Urinary Pharmacokinetics Research Articles

Pharmacokinetics of tenofovir alafenamide, emtricitabine, and dolutegravir in a patient on peritoneal dialysis

IntroductionPeritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited.MethodsA single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose.ResultsPlasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR.ConclusionsIn a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.

Meta-analysis guided development of a standard artificial urine

In this study, we present the first meta-analysis of human urine reported in the literature, drawing data from a total of 35 articles with a combined participant count of 14,021. Through this analysis, we have developed an artificial urine (AU) composition that can be adjusted within typical physiological parameters for in vitro applications. Our findings demonstrate the utility of this AU in determining the solubility of nitrofurantoin, particularly in the context of crystalluria. Notably, we observe that in saline, nitrofurantoin solubility, within the framework of its urinary pharmacokinetics, suggests a risk of crystalluria. However, in AU, this risk is mitigated due to complexation with urea. More broadly, we anticipate that our developed formulation will serve as a foundation for translational studies across biomedical and pharmaceutical sciences.

Pharmacokinetics of Edaravone Oral Suspension in Patients With Amyotrophic Lateral Sclerosis

Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration. Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated. After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported. In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS. ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www. gov.

Impact of antibiotic pharmacokinetics in urine on recurrent bacteriuria following treatment of complicated urinary tract infections.

The clinical relevance of bacteriuria following antibiotic treatment of complicated urinary tract infections in clinical trials remains controversial. We evaluated the impact of urine pharmacokinetics on the timing of recurrent bacteriuria in a recently completed trial that compared oral tebipenem pivoxil hydrobromide to intravenous ertapenem. The urinary clearance and urine dwell time of ertapenem were prolonged relative to tebipenem and were associated with a temporal difference in the repopulation of bladder urine with bacteria following treatment, potentially confounding the assessment of efficacy.

Evaluation of plasma and urine pharmacokinetics of tranexamic acid for equine medication control.

This study aimed to evaluate the pharmacokinetics (PK) of tranexamic acid (TXA) in horses and estimate its irrelevant plasma and urine concentrations using the pharmacokinetic/pharmacodynamic (PK/PD) approach by applying the Pierre-Louis Toutain model. TXA was intravenously administered to eight thoroughbred mares, and plasma and urine TXA concentrations were quantified by liquid chromatography/tandem mass spectrometry. The quantified data were used to calculate the PK parameters of TXA in horses. The plasma elimination curves were best-fitted to a three-compartment model. Using the Toutain model approach, irrelevant plasma and urine TXA concentrations were estimated to be 0.0206 and 0.997 μg/mL, respectively. The typical values of clearance, steady-state volume of distribution, and steady-state urine-to-plasma ratio were 0.080 L/kg/h, 0.86 L/kg, and 49.0, respectively. The obtained irrelevant concentrations will be useful for establishing relevant regulatory screening limits for effective control of TXA use in horse racing and equestrian sports.

Population plasma and urine pharmacokinetics and the probability of target attainment of fosfomycin in healthy male volunteers

PurposeA population pharmacokinetic model of fosfomycin was developed in healthy volunteers after intravenous administration, and different dosing regimens were evaluated in terms of the probability of target attainment for Escherichia coli using both plasma and urinary pharmacokinetic/pharmacodynamic targets.MethodsEight healthy men received fosfomycin as both intermittent 8 g q8h and continuous infusion 1 g/h with a loading dose of 8 g in a crossover study design. Dense sampling was conducted during both regimens. Population pharmacokinetic modelling was performed using NONMEM. Monte Carlo simulations were conducted to evaluate the Probability of Target Attainment (PTA) of different dosing regimens using bactericidal (AUC24h/MIC of 83 and 75%T>MIC) and bacteriostatic (AUC24h/MIC of 25) plasma targets and bacteriostatic (AUC24h/MIC of 3994) urine target.ResultsA total of 176 plasma and 86 urine samples were available for PK analysis. A two-compartment model with a urine compartment best described the data. Glomerular filtration rate (GFR) showed a significant correlation with renal clearance and was implemented in the final model. Simulation results show that the dose of 4 g q8h reached 100% of PTA using bactericidal and bacteriostatic targets for MIC up to 16 mg/L.ConclusionFor the clinical breakpoint of 32 mg/L, the standard dosing regimen (4 g q8h) might not be sufficient to reach the bactericidal target. Higher dosing of 8 g q8h as an intermittent infusion or 0.75 g/h as a continuous infusion might be required. Continuous infusion resulted in better attainment of the %T>MIC target than intermittent infusion.

Urine concentrations of vilanterol and its metabolites, GSK932009 and GW630200, after inhalation of therapeutic and supratherapeutic doses.

The 2023 Prohibited List issued by the World Anti-Doping Agency (WADA) permits athletes to inhale the beta2 -agonist vilanterol at a standard dose of 25 μg daily. However, given limited data on urine pharmacokinetics, vilanterol has no urinary threshold or decision limit to discriminate therapeutic from supratherapeutic use. We investigated urine concentrations of vilanterol and its main metabolites GSK932009 and GW630200 over 0-72 h following inhalation of therapeutic (25 μg) or supratherapeutic (100 μg) doses and repeat-dose administration for 7 days of 25 or 100 μg·day-1 in 25 trained men and women. Vilanterol administration was followed by 1 h of exercise. GW630200 urine concentrations were low and insufficient for threshold purposes, and while GSK932009 had higher urine concentrations, it could not discriminate between therapeutic and supratherapeutic use. Mean (range) maximum urine concentrations of parent vilanterol were 1.2 (0.2-4.1) and 6.2 (1.4-14.3)ng·ml-1 for single-dose 25 and 100 μg vilanterol, respectively, and 2.0 (0.3-4.8) and 22.4 (6.4-42.1)ng·ml-1 for repeat-dose 25 and 100 μg·day-1 vilanterol. In 333 samples collected 6 h post-administration and considering WADA TD2022DL, a 3.1 ng·ml-1 vilanterol cut-off showed 30% sensitivity in detecting supratherapeutic use at 100 μg versus therapeutic use at 25 μg. Considering inter- and intra-individual variability and guard bands in doping analysis, a 6 ng·ml-1 decision limit, which could be shifted upwards in samples with specific gravity >1.018, appears sufficiently high to minimize risk of samples exceeding the decision limit after therapeutic use of vilanterol, while demonstrating the ability to detect supratherapeutic use at 100 μg.

Sustained Consumption of a Decaffeinated Green Coffee Nutraceutical Has Limited Effects on Phenolic Metabolism and Bioavailability in Overweight/Obese Subjects.

Knowledge on the bioavailability of coffee (poly)phenols mostly come from single dose postprandial studies. This study aimed at investigating the effects of regularly consuming a green coffee phenolic extract (GCPE) on the bioavailability and metabolism of (poly)phenols. Volunteers with overweight/obesity consumed a decaffeinated GCPE nutraceutical containing 300 mg hydroxycinnamates twice daily for two months. Plasma and urinary pharmacokinetics, and fecal excretion of phenolic metabolites were characterized by LC-MS-QToF at weeks 0 and 8. Fifty-four metabolites were identified in biological fluids. Regular consumption of the nutraceutical produced certain changes: reduced forms of caffeic, ferulic and coumaric acids in urine or 3-(3′-hydroxypenyl)propanoic, and 3,4-dihydroxybenzoic acids in feces significantly increased (p < 0.05) after 8 weeks; in contrast, coumaroylquinic and dihydrocoumaroylquinic acids in urine decreased (p < 0.05) compared to baseline excretion. The sum of intestinal and colonic metabolites increased after sustained consumption of GCPE, without reaching statistical significance, suggesting a small overall effect on (poly)phenols’ bioavailability.

Fosciclopirox clinical proof of concept in patients with nonmuscle invasive and muscle-invasive bladder cancer.

e16557 Background: Fosciclopirox (F) is being developed for the treatment of non-muscle invasive (NMIBC) and muscle invasive (MIBC) bladder cancer. F is a prodrug which is rapidly and completely metabolized in blood to its active metabolite, ciclopirox (CPX). In preclinical models of bladder cancer, CPX acts in part as a γ-secretase inhibitor by binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, resulting in Notch and Wnt inhibition. The F Recommended Phase 2 Dose (RP2D), 900 mg/m2 administered IV over 20 minutes, was identified in the Phase 1 dose escalation trial (NCT03348514) in advanced solid tumor patients. Methods: The F RP2D was investigated in two early phase NMIBC and MIBC clinical proof of concept trials. In NCT04608045, neoadjuvant F was administered as monotherapy in cisplatin-ineligible (C-I) MIBC patients and in combination with gemcitabine + cisplatin in chemotherapy-eligible (C-E) MIBC patients. Clinical stage was assessed in pre-treatment (TURBT/CT) and post-treatment pathological state determined at radical cystectomy, (RC). The steady-state plasma and urine pharmacokinetics of F were also characterized. In NCT04525131, F was administered once daily for five days prior to TURBT. Pre- and post-treatment (at TURBT) bladder tumor samples underwent single cell sequencing to identify treatment effects on gene expression. Plasma, urine, and bladder tumor concentrations of F and its metabolites were determined in samples collected at TURBT. Results: Five C-E and 4 C-I MIBC patients received neoadjuvant F prior to RC. Twelve NMIBC patients received F prior to TURBT. There were no treatment-related serious adverse events observed in either study. Each patient experienced at least one treatment-emergent adverse event (TEAE), none of which resulted in study discontinuation. The most common TEAEs were nausea, fatigue, and constipation. Pathologic downstaging (&lt; ypT2) of bladder tumors was observed in 3 C-E MIBC patients with 2 CRs (ypT0). Two of 4 C-I patients had evident clinical response by CT scan with only microscopic residual ypT2 disease. Treatment-related changes in expression of Notch 1, Notch 2, Hes 1, Hey-1, c-Myc, ß-catenin and survivin were observed in the majority of NMIBC patients. F disappeared from plasma within 2 hours of administration. The mean CPX elimination half-life of CPX, apparent systemic clearance, and volume of distribution values were 8.8 hours, 46 L/hr and 549 L, respectively. Mean plasma, tumor and urine concentrations of CPX at TURBT were approximately 27, 9 and 100 µM, respectively. Conclusions: To date, fosciclopirox is well tolerated and achieves sufficient systemic, tumor, and urine CPX exposure at the RP2D. Evidence of target inhibition was demonstrated in NMIBC tumors and preliminary signs of clinical activity observed in MIBC patients. Safety and efficacy trials are planned to confirm and expand findings in NMIBC and MIBC patients. Clinical trial information: NCT04608045; NCT04525131.

Vancomycin-arginine (STM-001) abrogates ESBL carrier and carbapenem-resistant Escherichia coli burden in a murine complicated urinary tract infection model.

ObjectivesSTM-001, a retargeted glycopeptide, is active against MDR E. coli expressing ESBLs including carbapenemases. Herein, we assessed its capability to combat E. coli complicated urinary tract infections (cUTI) in mice driven by clinically important serine (CTX-M-15) and metallo-β-lactamases (NDM-1).MethodsPlasma and urine pharmacokinetics following IV administration of STM-001 (1–50 mg/kg) were determined in mice via LC-MS/MS. The effects on bacterial burden (kidney, bladder and urine) were determined in a 7 day mouse cUTI model whereby STM-001 was administered q12h or q24h at 2–100 mg/kg/day from Day 4. Efficacy was assessed by the change in log10 cfu/g or log10 cfu/mL from vehicle-treated infected mice.ResultsMICs of STM-001 for CTX-M-15 and NDM-1 E. coli were 8 and 16 mg/L, respectively. Blood pharmacokinetic profile was linear and dose-dependent with low clearance of 9.49 ± 0.31 mL/min/kg, V = 0.63 ± 0.02 L/kg and t½ = 1.16 ± 0.03 h. High STM-001 concentrations were recovered in urine 0–8 h post-administration, reaching up to 120-fold above its MIC. In cUTI efficacy studies, STM-001 (1–50 mg/kg, q12h) reduced CTX-M-15 burden by log10 4.31 (kidney), 3.95 (bladder) and 4.82 (urine) compared with vehicle-treated animals (P < 0.0001). STM-001 also reduced NDM-1 burden by log10 3.89 (kidney), 3.76 (bladder) and 3.08 (urine) (P < 0.0001), with similar inhibitory effects following q24h dosing.ConclusionsSTM-001 was highly effective in reducing E. coli burden in kidney, bladder and urine in mouse cUTI models. The observed efficacy with either dosing regimen indicates potential low humanized doses of 1–5 mg/kg. These data support further development of STM-001 as an innovative, carbapenem-sparing antibiotic to combat human cUTIs.

Urinary Pharmacokinetics of Immediate and Controlled Release Oxycodone and its Phase I and II Metabolites Using LC-MS-MS.

Oxycodone (OC) is a schedule II semisynthetic opioid in the USA that is prescribed for its analgesic effects and has a high potential for abuse. Prescriptions for OC vary based on the dosage and formulation, immediate release (IR) and controlled release (CR). Monitoring OC metabolites is beneficial for forensic casework. The limited studies that involve pharmacokinetics of the urinary excretion of OC metabolites leave a knowledge gap regarding the excretion of conjugated and minor metabolites, pharmacokinetic differences by formulation, and the impact of CYP2D6 activity on the metabolism and excretion of OC. The objectives of this study were to compare urinary excretion of phase I and II metabolites by formulation and investigate if ratio changes over time could be used to predict the time of intake. Subjects (n = 7) received a single 10mg IR tablet of Oxycodone Actavis. A few weeks later the same subjects received a single 10mg CR tablet of Oxycodone Actavis. During each setting, urine was collected at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 9, 10, 12, 14, 24, 48 and 72 h. Urine samples (100 µL) were diluted with 900 µL internal standard mixture and analyzed on an Acquity UPLC® I-class coupled to a Waters Xevo TQD using a previously validated method. The CYP2D6 phenotypes were categorized as poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM). Comparisons between IR and CR were performed using two-tailed paired t-test at a significance level of P = 0.05. The metabolite ratios showed a general increase over time. Four metabolite to parent ratios were used to predict the time of intake showing that predictions were best at the early time points.

Plasma and urine pharmacokinetics of hydroxyzine and cetirizine following repeated oral administrations to exercised horses.

Hydroxyzine and cetirizine are first- and second-generation oral antihistamine drugs, respectively, used to treat allergic reactions in horses. Cetirizine is also a metabolite of hydroxyzine, which may lead to complexities in regulating their use in equine sporting events. The aim of the research was to be able to provide detection times (DT) from pharmacokinetic studies in thoroughbred horses to better inform trainers, and their veterinary surgeons, prescribing these substances for treatment of Thoroughbred racehorses. Six and two horses were given 9 repeated administrations of hydroxyzine HCl (500mg BID) or cetirizine HCl (190mg BID), respectively. Plasma and urine hydroxyzine and cetirizine concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A holistic non-linear mixed effects PK model was developed that described both plasma and urine concentrations of hydroxyzine and cetirizine, either from administration of each individually or cetirizine as a metabolite of hydroxyzine. Using the parameters obtained from this PK model in conjunction with methodology developed by Toutain afforded possible screening limits (SL) that can regulate for a DT of 4days in either plasma or urine. Hydroxyzine and cetirizine concentration prediction intervals for the 80th , 95th and 99th percentiles of a virtual horse population were performed in order to assess the statistical protection of the DT. However, it is down to the individual racing authorities to apply their own risk management.

Urinary Pharmacokinetic Profile of Cannabidiol (CBD), Δ9-Tetrahydrocannabinol (THC) and Their Metabolites following Oral and Vaporized CBD and Vaporized CBD-Dominant Cannabis Administration.

The market for products containing cannabidiol (CBD) is booming globally. However, the pharmacokinetics of CBD in different oral formulations and the impact of CBD use on urine drug testing outcomes for cannabis (e.g., 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (Δ9-THCCOOH)) are understudied. This study characterized the urinary pharmacokinetics of CBD (100 mg) following vaporization or oral administration (including three formulations: gelcap, pharmacy-grade syrup and or Epidiolex) as well as vaporized CBD-dominant cannabis (containing 100 mg CBD and 3.7 mg Δ9-THC) in healthy adults (n = 18). A subset of participants (n = 6) orally administered CBD syrup following overnight fasting (versus low-fat breakfast). Urine specimens were collected before and for 58 h after dosing on a residential research unit. Immunoassay (IA) screening (cutoffs: 20, 50 and 100 ng/mL) for Δ9-THCCOOH was performed, and quantitation of cannabinoids was completed via LC-MS-MS. Urinary CBD concentrations (ng/mL) were higher after oral (mean Cmax: 734; mean Tmax: 4.7 h, n = 18) versus vaporized CBD (mean Cmax: 240; mean Tmax: 1.3 h, n = 18), and oral dose formulation significantly impacted mean Cmax (Epidiolex = 1,274 ng/mL, capsule = 776 ng/mL, syrup = 151 ng/mL, n = 6/group) with little difference in Tmax. Overnight fasting had limited impact on CBD excretion in urine, and there was no evidence of CBD conversion to Δ8- or Δ9-THC in any route or formulation in which pure CBD was administered. Following acute administration of vaporized CBD-dominant cannabis, 3 of 18 participants provided a total of six urine samples in which Δ9-THCCOOH concentrations ≥15 ng/mL. All six specimens screened positive at a 20 ng/mL IA cutoff, and two of six screened positive at a 50 ng/mL cutoff. These data show that absorption/elimination of CBD is impacted by drug formulation, route of administration and gastric contents. Although pure CBD is unlikely to impact drug testing, it is possible that hemp products containing low amounts of Δ9-THC may produce a cannabis-positive urine drug test.

Plasma and urine pharmacokinetics of two formulations of dexamethasone in greyhound dogs.

Dexamethasone, formulated as sodium phosphate and as phenylpropionate combined with sodium phosphate, was administered subcutaneously to six greyhounds. Plasma and urine were collected for up to 240h and analysed with a limit of quantification (LOQ) of at least 100pg/ml for dexamethasone. Dexamethasone, formulated as sodium phosphate, terminal half-life was 10.4h in plasma and approximately 16h in urine, and at 96h, plasma hydrocortisone concentrations returned to background with dexamethasone levels around the LOQ. Dexamethasone, formulated as phenylpropionate combined with sodium phosphate, terminal half-life, was 25.6h in plasma and approximately 26h in urine, and at 96h, plasma hydrocortisone concentrations returned to background with dexamethasone levels in three of the six greyhounds around the LOQ. Critical assessment of the pharmacokinetic and pharmacodynamic data indicated how it might be utilized for medication control in racing greyhounds.

Pharmacokinetic/Pharmacodynamic Interactions Between Evogliptin and Glimepiride in Healthy Male Subjects.

PurposeEvogliptin, a dipeptidyl peptidase-4 inhibitor, and glimepiride, a sulfonylurea, are used to treat type 2 diabetes mellitus. In this study, we aimed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between evogliptin and glimepiride.Materials and MethodsA randomized, open-label, 3-period, 3-treatment, 2-sequence crossover study was conducted in healthy male subjects. During each period, subjects received multiple doses of evogliptin 5 mg alone (EVO), glimepiride 4 mg alone (GLI), or a combination of the two (EVO+GLI). Serial blood and urine samples were collected 168 and 24 h post dosing, respectively, for PK and PD analyses.ResultsThirty-four subjects completed the study. The co-administration of evogliptin and glimepiride did not alter their plasma and urine PK profiles. For evogliptin, the geometric mean ratio (GMR) (90% confidence intervals) for the maximum plasma concentrations at steady-state (Cmax,ss) and the area under the curve during dosing interval at steady-state (AUCτ,ss) of EVO+GLI to E were 1.02 (0.98–1.06) and 0.97 (0.95–1.00), respectively. For glimepiride, the corresponding values of EVO+GLI to GLI were 1.08 (1.01–1.17) and 1.08 (1.02–1.14), respectively. All values were within the regulatory bioequivalence criteria of 0.8–1.25. Glucose excursion decreased with the co-administration of evogliptin and glimepiride compared with that observed with the evogliptin or glimepiride monotherapy.ConclusionEvogliptin and glimepiride had no PK interactions when co-administered, while the combination therapy showed an additive glucose-lowering effect compared to those of evogliptin or glimepiride monotherapy.

Similar pharmacokinetics of three dosing regimens comprising two oral delayed-release mesalamine formulations in healthy adult volunteers: Randomised, open-label, parallel-group study.

AimsMesalamine is the first‐line therapy for treating mild‐to‐moderate ulcerative colitis. Multiple mesalamine formulations are available, with similar safety and efficacy profiles. Mesalamine is commonly administered as divided dosing, although once‐daily dosing may provide benefits for patients. We evaluated the pharmacokinetics of three dosing regimens of two oral delayed‐release mesalamine formulations in healthy adult volunteers.MethodsA randomised, open‐label, parallel‐group study of mesalamine pharmacokinetics following Lialda 2 × 1.2 g once daily (QD) (dose A), Asacol 6 × 400 mg QD (dose B), or Asacol 2 × 400 mg three times daily (TID) (dose C) over 7 days. Assessments included 5‐aminosalicylic acid (5‐ASA) and N‐acetyl 5‐aminosalicylic acid (N‐Ac‐5‐ASA, primary metabolite) pharmacokinetics (A e(%), AUC0‐24 and C max), safety and tolerability.ResultsAll enrolled volunteers (n = 37) completed the study. Steady state was achieved for all treatments by day 4. Ratios (95% CI) of means for steady‐state AUC0‐24 (dose A vs B 90.3% [39.8, 204.8], dose A vs C 123.5% [55.3, 275.7], dose B vs C 136.8% [61.3, 305.5]) and C max (dose A vs B 106.0% [46.4, 242.2], dose A vs C 133.0% [59.1, 299.0], dose B vs C 125.5% [55.8, 282.1]) were similar for all 5‐ASA treatments. Mean urinary excretion of 5‐ASA plus N‐Ac‐5‐ASA was comparable between treatments (dose A 21.3%, dose B 20.2%, dose C 17.9%). All treatment regimens were well tolerated; no safety issues were observed.ConclusionsPlasma and urine pharmacokinetics for Asacol TID, Asacol QD, and Lialda QD are similar, suggesting similar daily systemic exposures can be obtained with either TID or QD dosing. NCT00751699.

Parameter Estimation and Reporting in Noncompartmental Analysis of Clinical Pharmacokinetic Data

The noncompartmental analysis (NCA) of pharmacokinetic (PK) data is important throughout all phases of clinical drug development. Although there are numerous regulatory guidances and articles in the literature concerned with best practices for the modeling of PK data, there are relatively few sources of information on how to conduct a high-quality NCA. This article provides a systematic review of issues related to the estimation of plasma and urine PK parameters with the intent of encouraging rigor in the performance of NCAs so as to provide reliable and informative analysis results.

SO052EFFECT OF SEVERE RENAL IMPAIRMENT OR END-STAGE RENAL DISEASE ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF ROXADUSTAT, AN ORAL HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITOR

Abstract Background and Aims Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor used at titrated doses to treat anaemia in CKD patients. This study investigated the pharmacokinetics (PK), metabolic profile, pharmacodynamics, and safety of roxadustat in subjects with different degrees of renal function (RF). Method This was a phase 1, open-label study conducted in Germany and the United Kingdom (EudraCT Number: 2015-002565-28). Subjects were enrolled in four RF groups: normal RF (eGFR ≥90 mL/min/1.73 m2); severely impaired RF (not on dialysis; eGFR &amp;lt;30 mL/min/1.73 m2); end-stage renal disease (ESRD) on continuous ambulatory or automated peritoneal dialysis (CAPD/APD); or ESRD on 4-hour haemodialysis or haemodiafiltration (HD/HDF). Subjects in the normal RF, severely impaired RF, and ESRD on CAPD/APD groups received a single dose of 100-mg oral roxadustat on Day 1. A single-sequence design with two treatment periods (P1/P2) separated by a washout period was used for subjects with ESRD on HD/HDF; a single administration of 100-mg oral roxadustat occurred 2 hours after completion of a HD/HDF session (P1) and 2 hours before initiation of a HD/HDF session, 2 days after the previous session (P2). Plasma and urine PK of roxadustat and its circulating metabolites (O-glucuronide-, O-glucoside-, and sulphate of hydroxy-roxadustat) and plasma erythropoietin (EPO) were evaluated. Continuous heart rate monitoring was conducted. Results Of 73 screened subjects, 34 (46.6%) were enrolled and received roxadustat (normal RF, n=12; severely impaired RF, n=9; ESRD on CAPD, n=1; ESRD on HD/HDF, n=12). The geometric least-square mean ratio of area under the plasma concentration-time curve (AUC) from administration to infinity (AUCinf) relative to subjects with normal RF was 223% (90% CI: 185, 268) and 195% (90% CI: 165, 229) in subjects with severely impaired RF and in those with ESRD on HD/HDF, respectively. Roxadustat’s maximum concentration (Cmax) and terminal elimination half-life (t1/2) were comparable between groups. The PK of roxadustat and its metabolites were not affected by HD/HDF. In subjects with normal RF, the amount of roxadustat excreted unchanged in urine was &amp;lt;1%; urinary excretion and renal clearance of roxadustat and its metabolites decreased with lower baseline RF. Mean AUCinf and t1/2 for roxadustat’s circulating metabolites were higher in subjects with severely impaired RF and with ESRD on HD/HDF than in those with normal RF. Metabolite to parent ratio of AUCinf was &amp;lt;1% for O-glucuronide- and O-glucoside-roxadustat and &amp;lt;10% for sulphate of hydroxy-roxadustat. EPO baseline-corrected AUC from administration to last measurable concentration and EPO maximum effect were higher in subjects with severely impaired RF or with ESRD on HD/HDF than in those with normal RF. Conclusion The AUC for roxadustat and its metabolites was higher in patients with severely impaired RF or with ESRD on HD/HDF than in those with normal RF. Roxadustat’s Cmax and t1/2 were comparable among all groups. Roxadustat and its metabolites were not significantly cleared by HD/HDF.

0198 Psychomotor/Cognitive Effects, Pharmacokinetics and Safety of V117957, a Novel, Highly Potent and Selective Partial Agonist for Nociceptin/Orphanin-FQ Peptide (NOP) Receptors, Administered in Combination with Alcohol in Healthy Subjects

Abstract Introduction V117957 is an investigational nociceptin/orphanin-FQ peptide (NOP) receptor partial agonist designed to treat insomnia by promoting sleep onset and maintenance with minimal residual next-day somnolence or psychomotor impairment. The satisfactory safety/tolerability profile of V117957 has been previously established in ~200 healthy subjects with maximum doses at 30mg following a single oral administration and 10mg once daily for 2 weeks. The present study was conducted to assess the safety/tolerability and pharmacokinetics (PK) of V117957 with co-administered alcohol. Methods A randomized, double-blind, double-dummy, placebo-controlled, balanced six-period crossover design was employed. Single doses (2mg, 6mg) of V117957 and placebo were administered orally to healthy subjects in the morning with and without alcohol (0.7g/kg). Pharmacodynamic (PD) effects of V117957 were assessed, and safety/tolerability and PK interactions were also characterized. The primary PD endpoints (body sway, Digit Vigilance Test, and numeric working memory) were measured through 12 hours postdosing. Results Forty-eight subjects were enrolled and randomized; 46 completed. Compared with placebo, alcohol alone showed an impairment on psychomotor/cognitive performances through 2 hours postdose. V117957 alone showed a dose-dependent impairment. Compared with V117957 alone and alcohol alone, co-administration of alcohol and V117957 showed greater impairment until 8 hours postdose. No subject discontinued due to an adverse event (AE). No clinically meaningful treatment-emergent (TE) changes in clinical laboratory values, vital signs, SpO2 measurements, or 12-lead ECG results were observed. The most common TEAE was somnolence. All plasma and urine PK parameters for V117957 and alcohol were comparable when V117957 or alcohol was administered alone or in combination. Conclusion Single oral doses of V117957, 2mg or 6mg, administered alone or in combination with alcohol in healthy subjects resulted in no notable PK interaction between V117957 and alcohol. A dose-effect relationship in the magnitude and duration of impairment was observed for most psychomotor/cognitive performance parameters. Greater effects of V117957 with alcohol were observed for most psychomotor/cognitive performance parameters up to 8 hours post-dose. Support Funded by Imbrium Therapeutics, a subsidiary of Purdue Pharma L.P.

Systemic Pharmacokinetics of Topical Intranasal Cocaine in Healthy Subjects.

Background Topical cocaine is currently available for local anesthesia of the upper airway mucous membranes. Objective The objective of this study was to define the safety and efficacy of topical intranasal cocaine for a subsequent phase II clinical trial. Methods This study was a single-dose, single-center, and open-label study of the plasma and urinary pharmacokinetics (PK) of 4% topical cocaine and its major metabolites, benzoylecgonine (BE) and ecgonine methyl ester (EME), in 30 healthy subjects. Subjects received the topical solution on cotton pledgets containing 4 mL of 4% topical cocaine applied for 20 minutes, which was equivalent to 160 mg of cocaine hydrochloride. Results A total of 30 subjects (14 males and 16 females) were enrolled, treated, and provided PK data for analysis. Mean plasma concentrations of cocaine rose rapidly during the intranasal exposure period, with peak levels (Cmax, 37.0 ± 17.3 ng/mL) observed at the time of pledget removal (Tmax, 0.43 ± 0.34 h). Mean plasma concentrations then fell rapidly and monoexponentially for the remainder of the study, with a mean half-life (t1/2) of 1.04 ± 0.35 hours. Following a 20-minute topical intranasal exposure to a 160 mg dose of cocaine 4% solution, the mean 0 to 12 hours recoveries of cocaine, BE, and EME were 117 ± 67 μg, 816 ± 440 μg, and 275 ± 113 μg, respectively. Plotting urinary recovery by collection interval showed that urinary excretion of cocaine closely followed the time course of plasma cocaine. Conclusions Cocaine was rapidly but incompletely absorbed and then rapidly eliminated. Only 4% of the administered cocaine dose appeared to be absorbed in this study. Cocaine appeared in the urine with a time course similar to that in plasma.