Maximum Plasma Concentration Research Articles

Lack of Clinically Meaningful Effect of Cariprazine on the Pharmacokinetics of a Combined Oral Contraceptive.

Cariprazine (CAR) is a potent dopamine receptor partial agonist antipsychotic approved by the EMA and the FDA. To address the uncertainty regarding the effectiveness of hormonal contraceptives during CAR co-administration and whether a second barrier method is necessary, a drug-drug interaction study with an oral contraceptive was conducted post-approval. The phaseI, fixed-sequence multicenter study involved two periods with 24 patients with schizophrenia, aiming to evaluate the effect of CAR on the pharmacokinetics (PK) of a combined oral contraceptive (COC) containing 30μg ethinylestradiol (EE) and 150μg levonorgestrel (LNG). In periodA, a single dose of COC alone was administered on day1. In periodB, the highest therapeutic dose of 6mg CAR was administered once daily from day4, and a second dose of COC was given concomitantly on day31. Overall, CAR had no clinically meaningful effect on the PK of the COC. The terminal half-life and the time of maximum plasma concentration of EE and LNG were not altered by CAR co-administration. The highest difference observed was a decrease of 14% in the maximum plasma concentration of EE, with only slight deviation of the 90% confidence interval (CI) of the test/reference ratio (77.09-96.81) from the generally accepted bioequivalence range of 80-125%, which is not considered clinically relevant. Confidence intervals of all other exposure measures were within the 80-125% range for both EE and LNG. According to these results, hormonal contraceptives can be considered effective during CAR treatment. Trial registration number (EudraCT) 2018-003722-80.

A Phase 1 Study to Evaluate the Pharmacokinetic Drug-Drug Interaction Between Islatravir and Methadone in Participants on Stable Methadone Therapy.

Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment of HIV-1. People living with HIV-1 receiving methadone maintenance therapy may benefit from islatravir. This study was designed to evaluate single-dose islatravir on steady-state methadone pharmacokinetics. A nonrandomized, open-label study (NCT04568603) was conducted and included adult participants receiving methadone therapy. Participants received their standard methadone therapy and a single oral dose of islatravir 60mg concomitantly. Blood samples were collected to determine methadone and islatravir pharmacokinetics. Fourteen participants aged 26-63years were enrolled; 13 completed the study. The geometric mean ratios for methadone area under the concentration-time curve from time 0 to 24hours (AUC0-24), maximum plasma concentration (Cmax), and concentration at 24hours (C24) were 1.03, 1.01, and 1.07, respectively. Similar effects were seen for the R- and S-enantiomer of methadone (R-methadone: AUC0-24, 1.03; Cmax, 1.02; and C24, 1.06; S-methadone: AUC0-24, 1.03; Cmax, 1.01; and C24, 1.08). For islatravir, based on a comparison with historical data, the geometric mean ratios for AUC0-inf and Cmax were 1.18 and 0.86, respectively. Coadministration of a single dose of islatravir and methadone was generally well tolerated. Single-dose islatravir did not affect steady-state methadone pharmacokinetics in a clinically meaningful way.

Microwave-aided sensitive and eco-friendly HPTLC method for estimation of mirabegron using NBD-Cl as bio-sensing fluorescent probe by Integration of principal component Analysis, response surface modelling and white analytical chemistry approach

A large number of analytical methods have been used in in-vivo pharmacokinetic investigations and assays of mirabegron, which is used to treat overactive bladder. Because mirabegron does not give fluorescence, there is no known chromatographic method that uses this property in conjunction with environmentally safe solvents. In order to develop and assess analytical procedures that are precise, sensitive, environmentally friendly, economical, and easy to use, white analytical chemistry was recently presented. Hence, a microwave-aided HPTLC method with fluorescence detection was developed and applied for mirabegron quantification; this method is both sensitive and environmentally acceptable, and it makes use of NBD-Cl, a bio-sensing fluorescent-probe. The analytical-QbD approach, which includes chemometric and response-surface modeling concepts, was used to design this targeted chromatographic method. Critical method variables and performance parameters were identified and optimized using principal component analysis and Box-Behnken design. The targeted method was used to estimate mirabegron through the development of method operable design range navigation and control strategy. A mobile phase consisting of ethyl-acetate and ethanol (8.0 + 2.0, v/v) was used to develop the chromatogram of NBD-Cl derivatised-mirabegron into 8.0 mm bands on a TLC-plate that was supported with aluminum and precoated with silica-gel G60 F254. In a mirabegron concentration range of 50–250 ng/band, the suggested method exhibited linearity. Results showed that the suggested method has a recovery rate of 98 % to 102 %. When estimating mirabegron, the %RSD for the precision and robustness study was determined to be less than 2.0. The mirabegron %assay in the commercially available formulations was determined to be between 98 % and 102 % of the labelled claimed value. Mirabegron had a limit of detection of 10 pg/band and a limit of quantification of 50 pg/band. Marketed tablet formulations of mirabegron had a maximum plasma concentration of 71.58 ng/mL in rats. Using metrics from green analytical chemistry and the RGB model scoring system, we compared the whiteness and greenness profiles of the published and suggested methods. The suggested method was found to be sensitive, eco-friendly, quick, cost-effective, and easy to use for estimation of mirabegron.

Phase I pharmacokinetic study of etmaben, a malonic acid derivative

Introduction. Etmaben is a malonic acid derivative that has shown cardiotropic activity and is a promising candidate for treating ischemic heart disease and chronic heart failure. It is currently undergoing Phase I clinical trials, and its pharmacokinetics have not yet been studied in humans.Aim. The aim of the study is to investigate the pharmacokinetics of Etmaben, film-coated tablets, 300 mg (SPCPU, Russia) in healthy volunteers after fasting administration of different doses following both single and multiple dosing over a 7-day period.Materials and methods. The open-label, non-randomized clinical trial involved 48 healthy volunteers divided into 6 cohorts. Volunteers in cohort 1 received a single dose of 600 mg of etmaben, cohort 2 received 900 mg, and cohort 3 received 1200 mg. Cohorts 4, 5, and 6 received daily doses of 600 mg, 900 mg, and 1200 mg, respectively. Plasma concentrations of etmaben were measured using high-performance liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameters were calculated using Microsoft Excel with the Boomer extension (Department of Pharmacokinetics and Drug Metabolism, Allergan, Irvine, CA 92606, USA).Results and discussion. Pharmacokinetic parameters were calculated for 6 cohorts of 8 volunteers after single and multiple dosing of Etmaben at doses of 600, 900, and 1200 mg. The maximum plasma concentration (Cmax) of etmaben was reached on average within 0.5 h. Cmax values ranged from 2.708 ± 1.461 µg/mL to 19.871 ± 4.415 µg/mL. The maximum half-life was 0.874 ± 0.236 h, with an elimination rate constant not exceeding 1.053 ± 0.149 h–1. The mean residence time (MRT) of etmaben in plasma did not exceed 1.527 ± 0.272 h. The average volume of distribution was above 45 L, and clearance exceeded 42 L, indicating significant tissue distribution and rapid drug elimination. Due to low area under the curve values and high elimination rates, the accumulation of etmaben is minimal.Conclusion. Pharmacokinetic parameters were calculated, and averaged pharmacokinetic profiles were constructed in linear and semilogarithmic coordinates after single and multiple dosing of various etmaben doses. This study represents the first investigation of etmaben pharmacokinetics in humans, paving the way for subsequent clinical trials.

Pharmacokinetics of Omadacycline in Adults with Cystic Fibrosis.

Omadacycline offers a potential advancement in the management of infections in people with cystic fibrosis (CF) because of its spectrum of activity, intrapulmonary penetration, and oral bioavailability. A prospective single-dose, single-arm study was conducted to characterize the pharmacokinetic (PK) profile of omadacycline in people with CF, considering the known alterations in PK observed in this population (NCT04460586, 2020-07-01). Plasma samples were obtained from nine adults with CF who received a single dose of intravenous omadacycline 100 mg over 0.5 h followed by a 1-week washout and an oral dose of omadacycline 300 mg. The data were analyzed using noncompartmental PK. The maximum plasma concentration (Cmax) and area under the curve extrapolated to infinity (AUC0-∞) after intravenous administration of omadacycline were similar between healthy volunteers and people with CF. The absorption kinetics of oral omadacycline, encompassing both the rate (Cmax and time to Cmax [tmax]) and the extent (AUC0-∞), also showed consistency between healthy volunteers and people with CF. The absolute bioavailability of the oral tablet formulation of omadacycline in people with CF (31.2%) was also consistent with that observed in healthy volunteers (34.5%). In comparing the two routes of administration, intravenous omadacycline 100 mg provided plasma exposures equivalent to those with oral omadacycline 300 mg in people with CF, as evidenced by geometric mean ratios for both AUC0-∞ (0.9381; 90% confidence intervals [CI] 0.6783-1.2975) and Cmax (0.7746; 90% CI 0.5478-1.0951). Overall, the similarity in plasma PK observed in this study when comparing healthy volunteers and infected patients indicates that no dosing alterations are necessary when using omadacycline in people with CF.

Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous and Intravenous Garadacimab Following Single-Dose Administration in Healthy Japanese and White Adults.

Garadacimab, an activated factor XII (FXIIa) inhibitor monoclonal antibody, is being evaluated for the long-term prophylaxis of hereditary angioedema. Here, we report the results from a two-part, phase 1, open-label, single ascending dose study assessing the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability after subcutaneous (SC) and intravenous (IV) administration of garadacimab in healthy Japanese and White participants. Part 1 assessed garadacimab PK after SC administration of a 200 mg dose in weight-matched White and Japanese participants, and 600 mg dose in Japanese participants. Part 2 assessed 3 and 10mg/kg IV doses in Japanese participants. Follow-up for safety was over 84 days post-dose. Overall, 37 participants received garadacimab dosing and 36 completed the study, with one participant lost to follow-up. Following SC administration, time to maximum plasma concentration (tmax) occurred at 7 days post-dose, and garadacimab exposure, based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC), increased less than 3-fold when tripling the dose. PK was comparable between Japanese and White participants, with geometric mean ratios for Cmax and AUC close to 100%. Following IV administration, tmax occurred at the end of infusion, and garadacimab exposure increased in a dose-proportional manner. Inhibition of FXIIa-mediated kallikrein activity versus baseline was observed in all participants receiving the SC and IV doses. No anti-drug antibodies against garadacimab were reported. Consistent with pivotal phase 3 (VANGUARD) outcomes, no safety concerns and no difference in the safety profile of garadacimab were observed between healthy Japanese and White participants.

PBPK modelling for the evaluation of drug-drug interaction between meropenem and valproic acid.

The present study aimed to quantitatively investigate the potential drug-drug interaction (DDI) mechanism between meropenem (MEPM) and valproic acid (VPA). In the present study, we firstly developed a physiologically based pharmacokinetic (PBPK) model of MEPM and VPA. The verified PBPK model was then used to quantitatively investigate the potential DDI between MEPM and VPA. The effect of genetic polymorphisms of acylpeptide hydrolase (APEH) on DDI was also evaluated. In our simulation, the plasma concentration of hydrolysate of VPAG decreased to 63% when combined with MEPM. Total plasma concentration of VPA before carbapenem use was 53.61 mg/L, whereas it was 45.42 mg/L during carbapenem use. The inhibition of hydrolysis of VPAG by MEPM alone could not result in a rapid and substantial decrease in the plasma concentration of VPA. Parameter sensitivity analysis showed that the changes of absorption played an important role in the maximum plasma concentration (Cmax) of VPA, whereas area under the plasma concentration-time profile (AUC) was more susceptible to elimination changes. In addition, a decrease in APEH activity had little impact on the plasma pharmacokinetics of VPA. The DDI between MEPM and VPA might be a comprehensive result of multiple factors. On the basis of our simulation, interval medication of MEPM injection and VPA immediate release tablet at 4-6h timed interval was recommended, or intravenous administration of VPA solution was preferred when combination regimen was necessary in a clinical setting.

Safety and pharmacokinetics of vepdegestrant in Japanese patients with ER+ advanced breast cancer: a phase 1 study.

Vepdegestrant (ARV-471) is an oral PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader. This phase 1 study (NCT05463952) investigated safety, pharmacokinetics, and antitumor activity of vepdegestrant in Japanese patients with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer at the 200-mg once daily (QD) recommended phase 3 dose. Eligible patients had ER+/HER2- advanced breast cancer resistant to standard therapy, with no standard therapy available, or had received two or more prior endocrine therapies in any setting. The primary endpoint was dose-limiting toxicities (DLTs) in cycle 1; secondary endpoints included safety, pharmacokinetics, and antitumor activity. Six female patients (median age, 58 [range: 47-62] years) were treated. For advanced disease, three (50.0%) patients received three or more prior regimens and five (83.3%) patients received prior cyclin-dependent kinase 4/6 inhibitors. At data cutoff, median treatment duration was 9.8 (range: 6-28) weeks; two patients remained on treatment. No DLTs were observed. Four (66.7%) patients experienced adverse events; none led to dose reduction or discontinuation. Four (66.7%) patients had treatment-related adverse events; all were grade 1 except anemia (grade 2). Geometric mean maximum plasma concentration and 24-h area under the plasma concentration-time curve of vepdegestrant were 630.9 ng/mL and 10,400 ng∙hr/mL after a single dose and 1056 ng/mL and 18,310 ng∙hr/mL after multiple doses. Two (33.3%) patients demonstrated stable disease at week 24. Vepdegestrant 200 mg QD was well tolerated in Japanese patients with ER+/HER2- advanced breast cancer with no notable differences in pharmacokinetics from Western patients. ClinicalTrials.gov: NCT05463952 (date of registration: July 19, 2022).

In Vitro Evaluation of CYP-Mediated Metabolism of Fezolinetant and Pharmacokinetic Interaction Between Fezolinetant and Fluvoxamine in Healthy Postmenopausal Smokers and Nonsmokers.

Fezolinetant is an oral, nonhormonal, neurokinin 3 receptor antagonist treatment option for moderate to severe vasomotor symptoms associated with menopause. An in vitro study using human recombinant cytochrome P450 (CYP) enzymes and human liver microsomes showed that fezolinetant is metabolized to its major but inactive metabolite, ES259564, predominantly through CYP1A2, with minor contributions from CYP2C9 and CYP2C19. The clinical impact of CYP1A2 inhibition and induction on single-dose pharmacokinetics of fezolinetant was assessed in an open-label, single-sequence, phase 1 study in healthy postmenopausal women, where the impact of fluvoxamine, a strong CYP1A2 inhibitor, and smoking, a moderate CYP1A2 inducer, were evaluated. In total, 18 participants, 9 of whom were smokers, were enrolled. Fezolinetant pharmacokinetics were evaluated after a single 30-mg dose on Day 1 and Day 7. Fluvoxamine 50 mg was administered as a single dose on Days 3 and 10 and twice daily from Days 4 to 9. Fluvoxamine increased geometric mean ratio of fezolinetant maximum plasma concentrations (Cmax) and area under the curve from time of dosing extrapolated to infinity (AUCinf) to 182% and 939%, respectively, while ES259564 Cmax decreased to 20.1% with no significant change in AUC. In smokers versus nonsmokers, when fezolinetant was administered alone, fezolinetant Cmax and AUCinf decreased to 71.7% and 48.3%, respectively, while ES259564 Cmax increased to 130.2% and AUCinf decreased to 81.8%. A single oral 30-mg dose of fezolinetant was considered safe and well tolerated when co-administered with fluvoxamine in healthy postmenopausal women.

Resveratrol Bioavailability After Oral Administration: A Meta-Analysis of Clinical Trial Data.

Annually, a growing body of studies substantiates the health advantages of polyphenolic compounds, yet their practical application is constrained by swift metabolism and low bioavailability. Resveratrol, a stilbene derivative showcasing typical polyphenolic traits, is particularly noteworthy. Despite abundant bioavailability data from invitro and animal studies, applying these findings to humans demands nuanced consideration. The objective of this article is to conduct a meta-analysis on clinical trial data, systematically assessing the oral bioavailability of resveratrol and deriving meaningful insights into its efficacy in humans. To achieve this goal, we thoroughly examined publications across five major global databases: PubMed, Cochrane Library, Scopus, Embase, and Science Direct. The study exclusively included clinical trials involving healthy adults, where pharmacokinetic parameters were measured following the oral administration of at least one dose of resveratrol as a single preparation. For the meta-analysis data extraction, the mean score and standard deviation (SD) were included. Heterogeneity, degree of inconsistency between studies, and meta-regression were assessed. From these searches, we scrutinized data from 84 oral administrations encompassing nine resveratrol doses ranging from 25 to 5000 mg. Our findings indicate a linear increase in the amount of free resveratrol entering the bloodstream with the administered dose, while Tmax values remain unaffected. The mean maximum plasma concentration of resveratrol (31.07 ng/mL) closely mirrors the mean Cmax observed in the group administered a medium resveratrol dose ranging from 100 to 500 mg (33.59 ng/mL). This similarity implies the appropriateness of employing these specific doses of resveratrol, taking into consideration both its bioavailability and very low risk of potential side effects. However, the analysis of available human oral bioavailability data is constrained by methodological inconsistencies prevalent in existing studies. The meta-analysis underscores substantial heterogeneity, underscoring the imperative for multiple studies to rectify this prevailing trend.

Comparison of a fixed-dose combination of Celecoxib/PG201 [Layla®] versus co-administration of individual formulations in healthy participants: A randomized trial.

Osteoarthritis (OA) is a prevalent joint disease affecting the spine, hands, hips, knees, and feet. However, definitive drugs for OA are lacking, and current treatments are limited owing to inconvenient administration, inadequate functional improvement, and long-term side effects including gastrointestinal and cardiovascular adverse events. Therefore, in this study, we aimed to assess the pharmacokinetics and safety profiles of PK101, a fixed-dose combination (FDC) comprising PG201, a 12-herb extract used in OA treatment in traditional East Asian medicine, and celecoxib, a selective cyclooxygenase-2 inhibitor, by comparing its administration as an FDC and the corresponding individual formulations in healthy subjects. A randomized, open-label, single-dose, 2 × 2 crossover design with a cohort of healthy participants. All subjects received a single FDC tablet (405.4 mg PG201 and 100 mg celecoxib) or the individual formulations, with 7-day washout period between administrations. The estimation of maximum plasma concentration and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration of celecoxib involved determining the geometric mean ratios and 90% confidence intervals of the FDC compared to its individual formulations. Forty-six participants were enrolled; however, only 44 completed the study. The geometric mean ratios (90% confidence intervals) for the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration and maximum plasma concentration of celecoxib were 1.1124 (1.0601-1.1672) and 1.2788 (1.1708-1.3969), respectively. The time of maximum plasma concentration range was 1.0 to 4.0 hours and 1.0 to 6.0 hours (minimum-maximum) for the FDC and individual formulations, respectively. Seven adverse events occurred in 6 subjects. The systemic exposure and safety profiles of the individual and FDC formulations were similar, supporting their potential as an innovative and effective therapeutic approach for OA treatment. All relevant data are within the paper and its Supporting Information files.

A Single-Dose Study to Evaluate the Relative Bioavailability, Safety, and Tolerability of Monthly Extended-Release Buprenorphine at Alternative Injection Locations in Adult Participants with Opioid Use Disorder.

Buprenorphine extended-release monthly formulation (BUP-XR, SUBLOCADE®) is approved for treatment of moderate-to-severe opioid use disorder (OUD) following subcutaneous injection in the abdomen. This open-label pharmacokinetic study assessed three alternative injection locations (upper arm, thigh, buttocks) to offer additional flexibility considering the chronic nature of the disease and patient preferences. Following stabilization on 12/3 mg/day of sublingual buprenorphine/naloxone for ≥ 7 days, participants with moderate-to-severe OUD were randomized to receive a single 300-mg BUP-XR injection in the upper arm, thigh, buttocks, or abdomen (reference). Serial blood samples were taken to measure buprenorphine plasma concentrations over 28 days and assess buprenorphine relative bioavailability. Safety evaluations included treatment-emergent adverse events and assessments of injection site pain, tenderness, erythema, induration, and swelling. A total of 88 participants received a single subcutaneous injection of 300-mg BUP-XR in the upper arm (N = 21), thigh (N = 23), buttocks (N = 22), or abdomen (N = 22); 81/88 (92%) completed the study. Buprenorphine plasma exposure (area under the plasma concentration-time curve over 28 days) was comparable across injection site groups with mean buprenorphine plasma concentrations sustained at approximately 2 ng/mL (therapeutic target concentration) or above. Buprenorphine maximum plasma concentration (Cmax) was approximately 39% and 52% higher after injection in the upper arm and thigh, respectively, versus the abdomen, while comparable between buttocks and abdomen. Higher Cmax values were not associated with an increased incidence of adverse events. Safety and injection site tolerability were comparable across injection groups. These pharmacokinetic and safety findings support BUP-XR injection into the upper arm, thigh, and buttocks. Clinicaltrials.gov: NCT05704543.

Dosing, Toxicity and Drug Concentrations for Ganciclovir/Valganciclovir in Preterm and Low Birthweight Infants Treated for Cytomegalovirus

Background: There is a lack of data regarding suitable dosage when administering intravenous ganciclovir (GCV) or oral valganciclovir (valGCV) to preterm and low birthweight infants with cytomegalovirus (CMV) disease. Methods: Data were collected for infants born before 32 weeks gestation and/or weighing less than 1.8 kg treated for CMV disease with GCV or valGCV between 2016 and 2023. Results: Twenty-four infants (58% males and 48% Asian ethnicity) with a median gestation of 31 weeks [interquartile range (IQR): 26.6–36.1], median weight of 950 g (IQR: 470–1692) and median age of 45 days (IQR: 6–84) at initiation of treatment were included. Seventeen infants were treated for symptomatic postnatal CMV and 7 for symptomatic congenital CMV. Most infants receiving GCV had 6 mg/kg twice daily dosing and most receiving valGCV had 16 mg/kg twice daily dosing. Fourteen infants had drug concentrations measured with combined geometric mean minimum blood plasma concentration (Cmin) of 2.44 mg/L and maximum blood plasma concentration of 7.98 mg/L for doses of 6 mg/kg GCV and 16 mg/kg valGCV, which is higher compared with term infants. The estimated area under the curve at 12 hours (AUC0–12h) was 54.34 mg × h/L, which doubled the value for term infants in a previous study. Notably, AUC0–12h had an inverse relationship with gestational age and weight. Infants with lower gestation and higher Cmin showed a higher tendency for more than 1 adverse effect. Conclusions: GCV and valGCV use among preterm and very low birthweight infants with CMV disease resulted in a higher incidence of adverse events, increased AUC0–12h and elevated Cmin compared with term infants. Further pharmacokinetic studies are necessary to determine the ideal dosage in this population.

Pharmacokinetics of Salbutamol in Thoroughbred Horses After a Single Intravenous or Inhaled Administration.

Salbutamol is a short-acting and selective beta-2 adrenergic agonist. Inhaled (IH) administration of salbutamol is widely used to control lower respiratory tract disease in horses. Here, we estimated the pharmacokinetic parameters of salbutamol after a single intravenous (IV) or IH administration in six horses, and we statistically analysed the detection times with various dosing regimens. Plasma and urine concentrations of salbutamol were measured by liquid chromatography-tandem mass spectrometry, and data were modelled by using a nonlinear mixed effect model followed by Monte Carlo simulation (MCS). With IH salbutamol, the maximum plasma concentration was 0.12 ± 0.06 ng/mL at 0.29 ± 0.17 h after administration. Typical values were, for clearance, 1.53 L/kg/h; distribution volume at steady state, 5.43 L/kg; terminal half-life, 6.06 h; IH bioavailability, 19.0%; and urine to plasma ratio, 2057. Statistically estimated 95th percentile detection times in the urine at levels below the international screening limit (0.5 ng/mL) proposed by the International Federation of Horseracing Authorities, as simulated in 5000 horses by MCS, were 44 h after 1.6 μg/kg q 24 and 54 h after 1.6 μg/kg q 4 h over a 3-day IH administration period.

Comparative Pharmacokinetics and Egg Residues of Amoxicillin, Single and in Combination with Bromhexine, in Laying Hens.

The need for antibiotics in commercial laying hens is increasing owing to intensive farming systems. Amoxicillin trihydrate (AMX), an aminopenicillin β-lactam antibiotic, exerts broad bactericidal activity. However, its short half-life necessitates frequent administration to ensure efficacy, thus limiting its use. Herein, we investigated the effect of concurrent administration of bromhexine hydrochloride (BRM), a mucolytic agent, on AMX pharmacokinetics, performing a comparative pharmacokinetic analysis of AMX administration alone and in combination with BRM. AMX (50 mg/kg) was administered by oral gavage once daily for three days alone or in combination with 10 mg/kg BRM. Plasma and egg samples were collected to evaluate pharmacokinetic profiles and egg residues. The area under the curve and maximum plasma concentration values were significantly higher in the AMX + BRM group than the AMX only group. However, there were no significant differences in AMX half-life in the elimination phase (T1/2), elimination rate constant (kel), or apparent clearance (CL/F) values. In the egg residue study, the withdrawal period for AMX was 5 days in both groups, with no significant difference when using the maximum residue limit (MRL) of 10 μg/kg. The concentration of BRM in the eggs remained at 100 μg/kg up to the fourth day following drug administration. Conclusion: These results confirmed that BRM co-administration increased systemic exposure to AMX, with a negligible residual impact of amoxicillin in eggs.

A Phase I Study of the Pharmacokinetics, Pharmacodynamics, and Safety of Liposomal Bupivacaine for Sciatic Nerve Block in the Popliteal Fossa for Bunionectomy.

This trial assessed the pharmacokinetics, pharmacodynamics, and safety of liposomal bupivacaine given via ultrasound-guided popliteal sciatic nerve block with or without immediate-release bupivacaine hydrochloride in adults having bunionectomies. Forty-five adults were enrolled into four sequential cohorts: (1) liposomal bupivacaine 266 mg with bupivacaine hydrochloride 50 mg; (2) liposomal bupivacaine 133 mg with bupivacaine hydrochloride 50 mg; (3) liposomal bupivacaine 266 mg; or (4) bupivacaine hydrochloride 100 mg. Outcomes included pharmacokinetics (e.g., bupivacaine maximum plasma concentration [Cmax]), onset and duration of motor and sensory nerve block, and safety. Liposomal bupivacaine admixed with bupivacaine hydrochloride produced biphasic bupivacaine plasma disposition profiles with two distinct peaks. Geometric mean Cmax of the early peak ranged from 235 to 421 ng/mL and the geometric mean of the late Cmax was ∼30%-50% lower than the early peak. Median time to sensory block onset was 18 to 29 min in all cohorts. Sensory blocks lasted about twice as long with liposomal bupivacaine (median, 119-167 h) than with bupivacaine hydrochloride alone (median, 67 h). There were no serious adverse events. In conclusion, liposomal bupivacaine provided prolonged sensory nerve block when given as popliteal sciatic nerve blocks with or without bupivacaine hydrochloride, and bupivacaine plasma concentrations were well below the lower bound of the toxicity threshold of 2000 ng/mL for all cohorts.

Comparative bioavailability of single-dose zavegepant during and between migraine attacks: A phase 1, randomized, open-label, fixed-sequence, two-period study.

To compare the rate and extent of absorption of zavegepant 10 mg (therapeutic dose) or 20 mg (supratherapeutic dose) nasal spray during a migraine attack versus non-migraine period, assess safety, and explore efficacy and the relationship between zavegepant concentration and therapeutic response. Physiologic changes occurring during a migraine attack could affect the pharmacokinetics of treatments for migraine. This was a Phase 1, multicenter, open-label, randomized, single-dose, two-period, fixed-sequence, comparative bioavailability study. Participants with a history of 2-8 migraine attacks per month of moderate or severe pain intensity were randomized to a single dose of zavegepant 10 or 20 mg, administered intranasally during a migraine attack (Period 1) and in a non-migraine period (Period 2). Blood samples were collected pre-dose and at pre-specified intervals up to 24 h post-dose for plasma zavegepant concentration measurement. Safety was monitored throughout, and efficacy (migraine pain intensity score, nausea, photophobia, phonophobia, aura, and functional disability) assessed during Period 1. Plasma zavegepant pharmacokinetic parameters were calculated by standard noncompartmental methods, including maximum plasma concentration (Cmax), area under plasma concentration-time curve from time zero to infinity (AUC0-inf), and time of Cmax (Tmax). A total of 37 participants were evaluable for pharmacokinetics. Following administration of zavegepant 10 mg, geometric mean ratios for Period 1/Period 2 were 82.8% (90% confidence interval [CI] 60.5-113.2) for Cmax and 90.1% (90% CI 70.2-115.5) for AUC0-inf. Following administration of zavegepant 20 mg, geometric mean ratios for Period 1/Period 2 were 72.5% (90% CI 57.9-90.8) for Cmax and 73.4% (90% CI 58.8-91.7) for AUC0-inf. Averaging over the study period, geometric mean ratios for zavegepant 20 mg/10 mg were 142.5% (90% CI 118.6-171.4) for Cmax and 157.0% (90% CI 133.6-184.5) for AUC0-inf. Median Tmax was 0.5 h for both doses regardless of Period. Zavegepant was well tolerated in both study periods and effective during Period 1 at both dose levels. There was no apparent correlation between concentration at 0.5 h or 2 h post-dose and efficacy outcomes. Zavegepant exposure was comparable during a migraine attack and a non-migraine period, particularly at the therapeutic dose of 10 mg. When averaging over migraine and non-migraine periods, there was a less-than-dose proportional increase in zavegepant exposure when the dose was doubled from 10 to 20 mg. The median Tmax was 0.5 h regardless of migraine attack or dose. Zavegepant 10 and 20 mg exhibited favorable safety profiles during migraine attacks and non-migraine periods, and were effective to relieve pain, associated symptoms, and functional disability during migraine attacks, with no apparent correlation between zavegepant concentration and efficacy outcomes.

Walnut-derived peptides cross the blood–brain barrier and ameliorate Aβ-induced hypersynchronous neural network activity

Walnut peptides exhibit promising neuroprotective effects; however, they must be absorbed in their intact form through the gastrointestinal tract into the bloodstream and brain. In this study, the effects of the walnut peptide TWLPLPR (TW-7) were evaluated in mice, including its absorption and distribution ability to cross the blood–brain barrier, and inhibitory effects on hyperactivity of primary hippocampal neurons. TW-7 was stable in plasma, and the peptide retention rate was 88.19 ± 0.70 % after 48 h. In vitro imaging indicated that TW-7 was distributed in the brain, liver, lungs, and kidneys of mice after gavage, and an immunofluorescence analysis indicated that TW-7 could accumulate in mouse brain parenchyma; in addition, TW-7 reached its maximum concentration (5.36 ± 1.59 µg/mL) in plasma 2 h after gavage, and reached its peak concentration (0.95 ± 0.19 µg/g) in brain tissue 4 h after gavage. Microelectrode array and immunofluorescence analyses confirmed that TW-7 ameliorates the overexcitation of primary hippocampal neurons induced by Aβ25–35 through inhibiting the excessive release of glutamate and protecting synaptic structure and function. These results suggest that TW-7 can penetrate the blood–brain barrier in mice and positively affect the electrophysiological activity of neurons. More broadly, these findings provide a theoretical basis for the development and application of walnut peptide-based functional food for Alzheimer’s disease intervention.

CYP3A4-mediated metabolism of artemisinin to 10β-hydroxyartemisinin with comparable anti-malarial potency.

The most widely used anti-malarial drug artemisinin (ART) is metabolized extensively, but the therapeutic capacity of its major metabolite remains unknown. Whether the major metabolite of ART (ART-M) contributes to its antiplasmodial potency was investigated in this study. The metabolite identification and enzyme phenotyping of ART were performed using human liver microsomes (HLMs). The stereostructure of the major metabolite ART-M was elucidated by spectroscopic and X-ray crystallographic analysis. The anti-malarial activity of ART-M against two reference Plasmodium strains (Pf3D7 and PfDd2) was evaluated. The pharmacokinetic profiles of ART and its metabolite ART-M were investigated in healthy Chinese subjects after a recommended two-day oral dose of ART plus piperaquine. Pharmacodynamic parameters based on minimum inhibitory concentration (MIC50) and free plasma concentration were employed to evaluate the therapeutic potency of ART-M, including fAUC0-t/MIC50, fCmax/MIC50 and T > MIC50. A major metabolite 10β-hydroxyartemisinin (ART-M) was found for ART in human, and CYP3A4/3A5 was the major enzymes responsible for ART 10β-hydroxylation. Compared with ART (MIC50, 10.1nM against Pf3D7), weaker antiplasmodial activity was found for ART-M (MIC50, 61.4nM against Pf3D7). However, a 3.5-fold higher maximal free plasma concentration was achieved for ART-M (fCmax, 180.0nM vs. 51.8nM for ART). ART-M displayed comparable antiplasmodial potency to ART, in terms of fAUC0-t/MIC50 (12.5h), fCmax/MIC50 (2.8) and T > MIC50 (5h). The major metabolite 10β-hydroxyartemisinin contributes to the antiplasmodial efficacy of ART, which should be considered when evaluation of ART dosing regimens and/or clinical outcomes.

A Pharmacokinetic and Bioavailability Study of Ecklonia cava Phlorotannins Following Intravenous and Oral Administration in Sprague-Dawley Rats.

This study examines the pharmacokinetics and bioavailability of phlorotannins from Ecklonia cava in rats following intravenous and oral administration. Known for their potent antioxidant, anti-inflammatory and many other bioactivities, these phlorotannins, particularly dieckol, 8,8'-bieckol, and phlorofucofuroeckol-A (PFF-A), were analyzed using high-performance liquid chromatography coupled with tandem mass spectrometry. Intravenous administration at 10 mg/kg allowed detectability in plasma for up to 36 h for dieckol and 8,8'-bieckol, but only 2 h for PFF-A. Oral administration at doses of 100 mg/kg and 1000 mg/kg showed limited detectability, indicating low bioavailability and rapid clearance, particularly for PFF-A. The pharmacokinetic data suggest non-linear increases in the maximum plasma concentration (Cmax) and area under the curve (AUC) with increasing doses, pointing to significant challenges in achieving systemic availability of these eckols through oral administration. This study underscores the necessity for advanced formulation strategies and alternative routes of administration to enhance systemic bioavailability. At the same time, this result also suggests their effects may be through non-systemic pathways such as gut microbiome modulation or lipid-rich tissue targeting. The findings lay a crucial foundation for the further development of Ecklonia cava phlorotannins as therapeutic agents, offering insights into their pharmacokinetic behavior and informing enhancements in future clinical utility.