Multiple-dose Pharmacokinetics Research Articles

Pharmacokinetics of Fipaxalparant, a Small-Molecule Selective Negative Allosteric Modulatorof Lysophosphatidic Acid Receptor 1, and the Effect of Food in Healthy Volunteers.

Dysregulated lysophosphatidic acid receptor 1 (LPAR1) signaling is implicated in fibrotic diseases, including systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Fipaxalparant (HZN-825) is a small molecule acting as a negative allosteric modulator of LPAR1 and is in phase 2 clinical evaluations for treating diffuse cutaneous SSc and IPF. This open-label, phase 1 study examined the pharmacokinetics (PKs), food effect, and safety of fipaxalparant in healthy volunteers. Dose proportionality was evaluated for fipaxalparant single doses of 150, 300, and 450mg under fasted conditions. Food effect was tested with a 450-mg single dose under fasted conditions or with a high-fat meal. Multiple-dose PKs for twice-daily dosing of either 300 or 450mg with low- or high-fat meals was also assessed. Fipaxalparant was safe and well tolerated in healthy volunteers (n = 36) under all conditions. Fipaxalparant exposure increased in a less than dose-proportional manner from 150 to 450mg. At 450mg, a high-fat meal increased the maximum observed concentration and area under the curve by approximately 1.9- and 2.1-fold, respectively. These results, combined with prior preclinical and phase 2a data, informed dose selection of fipaxalparant 300mg once and twice daily with a meal for phase 2b studies.

Pharmacokinetics of intravenous piperacillin/tazobactam among patients with peritoneal dialysis-associated peritonitis.

Currently, pharmacokinetic information on intravenous (IV) piperacillin/tazobactam in patients with peritoneal dialysis-associated peritonitis (PD peritonitis) is limited. This study employed a prospective single-dose pharmacokinetic design to assess the pharmacokinetics of IV piperacillin/tazobactam in these patients. Four patients with PD peritonitis who received an IV loading dose of 4000 mg/500 mg piperacillin/tazobactam were enrolled in this study. The concentrations of piperacillin and tazobactam in plasma, peritoneal dialysis fluid (PDF) and urine were determined by high-performance liquid chromatography. Non-compartmental methods were used for pharmacokinetic analysis. During a 6-h dwell time for chronic ambulatory peritoneal dialysis (CAPD), 9.23 ± 4.01% of the piperacillin was recovered in the PDF. This result is greater than that observed in patients without peritonitis in prior research. Piperacillin's PD clearance (CLPD), steady-state volume of distribution (Vss) and terminal half-life (t 1/2) were 5.79 ± 2.55 mL/min, 24.35 ± 11.26 L and 5.74 ± 1.53 h, respectively. These values are also higher than those of patients without peritonitis in a prior study. Eight hours following the loading dosage, the plasma and PDF piperacillin concentrations of all patients (98.25 ± 26.03 and 52.70 ± 22.99 mg/L, respectively) surpassed the Pseudomonas aeruginosa and Enterobacterales Clinical and Laboratory Standards Institute susceptible breakpoints. In summary, the CLPD, Vss and t 1/2 for piperacillin were found to be greater in patients with PD peritonitis than in CAPD patients without peritonitis when compared with the results of a previous study. The IV loading dose of 4000 mg/500 mg piperacillin/tazobactam is sufficient to treat peritonitis caused by susceptible P. aeruginosa and Enterobacterales. The multiple-dose pharmacokinetics of IV piperacillin and tazobactam in this specific patient group should be further investigated.

Single- and Multiple-Dose Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist, in Healthy Adults.

Gefapixant (MK-7264, RO4926219, AF-219) is a first-in-class P2X3 antagonists being developed to treat refractory or unexplained chronic cough. The initial single- and multiple-dose safety, tolerability, and pharmacokinetics of gefapixant at doses ranging from 7.5 to 1800 mg were assessed in four clinical trials. Following single-dose administration of 10-450 mg, the pharmacokinetic (PK) profile of gefapixant in plasma and urine demonstrated low inter-subject variability and a dose-proportional exposure. Following administration of multiple doses twice daily, the plasma exposures were dose-proportional at doses ranging from 7.5 to 50 mg and less than dose-proportional at doses ranging from 100 to 1800 mg. The time to mean peak drug concentration ranged from 2 to 3 h post-dose, and steady state was achieved by 7 days after dosing, with an accumulation ratio of approximately 2, comparing data from day 1 to steady state. The mean apparent terminal half-life ranged from 8.2 to 9.6 h. Gefapixant was primarily excreted unmodified in urine. Gefapixant was well tolerated following single-dose administration up to 1800 mg and multiple doses up to 1800 mg twice daily; there were no serious adverse events (AEs) reported. The most common AE reported was dysgeusia. The PK profile supports a twice-daily dosing regimen.

Nonlinear Pharmacokinetics of Topical Flurbiprofen Gel in a Phase I Study Among Chinese Healthy Adults.

PDX-02 (Flurbiprofen sodium) is a topical nonsteroidal anti-inflammatory drug in gel formulation for local analgesia and anti-inflammation. A Phase I clinical trial was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of PDX-02 gel in Chinese healthy adults. The trial comprised three parts: (1) a single-dose ascending study with three dose levels (0.5%, 1% to 2% PDX-02 gel) applied on a 136 cm2 skin area; (2) a multiple-dose study with either 1% or 2% PDX-02 gel applied on a 136 cm2 skin area for 7 consecutive days; and (3) a high dose group with 2% PDX-02 gel on an 816 cm2 skin area and a frequent multiple dose group with 2% PDX-02 gel on a 272 cm2 skin area four times a day for 7 consecutive days. The safety, tolerability and pharmacokinetics of the PDX-02 gel were evaluated in each part. A total of sixty participants completed the trial, with all adverse events recovered and all positive skin reaction being transient and recovered. The overall absorption of topical PDX-02 gel was slow with a mean peak time exceeding 9h. The elimination rate remained consistent between dose groups. A less-than-dose-proportional nonlinear pharmacokinetics relationship was observed within the studied dose range, and this is likely due to the autoinduction of skin first-pass metabolism. The topical PDX-02 gel showed favorable safety and tolerability in both single and multiple dosing studies, with a less-than-dose-proportional nonlinear pharmacokinetics observed.

First-In-Human Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of AZP2006, A Synthetic Compound for the Treatment of Alzheimer's Disease and Related Diseases.

Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) are major neurodegenerative conditions with tau pathology in common but distinct symptoms-AD involves cognitive decline while PSP affects balance and eye movement. Progranulin (PGRN) is a growth factor implicated in neurodegenerative diseases, including AD and PSP. AZP2006, a synthetic compound, targets tauopathies by stabilizing PGRN levels and reducing tau aggregation and neuroinflammation. Evaluate the safety, tolerability, and pharmacokinetics of AZP2006. A first-in-Human phase 1 study comprised a single ascending dose (SAD) and a multiple ascending dose study (MAD). The SAD study included 64 healthy male volunteers and tested singles oral doses of 3 to 500 mg of AZP2006 free base equivalent or placebo. In the MAD study, 24 healthy male volunteers were administered oral doses of 30, 60, and 120 mg per day of AZP2006 or placebo for 10 days. No serious adverse events were observed. Clinical, biological, and electrocardiogram findings were non-relevant. Nineteen minor adverse events resolved before study completion. The safety profile indicated no specific risks. The multiple ascending dose study was halted, and the optional dose level of 180 mg was not performed due to high levels of M2 metabolite in plasma that necessitated additional preclinical evaluation of M2. Both AZP2006 and its M2 metabolite were quickly absorbed and widely distributed in tissues. Exposure increased more than proportionally with dose. AZP2006 had a favorable safety profile and was rapidly absorbed. Elevated M2 metabolite levels necessitated further studies to clarify excretion and metabolism mechanisms.

Pharmacokinetics, pharmacodynamics and safety of 15mg-tolvaptan administered orally for 7 consecutive days to Chinese patients with child-Pugh B cirrhosis.

Background: Tolvaptan, a selective vasopressin V2-receptor antagonist, can elicit a diuretic effect without significant electrolyte loss. The aims were to evaluate multiple-dose pharmacokinetics, pharmacodynamics and safety of daily administration of 15mg tolvaptan in Chinese adult patients with confirmed Child-Pugh Class B cirrhosis accompanied by ascites. Methods: This was an open-label, single-center, single- and multiple-dose study. All patients received a daily 15mg dose of tolvaptan for 7 consecutive days. The plasma concentrations of tolvaptan and its two metabolites (DM-4103, DM-4107) were measured using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). In addition, various pharmacokinetics parameters were calculated. The pharmacodynamic outcomes evaluated changes in serum sodium and potassium concentrations, daily urine volume, daily water consumption, fluid balance and body weight. Safety profiles, including the incidence of treatment-emergent adverse events (TEAEs), were carefully recorded. Results: Eleven patients with Child-Pugh B cirrhosis were eventually enrolled in the study. Plasma concentrations of tolvaptan and DM-4107 reached steady-states after 7 days of consecutive oral administration. No accumulation of tolvaptan or DM-4107 was found, but DM-4103 accumulated 18.2-fold after multiple-dosing. The daily urine volume and daily water consumption were statistically significantly increased after administration of tolvaptan from Day 1 to Day 7 (all p < 0.05), accompanied by an increased serum sodium concentration. Of 11 patients, 9 (81.8%) reported 20 TEAEs, with the majority being mild to moderate in severity. The most commonly occurring TEAEs were thirst (45.5%), pollakiuria (36.4%) and dry mouth (27.3%). Conclusion: Tolvaptan at a daily dose of 15mg had a diuretic effect but did not increase serum sodium excretion or lead to tolvaptan accumulation. It is therefore can be safely used for short-term treatment of Chinese adult patients with confirmed Child-Pugh B cirrhosis. Clinical Trial Registration: https://clinicaltrials.gov/search?term=NCT01359462, identifier NCT01359462.

Improving brain penetration using elacridara P-glycoprotein and BCRP inhibitor

The central nervous system (CNS) is a site for a myriad of disorders and diseases, such as schizophrenia, Alzheimers disease, and Parkinsons disease. Many medications targeting these illnesses remain challenged due to efflux transporters forming a blood-brain barrier (BBB). To combat such challenges, elacridar shown promise at inhibiting such transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), therefore improving brain penetration. However, as an early clinical candidate, many remain unknown about elacridars pharmacokinetic (PK) properties in the human body. This paper aims to obtain a better understanding of elacridars pharmacokinetic profile and predict the optimal dose and dose interval for its application in the clinic. To begin with, a series of basic PK models were created using fundamental PK equations and the models were fit to elacridar clinical data to obtain elacridar-specific PK parameters. Next, elacridar preclinical PK as well as in vitro inhibition assay were used to determine the therapeutic window. Our final, multiple-dose extravascular PK model reveals that the most convenient and effective dose regimen is 900 mg BID (bis in die; twice per day). With this elacridar PK model, researchers can leverage elacridar human PK to improve clinical outcomes.

Population Pharmacokinetic Modeling of Different Formulations of Inclacumab Using Phase 1 Data in Healthy Participants

Introduction: P-selectin is a cell adhesion molecule that contributes to vaso-occlusive crises (VOCs) in sickle cell disease (SCD). Inclacumab is a recombinant, fully human, immunoglobulin G4 monoclonal antibody that selectively binds to P-selectin to prevent binding with P-selectin glycoprotein ligand-1. Inclacumab was previously evaluated by Roche in clinical trials with healthy participants and patients with cardiovascular disease and is now being developed as a potential treatment to reduce the frequency of VOCs in individuals with SCD. Changes in the manufacturing of inclacumab have resulted in 3 formulations/drug materials: Roche v0.1, Roche v0.2, and Global Blood Therapeutics (GBT). GBT-manufactured inclacumab utilizes a similar formulation and the same cell line as Roche v0.2 (Roche v0.1 utilizes a different cell line), and analytical and nonclinical comparability between Roche v0.2 and GBT inclacumab have been demonstrated (Mihaila et al. Expert Opin Biol Ther 2022). Here we report results from a population pharmacokinetic (PopPK) model developed to compare the pharmacokinetics (PK) of different formulations using data from 4 phase 1 clinical studies in healthy participants administered Roche v0.1, Roche v0.2, or GBT inclacumab. The objectives were to develop a PopPK model to describe inclacumab PK in healthy adult participants and to quantify potential differences in inclacumab PK associated with different formulations/drug materials. Methods: A PopPK model was developed using single- and multiple-dose PK data from healthy participants who received intravenous (IV) inclacumab across 4 studies (BP21112 [Roche v0.1, single ascending dose (SAD)], BP21617 [Roche v0.1, multiple ascending dose], BP28134 [Roche v0.2, SAD], and GBT2104-111 [GBT, SAD]). Evaluable participants had ≥1 measurable postdose concentration with an associated sample time, relevant dosing information prior to each measurable concentration, and no protocol violation that could confound PK analyses. A nonlinear mixed effects model was fit to the inclacumab plasma concentration-time data using first-order conditional estimation with eta-epsilon interaction in NONMEM ® (v7.3). Model selection was based on the plausibility of parameter estimates, goodness-of-fit plots, and the objective function value. The final model was evaluated using a prediction-corrected visual predictive check (pcVPC). Results: The PopPK dataset comprised 145 healthy participants, of which 2622 inclacumab plasma concentrations (84.9%) from 143 participants were evaluable (Roche v0.1: n=68 [47.6%]; Roche v0.2: n=60 [42.0%]; GBT: n=15 [10.5%]). Median (range) age and body weight were 42 (21-63) years and 73.2 (45.8-109) kg, respectively. Nominal doses ranged from 0.03 to 40 mg/kg IV; 23.8% of participants received 3 mg/kg and 29.4% received 20 mg/kg. A 3-compartment disposition model with parallel linear clearance (CL=0.125 L/d) and nonlinear (concentration-dependent; V max=1.19 mg/d; K m=0.784 μg/mL) clearance from the central compartment described the plasma concentration-time data. The effect of drug material was incorporated a priori as relative bioavailability term F in the base model using exploratory analyses of observed exposures. Dosing of Roche v0.1 and Roche v0.2 inclacumab resulted in 23% and 2% higher exposure than GBT inclacumab, respectively. Between-subject variability was estimated for linear clearance, nonlinear clearance, and all volume parameters, and residual error was described using a proportional model (Table). Of the tested covariates, baseline body weight was a statistically significant covariate effect and was included on all linear clearance and volume terms. Model qualification by pcVPC showed good predictive performance of the final model. Conclusions: The PopPK of IV inclacumab in healthy participants was described by a 3-compartment disposition model with parallel linear and nonlinear clearances. Estimated relative exposure of Roche v0.2 and GBT-manufactured inclacumab was similar, indicating comparability in drug exposure. Understanding the relationship between exposure and dose for different formulations facilitates more accurate assessment of safety data across multiple clinical studies. These data provide support for the ongoing phase 3 clinical development in SCD using GBT-manufactured inclacumab without further clinical comparability testing.

Single- and multiple-dose pharmacokinetics of sotalol hydrochloride in healthy cats

Introduction/objectivesThe objective of this study was to describe the single- and multiple-dose pharmacokinetics and urinary elimination of sotalol in healthy cats. AnimalsSix adult purpose-bred cats Materials and methodsCats were administered 2 mg sotalol/kg body weight as a single intravenous bolus and as a single oral dose in a randomized crossover study with a two-week washout period. The same cats then received 3 mg sotalol/kg orally every 12 h for two weeks. Blood samples were collected at predetermined time points for 48 h postdose for quantification of sotalol using ultra-high-pressure liquid chromatography with mass spectrometry. Non-compartmental analysis was used to obtain pharmacokinetic parameters. Data are presented as median (min–max). ResultsFollowing intravenous administration, plasma clearance and volume of distribution were 9.22 mL/min/kg (5.69–10.89 mL/min/kg) and 2175.56 mL/kg (1961–2341.57 mL/kg), respectively. Bioavailability was 88.41% (62.75–130.29) following a single oral dose. Peak plasma concentration (Cmax) and time to Cmax were 0.94 μg/mL (0.45–1.17 μg/mL) and 1.5 h (0.5–4 h) after a single oral dose (2 mg/kg), and 2.29 μg/mL (1.91–2.48 μg/mL) and 1.0 h (0.5–1.5 h) with chronic oral dosing (3 mg/kg), respectively. Elimination half-life was 2.75 h (2.52–4.10 h) and 4.29 h (3.33–5.53 h) for single and chronic oral dosing, respectively. Accumulation index was 1.17 (1.09–1.29) after chronic dosing. Urinary sotalol recovery was 81–108% of the intravenous dose. ConclusionsOral sotalol administration resulted in plasma concentrations reportedly efficacious in other species, with good to excellent oral bioavailability. Urinary excretion appears to be a major route of elimination. Following repeated oral dosing, minimal drug accumulation was estimated. Additional studies in cats are recommended due to the possibility of nonlinear kinetics.

Safety, Tolerability, and Pharmacokinetics of Zagotenemab in Participants with Symptomatic Alzheimer's Disease: A Phase I Clinical Trial.

Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer's disease (AD). The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed.Clinicaltrials.gov: NCT03019536.

The effects of orally administered trazodone on ambulation and recumbency in healthy horses.

Trazodone, a serotonin receptor antagonist and reuptake inhibitor, might be a useful adjunctive treatment in the initial management of horses with acute laminitis if it minimizes ambulation or encourages recumbency. (1) Evaluate the effects of PO trazodone on ambulatory activity and recumbency in healthy horses; and (2) assess the pharmacokinetics of multiple PO doses of trazodone. In a randomized cross-over design, 8 healthy horses received placebo or trazodone at 2 doses (2.5 and 7.5 mg/kg) PO q12h for 48 hours with a 14-day washout period between treatments. Forelimb step frequency was measured using a hoof-mounted accelerometer and continuous video monitoring was used to detect recumbency. Groups were compared using repeated measures analysis of variance with Tukey's post hoc test. Trazodone and m-chlorophenylpiperazine (m-CPP) plasma concentrations were determined by ultra-high performance liquid chromatography-tandem mass spectrometry and pharmacokinetics were analyzed using noncompartmental methods. Step frequency was lower in horses receiving 7.5 mg/kg trazodone than in the control group (mean step reduction: 44% ± 11%). Steps-area under the curve were significantly lower in the 7.5 mg/kg group (mean ± SD: 3375 ± 525 steps × hour) as compared to the 2.5 mg/kg group (mean ± SD: 5901 ± 2232; P = .02) and compared to control (mean ± SD: 6590 ± 1241; P = .001). No difference was found in the number of recumbent episodes (P = .92) or total duration of recumbency (P = .9). Trazodone and m-CPP achieved steady-state concentrations, with an accumulation ratio of 1.45 ± 0.2. Although it did not affect recumbency, trazodone at 7.5 mg/kg q12h decreased step frequency by approximately 44%.

JSKN003, A NOVEL BIPARATOPIC ANTI-HER2 ANTIBODY-DRUG CONJUGATE, EXHIBITS POTENT ANTITUMOR EFFICACY

Abstract In human advanced solid tumors, expression of HER2 protein has been reported in various tumor tissues and a variety of cultured tumor cell lines including breast cancer, gastric cancer, pancreatic cancer, lung cancer, colorectal cancer, and ovarian cancer. Due to the critical roles of HER2 in carcinogenesis, two main targeted therapies have been developed in the past two decades to block the HER2-driven pathways, which include small molecule compounds that inhibit the tyrosine kinase activity of the intracellular domain, and mono-antibodies (mAbs) that target the extracellular domain (ECD) of the receptors. JSKN003 is an antibody-drug conjugate (ADC) comprised of a recombinant, humanized anti-human epidermal growth factor receptor 2 (HER2) bispecific antibody conjugated to a topoisomerase I inhibitor via a dibenzocyclooctyne tetrapeptide linker. The anti-HER2 component, KN026, is a recombinant, humanized bispecific antibody that targets both extra-cellular domains II (pertuzumab binding site) and IV (trastuzumab binding site) of HER2. JSKN003 showed high affinity binding to human HER2 with KDs of 2.209 E-10M, which is comparable to its parental antibody KN026 and bound to NCI-N87 and BxPC-3 cells in a concentration-dependent manner. At the same time JSKN003 showed more extensive and faster internalization than DS8201 on NCI-N87 cells. As expected, JSKN003 showed directly inhibits growth by targeting HER2 positive tumor model (NCI-N87 and BT474 cell models). The single dose and multiple dose pharmacokinetics study in cynomolgus monkey indicated that JSKN003, total antibody and DXd had general linear dynamic characteristics, and pharmacokinetics parameters showed no significant differences between males and females in the range 0.3-30 mg/kg. The HNSTD (highest non-severely toxic dose) of JSKN003 was determined as 30mg/kg in cynomolgus monkeys. These preclinical data suggest that JSKN003 could potentially benefit patients with tumors co-expressing HER2 through improved drug selectivity and efficacy. JSKN003’s safety, tolerability and preliminary anti-tumor activity are currently being evaluated in a first-in-human phase I study in advanced stage solid tumors in Australia (NCT05494918) using a BOIN design. This ADC is targeted on the subjects who has HER2 expression and/or HER2-gene mutation and may address an unmet medical need for these patients.

A One Health perspective on comparative cannabidiol and cannabidiolic acid pharmacokinetics and biotransformation in humans and domestic animals

The goal of pharmacokinetic (PK) studies is to provide a basis for appropriate dosing regimens with novel therapeutic agents. With a knowledge of the desired serum concentration for optimum pharmacological effect, the amount and rate of drug administration can be tailored to maintain that concentration based on the 24-hour PK modeling (eg, every 24 hours, every 12 hours) to achieve therapeutic ranges. This dosing and PK information are tailored to maintain that concentration. Typically, these optimum serum concentrations pertain across species. Single-dose PK modeling provides fundamental parameters to suggest dosing regimes. Multiple-dose PK studies provide information on steady-state serum levels to assure that desired therapeutic levels are maintained during chronic administration. Clinical trials using dosing suggested by these PK determinations provide proof that the compound is producing the desired therapeutic effect. A number of PK studies with cannabinoids in humans and domestic animals have been conducted with the goal of determining appropriate clinical use with these plant-derived products. The following review will focus on the PK of cannabidiol (CBD) and the lesser-known precursor of CBD, cannabidiolic acid (CBDA). Although Δ9-tetrahydrocannabinol (THC) has profound pharmacological effects and may be present at variable and potentially violative concentrations in hemp products, PK studies with THC will not be a major consideration. Because, in domestic animals, hemp-CBD products are usually administered orally, that route will be a focus. When available, PK results with CBD administered by other routes will be summarized. In addition, the metabolism of CBD across species appears to be different in carnivorous species compared with omnivorous/herbivorous species (including humans) based on current information, and the preliminary information related to this will be explained with the therapeutic implication being addressed in Currents in One Health by Ukai et al, JAVMA, May 2023.

Olaparib in an ovarian cancer patient with end-stage renal disease and hemodialysis

PurposeFor patients with severe renal impairment (CrCl ≤ 30 ml/min) or end-stage renal disease (ESRD), olaparib intake is not recommended as the pharmacokinetics and safety of olaparib have not been evaluated in this patient group. Therefore, this valuable patient group is generally excluded from poly(ADP-ribose) polymerase inhibitor (PARPi) therapy. Here we report the pharmacokinetics (PK), efficacy, safety and tolerability of olaparib capsules 200 mg BID in a patient with recurrent epithelial ovarian cancer (EOC) and ESRD requiring hemodialysis.MethodsBlood and dialysate samples of the patient were collected on a dialysis and non-dialysis day. Olaparib total plasma concentrations were determined through high-performance liquid chromatography with tandem mass spectrometric detection. Actual scheduled sample times were used in the PK analysis to determine multiple dose PK parameters at steady state.ResultsMaximum concentration was achieved 1.5 h after drug administration on non- dialysis and after 1 h on dialysis day. The steady-state trough concentration and the maximal plasma concentration were similar on dialysis and non- dialysis day. On non-dialysis day, the AUCss was 30% higher (24.0 µg.h/mL vs. 16.9 µg.h/ml) than on dialysis day. The plasma clearance CLss/F was lower on non-dialysis day. Olaparib was not detectable in the dialysate samples.ConclusionA total dose of olaparib 200 mg BID capsule formulation was well tolerated by our patient with ESRD and hemodialysis. Moreover, this maintenance therapy led to 16 months of progression free survival. Further trials on PARPi therapy in patients with hemodialysis are warranted.

Single- and Multiple-dose Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP1128, a Novel Peroxisome Proliferator-activated Receptor δ Modulator, in Healthy Participants.

Peroxisome proliferator-activated receptor δ (PPARδ) plays a central role in modulating mitochondrial function in ischemia-reperfusion injury. ASP1128, a potent and selective modulator of PPARδ, is currently under investigation for treating acute kidney injury. This randomized, first-in-human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ASP1128 administered intravenously in healthy participants. Forty-nine participants received a single dose of ASP1128 0.3-10mg (n=37) or placebo (n=12) and 53 received daily (7days) doses of ASP1128 3-100mg (n=39) or placebo (n=14), including a cohort aged ≥65years (ASP1128 100mg, n=3; placebo, n=2). Treatment-emergent adverse events occurred in 37.8%, 59.0%, and 33.3%-35.7% of participants in the single ASP1128, multiple ASP1128, and placebo groups, respectively. All were mild in severity, and the frequency of adverse events did not appear to be dose-related. One participant (multiple ASP1128 3mg group) withdrew with an infusion site erythema, possibly related to study drug. Exposure was roughly dose-proportional, and elimination was generally consistent across doses (mean t½ 14.6-17.4hours in the 10, 30, and 100mg groups on day 7). There was little accumulation in plasma following multiple dosing; steady state was reached after ∼4days. ASP1128 treatment led to rapid and dose-related upregulation of six fatty acid oxidation-related PPARδ target genes at ≥10mg, which lasted >24hours postdose. In conclusion, single and multiple intravenous doses of ASP1128 were generally well tolerated, with dose-dependent pharmacokinetics and target gene engagement in healthy participants.

A multi-center, open-label, randomized dose expansion study of PF-06821497, a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), in patients with metastatic castration-resistant prostate cancer (mCRPC).

TPS282 Background: Enhancer of zeste homolog 2 (EZH2) encodes the histone methyltransferase component of the polycomb repressive complex-2, inducing transcriptional silencing of target genes, and is altered in cancers such as follicular lymphoma (FL), small cell lung cancer (SCLC), and metastatic castration-resistant prostate cancer (mCRPC). We evaluated the pharmacokinetics (PK), safety, and antitumor activity of PF-06821497, a potent and selective inhibitor of EZH2, in an ongoing phase I trial (NCT03460977 ) in patients (pts) with SCLC, CRPC, and FL as monotherapy and in combination with standard of care therapies. For pts with CRPC, the PF-06821497 recommended dose for expansion (RDE) is 1250 mg BID, in combination with enzalutamide plus androgen deprivation therapy (E). Part 2B of this trial further explores outcomes for pts dosed with PF-06821497 and E compared with E monotherapy. Methods: Part 2B compares the safety and efficacy of twice-daily PF-06821497 in combination with E (160 mg daily) (treatment arm) versus E monotherapy (control arm) administered continuously in patients with mCRPC previously treated with abiraterone. At trial entry, all pts will have evidence of prostate cancer progression per the modified Prostate Cancer Working Group 3 Criteria. Prior treatment with E is not allowed. Approximately 80 participants will be randomized in a 1:1 fashion into two arms, in US, Spain, and other countries. Approximately 40 participants are required in each arm to have 80% power in the study in order to detect a hazard ratio of 0.5 (E plus PF-06821497: E alone). Patients randomized to E alone have the option to add PF-06821497 to their regimen upon confirmed radiographic disease progression. The primary objectives are to confirm the safety and tolerability of PF-06821497 in combination with E in pts with mCRPC, and to assess the effect of PF-06821497 in combination with E versus E monotherapy on radiographic progression free survival. Secondary objectives include further evaluation of anti-tumor activity of PF-06821497, and assessment of single and multiple dose PK when given in combination with E. The impact of PF-06821497 in combination with E and of E alone in men with mCRPC on patient reported outcomes will also be assessed. Clinical trial information: NCT03460977 .

Safety, Tolerability and Pharmacokinetics of Single and Multiple Doses of Mirogabalin in Healthy Chinese Participants: A Randomized, Double-Blind, Placebo-Controlled Study.

Mirogabalin is a treatment option for patients with neuropathic pain; however, safety, tolerability, and pharmacokinetics (PK) data specifically for Chinese individuals are limited to a single-dose study. We aimed to assess these for both single- and multiple-dose mirogabalin in healthy Chinese participants. In this randomized, double-blind, placebo-controlled, phase I study, 54 healthy Chinese men and women aged 18-45years were randomly allocated to receive single- (5, 10, or 15mg, daily) or multiple-dose (5mg titrated to 15mg, twice-daily, over 22days) oral mirogabalin or placebo. In each of three single-dose groups, 10 participants received mirogabalin and 2 received placebo; in the multiple-dose group, 14 participants received mirogabalin and 4 received placebo. The primary endpoints were PK, safety, and tolerability variables, including treatment-emergent adverse events (TEAEs), laboratory tests, and vital signs. PK data were collected for both single- and multiple-dose cohorts and evaluated by non-compartmental analysis. Single- and multiple-dose mirogabalin was generally well tolerated with no deaths, serious TEAEs, or TEAEs leading to treatment discontinuation. Frequently reported TEAEs included dizziness, nystagmus, increased blood triglycerides, headache, and increased blood uric acid and creatine phosphokinase. Single-dose mirogabalin was rapidly absorbed (median time to maximum plasma concentration, 1.00h) and eliminated (mean terminal elimination half-life, 2.57-3.08h). The exposure was approximately dose-proportional. In the multiple-dose cohort, the trough plasma concentration increased dose-proportionally, and exposure and clearance were comparable to that following a single 15-mg dose. The mean cumulative amount excreted into urine up to 48h post-dose increased in a dose-proportional manner, the mean cumulative percentage excreted into urine was 61.9%-74.3%, and renal clearance remained relatively constant. Consistent with previous phase I studies in other populations, mirogabalin was safe and well tolerated in healthy Chinese participants at single and multiple doses of up to 15mg twice-daily.

A Single- and Multiple-Dose Pharmacokinetic Study of Oral Perampanel in Healthy Chinese Subjects.

Perampanel is a once-daily oral anti-seizure medication indicated for focal-onset seizures and generalized tonic-clonic seizures. This study investigated the single- and multiple-dose pharmacokinetics of perampanel in healthy Chinese adults. Study 052 (NCT03424564) was a phase I, single-center, open-label, parallel-group study. In the single-dose part of the study, subjects received a single oral dose of perampanel 2, 4, or 8 mg. In the multiple-dose part, subjects received once-daily oral perampanel 2 mg on Days 1-7 and 4 mg on Days 8-21. Pharmacokinetic parameters were determined from perampanel plasma concentrations using non-compartmental analysis. Dose proportionality after single doses of perampanel was assessed. Safety and tolerability were evaluated. In the single-dose part (N=30), median time to reach maximum concentration (tmax) was 0.75-1.0h, mean terminal elimination phase half-life (t½) was 85.6-122h, mean maximum observed concentration (Cmax) was 77.9-276 ng/mL, and mean area under the concentration-time curve from time zero to time of the last quantifiable concentration (AUC(0-t)) was 4070-15100 ng·h/mL. Single-dose pharmacokinetics were linear for perampanel 2-8 mg. In the multiple-dose part (N=12), Day 21 steady-state (4 mg/day) parameters were median time at which the highest drug concentration occurs at steady state (tss,max), 1.25h; mean t½, 109h; mean maximum observed concentration at steady state (Css,max), 453ng/mL; and mean area under the concentration-time curve over the dosing interval on multiple dosing (AUC(0- τ)), 7540 ng·h/mL. For single- and multiple-dose perampanel, the most common treatment-emergent adverse events were dizziness and somnolence. Single- and multiple-dose pharmacokinetics of perampanel in healthy Chinese adults revealed rapid perampanel absorption, slow elimination, and a linear relationship with single perampanel doses of 2-8 mg. Findings were consistent with previous studies of perampanel pharmacokinetics in other ethnic/racial populations of healthy subjects. Single and multiple doses of perampanel were generally safe and well tolerated. NCT03424564; registered February 2018.

216. A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of the Beta-lactamase inhibitor Xeruborbactam Alone and in Combination Meropenem in Healthy Adult Subjects

Abstract Background Xeruborbactam (XERU) is a member of a new class of cyclic boronic acid β-lactamase inhibitors with inhibitory activity against major members of Class A, B, C, and D beta-lactamases. This report describes the safety and pharmacokinetics of XERU following multiple doses alone and in combination with meropenem. Methods Twenty-four healthy subjects were enrolled into one of 3 cohorts with XERU alone. XERU was administered as a 500 mg loading dose followed by 250 mg q8h or 1000 mg loading dose followed by 500 mg q8h. 15 healthy subjects were enrolled in a single cohort of meropenem alone administered as a 4000 mg loading dose followed by 2000 mg q8h or meropenem in combination with XERU administered as a 500 mg loading dose followed by 250 mg q8h for 10 days. Intensive plasma sampling was obtained after dosing and assayed for drug content using validated LC-MS/MS methods. Results XERU and Meropenem Steady State pharmacokinetic parameters are shown in the table below. No subjects discontinued due to AEs and no SAEs were observed. There was no evidence of increasing numbers or severity of AEs with increasing dose. All AEs were mild or moderate in severity. Conclusion XERU was safe and well-tolerated when administered alone and in combination with meropenem. XERU has unique PK properties that includes a long elimination half-life that provides sustained plasma concentrations. The loading dose of XERU allows for rapid achievement of steady state plasma levels of XERU within the first day of treatment. XERU plasma PK properties, along with a broad spectrum of inhibitory activity, facilitates its use with multiple beta-lactam antibiotics including meropenem. Disclosures David Griffith, n/a, Qpex Biopharma: Employee Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Elizabeth Morgan, n/a, Qpex Biopharma: Employee Shawnee Gehrke, n/a, Qpex Biopharma: Employee Michael Dudley, n/a, ArrePath: Board Member|Qpex Biopharma: Board Member|Qpex Biopharma: Employee Jeff Loutit, MBChB, Qpex Biopharma: Employee.

217. A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of the Lipopeptide QPX9003 in Healthy Adult Subjects

Abstract Background QPX9003 is a fully synthetic lipopeptide with potent activity against MDR Pseudomonas and Acinetobacter spp. This report describes the safety and pharmacokinetics of QPX9003 following single and multiple doses. Methods Twelve healthy subjects were enrolled in 2 cohorts of up to 8 subjects (each cohort randomized to have up to 6 active and 2 placebo) each in the multiple ascending dose phase (100 or 200 mg every 6 hrs). Subjects received a single dose of QPX9003 followed by 48 hours of washout, then were administered QPX9003 q6h for 7 days. All infusions were administered over 1 hour. Intensive plasma sampling was obtained after dosing and assayed for QPX9003 content using validated HPLC/MS methods. Results Single and multiple dose QPX9003 pharmacokinetic parameters (mean +/- SD) are shown below: No subjects discontinued due to AEs and no SAEs were observed. There was no evidence of increasing numbers or severity of AEs with increasing dose, and all AEs were mild or moderate in severity. Conclusion QPX9003 was safe and well tolerated at all doses tested. QPX9003 plasma AUC and Cmax increased with increasing dose. QPX9003 plasma exposure accumulated ∼ 1.5 fold over 7 days of q6h dosing consistent with its plasma half-life. Based on the PK and safety profile, QPX9003 produces plasma exposures that exceed the PK-PD target safely and warrants further clinical development. Disclosures David Griffith, n/a, Qpex Biopharma: Employee Yehuda Carmeli, MD, Allecra Therapeutics: Advisor/Consultant|MSD: Advisor/Consultant|Nabriva: Advisor/Consultant|Pfizer: Advisor/Consultant|Qpex Pharmaceuticals: Advisor/Consultant|Roche: Advisor/Consultant|Shinogi: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant Shawnee Gehrke, n/a, Qpex Biopharma: Employee Elizabeth Morgan, n/a, Qpex Biopharma: Employee Michael Dudley, n/a, ArrePath: Board Member|Qpex Biopharma: Board Member|Qpex Biopharma: Employee Jeff Loutit, MBChB, Qpex Biopharma: Employee.