical as there is little information about its disposition and optimal therapeutic dosing. Our collaborator, Dr. Jamie Renbarger and her group have reported that CYP3A5 enzyme generates the major VCR metabolite, M1, more efficiently than CYP3A4 enzyme. This finding maybe clinically significant because CYP3A5 expression varies with up to 90%, 70% and 10-20% of expressions in Kenyans, African Americans and Caucasians, respectively. Therefore, it is crucial to monitor M1 and characterize its disposition in humans to provide an insight of inter-ethnic variability in VCR metabolism and clearance. Methods: Kenyan pediatric cancer patients (8 males:8 females, age range: 1-13 years, weight range: 7.0 - 36.6 kg, body surface area: 0.36 - 1.24 m2) were intravenously administered with VCR (delivered dose, 0.4 - 2.5 mg). Blood samples were collected using human dried blood spot (DBS) collection paper via finger prick at various time points depending on the feasibility and duration of patient stay for care in the hospital. Using a developed LC-MS-MS assay, the concentrations of VCR and M1 were measured from patient DBS samples. A PK compartmental model was developed through co-modeling of VCR and M1 using Phoenix (version 8.0). The model was selected based on comparison of quality of fit plots and on the likelihood ratio test on the difference of criteria (-2LL). Results: The best fit structural model for VCR and its M1 metabolite was established. The model consists of a one-way metabolite formation transfer from VCR to M1 compartments. Good correlations were observed between observed and predicted values of VCR and M1 in the subjects used. The best-fit PK parameter estimates were derived from the PK compartmental model. In one subject, values estimated for PK parameters that only our study could derive include: conversion rate constant from VCR to M1 of 0.04 1/hr, M1 metabolite volume of distribution of 51.49 L, and M1 metabolite elimination rate constant of 0.44 1/hr. Conclusion: For the first time, a compartmental PK model that could determine the PK parameters of VCR and its M1 metabolite from DBS samples through co-modeling was developed. The model resulted in a good fit for the subjects used. The model will be validated after further adjustments and could potentially be used to rationally modify future VCR dosing regimen for Kenyan pediatric patients. Further, this modification could be possibly extrapolated for African American pediatric patients. Additionally, using our validated model, we will characterize and predict the population PK of VCR and its M1 metabolite among different ethnic groups. Citation Format: Lorita Agu, Jamie Renbarger, Diana S-L. Chow. Pharmacokinetic analysis of vincristine and its m1 metabolite in Kenyan pediatric cancer patients through co-modeling [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C008.

Background: Riluzole is a sodium channel-blocking agent used in treating amyotrophic lateral sclerosis. It has been approved by the U.S. Food and Drug Administration, Canadian and Australian authorities, and in many other countries. A phase I trial of riluzole for acute spinal cord injury (SCI) provided safety and pharmacokinetic data and suggested neuroprotective benefits. A phase IIB/III double-blinded randomized controlled trial (RCT) started in January 2014 (https://clinicaltrials.gov, NCT01597518). This article describes the pathophysiological rationale, preclinical experience and design of the phase IIB/III RCT of Riluzole in Acute Spinal Cord Injury Study (RISCIS). Objectives: The primary objective of the trial is to evaluate the superiority of riluzole, at a dose of 100 mg BID in the first 24 h followed by 50 mg BID for the following 13 days post injury, compared with placebo in improving neurological motor outcomes in patients with C4–C8 level, International Standards for Neurological Classification of Spinal Cord Injury Examination (ISNCSCI) grade A, B or C acute (within 12 h post injury) SCI. Setting: Acute trauma centers worldwide Methods: A double-blind, multi-center, placebo-controlled RCT will enroll 351 participants randomized 1:1 to riluzole and placebo. The primary end point is the change between 180 days and baseline in ISNCSCI Motor Score. This study has 90% power to detect a change of nine points in ISNCSCI Motor Score at one-sided α=0.025. Results: Currently enrolling in 11 centers. Conclusion: This study will provide class I evidence regarding the safety and neuroprotective efficacy of riluzole in patients with acute cervical SCI.

Irinotecan is a chemotherapeutic drug used in the treatment of advanced colorectal cancer and elevated blood concentrations of its active metabolite, SN-38 leads to increased gastrointestinal (GI) toxicity and diarrhea in patients. In this study, we investigated the effects of inflammation on the pharmacokinetics (PK) of irinotecan (CPT-11) and its active metabolite, SN-38. Mice were i.p.-injected with either saline or lipopolysaccharide (LPS) to induce inflammation. After 16 h, irinotecan was administered orally. Blood was collected from the tail vein of mice from 0 to 24 h after dosing. Concentrations of irinotecan, SN-38 and SN-38G were analyzed using LC-MS/MS. The AUC, Cmax, and tmax were derived using WinNonlin® 5.2. A PK model was developed using Phoenix NLME® to describe the PK of irinotecan and SN-38 during inflammation. Results indicated a significant increase in the blood concentrations of irinotecan and SN-38 in mice during inflammation. The AUC of irinotecan and SN-38 in LPS group were 2.6 and 2-folds, respectively, of those in control saline-treated mice. The Cmax of irinotecan and SN-38 in LPS treated mice were 2.4 and 2.3-folds of those in saline-treated mice. The PK model was successfully developed and validated. The best-fit plots of individual PK analysis showed a good correlation between observed and predicted concentrations of irinotecan and SN-38. Together, this study reveals that SN-38 concentrations are elevated during inflammation, which may increase the GI toxicity and diarrhea in patients who receive irinotecan; and the developed PK model can quantitatively describe the PK of irinotecan and SN-38 during inflammation.

Astronauts experience Space Motion Sickness requiring treatment with an anti-motion sickness medication, scopolamine during space missions. Bioavailability after oral administration of scopolamine is low and variable, and absorption form transdermal patch is slow and prolonged. Intranasal administration achieves faster absorption and higher bioavailability of drugs that are subject to extrahepatic, first pass metabolism after oral dosing. We examined pharmacokinetics of 0.1, 0.2, and 0.4 mg doses of the Investigational New Drug formulation of intranasal scopolamine gel (INSCOP) in 12 healthy subjects using a randomized, double-blind cross-over study design. Subjects received one squirt of 0.1 g of gel containing either 0.1 mg or 0.2 mg/0.1 mL scopolamine or placebo in each nostril. Serial blood samples and total urine voids were collected after dosing and drug concentrations were determined using a modified LC-MS-MS method. Results indicate dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range tested. Plasma drug concentrations were significantly lower in females than in males after administration of 0.4 dose. All three doses were well tolerated with no unexpected or serious adverse side effects reported. These results suggest that intranasal scopolamine gel formulation (INSCOP) offers a fast, reliable, and safe alternative for the treatment of motion sickness.

Polymyxin B (PB) is increasingly used as the last treatment for multidrug-resistant (MDR) Gram-negative bacterial infections. In this study, serum and epithelial lining fluid (ELF) pharmacokinetics and the efficacy of a PB liposomal formulation were investigated. Two groups of 24 Swiss Webster mice were intravenously administered PB liposomes or PB aqueous solution at ca. 3 mg/kg. Serum and ELF samples were collected for up to 6 h to quantify major PB components. Three groups of neutropenic mice (n = 6/group) were infected with a clinical MDR Pseudomonas aeruginosa strain followed by intravenous administration of PB liposomes or PB aqueous solution at 3 mg/kg every 6 h or sham (drug-free) liposomes every 6 h. Bacterial burden in animal lung tissues was quantified after 24 h of therapy and was compared using one-way ANOVA. Survival of infected animals over time (n = 10/group) was evaluated by Kaplan-Meier analysis and log-rank test. In the pharmacokinetic study, the AUC ratio in ELF between liposome and aqueous solution groups ranged from 4.6 to 11.1 for various major PB components. In the efficacy study, for strain PA 9019 a significantly lower bacterial burden was seen in the liposomal group (3.8 ± 0.7 vs. 7.9 ± 0.8 log(10)CFU/g in the aqueous solution group), which subsequently prolonged survival of infected animals. In this study, treatment with a PB liposomal formulation yielded higher drug penetration into pulmonary ELF, which resulted in superior efficacy. However, further investigations on the clinical utility of the PB liposomal formulation are warranted.

Roux-en-Y gastric bypass procedure is the most frequently performed bariatric surgery for the extremely obese in USA. However, the information about the effects of racial/ethnic differences, comorbidities, and medication use on weight loss outcomes is limited. The objectives of this study were to investigate if race/ethnicity, comorbidities, and medication use affect weight loss effectiveness after the surgery. This is a retrospective observational study conducted at one teaching hospital at Houston metropolitan area, TX, USA. Patients between 18 and 64 years, with body mass index (BMI) of ≥40 or BMI of ≥35 with comorbidities, who had completed medical evaluations/consultations and met insurance policy requirements, were included in the study. From a total of 40 patients in the study (40 % African Americans, 35 % Caucasians, 17.5 % Hispanics, 7.5 % others), the weight loss was significantly greater in Caucasian patients at 6 months after the surgery, with mean percentage excess weight loss (%EWL) of 40.6 ± 17.3, as compared to all other racial groups combined at %EWL of 30.9 ± 11.5 (p value 0.04). No association was found between the 6-month weight loss and other variables including age, gender, BMI prior to surgery, comorbidities, and total number of medications taken before the surgery. This study found that Caucasian patients had a significantly greater %EWL at 6 months post-op as compared to their African-American and Hispanic counterparts. No other variables exhibited significant impact on the weight loss. Further studies with a larger sample size are needed to confirm the results from this study.

Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is widely used as a maintenance immunosuppressive regimen in solid organ transplant patients. It is increasingly used for the prophylaxis and treatment of graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT) patients. MPA displays extensive binding to serum albumin and glucuronidation to the inactive MPA-7-O-glucuronide (MPAG). Here, we review and discuss the pertinent information regarding the clinical pharmacokinetics of MPA in HSCT patients. The pharmacokinetics of MPA are altered in HSCT patients with lower oral bioavailability, shorter half-life and higher clearance than those in healthy volunteers and renal transplant recipients. Moreover, clearance may be increased in young pediatric patients. The optimal MMF dosing and preferred targets are still under investigation in HSCT patients due to the substantial intra- and inter-individual pharmacokinetic variability of MPA and broad range of transplants (malignant vs. nonmalignant, related vs. unrelated donor, and human leukocyte antigen mismatch). The complex pharmacokinetics of MPA have partly hampered the efficient use of MMF, and pharmacokinetic studies in HSCT patients have been limited in size and mostly inconclusive. Future research should be multi-institutional and focus on developing clinical decisions with adequate statistical power to improve clinical care of HSCT recipients.

A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group.

Riluzole, a sodium/glutamate antagonist has shown promise as a neuroprotective agent. It is licensed for amyotrophic lateral sclerosis and is in clinical trial development for spinal cord injury (SCI). This study investigated the therapeutic time-window and pharmacokinetics of riluzole in a rodent model of cervical SCI. Rats were treated with riluzole (8 mg/kg) at 1 hour (P1) and 3 hours (P3) after injury or with vehicle. Afterward, P1 and P3 groups received riluzole (6 (mg/kg) every 12 hours for 7 days. Both P1 and P3 animals had significant improvements in locomotor recovery as measured by open field locomotion (BBB score, BBB subscore). Von Frey stimuli did not reveal an increase in at level or below level mechanical allodynia. Sensory-evoked potential recordings and quantification of axonal cytoskeleton demonstrated a riluzole-mediated improvement in axonal integrity and function. Histopathological and retrograde tracing studies demonstrated that delayed administration leads to tissue preservation and reduces apoptosis and inflammation. High performance liquid chromatography (HPLC) was undertaken to examine the pharmacokinetics of riluzole. Riluzole penetrates the spinal cord in 15 min, and SCI slowed elimination of riluzole from the spinal cord, resulting in a longer half-life and higher drug concentration in spinal cord and plasma. Initiation of riluzole treatment 1 and 3 hours post-SCI led to functional, histological, and molecular benefits. While extrapolation of post-injury time windows from rat to man is challenging, evidence from SCI-related biomarker studies would suggest that the post-injury time window is likely to be at least 12 hours in man.

Object The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18–70 years old with acute spinal cord injury (SCI). Methods Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A–C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (Cmax), trough concentration (Cmin), systemic exposure (AUC0–12), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F). Results The Cmax and AUC0–12 achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (Cmax, Cmin, AUC0–12, CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that Cmax, Cmin, and AUC0–12 (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng × hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng × hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed. Conclusions This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The Cmax and AUC0–12 achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.

Lazaroid U-74389G (LAZ) has potential radio-protective and anti-proliferative activities in treatment of glioblastoma, but it exhibits poor brain penetration and high hepatic clearance. To increase the brain exposure of LAZ, we formulated LAZ in co-solvent system and as nanostructured lipid carriers (NLC). The rationale behind this approach is that LAZ formulations due to their high drug payload for administration at higher doses and prolonged circulation results in greater systemic exposure compared to unformulated LAZ solution. The purpose of this study was to comparatively evaluate the brain exposures of unformulated LAZ solution in citrate buffer (pH 3), LAZ co-solvent formulation in mixture of propylene glycol and citrate buffer (pH 3), and LAZ NLC, prepared using ultra-sonication and optimized using Central Composite Design (CCD). Statistical analysis was carried out using Student's t-test. Male Sprague Dawley rats were randomized into 3 groups and were administered unformulated LAZ solution at 5 mg/kg dose and LAZ co-solvent and LAZ NLC at 15 mg/kg dose, intravenously through jugular vein cannula. The brain tissues were homogenized in normal saline and LAZ in the brain tissue was quantified using Absciex Qtrap 5500 LC/MS/MS with linear range of 1 (LLOQ) - 250 ng/mL. The concentrations of unformulated LAZ solution and the LAZ co-solvent solution were 2 mg/mL and 8.5 mg/mL, respectively. The optimized LAZ NLC had particle size of 150 ± 2.86 nm, zeta potential of (-6.79) ± 0.39 mV, encapsulation efficiency of 81.34 ± 6.06%. The LAZ NLC preparation is monodisperse with polydispersity index of 0.158 ± 0.01 (N = 3). The amount of LAZ in brain tissues after 4 hours is significantly higher in formulation groups (LAZ co-solvent 37.48 ± 7.06 ng/gm and LAZ NLC 27.49 ng/gm) than the unformulated groups (LAZ solution 6.84 ± 1.87 ng/gm). Upon dose normalization there was a significant increase in amount of LAZ in brain tissues (N = 3 each) after 4 hours in LAZ co-solvent group (2.72 ± 0.53 ng/gm/mg) in comparison to unformulated LAZ solution group (1.37 ± 0.37 ng/gm/mg), at p Developing LAZ formulations will offer potential merits of enabling administrations at higher doses, facilitating LAZ delivery to the brain at therapeutic levels and decreasing its systemic clearance. LAZ formulations are capable of incorporating LAZ at higher drug payload than unformulated solution. Upon dose normalization, the amount of LAZ in brain tissue at 4 hours is significantly higher (1.5-2 times) in LAZ formulations in comparison to LAZ unformulated group. This study helps to build a strong foundational background for use of LAZ as an alternative agent in treatment of glioblastoma utilizing its dual properties of lipid peroxidation inhibition and anti-proliferation. Citation Format: Prajakta Gadgil, Diana S-L. Chow, Pamela New, Jaymin Shah. Lazaroid formulations for brain delivery in treatment of glioblastoma multiforme. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4402. doi:10.1158/1538-7445.AM2015-4402

Purpose: Lazaroid U-74389G (LAZ) is a 21-aminosteroid that has radioprotective effect against radiation-induced lipid peroxidation. In-vitro antiproliferative effect was reported against Glioblastoma primary cell lines. The aim of this study was to use a liposomal formulation in a proof-of-concept efficacy study to evaluate LAZ radioprotective and antiproliferative effects in Glioblastoma mouse model. Methods: LAZ PEGylated liposomes (Lipo G) were developed in our laboratory. Lipo G size was 80-90 nm with Zeta potential of -22mv. Glioblastoma cell line U87-Lexpressing firefly luciferase reporter gene (100,000 cells in 2 μL) was injected intracranially in each male SCID hairless outbred mouse. The mice were randomized among 4 treatment groups (n=8-9, each): brain model (M) without treatment (control), radiation of 2Gy once a week (M+R), Lipo G at 5 mg/kg dose IP twice a week (M+L) and radiation with Lipo G (M+R+L). The treatment lasted three weeks. The tumor size was monitored using non-invasive bioluminescence imaging (BLI), in each mouse, expressed as the relative BLI photon intensity on the second and third week to that of the first measurement. The mice were sacrificed at the end of the third week and the whole brain was harvested for immunohistochemistry examinations. Lipid peroxidation of brain tissues was quantified by measuring malondialdehyde (MDA) as a surrogate biomarker. The survival was evaluated using Kaplan Meier analysis at P = 0.05. Results: The relative BLI intensity was 4002.03±1737.67, 2034±737.72, 1387.36±684.53 and 2498.89±2521.32 % for M, M+R, M+L and M+R+L, respectively. The tumor size of the M+L group was reduced by 65% compared to the control group. For the radiation treated groups (M+R and M+R+L), there was no significant difference in the tumor size suppression compared to the control group. MDA brain concentration in M+L and M+R+L groups was significantly less than that in M+R group (8.27±0.78 and 10.37±3.30 µM/gm vs. 23.09± 3.79 µM/gm). The survival mean was 22.67, 25.33, 25.22 and 27.13 days for M, M+R, M+R+L and M+L groups, respectively. The mean survival duration of LAZ treated groups (M+L and M+R+L) was significantly longer than that of the control group (27.13 and 25.22 day vs. 22.67 day, respectively). Conclusion: LAZ liposomal formulations administered at 5 mg/kg dose delivered a therapeutic concentration of LAZ to the brain for the efficacy of suppressing Glioblastoma tumor growth (65% reduction). The liposomal LAZ also protected the brain tissue from radiation-induced lipid peroxidation by reducing MDA concentration (lipid peroxidation surrogate) to 50%. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5460. doi:10.1158/1538-7445.AM2011-5460

The unpredictable intestinal absorption and erratic bioavailability of oral busulfan (Bu) has limited the drug's use in high-dose pretransplantation conditioning therapy. To standardize drug delivery, we solubilized Bu for parenteral use. This new intravenous (i.v.) Bu formulation was combined with oral Bu and cyclophosphamide (Cy) to evaluate (1) the human acute toxicity of i.v. Bu and its solvent system and (2) the pharmacokinetics of Bu in patients undergoing hematopoietic progenitor cell transplantation (HPCT). One dose of i.v. Bu (escalating from 0.08 to 0.8 mg/kg) was given over 2 hours by pump; 6 hours later, an oral Bu regimen was begun, consisting of 1 mg/kg every 6 hours for 15 doses, followed by Cy, 60 mg/kg daily for 2 days. After 1 day of rest, HPCT was performed. The i.v. Bu dose was well tolerated and did not produce any acute toxicity reaction that could be attributed to the solvent system of dimethylacetamide and polyethylene glycol (PEG)-400. All observed treatment-related toxicity was as would be expected after high-dose oral Bu plus Cy. When the i.v. Bu was used as reference solution, the pharmacokinetic analysis indicated an average bioavailability of oral high-dose Bu of 69%, ranging from