Single-dose Pharmacokinetics Research Articles

Single-dose and steady-state pharmacokinetics of clomipramine, yohimbine and clomipramine/yohimbine combination: A clinical drug-drug interaction study.

Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile. A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug-drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80-125%. The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104-120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112-168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported. A PK assessment of clomipramine and yohimbine indicated a clinically significant drug-drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25-<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies.

Impact of renal impairment on the pharmacokinetic profile of intravenous difelikefalin, a kappa opioid receptor agonist for the treatment of pruritus

BackgroundDifelikefalin is a selective kappa opioid receptor agonist that is approved for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis (HD). In this study, we assessed the pharmacokinetics (PK) of intravenous (IV) difelikefalin in healthy subjects, in non–dialysis-dependent (NDD) subjects with varying stages of kidney disease, and in subjects with end-stage renal disease (ESRD) undergoing HD.MethodsThe PK and safety of single IV doses of difelikefalin (3.0 mcg/kg) were initially evaluated in NDD subjects with mild, moderate, or severe renal impairment compared with matched healthy subjects. Based on those data, the PK and safety of 3 dose levels of IV difelikefalin (0.5, 1.0, or 2.5 mcg/kg) were compared with matched placebo in subjects undergoing HD with each dose administered following dialysis, 3 times over a 1-week treatment period).ResultsSingle IV dosing of difelikefalin in NDD subjects (N = 36) with mild renal impairment demonstrated comparable exposure to healthy subjects with normal renal function, while subjects with moderate or severe renal impairment had higher total exposure. NDD subjects with severe renal impairment had higher total exposure compared with those with moderate renal impairment (i.e., exposure in severe NDD > moderate NDD > mild NDD ≈ healthy subjects). Clearance of difelikefalin correspondingly decreased with increasing renal impairment. In the multiple-dose study in subjects with ESRD undergoing HD (N = 19), IV difelikefalin demonstrated dose proportionality and was shown to be mostly cleared by dialysis; steady state was achieved with the second dose on day 3. Safety findings for all subjects were consistent with the known profile of IV difelikefalin.ConclusionsIV difelikefalin was well tolerated. Similar exposure was observed in NDD subjects with mild renal impairment compared with healthy subjects with normal renal function, with reduced clearance and higher exposure in NDD subjects with moderate or severe renal impairment. Dose proportionality was demonstrated in subjects with ESRD undergoing HD administered IV difelikefalin 3 times per week following dialysis and was shown to be mostly cleared by dialysis.Trial registrationSingle-dose study: NA; multiple-dose study: ClinicalTrials.gov registration number NCT02229929, first registration 03/09/2014.

Single-Dose Tolerability and Pharmacokinetics of Onradivir in Chinese Patients with Hepatic Impairment and Healthy Matched Controls.

This study compared the safety and pharmacokinetics of a single oral dose of onradivir, an inhibitor of polymerase basic protein 2 in influenza A virus, in patients with hepatic impairment and healthy participants with normal hepatic function. Eight participants with mild hepatic impairment (Child-Pugh A), eight participants with moderate hepatic impairment (Child-Pugh B), and eight healthy matched controls were enrolled in this open-label, parallel-group clinical trial. After the administration of 600 mg of onradivir, pharmacokinetic parameters were calculated for each cohort and compared. Onradivir was generally well tolerated by all participants. No serious adverse events (AEs) and no deaths were reported during the study. Six patients with moderate hepatic impairment and three patients with mild hepatic impairment reported AEs, all of which were mild and quickly resolved. Compared with the normal liver function group, the maximum concentration, area under the curve from time zero to the last measurable concentration, and area under the curve from time zero to infinity were 103%, 68.5%, and 69.2% higher, respectively, in the mild hepatic impairment group. In the moderate hepatic impairment group, these increases were 101%, 197%, and 204%, respectively. Overall, there were clinically relevant differences in onradivir exposure between patients with mild or moderate hepatic impairment and normal controls. These data imply that onradivir dose adjustment is warranted in patients with mild or moderate hepatic impairment. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT05856513).

Assessment of Single-Dose Pharmacokinetics of Oxolinic Acid in Rainbow Trout and Determination of InVitro Antibacterial Activity Against Pathogenic Bacteria From Diseased Fish.

In response to the heightened risk of bacterial diseases in fish farms caused by increased demand for fish consumption and subsequent overcrowding, researchers are currently investigating the efficacy and residue management of oxolinic acid (OA) as a treatment for bacterial infections in fish. This research is crucial for gaining a comprehensive understanding of the pharmacokinetics of OA. The present study investigates pharmacokinetics of OA in juvenile rainbow trout. The fish were given a 12 mg kg-1 dose of OA through their feed, and tissue samples were collected of the liver, kidney, gill, intestine, muscle, and plasma for analysis using LC-MS/MS. The highest concentrations of the drug were found in the gill (4096.55 μg kg-1) and intestine (11592.98 μg kg-1), with significant absorption also seen in the liver (0.36 L/h) and gill (0.07 L/h) (p < 0.05). The liver (0.21 L/h) and kidney (0.03 L/h) were found to be the most efficient (p < 0.05) at eliminating the drug. The study also confirmed the drug antimicrobial effectiveness against several bacterial pathogens, including Shewanella xiamenensis (0.25 μg mL-1), Lactococcus garvieae (1 μg mL-1), and Chryseobacterium aquaticum (4 μg mL-1). The study concludes significant variations among different fish tissues, with higher concentrations and longer half-lives observed in the kidney and intestine. The lowest MIC value recorded against major bacterial pathogens demonstrated its therapeutic potential in aquaculture. It also emphasizes the importance of understanding OA pharmacokinetics to optimize antimicrobial therapy in aquaculture.

Safety, Tolerability, and Pharmacokinetics of Single Doses of Exidavnemab (BAN0805), an Anti-α-Synuclein Antibody, in Healthy Western, Caucasian, Japanese, and Han Chinese Adults.

Exidavnemab is a monoclonal antibody (mAb) with a high affinity and selectivity for pathological aggregated forms of α-synuclein and a low affinity for physiological monomers, which is in clinical development as a disease-modifying treatment for patients with synucleinopathies such as Parkinson's disease. Safety, tolerability, pharmacokinetics, immunogenicity, and exploratory biomarkers were assessed in two separate Phase 1 single ascending dose studies, including single intravenous (IV) (100 to 6000 mg) or subcutaneous (SC) (300 mg) administration of exidavnemab in healthy volunteers (HVs). Across the two studies, a total of 98 Western, Caucasian, Japanese, and Han Chinese HVs were enrolled, of which 95 completed the study. Exidavnemab was generally well tolerated. There were no serious adverse events or safety issues identified in laboratory analyses. Headache, asymptomatic COVID-19, back pain, and post lumbar puncture syndrome were the most frequently reported treatment-emergent adverse events. Following IV infusion, the pharmacokinetics of exidavnemab was approximately dose linear in the range 100-6000mg. The terminal half-life was approximately 30 days, and the exposure was comparable across Western, Caucasian, Japanese, and Han Chinese volunteers. The absolute SC bioavailability was ∼71%. Cerebrospinal fluid exposure relative to serum after single dose was within the range expected for mAbs (approximately 0.2%). The anti-drug antibody rates were low and there was no effect of immunogenicity on the pharmacokinetics or safety. Dose-dependent reduction of free α-synuclein in plasma was observed. In summary, exidavnemab was found to have an excellent pharmacokinetic profile and was well tolerated in HVs, supporting the continued clinical development.

Effects of Short-Term Creatine Nitrate Plus Creatinine Intake on Creatine Pharmacokinetics and Safety Biomarkers in Healthy Adults

Background: A blend of creatine nitrate and creatinine has demonstrated promising bioavailability; however, prior studies have not thoroughly examined its pharmacokinetics and safety profiles, particularly its impact on kidney stress indicators, such as serum cystatin C. Objective: This study aimed to assess the effects of varying doses of creatine nitrate-creatinine intervention on pharmacokinetics and safety in healthy humans. Methods: Ten young adults (mean age 26.1 ± 5.0 years; 5 females) volunteered for this double-blind, crossover, randomized controlled trial. The participants were randomly assigned to receive either a low-dose creatine nitrate-creatinine mixture (CN-CRN-Low; 1.5 g of creatine nitrate and 1.5 g of creatinine), a high-dose creatine nitrate-creatinine mixture (CN-CRN-High; 3 g of creatine nitrate and 3 g of creatinine), or 1.5 g of creatine nitrate (CONTROL) in both a single-dose pharmacokinetics experiment, and a 14-day safety trial. Results: Both CN-CRN-Low and CN-CRN-High interventions displayed increased volume of distribution and total clearance compared to the CONTROL intervention (P &lt; 0.05) in a single-dose pharmacokinetics experiment. Additionally, the CN-CRN-High intervention showed significantly higher creatine maximum serum concentrations compared to the other interventions (P &lt; 0.05). Serum cystatin C levels remained unchanged across all interventions (P = 0.65), with no participants experiencing abnormal cystatin C concentrations or major changes in other safety biomarkers. Conclusion: The present study demonstrates dose-specific utilization of creatine nitrate-creatinine intervention, with the mixture induced no kidney damage. Further studies are needed to explore the potential functional and performance benefits of creatine nitrate-creatinine supplementation in diverse clinical and athletic cohorts.

Single intravenous and oral dose pharmacokinetics of the antiseizure medication brivaracetam in healthy cats.

The number of available antiseizure medications with demonstrated efficacy in cats is limited. As such, there is a need to evaluate the pharmacokinetics of newer medications so that proper dosing regimens can be made. Brivaracetam (BRV) is a more potent analogue of levetiracetam, and is Food and Drug Administration approved for use in people. The goal of this study was to describe the pharmacokinetics of intravenous and oral doses of BRV in healthy cats. A cross-over study involving eight healthy cats, that were administered 10 mg of BRV intravenously as a bolus and orally in the fasted state. Blood samples were collected over 24 h. Analysis was performed using liquid chromatography-mass spectrometry. Data were subjected to non-compartmental analysis. Median (min-max) of maximal concentration, time to maximal concentration, area under the curve, elimination half-life and oral absolute bioavailability were 902 (682-1036) ng/mL, 0.6 (0.5-2.0) h, 6.4 (5.2-7.2) h, 8145 (6669-9351) ng × h/mL and 100% (85-110) respectively. BRV appeared to be well tolerated by all cats. A single dose of BRV is well tolerated both orally and intravenously. Maximal concentrations are produced rapidly and within the human reference interval considered to be therapeutic.

Preclinical pharmacokinetics, pharmacodynamics, and toxicity of novel small-molecule GPR119 agonists to treat type-2 diabetes and obesity

The escalating global prevalence of type-2 diabetes (T2D) and obesity necessitates the development of novel oral medications. Agonism at G-protein coupled receptor-119 (GPR119) has been recognized for modulation of metabolic homeostasis in T2D, obesity, and fatty liver disease. However, off-target effects have impeded the advancement of synthetic GPR119 agonist drug candidates. Non-systemic, gut-restricted GPR119 agonism is suggested as an alternative strategy that may locally stimulate intestinal enteroendocrine cells (EEC) for incretin secretion, without the need for systemic drug availability, consequently alleviating conventional class-related side effects. Herein, we report the preclinical acute safety, efficacy, and pharmacokinetics (PK) of novel GPR119 agonist compounds ps297 and ps318 that potentially target gut EEC for incretin secretion. In a proof-of-efficacy study, both compounds demonstrated glucagon-like peptide-1 (GLP-1) secretion capability during glucose and mixed-meal tolerance tests in healthy mice. Furthermore, co-administration of sitagliptin with investigational compounds in diabetic db/db mice resulted in synergism, with GLP-1 concentrations rising by three-fold. Both ps297 and ps318 exhibited low gut permeability assessed in the in-vitro Caco-2 cell model. A single oral dose PK study conducted on healthy mice demonstrated poor systemic bioavailability of both agents. PK measures (mean ± SD) for compound ps297 (Cmax 23 ± 19 ng/mL, Tmax range 0.5 – 1 h, AUC0–24 h 19.6 ± 21 h*ng/mL) and ps318 (Cmax 75 ± 22 ng/mL, Tmax range 0.25 – 0.5 h, AUC0–24 h 35 ± 23 h*ng/mL) suggest poor oral absorption. Additionally, examinations of drug excretion patterns in mice revealed that around 25 % (ps297) and 4 % (ps318) of the drugs were excreted through faeces as an unchanged form, while negligible drug concentrations (<0.005 %) were excreted in the urine. These acute PK/PD assessments suggest the gut is a primary site of action for both agents. Toxicity assessments conducted in the zebrafish and healthy mice models confirmed the safety and tolerability of both compounds. Future chronic in-vivo studies in relevant disease models will be essential to confirm the long-term safety and efficacy of these novel compounds.

Effect of Activated Charcoal on Mavacamten Pharmacokinetics in Healthy Participants.

To assess the effect of activated charcoal on the single-dose pharmacokinetics of mavacamten when administered 2 h or 6 h after mavacamten dosing. In this open-label, randomized, parallel-group study, healthy adults were randomized into three groups to receive mavacamten 15 mg alone or mavacamten 15 mg plus activated charcoal 50 g administered either 2 h or 6 h after mavacamten dosing. Pharmacokinetic parameters were derived from plasma concentration-time data using noncompartmental methods. Of the 45 participants randomized, 37 completed the study. When activated charcoal was administered 2 h after mavacamten dosing, mavacamten absorption and exposure were reduced compared with when mavacamten was administered alone: the area under the concentration-time curve from 0 to 72 h (AUC0-72) and area under the concentration-time curve from time 0 extrapolated to infinity (AUCINF) were reduced by 14% and 34%, respectively. The maximum plasma concentration (Cmax) was also slightly lower when activated charcoal was administered 2 h after mavacamten dosing than with mavacamten alone. Pharmacokinetic profiles were similar for mavacamten alone and mavacamten plus activated charcoal administered 6 h after mavacamten dosing. Activated charcoal was successful in reducing mavacamten absorption and exposure when administered as soon as possible after identification of a need for adsorption (2 h after mavacamten dosing). No change in exposure was observed when activated charcoal was administered 6 h after mavacamten dosing. NCT05320094.

Effects of Quinidine or Rifampin Co-administration on the Single-Dose Pharmacokinetics and Safety of Rilzabrutinib (PRN1008) in Healthy Participants.

This open-label, phase 1 study was conducted with healthy adult participants to evaluate the potential drug-drug interaction between rilzabrutinib and quinidine (an inhibitor of P-glycoprotein [P-gp] and CYP2D6) or rifampin (an inducer of CYP3A and P-gp). Plasma concentrations of rilzabrutinib were measured after a single oral dose of rilzabrutinib 400mg administered on day 1 and again, following a wash-out period, after co-administration of rilzabrutinib and quinidine or rifampin. Specifically, quinidine was given at a dose of 300mg every 8hours for 5 days from day 7 to day 11 (N = 16) while rifampin was given as 600mg once daily for 11 days from day 7 to day 17 (N = 16) with rilzabrutinib given in the morning of day 10 (during quinidine dosing) or day 16 (during rifampin dosing). Quinidine had no significant effect on rilzabrutinib pharmacokinetics. Rifampin decreased rilzabrutinib exposure (the geometric mean of Cmax and AUC0-∞ decreased by 80.5% and 79.5%, respectively). Single oral doses of rilzabrutinib, with or without quinidine or rifampin, appeared to be well tolerated. These findings indicate that rilzabrutinib is a substrate for CYP3A but not a substrate for P-gp.

Abstract CT131: Effect of rivoceranib administered as 200 mg once daily on the pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates

Abstract Title: Effect of Rivoceranib Administered as 200 mg Once Daily on the Pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 Substrates Background: Rivoceranib is a selective vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor with potent antitumor activity. The purpose of this study is to evaluate the effect of rivoceranib on the pharmacokinetics of various CYP substrates in healthy subjects following administration of rivoceranib 200 mg once daily (QD), which is similar to the proposed rivoceranib dosing regimen (250 mg QD) in combination with camrelizumab for the treatment of hepatocellular carcinoma. Methods: This open-label, fixed-sequence, crossover drug-drug interaction phase 1 study evaluated the impact of multiple oral doses of rivoceranib at 200 mg QD on the pharmacokinetics of single oral doses of CYP enzyme substrates included in the Cooperstown 5+1 cocktail (midazolam 2 mg [CYP3A4/5 substrate], warfarin 10 mg [CYP2C9 substrate]/vitamin K 10 mg, dextromethorphan 30 mg [CYP2D6 substrate], omeprazole 40 mg [CYP2C19 substrate], and caffeine 200 mg [CYP1A2 substrate]). On Day 1, subjects received a single oral dose of the Cooperstown cocktail. Blood samples were collected predose on Day 1 and up to 120 hours post-dose for pharmacokinetic analyses. On Days 6-15, subjects received rivoceranib at 200 mg QD. On Day 11, a single dose of the Cooperstown Cocktail was co-administered with rivoceranib at 200 mg. Each dose was administered under postprandial conditions except for Day 11 when subjects fasted. Blood samples were collected predose on Day 11 and up to 120 hours post cocktail dosing for pharmacokinetic analyses. Subjects returned on any day between Days 21-25 for safety follow-up. Results: Rivoceranib 200 mg QD increased dextromethorphan AUC0-inf by 144% and Cmax by 70%, increased midazolam AUC0-inf by 65% and Cmax by 16%, increased the warfarin AUC0-inf by 28% and Cmax by 5%, increased omeprazole AUC0-inf by 77% and Cmax by 62%, and decreased caffeine AUC0-inf by 20% and Cmax by 7%. Cooperstown Cocktail alone or coadministration of Cooperstown Cocktail and rivoceranib was generally well tolerated. Conclusions:Rivoceranib at 200 mg QD does not substantially affect the exposure of the substrates of CYP3A4/5, CYP2C9, CYP2C19, and CYP1A2. Recommendation of dose adjustment of these CYP substrates is not needed when administered with rivoceranib at 200 mg QD. Rivoceranib may increase the exposure of the substrate of CYP2D6 by approximately 100%, indicating that a dose adjustment of CYP2D6 substrates and/or close monitoring patients should be considered when administered with rivoceranib 200 mg QD. Citation Format: Seong Jang, Xiaohui (Tracey) Wei, Xianzhang Meng, Joseph Reitano, Vinoo Urity, Cheol Hee Park, Bill Strickland, Grace Lee, David Nguyen. Effect of rivoceranib administered as 200 mg once daily on the pharmacokinetics of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 substrates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT131.

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

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

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

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

Pharmacokinetics of soy-derived lysophosphatidylcholine compared with that of glycerophosphocholine: a randomized controlled trial.

Lysophosphatidylcholine (LPC) is present in various foods and contains a choline moiety such as in glycerophosphocholine (GPC). However, the potential of LPC as a choline source remains unclear. This study investigated the single-dose pharmacokinetics of 480mg soy-derived LPC in 12 healthy men compared with that of either soy oil with the same lipid amount (placebo) or GPC with the same choline amount. Both LPC and GPC supplementation increased plasma choline, serum phospholipid, and serum triglyceride concentrations, but neither of them significantly elevated plasma trimethylamine N-oxide concentration. In addition, although the intake of LPC slightly increased plasma LPC16:0, LPC18:2, and total LPC concentrations, their concentrations remained within physiological ranges. No adverse events were attributed to the LPC supplementation. To the best of our knowledge, this study is the first to compare LPC and GPC pharmacokinetics in humans and shows that LPC can be a source of choline.

Integrating Full Bayesian Inference and Student's t-Distribution Method for Enhanced Outlier Handling in Caffeine Population Pharmacokinetics: Assessing Drug-Drug Interactions with Enasidenib in Relapsed or Refractory AML and MDS Patients.

As the first-in-class, selective, and potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation. Known for its interactions with various cytochrome P450 (CYP)enzymes and transporters in vitro, a clinical pharmacokinetics (PK) trial was initiated to assess the impact of multiple doses of enasidenib on the single-dose PK of sensitive probe substrates of several cytochrome P450 enzymes and transporters. In this study, a population pharmacokinetic analysis approach was employed to address challenges posed by high, nonzero baseline caffeine concentrations. Moreover, we integrated full Bayesian inference into this approach innovatively for a more detailed understanding of parameter uncertainty and greater modeling flexibility, alongside Student's t-distribution for robust error modeling in handling the abnormal outlier caffeine concentration data observed in this trial. Our analyses demonstrated that multiple doses of enasidenib altered caffeine clearance to a clinically meaningful extent, as evidenced by an approximate 8-fold decrease. This finding led to a specific recommendation in the package insert to avoid the concurrent use of certain CYP1A2 substrates with enasidenib, unless directed otherwise in the prescribing information. Furthermore, this research underlines the technical benefits of integrating full Bayesian inference and incorporating Student's t-distribution for residual error modeling in the PK field.

Pharmacokinetics of Ubrogepant in Healthy Japanese and White Adults.

Ubrogepant is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults. The objectives of this study were to evaluate (1) single-dose pharmacokinetics (PK) and dose proportionality of ubrogepant in Japanese participants, (2) the safety and tolerability of ubrogepant in healthy Japanese and White participants, and (3) to compare the PK of ubrogepant in Japanese versus White participants. A total of 48 participants were enrolled into 4 cohorts (N = 12 [9 active + 3 placebo] per cohort). A single dose was administered on Day 1 following an overnight fast to assess the PK of ubrogepant at 3 dose levels and test dose proportionality between 25 and 100mg in Japanese participants. White participants were randomly assigned to ubrogepant (100mg) or placebo. Dose proportionality was observed in the dose range of 25-100mg in Japanese participants. Systemic exposure was 20% lower in Japanese participants as compared with White participants, but this difference is unlikely to be clinically relevant. Single doses of ubrogepant (25-100mg) had a safety profile similar to placebo, and no differences in the safety profile of ubrogepant 100mg were observed between Japanese versus White participants.

Compatible co-administration of BioThrax® vaccine and ciprofloxacin—Results of a randomized open-label drug-vaccine interaction trial

The recommended treatment for post-exposure prophylaxis (PEP) following known/suspected exposure to Bacillus anthracis involves immunization with anthrax vaccine adsorbed (AVA, i.e., BioThrax® vaccine) and a course of antimicrobial therapy. A drug-vaccine interaction clinical trial was conducted to determine whether this combined treatment might modify antimicrobial exposure or vaccine immunogenicity.A Phase 2, randomized, open-label, multi-center trial involving 154 healthy adult participants was completed to evaluate the effect of AVA immunization (three doses administered subcutaneously (SC) at weeks 0, 2 and 4) on the pharmacokinetics (PK) of ciprofloxacin, as well as the effect of ciprofloxacin administration (500 mg po bid) on the immunogenicity of AVA. PK parameters were derived using noncompartmental analysis of ciprofloxacin serum concentrations. Immunogenicity was assessed using a toxin neutralizing antibody (TNA) assay resulting in 50 % neutralization factor (NF50) values. Safety was assessed via reports of adverse events (AEs), clinically significant changes in laboratory parameters and vital signs, and collection of solicited local and systemic reactogenicity reactions.Statistical analyses of the steady state (SS) and single dose PK parameters Cmax and AUC0-–12h indicated that the AVA PEP regimen did not significantly modify ciprofloxacin exposure. Comparison of the geometric mean TNA NF50 values between participants receiving AVA + ciprofloxacin and those receiving AVA alone showed that the combined treatment was non-inferior to AVA alone. The trial met all prospectively defined success criteria for the primary PK endpoint and for the secondary PK and immunogenicity endpoints. There were no deaths, SAEs or AEs leading to drug discontinuation or study withdrawal during the trial.Overall, concomitant administration of ciprofloxacin and AVA produced no significant changes in the PK profile of ciprofloxacin nor in the immunogenicity of AVA. Furthermore, this trial demonstrated that the co-administration of ciprofloxacin and AVA was well tolerated in healthy adult participants.

Impact of lactoferrin supplementation on cotrimoxazole pharmacokinetics: A preliminary clinical investigation.

Cotrimoxazole, a commonly prescribed antibiotic, has substantial resistance, especially in Indonesia, with its uropathogenic resistance reaching 67% in 2017. Although cotrimoxazole has been suggested to be co-administered with lactoferrin to enhance its antibacterial effectiveness and this practice has been widely adopted since the Covid-19 pandemic, the impact of lactoferrin on the pharmacokinetics of cotrimoxazole remains relatively unknown. This study aims to conduct a preliminary clinical investigation into the impact of lactoferrin supplementation on the pharmacokinetics of cotrimoxazole, focusing on the elimination rate and excretion of unchanged drug in urine. This study employed a blinded, cross-over, single-dose pharmacokinetics investigation, which included five healthy volunteers as participants. In the initial period, the first group received cotrimoxazole (80 mg trimethoprim and 400 mg sulfamethoxazole) along with a lactoferrin-containing supplement, while the second group only received cotrimoxazole. Subsequently, after a washout period, the conditions were reversed. Urine sampling was conducted at intervals from 0 to 24 hours post-medication, and drug levels in the urine were determined using high-performance liquid chromatography. The population-based pharmacokinetic analysis revealed that the optimal model was the one-compartment model with first-order elimination and proportional residual error. The findings show that the administration of lactoferrin-containing supplements did not significantly influence the covariate model and, therefore, did not alter the pharmacokinetics parameter of cotrimoxazole in urine with a single administration, implying that lactoferrin did not cause drug interaction problems when given simultaneously.

Mixing energy as an adjustment tool for aerodynamic behaviour of an inhaled product: In-vitro and in-vivo effects

This paper describes the development of a fixed dose dry powder combination of indacaterol maleate (Inda) and glycopyrronium bromide (Glyco) in Easyhaler® inhaler for a comparative pharmacokinetic (PK) study, as well as the outcome of such a study. The development aim was to produce formulations with three different in vitro dispersibility profiles for both Inda and Glyco. This so-called ‘rake’ approach allows for quantitation of the candidate formulations relative to the reference product Ultibro® Breezhaler® in terms of the key PK parameters.Three formulations (A, B and C) were produced based on the mixing energy concept. For both APIs, formulation A (lowest mixing energy) displayed the highest fine particle fractions and formulation C (highest mixing energy) the lowest. GMP manufacturing confirmed the performance of the three formulations.The candidate formulations were tested against the reference product in a single dose PK study in healthy volunteers. Clear differences in Inda plasma concentration profiles were observed between the treatments when administered concomitantly with charcoal, with Easyhaler A showing the highest Cmax value and Easyhaler C the lowest. Easyhaler B was bioequivalent to Ultibro Breezhaler with regard to the primary PK parameters of Inda, Cmax and AUC72h. For Glyco, Easyhaler formulations A, B and C provided lower peak concentrations than Ultibro Breezhaler. For AUC72h of Glyco, Easyhaler B was bioequivalent to the reference product. Additional measures for adjustment of formulation performance can be foreseen, whose effects can be predicted based on mixing energy theory.

Development and characterization of NILK-2301, a novel CEACAM5xCD3 κλ bispecific antibody for immunotherapy of CEACAM5-expressing cancers

BackgroundT-cell retargeting to eliminate CEACAM5-expressing cancer cells via CEACAM5xCD3 bispecific antibodies (BsAbs) showed limited clinical activity so far, mostly due to insufficient T-cell activation, dose-limiting toxicities, and formation of anti-drug antibodies (ADA).MethodsWe present here the generation and preclinical development of NILK-2301, a BsAb composed of a common heavy chain and two different light chains, one kappa and one lambda, determining specificity (so-called κλ body format).ResultsNILK-2301 binds CD3ɛ on T-cells with its lambda light chain arm with an affinity of ≈100 nM, and the CEACAM5 A2 domain on tumor cells by its kappa light chain arm with an affinity of ≈5 nM. FcγR-binding is abrogated by the “LALAPA” mutation (Leu234Ala, Leu235Ala, Pro329Ala). NILK-2301 induced T-cell activation, proliferation, cytokine release, and T-cell dependent cellular cytotoxicity of CEACAM5-positive tumor cell lines (5/5 colorectal, 2/2 gastric, 2/2 lung), e.g., SK-CO-1 (Emax = 89%), MKN-45 (Emax = 84%), and H2122 (Emax = 97%), with EC50 ranging from 0.02 to 0.14 nM. NILK-2301 binds neither to CEACAM5-negative or primary colon epithelial cells nor to other CEACAM family members. NILK-2301 alone or in combination with checkpoint inhibition showed activity in organotypic tumor tissue slices and colorectal cancer organoid models. In vivo, NILK-2301 at 10 mg/kg significantly delayed tumor progression in colon- and a pancreatic adenocarcinoma model. Single-dose pharmacokinetics (PK) and tolerability in cynomolgus monkeys at 0.5 or 10 mg/kg intravenously or 20 mg subcutaneously showed dose-proportional PK, bioavailability ≈100%, and a projected half-life in humans of 13.1 days. NILK-2301 was well-tolerated. Data were confirmed in human FcRn TG32 mice.ConclusionsIn summary, NILK-2301 combines promising preclinical activity and safety with lower probability of ADA-generation due to its format compared to other molecules and is scheduled to enter clinical testing at the end of 2023.