Average Plasma Concentration Research Articles

Determination of pharmacokinetic-pharmacodynamic cutoff values of oxytetracycline in calves and adult cattle using population pharmacokinetic modeling.

A harmonized clinical breakpoint for interpreting antimicrobial susceptibility testing of oxytetracycline in cattle is currently lacking in Europe. This study aimed to establish a pharmacokinetic/pharmacodynamic (PK/PD) cutoff to propose clinical breakpoints, facilitating reliable interpretation of antimicrobial susceptibility results in cattle. A meta-analysis of oxytetracycline pharmacokinetic data from 69 cattle was conducted, including 1,730 plasma concentration samples from animals administered 20 mg/kg intramuscularly and/or 20 or 40 mg/kg intravenously. A three-compartment model with two absorption phases was selected, incorporating age as a covariate for clearances and distribution volumes. The PK/PD cutoff was defined as the maximum MIC for which the fAUC/MIC index achieves the pharmacodynamic target in 90% of cattle given the standard dosing regimen. The pharmacodynamic index (PDI) target selected was established to 24 h, i.e., the average free plasma concentration of oxytetracycline over the 24-h dosing interval, under steady-state conditions, is equal to the selected MIC. Simulations indicated a PK/PD cutoff of 2 mg/L in adult cattle and 1 mg/L in calves for intramuscularly administered long-acting products at 20 mg/kg with a 48-hour efficacy duration. The difference is attributed to higher clearance rates in calves. The established PK/PD cutoffs, when used alongside the wild-type bacterial epidemiological cutoff, can aid in setting clinical breakpoints for oxytetracycline, supporting effective antimicrobial therapy in cattle and accounting for age-related pharmacokinetic differences.

Dosing of Venetoclax in Pediatric Patients with Relapsed Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships

This work aimed to characterize the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) to identify venetoclax doses to be administered to pediatric patients in the phase 3 study. Data from 121 patients across three phase 1 studies enrolling pediatric patients with R/R malignancies were utilized to develop a population pharmacokinetic model to describe venetoclax pharmacokinetics in pediatric patients. Individual patient average venetoclax plasma concentration up to the event of interest, derived based on the population pharmacokinetics analysis, was used to evaluate the exposure-response relationships to efficacy (complete response) and safety (neutropenia and thrombocytopenia) endpoints for patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine (n = 36). The population pharmacokinetic model was then used to simulate exposures in pediatric age- and weight-based subgroups to identify the venetoclax doses for pediatric patients. The pharmacokinetic data were adequately described by the two-compartment population pharmacokinetic model with first-order absorption and elimination. The model accounted for cytochrome P450 3A developmental changes using a maturation function and incorporated allometric scaling to account for growth and body size effect. Weight was identified as a statistically significant covariate on clearance and volume of distribution and retained in the final model. Population pharmacokinetic estimates were comparable to previously reported estimates in adults. Exposure-response analyses suggested that the clinical efficacy of venetoclax in combination with high-dose cytarabine (HDAC) is maximized at 600 mg adult-equivalent, and higher doses are unlikely to enhance clinical efficacy. Venetoclax 600 mg adult-equivalent was selected for further development in combination with HDAC. Additionally, venetoclax 400 mg adult-equivalent was selected for bridging/maintenance therapy in combination with azacitidine. Flat exposure-response relationships were observed with Grade ≥3 neutropenia and thrombocytopenia. Doses were selected based on weight (allometric scaling) for children aged ≥2 years old and based on weight and CYP3A ontogeny for children aged <2 years. The selected age- and weight-based dosing scheme of venetoclax is projected to achieve venetoclax exposures in pediatric subgroups comparable to those observed in adults receiving venetoclax 400 mg or 600 mg. This work characterized the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients and guided the selection of pediatric dosing regimens in support of the venetoclax phase 3 trial in pediatric AML (NCT05183035). NCT03236857, NCT03181126, and NCT03194932.

A Pharmacologic Evaluation of Buprenorphine in Pregnancy and the Postpartum Period.

The dosing regimen in the package insert for sublingual buprenorphine is similar for pregnant and nonpregnant people despite the physiologic changes seen during pregnancy. To compare plasma buprenorphine pharmacokinetics during and after pregnancy and relate buprenorphine concentration to the pharmacodynamic endpoints of pupil diameter, Clinical Opioid Withdrawal Scale (COWS), and craving scores. Prospective cohort of 22 pregnant people undergoing 33 pharmacologic studies (6-8 hours each) during pregnancy or postpartum. Participants were on a stable daily dose of 2-8 mg sublingual buprenorphine every 6 or 8 hours. The dosing frequency was selected by the participant. On study day, baseline measurements of plasma buprenorphine, pupil diameter, COWS, and craving scores were obtained, then the usual morning dose was taken, and measurements were repeated several times over 1 dosing interval. The dose-normalized area under the plasma buprenorphine concentration time curve was significantly (P = 0.036) lower during pregnancy (155 ± 52 ng × min/mL) than postpartum (218 ± 113 ng × min/mL). Buprenorphine trough concentrations were similar at the start (1.1 ± 0.7 ng/mL) and end of a dosing cycle (1.2 ± 0.8 ng/mL) regardless of dosing frequency. Pupillary diameter, COWS, and craving scores returned to baseline as buprenorphine concentrations approached ~1 ng/mL. Pregnant people require a higher dose of buprenorphine to achieve concentrations comparable to nonpregnant people. There is a temporal relationship between the plasma buprenorphine concentration and the pharmacodynamic markers of pupillary diameter, COWS, and craving scores. An average plasma concentration of ~1 ng/mL was associated with the lowest level of COWS and craving scores.

Effects of CYP3A4 genetic polymorphisms on the pharmacokinetics and efficacy of perampanel in Chinese pediatric patients with epilepsy

ObjectiveThis study was the first to evaluate the effect of CYP3A4 gene polymorphisms on the plasma concentration and effectiveness of perampanel (PER) in Chinese pediatric patients with epilepsy. MethodsWe enrolled 102 patients for this investigation. The steady-state concentration was determined after patients maintained a consistent PER dosing regimen for at least 21 days. Plasma PER concentrations were measured using liquid chromatography–tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final check-up. ResultsThe CYP3A4×10 GC phenotype exhibited the highest average plasma concentration of PER at 491.1 ± 328.1 ng/mL, in contrast to the CC phenotype at 334.0 ± 161.1 ng/mL. The incidence of adverse events was most prominent in the CYP3A4×1 G TT and CYP3A4×10 GC groups, with rates of 77.8 % (7 of 9 patients) and 50.0 % (46 of 92 patients), respectively. Moreover, the percentage of patients for whom PER was deemed ineffective was least in the CYP3A4×1 G TT and CYP3A4×10 CC groups, recorded at 11.1 % (1 of 9 patients) and 10.0 % (1 of 10 patients), respectively. There was a significant correlation between PER plasma concentration and either exposure or toxicity (both with p < 0.05). We suggest a plasma concentration range of 625–900 ng/mL as a suitable reference for PER in Chinese patients with epilepsy. ConclusionThe CYP3A4×10 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A4 genetic phenotype should be factored in when prescribing PER to patients with epilepsy.

A simple accurate method for concentration-QTc analysis in preclinical animal models

IntroductionIn preclinical cardiovascular safety pharmacology studies, statistical analysis of the rate corrected QT interval (QTc) is the focus for predicting QTc interval changes in the clinic. Modeling of a concentration/QTc relationship, common clinically, is limited due to minimal pharmacokinetic (PK) data in nonclinical testing. It is possible, however, to relate the average drug plasma concentration from sparse PK samples over specific times to the mean corrected QTc. We hypothesize that averaging drug plasma concentration and the QTc-rate relationship over time provides a simple, accurate concentration-QTc relationship bridging statistical and concentration/QTc modeling. MethodsCardiovascular telemetry studies were conducted in non-human primates (NHP; n = 48) and canines (n = 8). Pharmacokinetic samples were collected on separate study days in both species. Average plasma concentrations for specific intervals (CAverage0-X) were calculated for moxifloxacin in canines and NHP using times corresponding to super-intervals for the QTc data statistical analysis. The QTc effect was calculated for each super-interval using a linear regression correction incorporating QT and HR data from the whole super-interval. The concentration QTc effects were then modeled. ResultsIn NHP, a 10.9 ± 0.06 ms (mean ± 95% CI) change in QTc was detected at approximately 1.5× the moxifloxacin plasma concentration that causes a 10 ms QTc change in humans, based on a 0-24 h super-interval. When simulating a drug without QT effects, mock, no effect on QTc was detected at up to 3× the clinical concentration. Similarly, in canines, a 16.6 ± 0.1 ms change was detected at 1.7× critical clinical moxifloxacin concentration, and a 0.04 ± 0.1 ms change was seen for mock. ConclusionsWhile simultaneous PK and QTc data points are preferred, practical constraints and the need for QTc averaging did not prevent concentration-QTc analyses. Utilizing a 0-24 h super-interval method illustrates a simple and effective method to address cardiovascular questions when preclinical drug exposures exceed clinical concentrations.

Dynamic Interplay of Age and Protein Malnutrition on the Pharmacokinetic Profile of Acetaminophen in Wistar Rats

Abstract Objectives Age and protein malnutrition (PMN) are well-known determinants of drug pharmacokinetics. The combined influence of age and nutrition on the pharmacokinetics of acetaminophen (APAP) remains insufficiently explored; therefore, this study investigates the role of age and PMN on APAP pharmacokinetics. Materials and Methods Wistar rat weanlings were divided into four groups. Groups ND-5 (n = 6) and ND-18 (n = 6) were fed with normal diet (ND, 18% protein) and groups LPD-5 (n = 6) and LPD-18 (n = 6) were fed with low-protein diet (LPD, 10%) for 5 and 18 months, respectively. Blood samples were collected at different time intervals (0, 0.5, 1, 3, 6, 24, 36, and 48 hours), and plasma was separated and analyzed for APAP using high-performance liquid chromatography. Pharmacokinetic data was analyzed by the noncompartmental model using Phoenix WinNonlin 8.3 software. Results The pharmacokinetic parameters of APAP were elevated in both LPD groups compared with their age-matched controls. The average area under the curve was increased by approximately 131% (LPD-5) and 17.57% (LPD-18), and the average maximum plasma concentrations (Cmax) was increased by 33.5% (LPD-5) and 26.3% (LPD-18) compared with their respective age-matched controls. The average mean retention time was approximately 114% (LPD-5) and 17.4% (LPD-18) higher than their respective age-matched controls, whereas the clearance rate (Cl/F) and volume distribution (Vz/F) of the drug were significantly lower. Consequently, there was a 68.5% (ND-5) and 4.73% (ND-18) prolongation in the mean half-life of APAP. Conclusion The altered pharmacokinetics may arise from the intricate interplay of dietary and age influences on physiology, protein binding, and cytochrome P450enzyme activity/expression. However, the exact reason requires further investigation for a better understanding of vulnerable populations.

EMITT-1: Proof-of-mechanism immunopeptidome (ImPD) effects at target PK exposure, in a phase 1 study of GRWD5769 (a first-in-class inhibitor of Endoplasmic Reticulum Aminopeptidase 1 [ERAP1]) in patients with solid malignancies.

2589 Background: GRWD5769 is a first-in-class, orally bioavailable ERAP1 inhibitor that significantly modulates the peptide repertoire displayed on MHC-1 on tumor cells, driving novel T cell response and causing tumor cell killing in preclinical studies. This unique approach has potential to overcome central mechanisms of immune resistance by driving de-novo recognition of previously hidden tumor neoantigens and addressing T cell exhaustion. Here we report initial safety, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints from Part A (monotherapy dose escalation) in the ongoing multicentre, modular phase I dose escalation study (ACTRN12623000108617). Methods: Patients with advanced refractory solid tumors are enrolled using a BOIN escalation design. GRWD5769 is administered BID on days 1-14 during 21-day cycles. The first cycle is the dose-limiting toxicity (DLT) observation period. The PK / PD relationship of GRWD5769 is being evaluated using mass spectrometry analysis of the ImPD. Tumor responses are evaluated by RECIST v1.1 / iRECIST. Results: As of 03 January 2024, a total of 12 patients had been treated with GRWD5769 in 3 dose cohorts (25 mg, 50 mg, 100 mg BID). On average patients have remained on treatment for 4 cycles (range 1-10) No Serious Adverse Reactions, DLTs, immune related AEs or deaths were reported. Two Gr 3 serious adverse events have occurred in 2 treated subjects (aspiration pneumonia and Urinary Tract Infection, neither attributable to GRWD5769). Gr 1+2 AEs were infrequent and manageable. PK analyses for the first 3 cohorts show dose proportional plasma levels, with Tmax at ~3 h and a ~8 h Thalf. The minimum biologically active dose (MBAD) is defined as an average steady state plasma concentration above the IC50 for ERAP1, which was achieved at the 100 mg BID dose level. PD data shows dose-dependent target engagement, with marked shifts in the ImPD. This is consistent with the expected mechanistic effects of ERAP1 inhibition seen in preclinical models and is the first demonstration that the human ImPD can be manipulated pharmacologically in cancer patients, potentially allowing T cells to recognise new targets on tumors. Dose escalation with GRWD5769 monotherapy continues to determine the recommended phase 2 dose (RP2D). GWRD5769 in combination with Immune Checkpoint Inhibition will be investigated in Part B now that the MBAD has been reached. Conclusions: GRWD5769 has been well tolerated at doses up to 100 mg BID. PK / PD data support dose-dependent target engagement of ERAP1. Proof of mechanism has been achieved for this first-in-class therapy, and this is the first demonstration that the human ImPD can be manipulated pharmacologically in cancer patients. Further PD analyses will explore shifts in the T cell repertoire and modulation of immune cell phenotypes. Clinical trial information: ACTRN12623000108617.

Effects of CYP3A5*3 genetic polymorphisms on the pharmacokinetics of perampanel in Chinese pediatric patients with epilepsy.

This study was the first to evaluate the effect of CYP3A5*3 gene polymorphisms on plasma concentration of perampanel (PER) in Chinese pediatric patients with epilepsy. We enrolled 98 patients for this investigation. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final checkup. The plasma concentration showed a linear correlation with the daily dose taken ( r = 0.17; P < 0.05). The ineffective group showed a significantly lower plasma concentration of PER (490.5 ± 297.1 vs. 633.8 ± 305.5 μg/ml; P = 0.019). For the mean concentration-to-dose (C/D) ratio, the ineffective group showed a significantly lower C/D ratio of PER (3.2 ± 1.7 vs. 3.8 ± 2.0; P = 0.040). The CYP3A5*3 CC genotype exhibited the highest average plasma concentration of PER at 562.8 ± 293.9 ng/ml, in contrast to the CT and TT genotypes at 421.1 ± 165.6 ng/ml and 260.0 ± 36.1 ng/ml. The mean plasma PER concentration was significantly higher in the adverse events group (540.8 ± 285.6 vs. 433.0 ± 227.2 ng/ml; P = 0.042). The CYP3A5*3 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A5*3 genetic genotype should be factored in when prescribing PER to patients with epilepsy.

Retrospective Analysis of Steady-State Sodium Valproate Plasma Concentrations in Chinese Patients With Bipolar Disorder: Impact of Demographic and Clinical Characteristics.

This study comprehensively examined the demographic and clinical characteristics of patients undergoing valproic acid therapy and explored their potential impact on plasma valproic acid concentrations. All enrolled patients were administered the extended-release formulation. An in-depth investigation of factors, including dose, age, sex, body mass index, co-administered medications, and laboratory test findings, was conducted to evaluate their potential influence on study outcomes. In total, 164 patients met the inclusion criteria and were included in the analysis. The patient age ranged from 13 to 60 years, with a median age of 25.71 years. Most patients (89%) received a daily dose of 1 g valproic acid. Co-administered psychiatric medications included aripiprazole, quetiapine, and lorazepam. Laboratory test results, such as hemoglobin and transaminase levels, were also collected as part of the study. The average plasma valproic acid plasma concentration was 79.8 mg/L. The dose significantly affected valproic acid concentrations, as a higher percentage of measurements exceeded the therapeutic range at a daily dose of 1 g. Furthermore, females exhibited significantly higher valproic acid concentrations compared with males at the same dose ( P < 0.05). However, different age groups showed no statistically significant differences in valproic acid concentrations ( P > 0.05). The co-administered antipsychotic and antidepressant medications significantly affected valproate concentrations, as reflected in the multiple regression model ( P < 0.01). This study offers valuable insights into the demographic and clinical characteristics of patients undergoing valproic acid therapy. It highlights the influence of dose, sex, and concomitant medications on plasma valproic acid concentrations. Overall, these findings can help guide dose adjustments and implement personalized treatment strategies in valproic acid therapy.

Modified Release of Acetaminophen from Matrix Tablet Formulations: Influence of Tablet Geometry

Background: Acetaminophen (APAP) or paracetamol is a widely used over-the-counter, analgesic (common conditions treated include headaches, backache, toothache, muscle aches, arthritis, sore throat etc.) and antipyretic drug. It can be administered orally, in the form of a tablet (plain, effervescent, orodispersable, etc.) or liquid, rectally in the form of a suppository or by injection (intravenously or intramuscularly). It is well absorbed orally with a plasma elimination half-life ranging from 1 to 4 h. The modified release oral formulation can prolong its therapeutic effects by maintaining APAP average plasma concentrations. Objective: In the context of this work, two APAP formulation tablets with different geometries were produced from standard pharmaceutical excipients to investigate the role of altered tablet geometry in modified oral drug delivery. Methods: APAP tablets were prepared by direct compression, using hydroxypropyl methylcellulose (HPMC K15M), polyvinylpyrrolidone (PVP, MW: 55,000) and magnesium stearate, as ingredients. The release profiles were probed in aqueous dissolution media (pH 1.2 and 6.8) to simulate the conditions in the gastrointestinal tract in a United States Pharmacopeia (USP) dissolution paddle apparatus II and analyzed using an ultraviolet (UV) spectrophotometer (λmax = 244 nm). Results: The results indicated that the tablets were within the acceptable range of all evaluation parameters (tablet dimensions, drug content, weight variation, and breaking force) as defined by the international standards stated in the US Pharmacopoeia. The dissolution results showed that the APAP’s release profile was controlled by the tablets’ different geometries and, specifically the surface area (SA) and the surface area/volume (SA/V) ratio of the different tablets. The tablets with smaller SA/V ratios and SA showed slower drug release, indicative of a modified release motif. Conclusion: Altered tablet geometry plays an important role in APAP-modified oral drug delivery.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ZY-IL1 in Three Patients with Cryopyrin-Associated Periodic Syndromes.

We present the first results of the proof-of-concept phase 2a study of oral NLRP3 inflammasome inhibitor in subjects with cryopyrin-associated periodic syndromes (CAPS). Three adult subjects with a confirmed diagnosis of CAPS were enrolled and administered 50mg of ZYIL1 twice daily for 7 days. A total of 5 treatment-emergent adverse events (TEAEs) were reported in 2 subjects. All 5 TEAEs were mild in severity and considered unrelated to the study drug. At steady state, the average plasma concentration and trough concentration ranged from 2.5 to 4.2 and 1.4 to 2.5µg/mL, respectively. Inflammatory markers and disease activity (physician and patient global assessment score) decreased notably 12 hours post-last dose.

Modeling population pharmacokinetics of morniflumate in healthy Korean men: extending pharmacometrics analysis to niflumic acid, its major active metabolite.

This study aimed to quantify and explain inter-subject variability in morniflumate pharmacokinetics and identify effective covariates through population pharmacokinetics modeling. Models were constructed using bioequivalence pharmacokinetics results from healthy Korean males and individual physiological and biochemical parameters. Additionally, we incorporated previously reported pharmacokinetics results of niflumic acid, a major active metabolite of morniflumate, to extend the established population pharmacokinetics model and predict niflumic acid pharmacokinetics. Moreover, we used quantitative reports of leukotriene B4 (LTB4) synthesis inhibition in response to niflumic acid exposure to predict drug efficacy using Sigmoid Emax model. Population pharmacokinetics profiles of morniflumate were described using a multi-absorption (5-sequential) two-compartment model, and analysis of inter-individual variability suggested that volume of distribution in peripheral compartment was correlated with body mass index (BMI). Model simulation results showed that individuals with lower BMI had higher plasma concentrations of morniflumate and niflumic acid, resulting in increased and sustained inhibition of LTB4 synthesis. Under steady-state conditions, average plasma concentrations of morniflumate and niflumic acid were 2.66-2.68 times higher in group with a BMI of 17.36kg/m2 compared to the group with a BMI of 28.41kg/m2. Additionally, inhibition of LTB4 synthesis was 1.02 times higher in group with a BMI of 17.36kg/m2 compared to group with a BMI of 28.41kg/m2, and the fluctuation was significantly reduced from 6.06 to 0.01%. These findings suggest that the concentration of active metabolite in plasma following morniflumate exposure was lower in the obese group compared to the normal group, thus potentially reducing the drug's efficacy.

Initial results from the phase (ph) 1 portion of a ph 1/2 study of THE-630 in patients (pts) with advanced gastrointestinal stromal tumor (GIST).

e23508 Background: Activating mutations in KIT are found in most pts with GIST. First-line imatinib provides initial clinical benefit in advanced disease, but prognosis is poor for pts whose tumors progress, despite 3 other approved tyrosine kinase inhibitors (TKIs). Resistance is typically driven by secondary KIT mutations in the ATP-binding pocket (exons 13/14) or activation loop (exons 17/18). No approved drug has potent activity against both classes of resistance mutations, and many pts have polyclonal resistance after multiple lines of therapy. THE-630 is an investigational pan-variant KIT inhibitor. Based on preclinical models, an average plasma concentration (Cav) of 100 nM is predicted to have potent activity against all major classes of KIT-activating and resistance mutations. Here, we report initial data from a first-in-human study in pts with advanced GIST (NCT05160168). Methods: This ph 1/2 study is assessing the safety (including dose-limiting toxicities [DLTs] and recommended ph 2 dose [RP2D]), pharmacokinetics (PK), and antitumor activity of THE-630. Pts enrolled in the ph 1 portion were ≥18 y, had unresectable or metastatic GIST previously treated with imatinib and ≥1 additional TKI, and had ECOG performance status ≤2. Pts received THE-630 (QD; 28-day cycles) in a 3+3 dose-escalation design. PK was assessed on days 1 and 15 in cycle 1, antitumor activity was assessed by modified RECIST 1.1, and circulating tumor DNA (ctDNA) was assessed using Guardant360. Results: As of 13 Jan 2023, 19 pts had been treated in the ph 1 portion at THE-630 daily doses of 3 mg (n = 3), 4 mg (n = 7), 6 mg (n = 3), 9 mg (n = 3), and 12 mg (n = 3). Median age was 57 y (range 39–72); 13 pts had ≥4 prior TKIs. Median treatment duration was 55 days (range 1–252). PK analysis shows approximately dose-proportional increase in systemic exposure across doses tested. Mean steady-state Cav at 12 mg was 47 nM. There was 1 DLT at 4 mg (grade 5 myocardial infarction in a pt with 8 prior TKIs and hyperlipidemia where relationship to THE-630 could not be incontrovertibly ruled out). No other DLTs or related serious adverse events have occurred; 13 pts had treatment-related AEs (TRAEs), 91% of which were grade 1–2. The most common TRAEs were fatigue (n = 4), dry mouth (n = 3), anemia, ALT increase, AST increase, diarrhea, dyspepsia, dyspnea, and hypertension (n = 2 each). Reductions in select KIT-mutant allele fractions in ctDNA were observed, consistent with THE-630 levels achieved thus far. Stable disease (SD) was the best response in 1/7 pts at 4 mg, 1/3 pts at 6 mg, and 3/3 pts at 9 mg. Post data cut, SD was seen in 3/3 pts at 12 mg. Dose escalation continues to determine the RP2D. Conclusions: THE-630 had an acceptable initial safety profile, and escalation continues, as target exposure for pan-variant KIT activity is not yet reached. Reduction in KIT-mutant allele fractions in ctDNA and initial evidence of disease control were observed. Clinical trial information: NCT05160168 .

Aripiprazole Plasma Concentrations Delivered from Two 2-Month Long-Acting Injectable Formulations: An Indirect Comparison.

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a novel long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, developed for the treatment of schizophrenia or maintenance monotherapy treatment of bipolar I disorder in adults (indication will vary by country). Aripiprazole lauroxil 1064 mg (AL 1064) is an LAI formulation of aripiprazole lauroxil, an aripiprazole prodrug, for administration once every 2 months, indicated for the treatment of schizophrenia in adults. This analysis provides an indirect comparison of aripiprazole plasma concentrations following multiple doses of either formulation. Clinical trial data were used to determine average steady-state aripiprazole plasma concentration (Cavg,ss), maximum aripiprazole plasma concentration (Cmax), and other pharmacokinetic parameters of either formulation following four administrations (96 patients received Ari 2MRTU 960; 28 patients received AL 1064). All pharmacokinetic parameters were considered in the context of a minimum aripiprazole therapeutic concentration (Cmin) of ≥95 ng/mL. An exposure-response analysis using data from two Phase III trials of aripiprazole once-monthly (an aripiprazole monohydrate LAI, administered monthly), showed that patients with a Cmin ≥95 ng/mL are 4.41 times less likely to relapse than patients with a Cmin <95 ng/mL. A similar analysis has not been performed for AL 1064. However, consensus guidelines for therapeutic drug monitoring recommend a range of 100-350 ng/mL for aripiprazole. Following four administrations, mean (standard deviation [SD]) Cavg,ss over the 2-month dosing interval was 263 (133) ng/mL for Ari 2MRTU 960 and 140.7 (57.3) ng/mL for AL 1064. Mean (SD) Cmax during the fourth dosing interval was 342 (157) ng/mL for Ari 2MRTU 960 and 188.8 (79.8) ng/mL for AL 1064. This indirect comparison showed that, following four administrations, Ari 2MRTU 960 and AL 1064 delivered mean aripiprazole plasma concentrations that remained above the minimum therapeutic concentration of aripiprazole over the 2-month dosing interval.

Pharmacological characterization of the selective orexin-1 receptor antagonist JNJ-61393215 in healthy volunteers.

Up to 40% of patients suffering from anxiety disorders do not benefit from currently available pharmacological treatments. Overactivity of the orexin-1 receptor (OX1R) has been implicated in anxiety- and panic-related states. We investigated the pharmacokinetics and characterized the pharmacodynamic (PD) profile of the OX1R antagonist JNJ-61393215 using a battery of central nervous system assessments investigating relevant functional domains such as alertness, attention, (visuo)motor coordination, balance, subjective effects and resting-state electroencephalography in a single ascending dose placebo-controlled study in doses from 1 to 90 mg inclusive, assessing PD up to 10 h after dosing, safety and pharmacokinetic in 48 healthy male subjects. Average time to maximal plasma concentration (Tmax) ranged between 1.0 and 2.25 h; average half-life ranged from 13.6 to 24.6 h and average maximum plasma concentration ranged from 1.4 to 136.8 ng/mL in the 1 and 90 mg groups, respectively. JNJ-61393215 did not demonstrate any statistically significant or clinically meaningful effects on any PD endpoint at any dose investigated at Tmax nor over the total period up to 10 h post-dose and was well tolerated. The reported somnolence rate was 16.7% (which was attributable to the cohorts receiving 6 mg and higher doses) compared to 12.5% in placebo. This observation is in line with our knowledge about the OX1R in preclinical studies, where only inconsistent and non-dose-dependent changes in electroencephalography or other behavioural measures were observed under non-challenged conditions, potentially exemplifying the need for a challenged subject.

Abstract CT238: Pharmacokinetic analyses and immunophenotyping of patients treated with Nelmastobart (hSTC810), a novel immune checkpoint inhibitor

Abstract A Phase I clinical trial is currently underway to test Nelmastobart (hSTC810), an antibody targeting butyrophilin 1A1 (BTN1A1), a novel immune checkpoint protein. This Phase I clinical trial is using a standard 3 + 3 escalation design to (i) explore safety, tolerability, dose-limiting toxicities, and pharmacokinetics, (ii) define a recommended Phase II dose, and (iii) evaluate preliminary efficacy in patients with advanced solid tumors. The current dose range for the clinical trial is 0.3 mg/kg to 15 mg/kg. Currently, all the dose levels have been completed without any dose-limiting toxicity having been observed. Here, we provide an update on the clinical trial data shown previously. First, we provide the results of the pharmacokinetics study of these patients for the selected doses and dosing intervals, including the peak plasma concentration (Cmax), the time to reach Cmax (tmax), and the average plasma concentration of hSTC810 over the dosing interval in steady state (Cavg). The change in cytokine expression and immune cell concentrations in patient blood samples were also analyzed. Specifically, a panel of cytokines was measured including IFN- γ, IL-2, IL-4, IL-6, IL-10, TNF-α, MCP-1, and TGF- β, while flow cytometry was used to detect a panel of immunological marker proteins including CD3, CD4, CD8, CD19, CD14, CD16, CD56, CD25, CD45. For pharmacokinetic studies, the concentrations of hSTC810 and anti-hSTC810 antibodies were quantified. Immunohistochemistry was performed on patient tumor biopsies that were stained for PD-L1, CD3, CD4, CD8, and BTN1A1 expression. The resultant slides were analyzed for PD-L1 tumor proportional score (TPS), PD-L1 combined positive score (CPS), BTN1A1 scoring, the percentage of CD3+ lymphocytes, CD4+ lymphocytes, CD8+ lymphocytes, tumor-infiltrating lymphocytes, and necrosis. Citation Format: Stephen Sunghan Yoo, Soohyeon Lee, Sangjoon Shin, Hyunjin Jung, David S. Hong. Pharmacokinetic analyses and immunophenotyping of patients treated with Nelmastobart (hSTC810), a novel immune checkpoint inhibitor [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 CT238.

Quantitative assessment of the relevance of organic-anion-transporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics

Fexofenadine is useful in various allergic disease treatment. However, the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking. This study aimed to verify the validity of previously proposed genetic factors through fexofenadine population pharmacokinetic modeling and to explore the quantitative correlations affecting the pharmacokinetic variability. Polymorphisms of the organic-anion-transporting-polypeptide (OATP) 1B1 and 2B1 have been proposed to be closely related to fexofenadine pharmacokinetic diversity. Therefore, modeling was performed using fexofenadine oral exposure data according to the OATP1B1- and 2B1-polymorphisms. OATP1B1 and 2B1 were identified as effective covariates of clearance (CL/F) and distribution volume (V/F)-CL/F, respectively, in fexofenadine pharmacokinetic variability. CL/F and average steady-state plasma concentration of fexofenadine differed by up to 2.17- and 2.20-folds, respectively, depending on the OATP1B1 polymorphism. Among the individuals with different OATP2B1 polymorphisms, the CL/F and V/F differed by up to 1.73- and 2.00-folds, respectively. Ratio of the areas under the curves following single- and multiple-administrations, and the cumulative ratio were significantly different between OATP1B1- and 2B1-polymorphism groups. Based on quantitative prediction comparison through a model-based approach, OATP1B1 was confirmed to be relatively more important than 2B1 regarding the degree of effect on fexofenadine pharmacokinetic variability. Based on the established pharmacokinetic-pharmacodynamic relationship, the difference in fexofenadine efficacy according to genetic polymorphisms of OATP1B1 and 2B1 was 1.25- and 0.87-times, respectively, and genetic consideration of OATP1B1 was expected to be important in the pharmacodynamics area as well. This population pharmacometrics study will be a very useful starting point for fexofenadine precision medicine.

Dosage Derivation of Marbofloxacin in Broiler Chickens based on Pharmacokinetic-Pharmacodynamic Integration

Marbofloxacin, a veterinary–exclusive antimicrobial drug of third–generation fluoroquinolone class, exhibits wide spectrum antimicrobial activity against Gram-negative as well as Gram-positive bacteria, and thus, is a promising agent to treat susceptible bacterial infections in poultry. Therefore, the present study was conducted to derive dosage regimen of marbofloxacin based on the results of intravenous and oral pharmacokinetic (PK) trial in sixteen healthy broiler chickens. Plasma concentrations of marbofloxacin were measured by optimized and in-house validated Ultra High Performance Liquid Chromatography (UHPLC) method. The PK parameters were calculated from plasma concentrations versus time data by non-compartmental analysis using ‘PK Solver 2.0’ software. Following oral administration of marbofloxacin at the dose rate of 5 mg/kg body weight, the mean maximal plasma concentration (Cmax: 2.193 µg/ml) was achieved at 1.68 h. Marbofloxacin showed long half-life (6.03 h), high volume of distribution (2.64 L/Kg) and good oral bioavailability (88.10 %). The average plasma concentration of marbofloxacin ≥ 0.32 µg/ml was maintained upto 12 h and 0.10 µg/ml at 24 h. Based on the values of PK-PD integrated indices, it is concluded that oral dose of marbofloxacin @ 5.0 mg/kg body weight, to be repeated at 24 h, would be efficient to treat common bacterial pathogens of broiler chickens having MIC ≤ 0.12 μg/ml.

Determination of polymyxin B in human plasma and epithelial lining fluid using LC-MS/MS and its clinical application in therapeutic drug monitoring

Polymyxin B (PB) is currently one of the last resort treatment options against carbapenem-resistant gram-negative bacterial pathogens. Pharmacokinetics/pharmacodynamics (PK/PD) guided therapeutic drug monitoring (TDM) of antibiotics is critical for optimizing dosage regimens to maximize efficacy, minimize toxicity, and delay the emergence of resistance. Currently, methods for determining PB in human plasma and epithelial lining fluid (ELF) are limited. In this study, we developed and validated a simple method for PB determination in human plasma and ELF using LC-MS/MS. Protein precipitation of the sample was conducted with 0.1% formic acid-acetonitrile. Polymyxin B1 and B2 were separated on a C18 column and detected within 4 min by the mass spectrometer in the positive mode coupled with multiple reaction monitoring. The calibration curve range was 0.156–10.0 and 0.0156–1.00 μg/mL in the plasma for polymyxin B1 and B2, respectively, and was 0.0625–2.00 and 0.00625–0.200 μg/mL for polymyxin B1 and B2, respectively in bronchoalveolar lavage fluid. The accuracy of the intra- and inter-assay studies ranged from 80.6% to 114.9%, and the coefficients of variation for intra- and inter-day assays were less than 14.8%. Among a considerable number of patients, the average steady-state plasma concentration of PB was suboptimal. Moreover, the exposure to PB in patients with acute kidney injury (AKI) was considerably higher than that in patients without AKI. Meanwhile, a higher concentration of PB in ELF could be achieved than that in plasma after PB nebulization treatment. The established method was proven to be rapid, simple, and suitable for TDM of PB and PK/PD studies in human plasma and ELF.

Evaluation of 28-day estradiol and progesterone vaginal rings in a phase 1 clinical pharmacokinetic study.

The aim of this work is to develop a combination of 17β-estradiol (E2) and progesterone (P4) in a single-dose intravaginal ring (IVR) for the treatment of vasomotor symptoms (VMS) and genitourinary syndrome of menopause while providing endometrial protection. The objective of this study was to evaluate DARE-HRT1, a 28-day IVR that continuously delivers E2 and P4, in a phase 1 clinical trial to assess its pharmacokinetics. This was an open-label, three-arm (group) study. Thirty-two (32) healthy postmenopausal women were recruited at two Australian sites. The average age was 57.2 years (47-69 y). The first arm received one ring for 28 days designed to release E2 at a rate of 80 μg/d and P4 at 4 mg/d (80/4 IVR); the second arm received a ring releasing E2 at 160 μg/d and P4 at 8 mg/d (160/8 IVR). The third arm received oral Estrofem (1 mg E2) and Prometrium (100 mg P4) both daily for 29 days. Blood samples were taken predose then intensively over the first day (day 1) and periodically thereafter over the remaining 27 days. After removal of the rings on the morning of day 29, intensive samples were collected. Similar procedures were conducted with women enrolled in the oral group. The plasma samples were analyzed for E2, estrone (E1), and P4 using validated bioanalytical methods. The baseline-adjusted steady-state plasma levels of E2 and P4 from 80/4 IVR were 20.4 ± 17.1 pg/mL and 1.32 ± 0.19 ng/mL (n = 10), respectively. The baseline-adjusted steady-state plasma levels of E2 and P4 from 160/8 IVR were 30.9 ± 8.7 pg/mL and 2.08 ± 0.50 ng/mL (n = 10), respectively. The baseline-adjusted average plasma concentrations of E2 and P4 at day 29 of the oral group were 35.4 ± 11.2 pg/mL and 0.79 ± 0.72 ng/mL (n = 11), respectively. The baseline-adjusted steady state of E1 from the 80/4 IVR and the 160/8 IVR were 22.1 ± 16.6 pg/mL (n = 10) and 25.2 ± 12.3 pg/mL (n = 10), respectively. The baseline-adjusted concentration of E1 in the oral arm was 209 ± 67.7 ng/mL (n = 11). The IVR were well tolerated, and no serious adverse events were reported. The 80/4 IVR and 160/8 IVR gave similar steady-state concentrations of E2 as seen with drug products approved by the US Food and Drug Administration for treatment of VMS and genitourinary symptoms of menopause. The E2 concentrations of this study support the potential of DARE-HRT1, a promising new option for hormone therapy for treatment of VMS and vaginal symptoms associated with menopause.