Mean AUCinf Research Articles

Characterization of rimegepant drug-drug interactions using the cytochrome P450 probe drugs, itraconazole, rifampin, fluconazole, and midazolam.

Reported here are the results of four rimegepant phase I studies, in healthy participants, aimed at determining the invivo potential of rimegepant (75 mg) for cytochrome P450 (CYP) 3A4-related drug-drug interactions (DDIs). Rimegepant orally disintegrating tablet (Pfizer Inc., New York, NY, USA) is a calcitonin gene-related peptide receptor antagonist approved for acute treatment of migraine and preventive treatment of episodic migraine. People with migraine commonly use multiple drug treatments, with the potential for DDIs. Each study was an open-label, single-arm, single-sequence, crossover study. Rimegepant was tested as a victim drug by separate co-administration of itraconazole (a strong CYP3A4 inhibitor and P-glycoprotein inhibitor) in Study 1, rifampin (a strong CYP3A4 inducer and moderate CYP2C9 inducer) in Study 2, and fluconazole (a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor) in Study 3, and as a perpetrator drug by co-administration with midazolam (a CYP3A4 substrate) in Study 4. Mean values of single-dose rimegepant maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC0-inf) increased with itraconazole co-administration (n = 22) by 1.42-fold (90% confidence interval [CI] 1.25-1.61) and by 4.14-fold (90% CI 3.87-4.44), respectively, and decreased with rifampin co-administration (n = 21) to 36% (90% CI 31.2-41.4%) and to 19% (90% CI 16.3-21.4%), respectively. Co-administration with fluconazole (n = 23) increased rimegepant mean AUC0-inf by 1.80-fold (90% CI 1.68-1.93), with no impact on Cmax (1.04-fold; 90% CI 0.94-1.15). Co-administration of rimegepant single dose (300 mg; n = 14) or multiple doses (150 mg/day; n = 14) increased the mean Cmax of midazolam by 1.38-fold (90% CI 1.13-1.67) and 1.53-fold (90% CI 1.32-1.78), respectively, and the AUC0-inf of midazolam by 1.86-fold (90% CI 1.58-2.19) and 1.91-fold (90% CI 1.63-2.25), respectively. Based on the magnitude of DDIs, these studies indicate the following: co-administration of rimegepant with a strong CYP3A4 inhibitor should be avoided; during co-administration with a moderate CYP3A4 inhibitor, another dose of rimegepant within 48 h should be avoided; co-administration of rimegepant with a strong or moderate CYP3A4 inducer should be avoided; CYP2C9 does not play a meaningful role in rimegepant metabolism; and there is no clinically meaningful CYP3A4 inhibition by rimegepant.

In Vitro/In Vivo Correlation of Two Extended-Release Cilostazol Formulations.

This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using the paddle and basket USP release apparatus. A single-dose, two-period crossover study design in beagle dogs was applied for the pharmacokinetic study. The fed and fast effects were considered for evaluation. Pseudo gastric release medium transfer setup study from pH 1.2 to pH 6.8 (+0.5% SLS) and pH 1.2 to pH 6.8 (+1.0% SLS) demonstrated that Pletaal® SR 200 mg capsules have higher drug release rates than Cilostan® CR 200 mg tablets. Similarly, in vivo study showed Cilostazol concentration in plasma and AUC was lower under the fast state than the fed state. The ratio of least squared geometric mean values, Cmax, AUC0-t, and AUC0-inf of Cilostazol were 2.53-fold, 2.89-fold, and 2.87-fold higher for Pletaal® SR 200 mg capsules compared with Cilostan® CR 200 mg tablets, respectively. Correlation of in vitro/in vivo data indicated that Pletal® SR 200 mg capsules have better release and pharmacodynamic effect than Cilostan® CR 200 mg tablets.

Pharmacokinetics and Safety of Intramuscular Injectable Benzathine Penicillin G in Japanese Healthy Participants.

An intramuscular (IM) suspension of benzathine penicillin G (BPG) has been used as first-line therapy for the treatment of syphilis worldwide since its approval in the 1950s. However, there are limited reports about the pharmacokinetics of BPG. A Phase 1 study was conducted on eight Japanese healthy participants to investigate the pharmacokinetics (samples collected predose to 648 h post-dose) and safety of 2.4 million units of BPG after a single IM injection. Following administration, penicillin G, the active moiety of BPG, was absorbed slowly from the injection site with a median time to Cmax (tmax) of 48 h post-dose. After the achievement of Cmax, concentrations of penicillin G declined slowly in a monophasic fashion with a mean apparent terminal half-life of 189 h. Geometric mean AUCinf and Cmax were 50770 ng•h/mL and 259 ng/mL, respectively. Median time (range) above the well-accepted therapeutic concentration (18 ng/mL) for syphilis treatment was 561 h (439-608 h [18-25 days]), which reached and exceeded the necessary duration of 7-10 days for syphilis treatment. Two participants were underdosed with residual drug left in the syringe due to the high viscosity of the drug product. Only one (12.5%) participant reported a mild adverse event of nasopharyngitis, which was considered not related to the study treatment. The study results supported BPG approval in Japan as an option for syphilis treatment.

Dasatinib anhydrate containing oral formulation improves variability and bioavailability in humans

Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both Cmax and AUC of dasatinib were within standard 80.00–125.00% range, while the intra- and inter-subject variability for AUC0-inf after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug–drug interaction study, omeprazole 40 mg reduced the mean AUC0-inf of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.

Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants.

To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and dabigatran (a P-glycoprotein substrate). PK was studied in 2 phase 1, open-label, fixed-sequence studies in healthy adults. Single oral doses of midazolam 2 mg (n= 12) or dabigatran 75 mg (n= 24) were administered alone and after steady state (i.e. ≥2 days) of nirmatrelvir/ritonavir 300 mg/100 mg and ritonavir 100 mg. Midazolam and dabigatran plasma concentrations and adverse events were analysed for each treatment. After administration of midazolam with nirmatrelvir/ritonavir (test) or alone (reference), midazolam geometric mean area under the concentration-time curve extrapolated to infinity (AUCinf ) and maximum plasma concentration (Cmax ) increased 14.3-fold and 3.7-fold, respectively. Midazolam coadministered with ritonavir (test) or alone (reference) resulted in 16.5-fold and 3.9-fold increases in midazolam geometric mean AUCinf and Cmax , respectively. After administration of dabigatran with nirmatrelvir/ritonavir (test) or alone (reference), dabigatran geometric mean AUCinf and Cmax increased 1.9-fold and 2.3-fold, respectively. Dabigatran coadministered with ritonavir (test) or alone (reference) resulted in a 1.7-fold increase in dabigatran geometric mean AUCinf and Cmax . Midazolam or dabigatran exposures were generally comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, with a slightly higher dabigatran Cmax with nirmatrelvir/ritonavir vs. ritonavir alone. Nirmatrelvir/ritonavir was generally safe when administered with or without midazolam or dabigatran. No serious or severe adverse events were reported. Coadministration of midazolam or dabigatran with nirmatrelvir/ritonavir increased systemic exposure of midazolam or dabigatran. Midazolam exposures were comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, suggesting no incremental effect of nirmatrelvir. Dabigatran Cmax was slightly higher when coadministered with nirmatrelvir/ritonavir compared with of ritonavir alone, suggesting a minor incremental effect of nirmatrelvir.

Abstract CT194: ETCTN 10388: a first in human phase I trial of triapine and lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs)

Abstract Background: Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme in the synthesis and repair of DNA, making RNR-targeted therapy a rationale therapeutic strategy for radiosensitization. ETCTN 10388 (NCT04234568) evaluated safety and efficacy of the combination of lutetium 177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. Method: This study was a multicenter phase 1 dose escalation trial [using the Bayesian optimal interval design (BOIN)] of triapine in combination with fixed dose lutetium Lu 177 DOTATATE for well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumor (GEP-NETs) after the failure of at least one line of prior systemic cancer treatment with an expansion cohort at the recommended phase 2 dose (RP2D). Oral triapine (100mg, 150mg, 200mg) was administered once daily on days 1-14 and Lu-177 DOTATATE [200 mCi] intravenously on day 1 of every 56-day cycle. A total of 4 cycles were administered. Response and adverse effects were assessed per RECIST and CTCAE 5.0, respectively. Exploratory correlative studies included tumor somatic and germline mutation testing, RNA sequencing, pharmacokinetics, deoxynucleosides and circulating cell free DNA analysis. Primary endpoints were safety and RP2D. Results: Overall, 31 patients were enrolled between 6 sites, 15 in the dose escalation phase and 16 in the dose expansion phase. Adverse events (AE) were assessed in all 31 patients per CTCAE 5.0. One DLT in dose level 1, seven DLTs in dose level 2, and one grade 5 DLT in dose level 3 were observed. The RP2D of the combination is triapine 150 mg QD (dose level 2) on days 1-14 in combination with Lu-177 DOTATATE on day 1 of every 56-day cycle. Detailed safety and adverse event data will be presented at the meeting. There were 28 patients evaluable for efficacy, of which 6 (21%) achieved a partial response. At 12 months, 6 patients had progressed, while 22 (86%) remained progression free. Median PFS has not been reached. PK data were available for 12 patients enrolled in the dose escalation cohort. The geometric mean (SD) AUC0-inf was 1159 (1.22) µg/L•h for the 100mg dose level and 1862 (1.76) µg/L•h for the 150 mg dose level, suggesting that exposure increased with dose, and inter-patient variability was as expected for an oral agent. Conclusion: The combination of triapine and Lu-177 DOTATATE was safe with preliminary efficacy signals, which will be further evaluated in ETCTN 10558, a randomized phase 2 study that is comparing the effectiveness of triapine and Lu-177 DOTATATE to Lu-177 DOTATATE alone. Citation Format: Aman Chauhan, Susanne Arnold, Jill Kolesar, William Carson, Heidi Weiss, Rani Jayswal, Donglin Yan, Riham El Khouli, Aman Khurana, Jan Beumer, Heloisa Soares, Mary Mulcahy, Thorvardur Halfdanarson, Daneng Li, Heather Jacene, Percy Ivy, Elise Kohn, John Wright, Larry Rubinstein, Zeta Chow, Piotr Rychahou, Mark B. Evers, Charles Kunos, Lowell Anthony, Bhavana Konda. ETCTN 10388: a first in human phase I trial of triapine and lutetium Lu 177 DOTATATE in well-differentiated somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT194.

Pharmacokinetics and RP2D analysis from ETCTN 10388: A phase I trial of triapine and lutetium Lu-177 dotatate in well-differentiated somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

648 Background: Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate, and thus repair of DNA in this setting. ETCTN 10388 evaluated safety of combination Lu-177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. Methods: This investigator initiated, NCI sponsored, multicenter phase 1 trial, enrolled a total of 31 patients in the dose escalation [using the Bayesian optimal interval design (BOIN)] and dose expansion cohorts. Oral triapine was administered on days 1-14 and Lu-177 DOTATATE [200 mCi] intravenously on day 1 of every 56-day cycle. A total of 4 cycles were administered. All enrolled patients had blood samples collected for triapine pharmacokinetic (PK) analysis in EDTA tubes prior to and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h after oral administration during cycle 1. Results: Five patients were enrolled in triapine Dose Level 1 (100 mg/day), twenty-five to dose level two (150 mg/day), and one patient to dose level three (200 mg/day). PK data were available for 12 patients enrolled in the dose escalation cohort. The geometric mean (SD) AUC0-inf was 1159 (1.22) µg/L•h for the 100mg dose level and 1862 (1.76) µg/L•h for the 150 mg dose level, suggesting that exposure increased with dose, and inter-patient variability was as expected for an oral agent. Triapine PK parameter values observed in this trial, were comparable to previous reports that used a previous formulation [ 1 ]. While exposure was similar, variability appeared smaller with the current oral formulation. Adverse events (AE) were assessed in all 31 patients per CTCAE 5.0. A total of one DLT in dose level 1, seven DLTs (Transient cytopenia; primarily neutropenia and rarely thrombocytopenia) in dose level 2, and one grade 5 DLT (Death probably from progressive cancer and carcinoid heart disease but possibly from trial drugs) in dose level 3 were observed. Detailed AE profile will be presented at the meeting. Conclusions: The RP2D of triapine is 150 mg QD on days 1-14 in combination with Lu-177 DOTATATE on day 1 of every 56-day cycle. Clinical trial information: 04234568 .

XS004 Dasatinib (XS004) Improves Variability and Bioavailability in Humans Using Amorphous Solid Dispersion Formulation of Dasatinib with Potential Implications for Its Clinical Use

Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients with chronic myeloid leukemia (CML). Dasatinib, one of the most utilized TKIs, is formulated as a crystalline dasatinib monohydrate. This results in a low and pH-dependent solubility with highly variable intestinal absorption and plasma pharmacokinetics (PK). Poor dissolution of an anti-cancer drug is generally expected to result in low and highly variable bioavailability and plasma exposure, consequently jeopardizing an optimal and anticipated therapeutic response. Applying bioavailability enhancement techniques, such as amorphous solid dispersion (ASD) formulations, will reduce variability in plasma PK as solubility and intestinal absorption improves, and most importantly increase patient compliance, safety, and efficacy. XS004 dasatinib (XS004) (Xspray Pharma, Solna, Sweden) is a novel immediate release and ASD formulation of dasatinib produced with the HyNap™ technique. XS004 is designed to provide an increased solubility of dasatinib in acidic to neutral pH conditions, mitigating gastric pH dependency and leading to reduced variability and increased absorption and bioavailability of dasatinib. Here we report the results of a clinical study comparing the PK of XS004 and the original dasatinib product (reference) (Sprycel®, Bristol-Myers Squibb Company, NJ, USA), and results of a comparative in vitro solubility study. Plasma PK parameters were compared following single doses of XS004 (100 mg dasatinib ASD) and the reference product (140 mg dasatinib non-ASD) in 107 healthy volunteers at fasting conditions in a randomized, single dose, laboratory-blinded, 2 treatments, 4 period, 2 sequence, full replicate crossover, bioavailability study. In the in vitro study, dasatinib ASD and dasatinib monohydrate solubility was determined in the gastrointestinal (GI) relevance pH-interval of 1.2 to 8.0 at 37°C. The plasma exposure of XS004 (100 mg dasatinib ASD) was equivalent for all PK parameters with the reference product (140 mg dasatinib non-ASD) with least square geometric mean Cmax, AUC0-24h and AUC0-inf ratios of 100.8 (CI 90%, 90.8-112.0%), 94.2 (CI 90%, 87.5-101.4) and 92.2 (CI 90%, 86.2-98.6), respectively (Table 1). The intra-subject variability (coefficient of variation (CV%)) for AUC0-24 and AUC0-inf for the reference was approximately 3-fold and 2.5-fold higher than for XS004 (Table 2). For Cmax, the intra-subject variability was approximately 2-fold greater with the reference compared to XS004 (Table 2). The inter-individual variability was generally higher in all plasma PK parameters for the reference formulation (range: 38-128%) when compared to XS004 (range: 20-48%). There was considerably greater inter-subject variability (CV%) in Cmax, AUC0-24 and AUC0-inf after single dose administration of the reference product, when compared with XS004 (Table 2). The inter-individual variability was 4.5-fold, 4.3-fold and 4.8-fold greater for the reference product when compared to the test formulation for the three PK parameters. The in vitro solubility study provided higher apparent solubility of dasatinib ASD compared to the original crystalline dasatinib, explaining the improved in vivo GI absorption for the new preparation. Dasatinib ASD was unaffected and kept in solution over at least 2 hours in the pH range 1.2 to 5.0 and the solubility was at least 10-fold higher for dasatinib ASD compared to the dasatinib monohydrate at pH-values in the range 5.0 to 8.0. In conclusion, XS004 displayed a more robust and consistent GI-absorption and bioavailability, with significantly reduced intra- and inter-individual variability in plasma dasatinib concentrations, compared to the original non-ASD formulated dasatinib. The in vitro data showed that the solubility of dasatinib ASD was substantially less pH-dependent at GI-relevant pH values of 2.0 to 5.0. The results suggest that XS004, an ASD formulation of dasatinib, with improved biopharmaceutical features, reduces the risk of both low exposure and high exposure outliers, with lower risk of exposure outside the therapeutic window. This would likely diminish the risk of adverse events and optimize the therapeutic efficacy of dasatinib in patients with CML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pharmacokinetics, Pharmacodynamics, and Tolerability of Olpasiran in Healthy Japanese and Non-Japanese Participants: Results from a Phase I, Single-dose, Open-label Study

PurposeOlpasiran, an N-acetyl galactosamine–conjugated, hepatocyte-targeted, small interfering RNA, is being developed to reduce plasma lipoprotein (Lp)-(a) concentration by directly targeting the LPA gene. This study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of a single SC injection of olpasiran in healthy, Japanese and non-Japanese participants. MethodsIn this Phase I, open-label, parallel-design study, Japanese participants were randomized in a 1:1:1:1 ratio to receive a single 3, 9, 75, or 225 mg dose of olpasiran. Non-Japanese participants received a single 75 mg dose of olpasiran. The primary end points were pharmacokinetic parameters, including Cmax, AUCinf, tmax, and t1/2. Tolerability and change in Lp(a) concentration were also assessed. FindingsA total of 27 enrolled participants had a mean (SD) age of 48.0 (12.5) years. Olpasiran Cmax and AUCinf were increased in an approximately dose-proportional manner in the Japanese groups. Mean (SD) Cmax values were 242 (121.0) and 144 (71.3) ng/mL, and mean (SD) AUCinf values were 3550 (592.0) and 2620 (917.0) h·ng/mL, in the Japanese and non-Japanese groups, respectively, given 75 mg of olpasiran. Median tmax ranged from 3.0 to 9.0 hours and mean (SD) t1/2 ranged from 4.0 (0.3) to 6.9 (1.6) hours across all groups. The maximal Lp(a) reduction occurred at day 57, with mean (SD) Lp(a) percentage reductions from baseline ranging from 56.0% (21.0%) to 99.0% (0.2%). A reductions in Lp(a) was observed as early as day 4. All adverse events were mild in severity, with no serious or fatal adverse events. No clinically important changes in tolerability-related laboratory analytes or vital signs were observed. ImplicationsIn this population of healthy Japanese participants, dose-proportional increases in exposure and reduced Lp(a) in a dose-dependent manner were found with single 3, 9, 75, and 225 mg doses of olpasiran. The magnitude and durability of Lp(a) reductions were similar between the Japanese and non-Japanese groups. Olpasiran was well tolerated, with no clinically important adverse events or laboratory or vital sign abnormalities.

Phase 1 study to evaluate the effects of rifampin on pharmacokinetics of pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors

SummaryPevonedistat (TAK-924/MLN4924) is an investigational small molecule inhibitor of the NEDD8-activating enzyme that has demonstrated clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase 1 study evaluating the effect of rifampin, a strong CYP3A inducer, on the pharmacokinetics (PK) of pevonedistat in patients with advanced solid tumors (NCT03486314). Patients received a single 50 mg/m2 pevonedistat dose via a 1-h infusion on Days 1 (in the absence of rifampin) and 10 (in the presence of rifampin), and daily oral dosing of rifampin 600 mg on Days 3–11. Twenty patients were enrolled and were evaluable for PK and safety. Following a single dose of pevonedistat at 50 mg/m2, the mean terminal half-life of pevonedistat was 5.7 and 7.4 h in the presence and in the absence of rifampin, respectively. The geometric mean AUC0–inf of pevonedistat in the presence of rifampin was 79% of that without rifampin (90% CI: 69.2%–90.2%). The geometric mean Cmax of pevonedistat in the presence of rifampin was similar to that in the absence of rifampin (96.2%; 90% CI: 79.2%–117%). Coadministration of pevonedistat with rifampin, a strong metabolic enzyme inducer, did not result in clinically meaningful decreases in systemic exposures of pevonedistat. The study results support the recommendation that no pevonedistat dose adjustment is needed for patients receiving concomitant CYP3A inducers.ClinicalTrials.gov identifierNCT03486314.

Pharmacokinetics/pharmacodynamics by race: Analysis of a peginterferon β-1a phase 1 study

Black/African American participants are underrepresented in clinical trials for multiple sclerosis but can experience a greater burden of disease than other racial groups in the United States. A phase 1, open-label, crossover study that demonstrated bioequivalence of subcutaneous and intramuscular injection of peginterferon β-1a in healthy volunteers enrolled similar proportions of Black and White participants, enabling a post hoc subgroup analysis comparing these groups. Peginterferon β-1a (125μg) was administered by subcutaneous or intramuscular injection, followed by a washout period before a second injection using the alternative method. The primary pharmacokinetic and pharmacodynamic endpoints were maximum observed concentration (Cmax) and area under the concentration-time curve from hour 0 to infinity (AUCinf) of study drug and serum concentration of neop-terin, respectively. Safety and tolerability were included as secondary endpoints. This analysis included 70 (51.5%) Black and 59 (43.3%) White participants. Peginterferon β-1a Cmax was 29.8% higher in Black than in White participants following subcutaneous administration but was similar following intramuscular administration. Mean AUCinf was 31.0% and 11.8% greater in Black than in White participants with subcutaneous and intramuscular administration, respectively. Pharmacodynamics and safety signals were similar between groups, although Black participants reported numerically fewer adverse events. No clinically meaningful differences were identified between Black and White participants related to peginterferon β-1a administration, supporting the approved dose of 125μg/mL peginterferon β-1a. Future clinical studies should include sufficiently diverse populations to ensure accurate assessments of treatment response. Funding for medical writing support was provided by Biogen (Cambridge, MA, USA).

Safety and efficacy of YBL-006, an anti-PD-1 monoclonal antibody in advanced solid tumors: A phase I study.

e14557 Background: YBL-006 is a fully human anti-programmed death-1 (PD-1) antibody under evaluating its safety and efficacy in phase I clinical trial. We have reported interim analysis of dose escalation cohort which showed a tolerable safety profile. Here, we present the updated clinical activity of YBL-006 in dose escalation and expansion cohorts. Methods: Dose escalation (0.5, 2, 5, 10 mg/kg) and dose expansion (flat doses of 200 mg every 2 weeks [Q2W] and 300 mg every 3 weeks [Q3W]) cohorts explored the safety, pharmacokinetics (PK) and objective response rate (ORR) in the patients with advanced solid tumors who failed or were ineligible to the standard of care. Adverse events (AEs) were graded using the CTCAE v5. ORR was assessed using the RECIST (v1.1). Lunit SCOPE IO, an H&E analysis tool, was applied as an exploratory biomarker, and samples with “Immune inflamed phenotype” were defined as those with high intratumoral TIL density in ≥ 20% of the tumor microenvironment. The cut-off date for analysis was Jan 4th, 2022. Results: A total of 67 patients (safety set) with advanced solid tumors were enrolled in the study. Median follow-up duration of the safety set was 1.6 months (range 0.2-16.8). There was no dose-limiting toxicity during dose escalation phase. Most frequent AEs were grade 1 or 2; fatigue (19.4%), pruritus (10.4%), and fever (7.5%), and two hypothyroidism (3.0%), one pneumonitis (1.5%), and one cytokine-releasing syndrome (1.5%) were observed. One subject experienced grade 3 diarrhea in the safety set. PK study showed that half-life was 8.0 days, and mean Cmax and AUC0-inf were 4.15 x 104 ng/ml and 1.12 x 107 ng/ml*h for 200 mg dose, and 6.26 x 104 ng/ml and 1.53 x 107 ng/ml*h for 300 mg dose, respectively. A total of 52 patients were evaluable for efficacy. ORR was 15.4%, including 1 complete response (penile squamous cell carcinoma [SqCC]), and 7 partial responses (two gastric adenocarcinomas, anal SqCC, paranasal sinus SqCC, nasopharyngeal carcinoma, neuroendocrine carcinoma, and thyroid Hurthle cell carcinoma). Durable responses were seen in 2 patients for over 12 months. Median duration of response was 4.9 weeks (range 1-65). Among efficacy set, 32 samples were available for Lunit SCOPE IO. ORR was significantly higher in inflamed immune phenotype compared to non-inflamed samples (62.5% vs 8.3% p = 0.005). Conclusions: Interim analysis of phase I trial of YBL-006 shows a tolerable safety profile and clinical activity. Notable anti-tumor efficacy was observed in inflamed immune phenotype. Clinical trial information: NCT04450901.

Abstract LB114: Tumor uptake and predictable PK of ST101 - a peptide antagonist of C/EBPβ - in patients with advanced unresectable and metastatic solid tumors

Abstract Background: Increased activation of transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) promotes tumor survival and proliferation and inhibits differentiation. ST101 is a therapeutic peptide designed to antagonize C/EBPβ; it penetrates the blood-brain barrier and has anti-tumor activity in multiple human cancer cell lines and animal models. Methods: This was a first-in-human, open-label, phase 1-2 dose-finding study. The primary objective was to evaluate safety and tolerability in patients with cancer. Secondary and exploratory objectives included ST101 pharmacokinetics (PK) and pharmacodynamics (PD). Phase 1 enrolled patients with advanced/metastatic solid tumors refractory or intolerant to all therapeutic options. Patients received ST101 intravenously 0.5, 1, 2, 4, 8 mg/kg QW and 16 mg/kg Q2W in a standard 3+3 design. The recommended phase 2 dose will be further investigated in expansion cohorts of patients with breast cancer, melanoma, glioblastoma, and castration-resistant prostate cancer. Results: As of 01.05.21 9 patients have enrolled into phase 1. Patients received 1-5 prior lines of therapy and had an ECOG status of 0 or 1. PK was predictable and consistent with pre-clinical data. Mean Cmax and AUC(0-t) increased proportionally with increasing dose. Maximum concentrations were observed at the end of 90-minute infusion and mean T1/2 was calculated as 18h and 31h, respectively in Cohort 1 and Cohort 2. Concentrations of ST101 were similar on Days 8 and 15 when compared to Day 1 in each cycle. Immunohistochemistry of tumor samples taken shortly after the 4th infusion from 2/2 patients in Cohort 1 and 1/1 patient in cohort 2 stained positive for ST101. No ST101-related serious adverse events were observed. There were no dose limiting toxicities, dose modifications or withdrawals due to toxicity. Symptoms of infusion related reactions (max grade 2) were reported in five patients and were managed with antihistamine and/or anti-inflammatory prophylaxis and by decreasing the infusion rate. Five patients withdrew due to progression of their cancer. Conclusions: ST101 was safe and well tolerated at the doses and schedule tested, and PK appeared predictable. ST101 was designed to have a prolonged plasma T1/2 and these results confirm preclinical observations, demonstrating a longer than expected T1/2 for a drug of this class. Tumor uptake of ST101 was demonstrated at the lowest dose level. ST101 dose(mg/Kg)CyclenMean Cmax (ng/mL)Mean Tmax (h)Mean AUC(0-t)(h*ng/mL)Mean Tlast (h)Mean AUC(0-inf)(h*ng/mL)Mean T1/2(h)Mean extrapolation(%)0.51316001.59000271500018230.52214001.539006NDNDND0.53211339001.5390007245000311512148001.5180008NDNDND131 Citation Format: Gerald Falchook, Meredith McKean, Nehal Lakhani, Tobias Arkenau, Stefan Symeonides, Jeff Evans, Emerson Lim, Jim Rotolo, Rob Michel, Alice Bexon. Tumor uptake and predictable PK of ST101 - a peptide antagonist of C/EBPβ - in patients with advanced unresectable and metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB114.

Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Refractory Multiple Myeloma

Introduction - Elevated expression of XPO1 (Exportin 1) increases the nuclear export / inactivation of tumor suppressor proteins (e.g. p53, IkB, p21, FOXO) and promotes the export / translation of eIF4E-bound oncoprotein mRNAs (e.g. c-MYC, BCL-2, Cyclin D). Selinexor, the first oral Selective Inhibitor of Nuclear Export (SINE) compound, inhibits XPO1 and has shown promising anti-cancer activity across hematological and solid tumors in Phase 1 and 2 clinical trials, including in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Considering the breadth of knowledge on selinexor ± dexamethasone (dex) in RRMM, eltanexor (KPT-8602), a second-generation oral SINE compound, was evaluated for safety and tolerability in this pt population. The primary objectives were to determine the safety, preliminary anti-MM activity, and the recommended Phase 2 dose (RP2D) of eltanexor ± dex.Methods - In this Phase 1/2 study, using a 3+3 dose escalation design, eltanexor is dosed orally (QDx5 or QoDx3 weekly) for a 28-day cycle with a starting dose of 5 mg. Pts with less than a minor response (MR) after 1 cycle or partial response (PR) after 2 cycles were permitted to add low dose dex. In some pts, dex was added from day 1. The pharmacokinetic (PK) and pharmacodynamic (XPO1 mRNA) profiles of eltanexor were evaluated.Results - As of 31-July-2017, 36 pts (23 M/13 F; median prior therapies: 7; median age: 66) with RRMM were enrolled; most with quad- or penta-refractory MM. Median duration of treatment is 76 days (range: 10 - 441). Most common drug related adverse events (AEs; >30%, any grade) are thrombocytopenia, nausea, neutropenia, anemia, leukopenia, fatigue, diarrhea, and dysgeusia. Grade ≥3 related AEs include thrombocytopenia (43%), neutropenia (26%), leukopenia (14%), and anemia (11%). Although 2 dose limiting toxicities (DLTs; >4 missed doses and Grade 4 thrombocytopenia) were observed in different cohorts, the protocol-defined maximum tolerated dose (MTD) was not reached. Further evaluation of 20 or 30 mg eltanexor QDx5 + dex is ongoing in expansion cohorts. The preliminary efficacy of eltanexor (Table 1) shows that eltanexor ± dex can induce responses and disease stabilization. A dose proportional PK profile without accumulation has been observed. Mean Cmax and AUC0-inf values for eltanexor doses of 5 - 60 mg ranged from 36.6 - 284 ng/mL and 164 - 2,581 ng*h/mL, respectively. Tmax and t½ ranged from 0.5 - 8.0 h and 4.0 - 7.1 h, respectively. For all cohorts evaluated, the fold-change maximum (Fmax) of XPO1 mRNA expression was achieved 4 - 8 h post-dose (tmax). The Fmax for XPO1 mRNA was roughly dose proportional to the Cmax of eltanexor. As expected, based on observations with other SINE compounds, the plateau for Fmax of XPO1 mRNA in treated pts was ~6 - 10-fold change and was achievable at 40 - 60 mg of eltanexor.Conclusions - Based on preliminary data, eltanexor is well tolerated and demonstrates promising activity in this heavily pre-treated RRMM population. The gastrointestinal and constitutional toxicities observed with <40 mg eltanexor QDx5 are low grade, transient, and do not limit dosing. Thrombocytopenia (with minimal clinical impact) was the most common hematologic toxicity and was expected in this population. As with selinexor, addition of low-dose dex (20 mg) twice weekly (BIW) to the eltanexor treatment regimen appeared to improve efficacy while maintaining tolerability. Of the 31 evaluable pts, 25 received dex with their eltanexor regimen. Therefore, both 20 and 30 mg eltanexor QDx5 + 20 mg dex BIW are being evaluated to clearly define the RP2D. Based on these results and anti-tumor activity previously observed with selinexor, pts with advanced colorectal cancer, castration resistant prostate cancer, and myelodysplastic syndrome are being enrolled. [Display omitted] DisclosuresRossi:Thrassos: Consultancy; Celgene: Consultancy. Baz:Sanofi: Research Funding; BMS: Research Funding; merck: Research Funding; takeda: Research Funding; celgene: Honoraria, Research Funding; karyopharm: Research Funding. Hofmeister:Roche: Research Funding; Celgene: Research Funding; Karyopharm: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding. Shustik:Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Richter:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau. Chen:Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Vogl:Teva: Consultancy; Karyopharm: Consultancy; Constellation: Research Funding; GSK: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy; Amgen: Consultancy; Calithera: Research Funding. Baloglu:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

To establish bioequivalence of 50mg Metoprolol Succinate extended release tablets in normal, healthy, adult, human subject under fasting condition

Oral drug delivery is the most preferred route for the various drug molecules among all other routes of drug delivery, because ease of administration which lead to better patient compliance. So, oral extended release drug delivery system becomes a very promising approach for those drugs that are given orally but having the shorter half-life and high dosing frequency. Extended release Extended-release systems allow for the drug to be released over prolonged time periods. By extending the release profile of a drug, the frequency of dosing can be reduced. The study was an open label, balanced, randomized, three-treatment, three-period, three-sequence, single oral dose, crossover, bioequivalence study in normal healthy adult human subjects under fasting condition, with a screening period of 28 days prior to IMP administration in Period-I. In each study period, 27 blood samples, including one pre-dose blood sample, were collected from each subject except for the discontinued / withdrawn subjects to analyze the pharmacokinetic profile of the two test products (T1 and T2) as well as the reference product. The pharmacokinetic parameters were calculated from the plasma concentration vs. time profile by non-compartmental model using Phoenix® WinNonlin® Version 6.4 (Certara L.P.) for Metoprolol. Out of 18 subjects enrolled, data of 13 subjects were analyzed. Mean Cmax is 31.634 ± 22.6007 ng/mL, 31.241 ± 20.6090 ng/mL and 31.773 ± 23.1819 ng/mL, mean AUCo-t is722.992 ± 584.3793 ng hr/mL, 658.192 ± 492.3416 ng hr/mL and 706.219 ± 546.5064 ng hr/mL, mean AUC0-inf is 751.204 ± 631.9623 ng hr/mL, 676.939 ± 519.1306 ng hr/mL and729.505 ± 578.1691 ng hr/mL for test product (T1), test product (T2) and reference product (R).Test Products (T1 and T2) when compared with the Reference Product-R meets the bioequivalence criteria with respect to Cmax, AUC0-t and AUC0-∞ for Metoprolol under fasting condition as per criteria set in the protocol.

Pharmacokinetics of Voxelotor in Patients With Renal and Hepatic Impairment

Two open‐label studies assessed the safety, tolerability, and pharmacokinetics of Oxbryta (voxelotor) in subjects with hepatic or renal impairment. Eight subjects with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) and 8 healthy age‐, sex‐, and body mass index–matched controls were administered a single oral dose of voxelotor 900 mg. Seven patients with mild (Child‐Pugh A), moderate (Child‐Pugh B), and severe (Child‐Pugh C) hepatic impairment and healthy age‐, sex‐, and body mass index–matched controls (7:7:7:7) were administered a single oral dose of voxelotor 1500 mg, except those with severe hepatic impairment (600 mg). There was no apparent effect of renal function on the excretion of voxelotor based on comparable half‐life values between subjects with severe renal impairment and healthy matched controls. Mean area under the concentration‐time curve from time 0 to infinity (AUC0‐inf) values were lower by approximately 50% (plasma) and 25% (whole blood) in subjects with severe renal impairment compared with controls. Accordingly, dose adjustment is not required in patients with severe renal impairment. Voxelotor plasma and whole‐blood exposures were slightly increased in subjects with mild and moderate hepatic impairment. Mean AUC0‐inf values were approximately 9% to 18% higher compared with those of healthy matched controls. Dose adjustment is therefore not required in patients with mild or moderate hepatic impairment. Voxelotor mean AUC0‐inf values were approximately 90% higher in subjects with severe hepatic impairment. A lower voxelotor dose (1000 mg) is recommended for patients with severe hepatic impairment. Voxelotor was well tolerated in all treatment groups.

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.

0743 The Pharmacokinetic Adverse Event Relationship for FT218, a Once-Nightly Sodium Oxybate Formulation

Abstract Introduction Sodium oxybate is an effective treatment for excessive daytime sleepiness and cataplexy in patients with narcolepsy. The approved formulation requires twice-nightly dosing: at bedtime and 2.5 - 4 hours later, which results in two distinct Cmax’s. FT218 is a controlled-release formulation of sodium oxybate intended for once-nightly dosing, using Avadel’s proprietary Micropump™ technology. The objective of this study was to evaluate the pharmacokinetic-adverse event (AE) relationship for FT218, an investigational once-nightly sodium oxybate formulation. Methods Six single-dose, randomized, crossover studies that assessed the pharmacokinetics of FT218 at 4.5, 6, 7.5 and 9 g in healthy voluntters were used in this analysis. Lattice plots, “spaghetti” plots, and scatter plots of individual gamma hydroxybutyrate concentrations and indicators when AEs by system, organ, or class (SOC) were created to determine any PK-AE relationship. Results A total of 129 healthy volunteers received single doses of FT218 between 4.5 - 9 g. Most AEs, specifically for the neurological and gastrointestinal SOC, occurred close to Tmax, during the Cmax period, which for FT218 was around 1.5-2 hours after dosing. These AEs were known AEs associated with sodium oxbyate. There appeared to be no clear correlation between individual plasma GHB concentrations levels and AEs between subjects. Individual AEs were equally distributed above and below the mean population Cmax and AUCinf for the dataset. Conclusion In general, adverse events for FT218 occurred around Tmax. There was no clear population toxicokinetic range for when AEs occur with FT218, but mostly individual thresholds. Since it appears AEs are related to Cmax, and FT218 only has one Cmax compared to two with the currently available product, it is hypothesized that FT218 will have a favorable safety profile compared to twice-nightly dosing. Support This work was supported by Avadel Pharmaceuticals

465 A Pharmacokinetic Bridging Study to Compare the Bioavailability of Budesonide Between Budesonide Oral Suspension and ENTOCORT EC in Healthy Subjects

INTRODUCTION: Budesonide oral suspension (BOS; TAK-721) is a viscous formulation of budesonide that is in development for the treatment of eosinophilic esophagitis in adults and adolescents. BOS was granted Breakthrough Designation by the FDA and is currently being evaluated in phase 3 trials. Several budesonide products are approved in the US for other indications, including ENTOCORT EC for mild to moderate active Crohn's disease; thus, the safety of budesonide has been evaluated extensively. The present study compared the bioavailability of BOS with ENTOCORT EC, aiming to provide the pharmacokinetic (PK) bridge to the safety data of ENTOCORT EC. METHODS: Healthy adults (n=22) were enrolled in an open-label, single-center, crossover study. Subjects received two treatments in a randomized sequence with a 48 h washout period between treatments: a single oral dose of BOS 2 mg and a single oral dose of ENTOCORT EC 9 mg. Serial blood samples were collected in each treatment period to determine plasma budesonide concentrations. PK parameters were calculated by non-compartmental analysis and compared between treatments using a mixed effects model with sequence and treatment as fixed effects and subject within sequence as a random effect. RESULTS: Plasma budesonide concentrations showed a faster absorption from BOS compared with ENTOCORT EC. Peak plasma concentrations were achieved ∼1.5 h post-dose for BOS and ∼4 h post-dose for ENTOCORT EC. Systemic exposure to budesonide after a single dose of BOS 2 mg was lower than that observed after a single dose of ENTOCORT EC 9 mg: the geometric mean AUC0-t, AUC0-inf and Cmax of budesonide after BOS 2 mg were 33.6%, 32.9% and 71.1% of those after ENTOCORT EC 9 mg, respectively. CONCLUSION: ENTOCORT EC 9 mg once daily (qd) is approved for induction treatment of Crohn's disease. The proposed clinical dosing regimen for BOS for induction treatment of eosinophilic esophagitis is 2 mg twice daily (bid). When taking into account the different dosing frequencies, the daily AUC and the Cmax of budesonide from BOS 2 mg bid at steady state are estimated to be 67% and 71% of those from ENTOCORT EC 9 mg qd, respectively. These results provide PK bridging data to compare BOS 2 mg bid to ENTOCORT EC with respect to safety information.

1719. Pharmacokinetics (PK) of Oritavancin in Children: The ORKIDS Trial

BackgroundOritavancin (ORI) is a lipoglycopeptide antibiotic approved in adults as a single 1,200 mg intravenous (IV) dose for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by Gram-positive organisms, including methicillin-resistant Staphylococcus aureus. The objective in children is to achieve a PK profile that is similar to that attained in adults. PK and safety data from the first 3 age-specified cohorts are presented.MethodsThe ORKIDS trial is a Phase 1 open-label, sequential, dose-finding study evaluating the PK, safety and tolerability of a single-dose 15 mg/kg (max 1,200 mg) IV infusion of oritavancin in children under 18 years. The first 3 age cohorts (12 to <18 years, 6 to <12 years, 2 to < 6 years) with 8 subjects in each cohort have completed the study. Subjects were required to have a suspected or confirmed Gram-positive bacterial infection for which they received standard-of-care antibiotic therapy. Following a single dose of ORI, PK samples were obtained at 3, 4, 9, 24, 48, 72, and 336 hours after the start of the 3-hour infusion. Plasma concentrations were analyzed by noncompartmental Methods. Subjects were evaluated for safety through Day 60. An independent data safety monitoring board evaluated the safety and PK data of each cohort prior to dosing the subsequent cohort.ResultsPK in children compared with adult data from the SOLO Phase 3 ABSSSI studies (Table 1).Table 1:Mean PK Parameters from Cohorts 1–3 and AdultsCohort 1, 12 to <18 years (n = 8)Cohort 2, 6 to <12 years (n = 8)Cohort 3, 2 to <6 years (n = 8)Range from Pooled Adult SOLO TrialsCmax (μg/mL)12713684106–170AUC0-inf (h μg/mL)4,0143,7091,9631,999–3,600ConclusionIn subjects 6 to <18 years, a single 15 mg/kg dose of ORI appears to be well tolerated and provides a PK profile similar to a single 1,200 mg dose in adults. Mean AUC0-inf of 1,963 h μg/mL in subjects 2 to <6 years is lower than the targeted exposure range in adults. A higher dose of ORI is currently being studied in this cohort.Disclosures J. Bradley, Melinta Therapeutics: Investigator, Research support. A. Arrieta, Melinta Therapeutics: Investigator, Research support. P. Bokesch, Melinta Therapeutics: Consultant, Consulting fee. K. Fusaro, Melinta Therapeutics: Employee, Salary. D. C. Griffith, Melinta Therapeutics: Consultant, Consulting fee. J. S. Loutit, Melinta Therapeutics: Consultant, Consulting fee.