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Therapeutic Drug Monitoring Oct 2023Despite its federally restricted status, cannabis is widely used medicinally and recreationally. The pharmacokinetics (PK) and central nervous system (CNS) effects of...
BACKGROUND
Despite its federally restricted status, cannabis is widely used medicinally and recreationally. The pharmacokinetics (PK) and central nervous system (CNS) effects of tetrahydrocannabinol (THC), the major psychoactive cannabinoid, are not well understood. The objective of this study was to develop a population PK model of inhaled THC, including sources of variability, and to conduct an exploratory analysis of potential exposure-response relationships.
METHODS
Regular adult cannabis users smoked a single cannabis cigarette containing 5.9% THC (Chemovar A) or 13.4% THC (Chemovar B) ad libitum. THC concentrations in whole blood were measured and used to develop a population PK model to identify potential factors contributing to interindividual variability in THC PK and to describe THC disposition. Relationships between model-predicted exposure and heart rate, change in composite driving score on a driving simulator, and perceived highness were evaluated.
RESULTS
From the 102 participants, a total of 770 blood THC concentrations were obtained. A two-compartment structural model adequately fit the data. Chemovar and baseline THC (THC BL ) were found to be significant covariates for bioavailability, with Chemovar A having better THC absorption. The model predicted that heavy users-those with the highest THC BL -would have significantly higher absorption than those with lighter previous use. There was a statistically significant relationship between exposure and heart rate, and exposure and perceived highness.
CONCLUSIONS
THC PK is highly variable and related to baseline THC concentrations and different chemovars. The developed population PK model showed that heavier users had higher THC bioavailability. To better understand the factors affecting THC PK and dose-response relationships, future studies should incorporate a wide range of doses, multiple routes of administration, and different formulations relevant to typical community use.
Topics: Adult; Humans; Marijuana Smoking; Dronabinol; Cannabis; Cannabinoids; Biological Availability
PubMed: 37199428
DOI: 10.1097/FTD.0000000000001104 -
European Journal of Pharmaceutical... Jan 2024Early-stage clinical evaluation of tinengotinib (TT-00420) demonstrated encouraging preliminary efficacies in multiple types of refractory cancers, including fibroblast...
In vitro and in vivo pharmacokinetics, disposition, and drug-drug interaction potential of tinengotinib (TT-00420), a promising investigational drug for treatment of cholangiocarcinoma and other solid tumors.
Early-stage clinical evaluation of tinengotinib (TT-00420) demonstrated encouraging preliminary efficacies in multiple types of refractory cancers, including fibroblast growth factor receptors (FGFR) inhibitors relapsed cholangiocarcinoma (CCA), castrate-resistant prostate cancer (CRPC), and HR+/HER2- breast cancer and triple negative breast cancer (TNBC). To further evaluate drug-like properties of the drug candidate, it is imperative to understand its metabolism and pharmacokinetic properties. This manuscript presented the investigation results of in vitro permeability, plasma protein binding, metabolic stability, metabolite identification, and drug-drug interaction of tinengotinib. Preclinical ADME (absorption, distribution, excretion, and metabolism) studies in rats and dogs was also conducted using a radioactive labeled tinengotinib, [C]tinengotinib. Tinengotinib was found to have high permeability and high plasma protein binding and equally distributed between blood and plasma. There were no unique metabolites in human liver microsomes and tinengotinib showed moderate hepatic clearance. Tinengotinib is neither a potential inhibitor nor an inducer of P450 enzymes at clinically relevant concentrations, and unlikely to cause drug-drug interactions when used in combination with other drugs mediated by a key transporter, either as victim or perpetrator. Taken together, tinengotinib demonstrated a minimal risk of clinically relevant drug-drug interactions. Tinengotinib showed good oral bioavailability and dose-dependent exposures in both rat and dog after oral administration. The total radioactivity was largely distributed in the gastrointestinal system and liver, and tinengotinib could not easily pass through the blood-brain barrier. The major drug-related component in rat and dog plasma was unchanged drug (>89 %) with primary route of elimination via feces (>93 % of the dose) and minor via renal excretion (<4 % of the dose). Tinengotinib metabolism is mediated largely by CYP3A4, with minor contributions from CYP2D6 and CYP2C8. Major metabolic pathways include oxidation, oxidative cleavage of the morpholine ring, glucuronide and glutathione conjugations. The overall preclinical pharmacokinetics profile supported the selection and development of tinengotinib as a clinical candidate.
Topics: Male; Rats; Humans; Animals; Dogs; Drugs, Investigational; Drug Interactions; Pharmaceutical Preparations; Biological Availability; Protein Kinase Inhibitors; Administration, Oral; Microsomes, Liver; Cholangiocarcinoma
PubMed: 38048851
DOI: 10.1016/j.ejps.2023.106658 -
Clinical Pharmacology in Drug... Apr 2024A novel, oral phosphodiesterase 4 (PDE4) inhibitor, ME3183, is under development for the treatment of psoriasis, atopic dermatitis, and other inflammatory diseases. To... (Randomized Controlled Trial)
Randomized Controlled Trial
A novel, oral phosphodiesterase 4 (PDE4) inhibitor, ME3183, is under development for the treatment of psoriasis, atopic dermatitis, and other inflammatory diseases. To evaluate its safety, tolerability, and pharmacokinetics, double-blind, placebo-controlled, single ascending dose (SAD), and multiple ascending dose (MAD) phase 1 studies were conducted in 126 healthy adults. The food effect was evaluated in a randomized, open-label, crossover manner (n = 5). ME3183 was safe and tolerable up to 25 mg in the SAD part and up to 10 mg twice daily in the MAD part. Frequently observed treatment-emergent adverse events included diarrhea and headache, as commonly reported for approved PDE4 inhibitors, providing no novel safety concerns. Pharmacokinetic analysis showed dose-dependent increases in C and AUC, with later t and longer t than apremilast, an approved PDE4 inhibitor. The food effect study showed slightly decreased systemic exposure. In the MAD part, plasma exposure levels of ME3183 were higher even at the minimal dose (2.5 mg twice daily) than the estimated therapeutically effective level. These results show the safe profile of ME3183 and support further studies to confirm the safety and efficacy of the drug in patients with psoriasis and other inflammatory diseases.
Topics: Adult; Humans; Phosphodiesterase 4 Inhibitors; Dose-Response Relationship, Drug; Headache; Area Under Curve; Psoriasis
PubMed: 38108569
DOI: 10.1002/cpdd.1351 -
Pakistan Journal of Pharmaceutical... Sep 2023S and S, two structurally similar quinazoline derivatives, are novel anticancer drugs targeting the PI3K/AKT/mTOR signaling pathway channel. However, their...
S and S, two structurally similar quinazoline derivatives, are novel anticancer drugs targeting the PI3K/AKT/mTOR signaling pathway channel. However, their pharmacokinetic and tissue distribution characteristics are unknown, which has hindered further development and in-depth studies. In this study, a simple, rapid and sensitive method using high performance liquid chromatography was established and validated to quantitatively study the pharmacokinetics and tissue distribution profiles of S and S in rats following intravenous injection. The results indicated that after intravenous injection, the elimination of S and S fit the two-compartment model and linear pharmacokinetics characteristics were observed. Furthermore, S and S2 were widely distributed and found in high concentrations in liver and kidney tissues and a small proportion of S and S could cross the blood-brain barrier and be distributed in the brain. The current findings will contribute to interpretation and understanding the relationship between dosage and pharmacodynamic effects of S and S.
Topics: Animals; Rats; Antineoplastic Agents; MTOR Inhibitors; Quinazolines; Tissue Distribution; TOR Serine-Threonine Kinases; Phosphoinositide-3 Kinase Inhibitors
PubMed: 37869929
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Nov 2023SPR206 is a novel polymyxin derivative with potent activity against susceptible and multidrug-resistant strains of , , , , and species. SPR206 is eliminated renally....
SPR206 is a novel polymyxin derivative with potent activity against susceptible and multidrug-resistant strains of , , , , and species. SPR206 is eliminated renally. The safety, tolerability, and pharmacokinetics (PK) of SPR206 were evaluated in healthy subjects with normal renal function (Cohort 1) and subjects with varying degrees of renal impairment (RI) (Cohorts 2-4) or end-stage renal disease (ESRD) on hemodialysis (HD) (Cohort 5). Subjects in Cohorts 1-4 received a 100-mg intravenous (IV) dose of SPR206. Subjects in Cohort 5 received a 100-mg IV dose within 2 h after HD on day 1 and 1 h before HD on day 5. Safety and PK analyses included 37 subjects. Mostly mild but no serious treatment-related adverse events were reported. Systemic exposure to SPR206 increased as renal function decreased, with mean area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC) values 39% to 239% greater in subjects with RI vs healthy subjects. Mean plasma clearance (CL) of SPR206 decreased with decreasing renal function (29% to 76% lower vs healthy subjects). In subjects with ESRD, AUC decreased by 51%, and CL increased by 92% for dialyzed vs nondialyzed conditions. SPR206 was excreted in urine within 12 h in healthy subjects and subjects with mild RI (Cohort 2) but was prolonged in those with moderate and severe RI (Cohorts 3 and 4, respectively). In summary, SPR206 was generally safe and well tolerated, and the PK of SPR206 was well characterized in subjects with RI.
Topics: Humans; Kidney Failure, Chronic; Renal Dialysis; Renal Insufficiency; Administration, Intravenous; Metabolic Clearance Rate; Area Under Curve
PubMed: 37823647
DOI: 10.1128/aac.00505-23 -
Journal of Ethnopharmacology Nov 2023Weikangling Capsules (WKLCs) have been used in the clinic for the treatment of gastrointestinal disorders for more than 30 years. However, the pharmacokinetic...
ETHNOPHARMACOLOGICAL RELEVANCE
Weikangling Capsules (WKLCs) have been used in the clinic for the treatment of gastrointestinal disorders for more than 30 years. However, the pharmacokinetic characteristics and tissue distribution of its major bioactive components in rats under different physiological and pathological conditions are unclear.
AIM OF THE STUDY
In this study, we aimed to clarify the differences in pharmacokinetic parameters and tissue distribution of the major active components in WKLCs under physiological and pathological states.
MATERIALS AND METHOD
Normal and ethanol-induced chronic gastritis rats received 2.16 g/kg WKLCs by gavage, and urine, feces, plasma, and tissue (heart, liver, spleen, lung, kidney, stomach, and small intestine) samples were obtained. The active components in urine, feces and plasma were detected by ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS). A rapid and sensitive analytical method, ultra-high-performance liquid chromatography coupled with triple-quadrupole linear ion-trap tandem mass spectrometry (UHPLC-QTRAP-MS/MS), was established and validated to clarify and compare the pharmacokinetics and tissue distribution of the major active components in normal and chronic gastritis rats.
RESULTS
A total of 36 chemical components in the feces, urine, and plasma of chronic gastritis rats were identified by UHPLC-Q-TOF-MS/MS. Among them, 20 were the prototype components of WKLCs, and 16 were metabolites. The pharmacokinetic characteristics and tissue distribution of 12 prototype components were successfully analyzed by UHPLC-QTRAP-MS/MS. The pharmacokinetic results showed that the C, AUC, and AUC of paeoniflorin, glycyrrhizic acid, and glycyrrhetinic acid were distinctly higher than those of the other components in normal and chronic gastritis rats. Compared to normal rats, the C, AUC, and AUC of albiflorin, liquiritin apioside, liquiritin, isoliquiritin, ononin, isoliquiritigenin, dactylorhin A, and glycyrrhizic acid were significantly increased in chronic gastritis rats (P < 0.05), while the C, AUC and AUC of militarine and liquiritigenin had significantly lower decreases in chronic gastritis rats (P < 0.05). The results of the tissue distribution showed that the 12 components were widely distributed in the heart, liver, spleen, lung, kidney, stomach, and small intestine of rats, of which the liver, kidney, stomach, and small intestine were the main accumulative organs. Compared with normal rats, the concentrations of 12 components in the liver, kidney, stomach, and small intestine of chronic gastritis rats were widely higher than those of normal rats at the same time points.
CONCLUSION
The pharmacokinetic characteristics and tissue distribution of 12 active components of WKLCs were comprehensively characterized and elucidated in normal and chronic gastritis rats. These findings laid a solid foundation for revealing the pharmacodynamic material basis of WKLCs in treating gastrointestinal disorders.
Topics: Rats; Animals; Tissue Distribution; Tandem Mass Spectrometry; Drugs, Chinese Herbal; Glycyrrhizic Acid; Capsules; Chromatography, High Pressure Liquid; Administration, Oral; Gastritis
PubMed: 37271330
DOI: 10.1016/j.jep.2023.116722 -
Clinical Pharmacology in Drug... Nov 2023Celecoxib is a sulfanilamide nonsteroidal anti-inflammatory drug that can selectively inhibit cyclooxygenase-2 to inhibit prostaglandin production, achieving...
Celecoxib is a sulfanilamide nonsteroidal anti-inflammatory drug that can selectively inhibit cyclooxygenase-2 to inhibit prostaglandin production, achieving anti-inflammatory and analgesic effects. This study investigated the pharmacokinetics, safety, and bioequivalence of a single oral dose of celecoxib capsule (the test or reference preparation) in healthy volunteers under fasting and fed conditions. A single-center, randomized, open, single-dose, double-cycle crossover self-control design was conducted: 40 healthy volunteers were enrolled in the fasting and fed groups, respectively. A completely randomized method was used, with one group taking the test celecoxib preparation (T) and the other taking the reference celecoxib preparation (R). During the administration period, the safety of the drug was evaluated simultaneously, and venous blood was collected at the corresponding time points. The concentration of celecoxib in plasma was measured by liquid chromatography-tandem mass spectrometry. The main pharmacokinetic parameters were logarithmically converted and analyzed for variance. The 90% confidence interval for the bioavailability of the T compared to the R was calculated using maximum drug plasma concentration, area under the plasma concentration-time curve from time zero to the last quantifiable concentration point, and area under the plasma concentration-time curve from time zero to infinity for a single oral dose in volunteers, and the data obtained were all between 80% and 125%, indicating that the T and R have bioequivalence and good safety during fasting and fed administration.
Topics: Humans; Anti-Inflammatory Agents; Celecoxib; East Asian People; Healthy Volunteers; Therapeutic Equivalency
PubMed: 37246720
DOI: 10.1002/cpdd.1270 -
International Journal of Molecular... Dec 2023Small molecule fluorophores often face challenges such as short blood half-life, limited physicochemical and optical stability, and poor pharmacokinetics. To overcome...
Small molecule fluorophores often face challenges such as short blood half-life, limited physicochemical and optical stability, and poor pharmacokinetics. To overcome these limitations, we conjugated the zwitterionic near-infrared fluorophore ZW800-PEG to human serum albumin (HSA), creating HSA-ZW800-PEG. This conjugation notably improves chemical, physical, and optical stability under physiological conditions, addressing issues commonly encountered with small molecules in biological applications. Additionally, the high molecular weight and extinction coefficient of HSA-ZW800-PEG enhances biodistribution and tumor targeting through the enhanced permeability and retention effect. The unique distribution and elimination dynamics, along with the significantly extended blood half-life of HSA-ZW800-PEG, contribute to improved tumor targetability in both subcutaneous and orthotopic xenograft tumor-bearing animal models. This modification not only influences the pharmacokinetic profile, affecting retention time and clearance patterns, but also enhances bioavailability for targeting tissues. Our study guides further development and optimization of targeted imaging agents and drug-delivery systems.
Topics: Animals; Humans; Serum Albumin, Human; Tissue Distribution; Neoplasms; Biological Availability; Drug Delivery Systems; Fluorescent Dyes; Ionophores
PubMed: 38203730
DOI: 10.3390/ijms25010559 -
Clinical Drug Investigation Oct 2023A reported clinical pharmacokinetics and safety study of suspension formulation of ensitrelvir, a therapeutic agent used in severe acute respiratory syndrome coronavirus... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A reported clinical pharmacokinetics and safety study of suspension formulation of ensitrelvir, a therapeutic agent used in severe acute respiratory syndrome coronavirus 2 infection, demonstrated favorable pharmacokinetics and was well tolerated in healthy male Japanese and White participants. Understanding the safety and pharmacokinetic features of ensitrelvir (using the formulation approved for clinical use) in various populations, and the effect of food, is crucial for optimal clinical use.
OBJECTIVES
The objectives of this study were to (1) assess the safety, tolerability, and pharmacokinetics of ensitrelvir following multiple-dose administration of ensitrelvir tablets in populations with different races, ages, and sex; and (2) assess the effect of food on the pharmacokinetics of ensitrelvir tablets in the fasted or fed state.
METHODS
A phase 1, multicenter, double-blinded, randomized, placebo-controlled study was conducted to evaluate the safety and pharmacokinetics of once-daily ensitrelvir tablets at loading/maintenance doses of 375/125 mg or 750/250 mg for 5 days in healthy Japanese females, Japanese elderly (only 375/125 mg), and White male and female participants. An open-label, two-group, two-period crossover study was also conducted to estimate the effect of food on the pharmacokinetics of ensitrelvir at single dose of 375 mg. The nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded in safety assessments in both studies.
RESULTS
The maximum plasma concentration (C) and area under the plasma concentration-time curve (AUC) were similar within these populations. The geometric mean half-life of ensitrelvir following multiple-dose administration was 48.7-58.9 h across all cohorts. The C and AUC increased in a dose-proportional manner in Japanese female participants, and increased in a less than dose-proportional manner in White participants. Furthermore, there was no clear relationship between the dose and geometric mean half-life of ensitrelvir. The plasma concentration at 24 h (C) after an initial dose of 375/125 mg exceeded the target plasma concentration (6.09 µg/mL) in all populations. Regarding the effect of food on the pharmacokinetics of ensitrelvir, although time to C in the fed state was delayed, there was no clinically meaningful difference in the exposure levels (C and AUC) of ensitrelvir between the fasted and fed states. Most treatment-emergent adverse events were mild in nature and had resolved.
CONCLUSION
Ensitrelvir (375/125 mg and 750/250 mg tablet formulation) was well tolerated, without any major safety concerns. The pharmacokinetics of ensitrelvir between all populations in the study were similar and C exceeded the target plasma concentration at 375/125 mg. These results suggest that ensitrelvir can be effectively administered with no necessity for dose adjustment for age, sex, and race without food restriction.
CLINICAL TRIAL REGISTRATION
Japan Registry of Clinical Trials identifier: jRCT2031210202, registered on 16 July 2021.
Topics: Adult; Humans; Male; Female; Aged; Cross-Over Studies; COVID-19; Tablets; Area Under Curve; Administration, Oral; Healthy Volunteers
PubMed: 37798608
DOI: 10.1007/s40261-023-01309-z -
Journal of Clinical Pharmacology Oct 2023
Topics: Humans; Aged; Drug Interactions; Models, Biological; Pharmacokinetics; Computer Simulation
PubMed: 37408371
DOI: 10.1002/jcph.2299