Terminal Elimination Half-life Research Articles

Clinical pharmacokinetics and pharmacodynamics of ongericimab: A potential long-acting PCSK9 monoclonal antibody in healthy subjects and patients with hypercholesterolemia: Randomized, double-blind, placebo-controlled phase Ia and Ib/II studies.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases plasma low-density lipoprotein-cholesterol (LDL-C) by decreasing the expression of the LDL-receptor on hepatic cells. Ongericimab (JS002) is a novel PCSK9 monoclonal antibody that exhibits a long-acting LDL-C lowering effect by exclusively inhibiting PCSK9 in pre-clinical studies. Two randomized, double-blind, placebo-controlled trials were conducted to evaluate the safety, tolerability, efficacy, immunogenicity, pharmacokinetic, and pharmacodynamic profiles of ongericimab in healthy subjects and patients with hypercholesterolemia. Eighty-four healthy subjects in the phase Ia study received a single dose of placebo or ongericimab (15-450 mg). Ninety patients with hypercholesterolemia in the phase Ib/II study received placebo or ongericimab 150 mg Q2W, 300 mg Q4W, or 450 mg Q4W for 12 weeks. Ongericimab exhibited non-linear kinetics. The apparent clearance decreased as the dosage increased, with terminal elimination half-life (t1/2) values of 4.5-6.5 days. Overall, ongericimab was well tolerated in both studies. A single dose of ongericimab reduced LDL-C levels by 30%-73% in healthy subjects, and repeated doses of ongericimab reduced LDL-C levels by 67%-80% in patients with hypercholesterolemia. At the end of the dosing interval in the phase Ib/II study, over 70% of patients' LDL-C levels decreased by more than 50% from baseline. The results showed that ongericimab had a significant long-acting LDL-C lowering effect with good safety and potential for clinical application.

Clinical Pharmacology of Asciminib: A Review.

Asciminib is a first-in-class allosteric inhibitor of the kinase activity of BCR::ABL1, specifically targeting the ABL myristoyl pocket (STAMP). This review focuses on the pharmacokinetic (PK) and pharmacodynamic data of asciminib, which is approved at a total daily dose of 80 mg for the treatment of adult patients with chronic myeloid leukemia in chronic phase who are either resistant or intolerant to ≥ 2 tyrosine kinase inhibitors or those harboring the T315I mutation (at a dose of 200 mg twice daily). Asciminib is predicted to be almost completely absorbed from the gut, with an absolute bioavailability (F) of approximately 73%. It should be administered in a fasted state, as food (particularly high-fat meals) reduces exposure. Asciminib displays a slightly greater than dose-proportional increase in exposure, with no time-dependent changes in PK observed following repeated dosing. This drug shows low clearance (6.31 L/h), with a moderate volume of distribution (111 L) and high human plasma protein binding (97.3%). The apparent terminal elimination half-life (t1/2) across studies was estimated to be between 7 and 15h. The PK of asciminib is not substantially affected by body weight, age, gender, race, or renal or hepatic impairment. Asciminib is primarily metabolized via CYP3A4-mediated oxidation (36.0%) and UGT2B7- and UGT2B17-mediated glucuronidation (13.3% and 7.8%, respectively); biliary secretion via breast cancer resistance protein contributes to about 31.1% to total systemic clearance, which is mainly through hepatic metabolism and biliary secretion through the fecal pathway, with renal excretion playing a minor role. The potential for PK drug interaction for asciminib both as a victim and a perpetrator has been summarized here based on clinical and predicted drug-drug interaction studies. Robust exposure-response models characterized asciminib exposure-efficacy and exposure-safety relationships. In patients without the T315I mutation, the exposure-efficacy analysis of the time course of BCR::ABL1IS percentages highlighted the existence of a slightly positive, albeit not clinically significant, relationship. Higher exposure was required for efficacy in patients harboring the T315I mutation compared with those who did not. The exposure-safety relationship analysis showed no apparent association between exposure and adverse events of interest over the broad range of exposure or dose levels investigated. Asciminib has also been shown to have no clinically relevant effect on cardiac repolarization. Here, we review the clinical pharmacology data available to date for asciminib that supported its clinical development program and regulatory applications.

Toward Analytical Performance Specifications for Immunosuppressive Drug Quantification in Transplantation: An Opinion Article.

Analytical methods require performance that meets the clinical needs. Different approaches for setting up permissible analytical imprecision goals (pCVA%) for drug analyses have been reported. The aim of this study was to calculate the pCVA% for cyclosporine, tacrolimus, everolimus, sirolimus, and mycophenolic acid using 4 alternative approaches, to compare the results and to critically discuss advantages and disadvantages of each model. The approaches to evaluate pCVA% were (A) based on biological variation observed in routine measurement results between 2022 and 2023 in the authors' laboratory, (B) derived from the terminal elimination half-life and dosing interval of the drugs, and (C and D) explored from the width of the therapeutic ranges (TR) by the 2 methods. For approach A, routine measurement data for cyclosporine and tacrolimus, obtained through liquid chromatography-tandem mass spectrometry and electrochemiluminescence immunoassays, were evaluated separately. The 4 alternative approaches for deriving pCVA% yielded similar results, for cyclosporine and tacrolimus in an analytical method dependent manner. The average pCVA% was 5.2%, 5.6%, 5.1%, 4.8%, and 7.7% for cyclosporine, tacrolimus, everolimus, sirolimus, and mycophenolic acid, respectively. The most challenging goals were those using TR-related approaches, while those using the biological variation approach were most easily achievable. Approach B resulted in more stringent goals for drugs with longer elimination half-lives (eg, everolimus and sirolimus). There is no single ideal approach for setting goals of drug analysis. However, the pCVA% values derived from the various approaches are similar and confirm that a <6% target proposed by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology is adequate and realistic in combination with state-of-the-art measurement technologies. In the authors' opinion, approaches based on the width of the TR are preferable, as they represent a common basis for clinical decisions and reflect elements of biological variation and analytics used to establish the TR.

Mosquitocidal efficacy and pharmacokinetics of single-dose ivermectin versus three-day dose regimen for malaria vector control compared with albendazole and no treatment: An open-label randomized controlled trial

ObjectivesWhen malaria vectors consume ivermectin in a blood meal, their survival probability decreases, potentially reducing malaria transmission during mass drug administrations. However, questions remain regarding the optimal dosing. This study aimed to compare the mosquitocidal effect and pharmacokinetics of two-dose regimens of ivermectin for malaria vector control. DesignWe conducted an open-label randomized control trial in Kenya, staggered in blocks with sequential intervention groups and parallel controls. Participants were randomly assigned (2:1:1:1) using computer random-sequence generation, unstratified, with one block of six pharmacokinetics-only participants (single-dose ivermectin) and six blocks of four participants (3:1 intervention vs control), to receive single-dose ivermectin (400 mcg/kg, n = 12), three daily doses (3-day regimen 300 mcg/kg, n = 6), albendazole (400 mg, n = 6), or no treatment (negative control, n = 6). Our primary outcome was Anopheles gambiae survival (time-to-event [days]) after blood feeding up to 10 days after drug administration. We also evaluated pharmacokinetics (peak plasma and capillary blood concentration, areas under the plasma and capillary blood concentration-time curve from time of last administration to time of last observation, time to reach peak plasma and capillary blood concentration, terminal elimination half-life) up to 7 days after treatment. ResultsA total of 36 healthy volunteers aged 21-32 years were recruited into the study and followed up to completion, with two participants not attending the visit on day 28. All drug regimens were well-tolerated. Both regimens showed significant mosquitocidal effect in the first 7 days. At 10 days after treatment, the single dose presented superior longevity of effect (adjusted hazard ratio = 3.91; 95% confidence interval = 1.93-7.93; P <0.001) compared with the triple dose (adjusted hazard ratio = 1.79; 95% confidence interval = 0.88-3.62; P = 0.0.11). Albendazole had, overall, no mosquitocidal effect. ConclusionsIt is unclear why a single dose led to increased bio-efficacy compared with a triple dose. We recommend trials investigating ivermectin mass drug administrations for malaria control to consider single-dose ivermectin. A single-dose regimen is also expected to present additional operational advantages compared with a 3-day regimen, leading to improved programmatic suitability.

Effect of Salbutamol on the Disposition Kinetics of Levofloxacin in the Plasma and Lung of Rats.

Antibiotics and bronchodilator drugs can be used together in respiratory distress caused by bacterial infections. Levofloxacin (LVX) and Salbutamol (SLB) can be used simultaneously in respiratory distress. However, there have been no investigations on how the concurrent use of SLB can affect the pharmacokinetics of LVX in rats. The purpose of this study was to investigate the influence of SLB on the plasma and lung pharmacokinetics of LVX in rats. A total of 132 rats were randomly assigned to two groups: LVX (n=66) and LVX+SLB (n=66). LVX (intraperitoneal) and SLB (oral) were administered to rats at doses of 50 and 3 mg/kg, respectively. The concentrations of LVX in the plasma and lungs were determined through the utilization of high-performance liquid chromatography along with UV. Pharmacokinetic parameters were assessed by non-compartmental analysis. The area under the curve from 0 to 16 h (AUC0-16), terminal elimination half-life, volume of distribution, total body clearance, and peak concentration of LVX in the plasma were 42.57 h*μg/mL, 2.32 h, 3.91 L/kg, 1.17 L/h/kg, and 23.96 μg/mL, respectively. There were no alterations observed in the plasma and lung pharmacokinetic parameters of LVX when co-administered with SLB. The AUC0-16 lung/AUC0-16 plasma ratios of LVX were 1.60 and 1.39 after administration alone and co-administration with SLB, respectively. The concentration of LVX in lung tissue was higher than that in plasma. SLB administration to rats did not affect the plasma and lung pharmacokinetics and lung penetration ratio of LVX. There is a need to reveal the change in the pharmacokinetics of LVX after multiple administration of both drugs and after administration of SLB by different routes.

Pharmacokinetics and Bioavailability Study of a Novel Smoothened Inhibitor TPB15 for Treatment of Triple-Negative Breast Cancer in Rats by High Performance Liquid Chromatography-Mass Spectrometry.

Smoothened (SMO), a key component of the hedgehog signaling pathway, represents a therapeutic target for triple negative breast cancer(TNBC), yet the chemotherapy response rate in TNBC patients is only 40-50%, underscoring the urgent need for the development of novel drugs to effectively treat this condition. The novel compound TPB15, an SMO inhibitor derived from [1,2,4] triazolo [4,3-α] pyridines, demonstrated superior anti-TNBC activity and lower toxicity compared to the first SMO inhibitor vismodegib in both in vitro and in vivo. However, the compound's pharmacokinetic properties remain unclear. The present work aims to develop a simple HPLC-MS/MS method to profile the pharmacokinetics and bioavailability of TPB15 in rats as a ground work for further clinical research. Separation was performed on an Agilent ZORBAX StableBond C18 column by gradient elution using acetonitrile and 0.1% formic acid as mobile phase at a flow rate of 0.3mL/min. Multiple reaction monitoring(MRM) in positive mode with the transitions of m/z 454.2 → 100.0, 248.1 → 121.1 was employed to determine TPB15 and internal standard tinidazole, respectively. The specificity, intra- and inter- day precision and accuracy, extraction recovery, stability, matrix effect, dilution integrity and carryover of the method was validated. The pharmacokinetics and bioavailability studyof TPB15 were carried out on rats through intravenous injection at the dose of 5 mg/kg and oral gavage at the dose of 25 mg/kg, and the pharmacokinetics parameters were calculated by the non-compartment analysis using the pharmacokinetics software DAS 2.1.1. The values of specificity, intra- and inter- day precision and accuracy, extraction recovery, stability, matrix effect, dilution integrity and carryover satisfied the acceptable limits. The lower limit of quantification of this method was 10 ng/mL with a linear range of 10-2000ng/mL. The validated method was then applied to pharmacokinetics and bioavailability studies in rat by dosing with gavage (25mg/kg) and intravenous injection(5mg/kg), and the oral bioavailability of TBP15 in rat was calculated as 16.4 ± 3.5%. The pharmacokinetic parameters were calculated as following: maximum of plasma concentration (Cmax) (PO: 2787.17 ± 279.45µg/L), Time to maximum plasma concentration (Tmax) (PO: 4.20 ± 0.90 h), the area under the concentration-time curve 0 to time (AUC0-t) (PO: 17,373.03 ± 2585.18 ng/mL·h, IV: 21,129.79 ± 3360.84ng/mL·h), the area under the concentration-time curve 0 to infinity (AUC0-∞) (PO: 17,443.85 ± 2597.63 ng/mL·h, IV: 17,443.85 ± 2597.63ng/mL·h), terminal elimination half-life (t1/2) (PO: 7.26 ± 2.16h, IV: 4.78 ± 1.09h). TPB15, a promising candidate for treating TNBC, hasdemonstrated outstanding efficacy and safety in vitro and in vivo. This study established a simple, sensitive, and rapid HPLC-MS/MS bioanalytical method, developed and validated in accordance with FDA and EMA guidelines, for conducting pharmacokinetic and bioavailability studies of TPB15. The results revealed a favorable pharmacokinetic profile owing to its long t1/2. Nevertheless, the next phase of research should include formulation screening to enhance bioavailability, as well as clinical trials, metabolism pathway analysis, and assessment of potential drug-drug interactions.

Ocular and Systemic Pharmacokinetics of Lotilaner Ophthalmic Solution, 0.25%, Following a Single Dose or Repeated Doses in Dutch-Belted Rabbits.

Purpose: To evaluate the ocular and systemic pharmacokinetics of lotilaner ophthalmic solution, 0.25%, following bilateral topical ocular administration of single and repeated doses in rabbits. Methods: Dutch-belted rabbits (n = 34) were administered lotilaner ophthalmic solution, 0.25%, eye drops, either in a single bilateral dose (Group 1) or twice a day bilaterally for 7 days and once on Day 8 (Group 2). The pharmacokinetics and tissue distribution levels of lotilaner were assessed following the single dose in Group 1 and the last dose in Group 2. The drug levels were examined in various ocular tissues and whole blood. The maximal concentration of the drug (Cmax), time to maximal concentration, the terminal phase elimination half-life, the area under the concentration-time curve (AUC), and total clearance of the drug were determined. Results: In the eyelid margins, lotilaner exhibited the highest observed concentrations at 0.25 hour (h), presenting a mean Cmax of 14,600 ng/mL in Group 1 and 20,100 ng/mL in Group 2. The highest AUC was in the eyelid margin at 242,000 h×ng/mL in Group 1 and 535,000 h×ng/mL in Group 2. In the eyelid margin, the observed clearance rate (0.634 mL/h in single dose, 0.288 mL/h in repeat dose) was the slowest among all ocular tissues in both groups, with the longest half-life of 152 h (∼6.3 days) observed in the repeat dose group. Conclusions: Lotilaner ophthalmic solution, 0.25%, demonstrated rapid ocular tissue absorption into the eyelid margin tissue with a long half-life of almost a week. No adverse effects were observed following topical ocular administration in Dutch-belted rabbits.

Estimation of withdrawal interval recommendations following administration of fenbendazole medicated feed to ring-necked pheasants (Phasianus colchicus).

Prescribing fenbendazole medicated feed for pheasants in the USA is considered extra-label drug use under CPG Sec 615.115, and a safe estimated withdrawal interval (WDI) must be applied following administration to this minor food-producing species. This study sought to determine the pharmacokinetic and residue depletion profile for fenbendazole and its major metabolites to estimate a WDI for pheasants following fenbendazole administration as an oral medicated feed. Pheasants (n = 32) were administered fenbendazole as an oral medicated feed (100 ppm) for 7 days. Fenbendazole, fenbendazole sulfoxide, and fenbendazole sulfone (FBZ-SO2) in liver and muscle samples were analyzed using HPLC-UV. Tissue WDIs were estimated using FDA, European Medicines Agency (EMA), and half-life multiplication methods for US poultry tolerances, EMA maximum residue limits, and the analytical limit of detection (LOD; 0.004 ppm). Terminal tissue elimination half-lives (T1/2) were estimated by non-compartmental analysis using a naïve pooled data approach. The tissue T1/2 was 14.4 h for liver, 13.2 h for thigh muscle, and 14.1 h for pectoral muscle. The maximum estimated withdrawal interval was 153 h (7 days) for FBZ-SO2 in pectoral muscle using the FDA tolerance method (95% confidence interval for the 99th percentile of the population), and the LOD as the residue limit. The results from this study support the use of FBZ-SO2 as the marker residue in the liver of pheasants and the provision of evidence based WDIs following the extra-label administration of fenbendazole medicated feed (100 ppm) for 7 days.

A Phase I Study To Determine the Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of Capivasertib in Healthy Male Participants.

An open-label, single-center, phase I study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, and excretion of capivasertib-a potent, selective AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose of capivasertib (400 mg; tablets) followed by a [14C]-radiolabeled intravenous microdose of capivasertib (100 μg). After a 14-day washout, five of the participants proceeded to part 2 and received a single oral dose of [14C]capivasertib (400 mg; solution). In part 1, median time of maximum observed concentration for capivasertib was 1.7 hours, geometric mean terminal elimination half-life was 12.9 hours, and absolute bioavailability was estimated at 28.6% (90% confidence interval, 23.9 to 34.2). In part 2, a high proportion of the administered radioactivity was recovered over the 168-hour sampling period [mean recovery: 95.1% (feces, 50.4%; urine, 44.7%)]. Unchanged capivasertib in urine accounted for 7.4% of the total dose and 21.1% of the systemically available drug. Geometric mean renal clearance was 8.3 L/h, suggesting active tubular secretion. Twelve metabolites were identified in plasma. M11 (AZ14102143)-the glucuronide conjugate of capivasertib, inactive as an AKT serine/threonine kinase inhibitor-was the most abundant, accounting for a mean 78.4% of the plasma drug-related area under the curve. Of 22 metabolites identified in excreta, M11 was the most abundant (mean 28.2% of administered dose), indicating direct glucuronidation as one of the major routes of metabolism. No new safety concerns were identified. SIGNIFICANCE STATEMENT: This study provides characterization of the pharmacokinetics of capivasertib-a potent, selective AKT serine/threonine kinase (AKT) inhibitor-including absolute bioavailability, mass balance, and metabolic fate in humans; the findings are being used to inform further clinical development. Absolute bioavailability was estimated at 28.6%, and mean recovery of the administered dose in excreta over 168 hours was 95.1%. M11 (AZ14102143)-the glucuronide conjugate, inactive as an AKT inhibitor-was the most abundant identified metabolite in plasma and excreta.

Exploring the multiple effects of nifedipine and captopril administration in spontaneously hypertensive rats through pharmacokinetic-pharmacodynamic analyses.

This study assessed the pharmacokinetics (PKs) and pharmacodynamics (PDs) of two antihypertensive drugs, nifedipine and captopril, by exploring their main (blood pressure [BP]) and secondary effects (heart rate [HR] and QT interval [QT]) in spontaneously hypertensive rats. This study aimed to assess the relationship between PKs and PDs. Using these PD parameters, BP, HR, and QT during coadministration were estimated. The coadministration of nifedipine and captopril resulted in an increase in nifedipine's total body clearance (CLtot) and a reduction in its mean residence time (MRT) with an increase in the terminal elimination half-life (t1/2) and volume of distribution at steady state (Vdss) of captopril. However, no significant PK interactions were observed. During monotherapy, BP reduced rapidly following nifedipine infusion. Subsequently, despite the increase in nifedipine plasma concentration, BP recovered, likely because of homeostasis. Similar results were observed with coadministration. Subsequently, BP demonstrated a sustained reduction that was greater than or equal to the additive effect estimated from each PK. Captopril exhibited a minimal effect on HR, except for a transient increase observed immediately after starting infusion, consistent with observations during coadministration. Subsequently, the HR reduction was nearly equal to that calculated from the nifedipine PK. QT prolongation was more rapid with captopril than with nifedipine. Although QT prolongation during the initial 60 min of coadministration was approximately the sum of both effects, the recovery period to baseline QT was faster than that in the simulation.

Pharmacokinetic study of Q808 in rhesus monkey using liquid chromatography-tandem mass spectrometry.

Q808 is a novel antiepileptic agent currently in development. In this study, we established and validated a LC-MS/MS method for the quantification of Q808 in Rhesus monkey plasma. Furthermore, we applied this method to investigate the pharmacokinetics of Q808 in Rhesus monkeys. Samples containing diazepam as an internal standard (IS) were subjected to liquid-liquid extraction (LLE) and separated using a Zorbax Extend C18 column. The detection of Q808 and IS was performed using multiple reaction monitoring mode (MRM), specifically monitoring precursor-to-product ion transitions at m/z 297.9 to 213.9 and m/z 285.2 to 193.1 for Q808 and IS, respectively. For the pharmacokinetic study of Q808, a total of 30 healthy Rhesus monkeys (half male and half female) were administered single oral doses, single IV doses, or multiple oral doses of Q808. Blood samples were collected at predetermined time points for subsequent pharmacokinetic analysis. The developed LC-MS/MS method exhibited linearity within the concentration range of 1.5-750ng/mL with intra-day precision ≤8.3% and inter-day precision ≤14.6%. Additionally, accuracy was found to be ≤ 3.4%. In the pharmacokinetic study involving single oral doses of Q808 in Rhesus monkeys, Q808 was absorbed with a median time to peak plasma concentration ranging from 4.50-6.00h and was eliminated with a terminal elimination half-life (t1/2) between 9.34-11.31h. No definitive conclusion regarding linear pharmacokinetic characteristics could be drawn. The absolute bioavailability was determined as 20.95%, indicating limited systemic exposure after oral administration. Multiple dosing did not result in significant accumulation based on an accumulation factor Rac value of 1.31. We have successfully developed and validated a rapid yet sensitive LC-MS/MS method for quantifying levels of Q808 in rhesus monkey plasma for the first time. The determination method and pharmacokinetic characteristics of Q808 in rhesus monkey support the next steps in drug development.

In vitro and in vivo studies on the metabolism and pharmacokinetics of the selective gut microbial β-glucuronidase targeting compound Inh 1

In vitro studies using rat, mouse, and human microsomes and hepatocytes on the bacterial β-glucuronidase inhibitor 1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea) (Inh 1) revealed extensive metabolism in all species. The intrinsic clearances of Inh 1 in human, mouse, and rat hepatic microsomes were 30.9, 67.8, and 201 µL/min/mg, respectively. For intact hepatocytes intrinsic clearances of 21.6, 96.0, and 129 µL/min/106 cells were seen for human, mouse and rat, respectively. The metabolism of Inh 1 involved an uncommon desulphurisation reaction in addition to oxidation, deethylation, and conjugation reactions at multiple sites. Six metabolites were detected in microsomal incubations in human and rat, and seven for the mouse. With hepatocytes, 18 metabolites were characterised, 9 for human, and 11 for mouse and rat. Following IV administration to mice (3 mg/kg), plasma concentrations of Inh 1 exhibited a monophasic decline with a terminal elimination half-life of 0.91 h and low systemic clearance (11.8% of liver blood flow). After PO dosing to mice (3 mg/kg), peak observed Inh 1 concentrations of 495 ng/mL were measured 0.5 h post dose, declining to under 10 ng/mL at 8 h post dose. The absolute oral bioavailability of Inh 1 in the mouse was ca. 26%.

Medication and supplement pharmacokinetic changes following bariatric surgery: A systematic review and meta-analysis.

To evaluate the impact of bariatric surgery on the pharmacokinetic (PK) parameters of orally administered medications and supplements. Systematic searches of bibliographic databases were conducted to identify studies. Pooled effect estimates from different surgical procedures were calculated using a random-effects model. Quantitative data were synthesized from 58 studies including a total of 1985 participants. Whilst 40 medications and 6 supplements were evaluated across these studies, heterogeneity and missing information reduced the scope of the meta-analysis to the following medications and supplements: atorvastatin, paracetamol, omeprazole, midazolam, vitamin D, calcium, zinc, and iron supplements. There were no significant differences in PK parameters post-surgery for the drugs atorvastatin and omeprazole, and supplements calcium, ferritin, and zinc supplements. Paracetamol showed reduced clearance (mean difference [MD] = -15.56L/hr, p = 0.0002, I2= 67%), increased maximal concentration (MD =6.90μg/ml, p = 0.006, I2= 92%) and increased terminal elimination half-life (MD =0.49 hr, p < 0.0001, I2=3%) post-surgery. The remaining 36 medications and 2 supplements were included in a systematic review. Overall, 18 of the 53 drugs and supplements showed post-operative changes in PK parameters. This study demonstrates heterogeneity in practice and could not reach conclusive findings for most PK parameters. Prospective studies are needed to inform best practice and enhance patient healthcare and safety following bariatric surgery.

Safety, Tolerability, and Pharmacokinetics of Oral BI 1358894 in Healthy Japanese Male Volunteers.

Male HVs were randomized to receive oral BI 1358894 (n = 18) or placebo (n = 6) after a high-fat, high-calorie meal within three dose groups (50mg, 100mg, 200mg), administered sequentially in dose-ascending order. The primary endpoint was number of HVs with drug-related adverse events (DRAEs). Secondary endpoints were the pharmacokinetic parameters of BI 1358894. Overall, 24 male HVs entered the trial [mean (standard deviation) age: 30.0 (7.6) years]. DRAEs occurred in 3/18 HVs (BI 1358894 100 mg group: one HV experienced dizziness and headache; BI 1358894 200 mg group: one HV experienced headache, another reported sleep disorder). BI 1358894 exposure increased dose dependently and proportionally, peaking 4-6h after administration before declining in a multiphasic manner with a terminal elimination half-life of ~70h in the 50 mg and 100 mg dose groups, and 203 h in the 200 mg dose group. BI 1358894 was well tolerated with a favorable pharmacokinetic profile in Japanese male HVs, similar to findings from a previous study in Caucasian male HVs. ClinicalTrials.gov (NCT03875001; 08-Mar-2019).

Cannabidiol Bioavailability Is Nonmonotonic with a Long Terminal Elimination Half-Life: A Pharmacokinetic Modeling-Based Analysis.

Background: Oral and inhalation-based cannabidiol (CBD) administration has been clinically evaluated for various therapeutic indications, alongside widespread off-label use. However, the long-term exposure kinetics and varied bioavailability have not been fully characterized. Methods: Human CBD plasma concentration-time profiles from six studies evaluating the oral administration of Epidiolex® and three studies evaluating inhalation-based delivery were obtained. A four-compartment pharmacokinetic (PK) model with Weibull-based oral absorption kinetics was employed to describe the long-term PKs of CBD. Furthermore, a Cedergreen-Ritz-Streibig model was applied to evaluate nonmonotonic oral bioavailability. Results: CBD was extensively distributed into tissue compartments with varied kinetics resulting in a long plasma terminal elimination half-life of >134 h in humans. For once-a-day oral dosing, the plasma trough concentrations require >70 days to reach a steady state. The oral bioavailability of CBD for different doses administered in fasted state follows a nonmonotonic pattern with an inverted U-shaped profile. Oral administration of CBD under fed state or subjects with hepatic impairment yields higher oral bioavailability with varied exposure. In contrast, inhalation-based delivery of CBD, while delivering a similar systemic delivered dose compared with oral dosing due to high device losses, bypasses first-pass metabolism and can be efficient. Conclusion: CBD PKs vary across different doses due to nonmonotonic oral bioavailability, and inhalation-based delivery could minimize such variability in humans. The delayed attainment of steady state and prolonged terminal half-life, resulting from differential but extensive tissue distribution, needs to be considered when dosing CBD in the long term. These fundamental findings are critical for establishing dose-exposure relationship for further clinical evaluation of novel CBD-based therapies.

Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method for the quantification of the antimalarial drug pyronaridine in human whole blood

Malaria remains a major health concern, aggravated by emerging resistance of the parasite to existing treatments. The World Health Organization recently endorsed the use of artesunate-pyronaridine to treat uncomplicated malaria. However, there is a lack of clinical pharmacokinetic (PK) data of pyronaridine, particularly in special populations such as children and pregnant women. Existing methods for the quantification of pyronaridine in biological matrices to support PK studies exhibit several drawbacks. These include limited sensitivity, a large sample volume required, and extensive analysis time. To overcome these limitations, an ultra-performance reversed-phase liquid chromatography tandem-mass spectrometry method to determine pyronaridine was developed and validated according to international guidelines. The method enabled fast and accurate quantification of pyronaridine in whole blood across a clinically relevant concentration range of 0.500–500 ng/mL (r2 ≥ 0.9963), with a required sample volume of 50 µL. Pyronaridine was extracted from whole blood using liquid-liquid extraction, effectively eliminating the matrix effect and preventing ion enhancement or suppression. The method achieved a satisfactory reproducible sample preparation recovery of 77%, accuracy (as bias) and precision were within ±8.2% and ≤5.3%, respectively. Stability experiments demonstrated that pyronaridine was stable for up to 315 days when stored at −70°C. Adjustments to the chromatographic system substantially reduced carry-over and improved sensitivity compared to prior methods. The method was successfully applied to quantify pyronaridine in whole blood samples from a selection of pregnant malaria patients participating in the PYRAPREG clinical trial (PACTR202011812241529) in the Democratic Republic of the Congo, demonstrating its suitability to support future PK studies. Furthermore, the enhanced sensitivity allows for the determination of pyronaridine up to 42 days post-treatment initiation, enabling assessment of the terminal elimination half-life.

Pharmacokinetics of a continuous intravenous infusion of hydromorphone in healthy dogs.

Dosing recommendations for hydromorphone intravenous constant rate infusion (IV CRI) are derived from simulations following IV bolus administration. While this extrapolated dose regimen has been described clinically, pharmacokinetics (PK) of hydromorphone infusions in dogs are not yet described. The study objective was to describe the PK of hydromorphone in healthy dogs receiving an IV bolus followed by an IV CRI for 48 h. A prospective, experimental study was performed involving the administration of hydromorphone (0.1 mg/kg IV bolus then IV CRI 0.01 mg/kg/h over a 48 h period) to 6 healthy Beagle dogs. Blood samples were collected at 16 time points between 0 and 58 h relative to the initial bolus. Plasma hydromorphone concentrations were analyzed by high pressure liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameter estimates were obtained with compartmental methods using commercially available software. A two-compartment model with first order elimination was used. At the end of the infusion, median (range) plasma hydromorphone concentrations were 6.8 (5.5-19.6) ng/mL. The median total body clearance was 30.4 (19.8-36.7) mL/min/kg; volume of distribution at steady state was 4.5 (3.2-7.8) L/kg; and terminal elimination half-life was 11.2 (7.6-24.3) h. Hydromorphone (0.1 mg/kg IV bolus then IV CRI of 0.01 mg/kg/h) maintained steady-state plasma concentrations above the minimum human analgesic target in healthy Beagle dogs with minimal side effects. Further studies are needed to determine the effective plasma concentrations of hydromorphone in painful dogs.

Phase 1, placebo-controlled, single ascending dose trial to evaluate the safety, pharmacokinetics and effect on altered states of consciousness of intranasal BPL-003 (5-methoxy-N,N-dimethyltryptamine benzoate) in healthy participants.

To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BPL-003, a novel intranasal benzoate salt formulation of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), in healthy participants. In all, 44 psychedelic-naïve participants enrolled in the double-blind, placebo-controlled single ascending dose study (1-12 mg BPL-003). Concentrations of 5-MeO-DMT and its pharmacologically active metabolite, bufotenine, were determined in plasma and urine. PD endpoints included subjective drug intensity (SDI) rating, the Mystical Experience Questionnaire (MEQ-30) and the Ego Dissolution Inventory (EDI). BPL-003 was well tolerated at doses up to 12 mg. There were no serious adverse events (AEs), and most AEs were mild; the most common being nasal discomfort, nausea, headache and vomiting. 5-MeO-DMT was rapidly absorbed and eliminated; the median time to peak plasma concentration was approximately 8-10 min and the mean terminal elimination half-life was <27 min. 5-MeO-DMT systemic exposure increased approximately dose-proportionally, while plasma bufotenine concentrations and urinary excretion of 5-MeO-DMT and bufotenine were negligible. The intensity of the SDI ratings was associated with plasma 5-MeO-DMT concentrations. MEQ-30 and EDI scores generally increased with the BPL-003 dose; 60% of participants had a 'complete mystical experience' at 10 and 12 mg doses. Profound and highly emotional consciousness-altering effects were observed with BPL-003, with a rapid onset and short-lasting duration. The novel intranasal formulation of BPL-003 was well tolerated with dose-proportional increases in PK and PD effects. The short duration of action and induction of mystical experiences suggest clinical potential, warranting further trials. NCT05347849.

The Toxicokinetics, Excretion Patterns, and Milk Transmission of Ochratoxin A in Lactating Sows.

Ochratoxin A (OTA), a mycotoxin commonly found in feedstuffs, is known for its detrimental effects on the kidneys and liver, posing significant health risks to animals and humans. This study investigated the toxicokinetics, excretion patterns, and milk transmission of Ochratoxin A (OTA) in lactating sows. The sows were administered a single oral dose of 500 μg/kg BW (body weight), followed by the systematic sampling of plasma, feces, urine, and milk. Plasma samples were collected at 0, 5, 15, and 30 min, and 1, 2, 3, 6, 9, 12, 24, 48, 72, 88, 96, and 120 h post administration. Feces samples were collected at 6 h intervals for the first 12 h, then at 12 h intervals until 120 h, while urine samples were collected at 6 h intervals up to 120 h. Milk samples were collected at 0, 6, 12, 24, 36, 48, 72, 96, and 120 h. The concentration of OTA and its primary metabolite OTα were quantitatively analyzed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The results revealed that the peak plasma concentrations of OTA (920.25 ± 88.46 μg/L) were observed at 9 h following administration. The terminal elimination half-life was recorded at 78.47 ± 7.68 h, with a volume of distribution of 0.16 ± 0.003 L/kg. Moreover, this study documented the excretion of OTA and OTα across a span of 120 h, revealing that feces and urine accounted for 18.70 ± 0.04% and 8.40 ± 0.002% of the total intake amounts, respectively (calculated based on substance amounts). Furthermore, this experiment detected OTA residues in the milk of lactating sows, with the milk-to-plasma (M/P) ratio initially increasing from 0.06 to 0.46 within the first 24 h following OTA ingestion. These findings offer an exhaustive temporal analysis of OTA's toxicokinetics in lactating sows, emphasizing its pervasive distribution and elimination through various bodily excreta.

Elimination profile of low-dose chlortalidone and its detection in hair for doping analysis-Implication for unintentional non-therapeutic exposure.

Chlortalidone (CLT) is a thiazide-type diuretic with high affinity for the erythrocyte carbonic anhydrase. Therapeutically, it is mostly used to treat edema and hypertension due to liver cirrhosis, heart insufficiency, or renal dysfunction. Although diuretics and masking agents are prohibited by the World Anti-Doping Agency (WADA) at all times in sports, substances belonging to this category are constantly detected in athlete samples, according to WADA's annual testing figures. Within this group of structurally diverse compounds, a threshold of 20 ng/mL has been introduced for six substances solely due to their presence as contaminants in other permitted drugs because of pharmaceutical production processes. In a recent presumptive doping case with a low urinary CLT concentration, the question of unintentional doping, for example, by contaminated non-steroidal anti-inflammatory drug intake, arose. To examine this potential scenario, a co-elimination of low-dose CLT and hydrochlorothiazide (HCTA; 20 × 50 μg, 0.2 mg/day each) was conducted on five consecutive days in two volunteers. Urine samples were subjected to liquid chromatography-tandem mass spectrometry (LC-MS/MS). Moreover, we examined the incorporation of CLT in scalp hair. HCTA is rapidly excreted renally in comparatively high concentrations. In contrast, the elimination of CLT is considerably slower (terminal elimination half-life extended by a factor of 12) and, consequently, much less concentrated in corresponding urine samples (45 and 53 ng/mL, respectively). Conversely, a higher hair incorporation of chlorthalidone was observed with simultaneous dosing of both. The results suggest that an unintentional intake of sub-therapeutic CLT doses due to contamination might result in an adverse analytical finding.