-
AAPS PharmSciTech Feb 2024Novel formulations are developed for dermatological applications to address a wide range of patient needs and therapeutic challenges. By pushing the limits of... (Review)
Review
Novel formulations are developed for dermatological applications to address a wide range of patient needs and therapeutic challenges. By pushing the limits of pharmaceutical technology, these formulations strive to provide safer, more effective, and patient-friendly solutions for dermatological concerns, ultimately improving the overall quality of dermatological care. The article explores the different types of novel dermatological formulations, including nanocarriers, transdermal patches, microsponges, and microneedles, and the techniques involved in the cutaneous pharmacokinetics of these innovative formulations. Furthermore, the significance of knowing cutaneous pharmacokinetics and the difficulties faced during pharmacokinetic assessment have been emphasized. The article examines all the methods employed for the pharmacokinetic evaluation of novel dermatological formulations. In addition to a concise overview of earlier techniques, discussions on novel methodologies, including tape stripping, in vitro permeation testing, cutaneous microdialysis, confocal Raman microscopy, and matrix-assisted laser desorption/ionization mass spectrometry have been conducted. Emerging technologies like the use of microfluidic devices for skin absorption studies and computational models for predicting drug pharmacokinetics have also been discussed. This article serves as a valuable resource for researchers, scientists, and pharmaceutical professionals determined to enhance the development and understanding of novel dermatological drug products and the complex dynamics of cutaneous pharmacokinetics.
Topics: Humans; Skin; Administration, Cutaneous; Skin Absorption; Technology, Pharmaceutical; Microdialysis
PubMed: 38413430
DOI: 10.1208/s12249-024-02763-4 -
Clinical Pharmacology in Drug... Dec 2023Two open-label, Phase 1 studies assessed the effects of omeprazole (a weak to moderate cytochrome P450 [CYP] 2C19 inhibitor) and verapamil (a moderate CYP3A4 inhibitor)...
Two open-label, Phase 1 studies assessed the effects of omeprazole (a weak to moderate cytochrome P450 [CYP] 2C19 inhibitor) and verapamil (a moderate CYP3A4 inhibitor) on the pharmacokinetics, safety, and tolerability of mavacamten. In the omeprazole study, healthy participants received mavacamten 15 mg alone or with a 31-day course of omeprazole 20 mg once daily. In the verapamil study, healthy participants received mavacamten 25 mg alone or with a 28-day course of verapamil 240 mg once daily. In the omeprazole study, 27 of 29 randomized participants completed the study. Nine participants receiving mavacamten alone were normal metabolizers (NMs) of CYP2C19 substrates, and 6 were rapid metabolizers; 8 NMs and 6 rapid metabolizers received mavacamten + omeprazole. In both studies, mavacamten showed no safety signals and was generally well tolerated. Overall mavacamten exposure (area under the plasma concentration-time curve) increased by approximately 50% with omeprazole coadministration; maximum observed concentration (C ), time to C , and elimination half-life were not affected appreciably. In the verapamil study, 25 of 26 randomized participants received the study drug(s) and were included in the pharmacokinetic analyses; 24 completed the study. In the pharmacokinetic population, 12 participants received mavacamten alone (11 NMs, 1 poor metabolizer) and 13 received mavacamten + verapamil (7 NMs, 4 intermediate metabolizers, 2 poor metabolizers). Following verapamil coadministration in NMs and intermediate metabolizers, mavacamten area under the plasma concentration-time curve was minimally increased (by less than 20%), and C was modestly increased (by 52%). These results suggest that mavacamten can be coadministered with weak CYP2C19 and moderate CYP3A4 inhibitors.
Topics: Humans; Omeprazole; Cytochrome P-450 CYP2C19; Verapamil; Healthy Volunteers; Drug Interactions; Area Under Curve
PubMed: 37771180
DOI: 10.1002/cpdd.1332 -
Drug Design, Development and Therapy 2023Empagliflozin is a sodium-glucose cotransporter 2 inhibitor that is commonly used for the treatment of type 2 diabetes mellitus. As cocrystal formulation can improve the... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Empagliflozin is a sodium-glucose cotransporter 2 inhibitor that is commonly used for the treatment of type 2 diabetes mellitus. As cocrystal formulation can improve the chemical properties of drugs, CKD-370 was newly developed as a cocrystal formulation of empagliflozin with solvate L-proline. This study aimed to compare the pharmacokinetics, safety, and tolerability of these two empagliflozin formulations in healthy Korean subjects.
METHODS
A randomized, open-label, two-sequence, two-period crossover study was conducted on healthy Korean participants. The subjects received a single oral 25 mg dose of either test (CKD-370) or reference treatment (Jardiance) tablet at each period. Plasma empagliflozin concentrations were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic (PK) parameters were analyzed using non-compartmental methods. The primary PK parameters included the maximum concentration (C) and the area under the concentration-time curve from 0 to last (AUC). The safety of both formulations was monitored and evaluated.
RESULTS
A total of 28 healthy Korean adult subjects were randomized, and 27 subjects were included in the PK analysis. The mean ± standard deviation values of the primary PK parameters, C and AUC after administration of the test treatment, were 442.02 ± 103.37 μg/L and 3131.08 ± 529.30 μg·h/L, respectively, and those after administration of the reference treatment were 436.29 ± 118.74 μg/L and 3006.88 ± 514.21 μg·h/L, respectively. The geometric mean ratio and its 90% confidence interval of test to reference treatment for C and AUC were 1.0221 (0.9527-1.0967) and 1.0411 (1.0153-1.0677), respectively, which were within the commonly accepted bioequivalence criteria of 0.80 to 1.25. Both treatments were well-tolerated.
CONCLUSION
The two formulations of empagliflozin showed similar PK characteristics and were generally well tolerated in healthy subjects.
Topics: Adult; Humans; Healthy Volunteers; Cross-Over Studies; Diabetes Mellitus, Type 2; Area Under Curve; Therapeutic Equivalency; Administration, Oral; Republic of Korea; Renal Insufficiency, Chronic; Tablets
PubMed: 37521035
DOI: 10.2147/DDDT.S409368 -
Molecules (Basel, Switzerland) Nov 2023Demethyleneberberine is an active component extracted from the Chinese herbal drug Cortex Phellodendri. It is also a metabolite of berberine in animals and humans....
Demethyleneberberine is an active component extracted from the Chinese herbal drug Cortex Phellodendri. It is also a metabolite of berberine in animals and humans. However, the pharmacokinetics, tissue distribution and excretion of demethyleneberberine have not been reported. The present study aimed to investigate the pharmacokinetic parameters of demethyleneberberine by applying high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). After intragastric administration of demethyleneberberine in rats and mice, the pharmacokinetics, tissue distribution and excretion of demethyleneberberine were comparatively studied for the first time. The plasma concentration of demethyleneberberine reached its peak within 5 min after intragastric administration in both rats and mice. Furthermore, its bioavailability was comparable, ranging from 4.47% to 5.94%, higher than that of berberine. The total excretion of demethyleneberberine in the urine, feces and bile was 7.28~9.77%. These findings provide valuable insights into the pharmacological and clinical research on demethyleneberberine.
Topics: Humans; Rats; Mice; Animals; Berberine; Tissue Distribution; Chromatography, Liquid; Tandem Mass Spectrometry; Chromatography, High Pressure Liquid
PubMed: 38067456
DOI: 10.3390/molecules28237725 -
Equine Veterinary Journal Nov 2023Intravenous pharmacokinetics and oral bioavailability of cannabidiol (CBD) with different formulations have not been investigated in horses and may represent a starting...
BACKGROUND
Intravenous pharmacokinetics and oral bioavailability of cannabidiol (CBD) with different formulations have not been investigated in horses and may represent a starting point for clinical studies.
OBJECTIVES
To describe pharmacokinetics after intravenous and oral administrations with oil and micellar formulations and simulate different treatments.
STUDY DESIGN
Single intravenous experiment and two-way randomised oral experiments, Latin-square design.
METHODS
Eight healthy horses received intravenous CBD at 1.00 mg/kg dose, oral CBD in sesame oil and in micellar formulation, both at 10.00 mg/kg. Concentrations were measured using LC-MS/MS and fitted by nonlinear mixed effect modelling. Parameters obtained were used to simulate single and multiple treatments at steady state.
RESULTS
Intravenous and oral concentrations were simultaneously fitted using a three-compartment model. Final estimates indicate that CBD has a volume of distribution of 36 L/kg associated with a systemic clearance of 1.46 L/h/kg and half-lives ranged between 24 and 34 h. Oral bioavailability was close to 14% for both oral administrations. Simulated dose regimen of CBD every 12 and 24 h predicted similar percentages to reach effective plasma concentration with both oral formulation at 10.00 mg/kg.
MAIN LIMITATIONS
A small horse population was used (8 horses per trial).
CONCLUSIONS AND CLINICAL IMPORTANCE
Oral bioavailability was low at the doses studied but fell within the range described for horse and other species. CBD had a high steady-state volume of distribution, a high clearance and long half-lives. No adverse reactions were detected at any dose or route. The micellar formulation showed a faster absorption and higher concentration peak, while the oil formulation presented lower levels, but more maintained over time. Simulations predicted that both could be useful in multiple oral dose treatments. These results indicated that CBD could be of interest, but further studies are needed to evaluate its clinical use in horses.
Topics: Horses; Animals; Cannabidiol; Biological Availability; Chromatography, Liquid; Tandem Mass Spectrometry; Administration, Oral
PubMed: 36624043
DOI: 10.1111/evj.13923 -
Platelets Dec 2023BMS-986141 is a novel, oral, protease-activated, receptor 4 (PAR4)-antagonist that exhibited robust antithrombotic activity and low bleeding risk in preclinical studies.... (Randomized Controlled Trial)
Randomized Controlled Trial
First-in-human study to assess the safety, pharmacokinetics, and pharmacodynamics of BMS-986141, a novel, reversible, small-molecule, PAR4 agonist in non-Japanese and Japanese healthy participants.
BMS-986141 is a novel, oral, protease-activated, receptor 4 (PAR4)-antagonist that exhibited robust antithrombotic activity and low bleeding risk in preclinical studies. The pharmacokinetic, pharmacodynamic, and tolerability profiles of BMS-986141 in healthy participants were assessed in a randomized, double-blind, placebo-controlled, single-ascending-dose (SAD; = 60) study; a multiple-ascending-dose (MAD; = 32) study; and a Japanese MAD (JMAD; = 32) study. Exposure was dose-proportional for BMS-986141 2.5 mg and 150 mg; maximum concentrations were 17.6 ng/mL and 958 ng/mL; and areas under the curve (AUC) to infinity were 183 h* × ng/mL and 9207 h* × ng/mL, respectively. Mean half-life ranged from 33.7 to 44.7 hours across dose panels. The accumulation index following once-daily administration for 7 days suggested a 1.3- to 2-fold AUC increase at steady state. In the SAD study, BMS-986141 75 and 150 mg produced ≥80% inhibition of 25-100 µM PAR4 agonist peptide (AP)-induced platelet aggregation, without affecting PAR1-AP-induced platelet aggregation, through ≥24 hours postdose. In the MAD and JMAD studies, BMS-986141 doses ≥10 mg completely inhibited 12.5 μM and 25 μM PAR4-AP-induced platelet aggregation through 24 hours. This study found BMS-986141 was safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range. ClinicalTrials.gov ID: NCT02341638.
Topics: Humans; Administration, Oral; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Healthy Volunteers; Hemorrhage; Platelet Aggregation; Platelet Aggregation Inhibitors
PubMed: 37394920
DOI: 10.1080/09537104.2023.2222846 -
Veterinary Anaesthesia and Analgesia Nov 2023To determine the pharmacokinetics and bioavailability of meloxicam following intravenous (IV), intramuscular (IM), and oral administrations at a dose of 1.0 mg kg in...
OBJECTIVE
To determine the pharmacokinetics and bioavailability of meloxicam following intravenous (IV), intramuscular (IM), and oral administrations at a dose of 1.0 mg kg in Pekin ducks.
STUDY DESIGN
Randomized experimental trial.
ANIMALS
A total of 18 clinically healthy male Pekin ducks.
METHODS
Pekin ducks were randomly assigned to three groups of six ducks: IV, IM and oral. Meloxicam (1.0 mg kg) was administered to each Pekin duck. A non-compartmental analysis was used to evaluate pharmacokinetic parameters.
RESULTS
No local or systemic adverse effects were observed in any bird. Meloxicam was detected in the plasma up to 120 hours following IV, IM or oral administration. The elimination half-life of the IV route was slightly shorter than that of the IM and oral routes (p < 0.05). Following IV administration, volume of distribution at steady state and total clearance were 133.17 mL kg and 6.68 mL kg hour, respectively. The mean absorption time was 2.29 hours for IM and 1.13 hours for oral route. There were significant differences between IM and oral administration for the peak plasma concentration (C), time to reach C and bioavailability (p < 0.05).
CONCLUSIONS AND CLINICAL RELEVANCE
Meloxicam showed long elimination half-life and high bioavailability following IM and oral administration. Meloxicam in Pekin ducks provided the effective therapeutic concentration indicated in other species for up to 48 hours. However, there is a need to determine the clinical efficacy of meloxicam in Pekin ducks.
Topics: Male; Animals; Meloxicam; Ducks; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Area Under Curve; Half-Life; Injections, Intravenous; Administration, Oral; Injections, Intramuscular; Administration, Intravenous
PubMed: 37620232
DOI: 10.1016/j.vaa.2023.07.007 -
European Journal of Drug Metabolism and... Sep 2023MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and has demonstrated... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
MHV370, a dual antagonist of human Toll-like receptors (TLR) 7 and 8, suppresses cytokines and interferon-stimulated genes in vitro and in vivo, and has demonstrated efficacy in murine models of lupus. This first-in-human study aimed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of MHV370 in healthy adults, as well as the effects of food consumption on a single dose of MHV370.
METHODS
This was a phase 1, randomised, placebo-controlled study conducted in three parts. In part A, participants received (3:1) a single ascending dose (SAD) of 1, 3, 10, 20, 40, 80, 160, 320, 640 and 1000 mg MHV370 or placebo. In part B, participants received (3:1) multiple ascending doses (MAD) of 25, 50, 100, 200 and 400 mg MHV370 twice daily (b.i.d) or placebo for 14 days. In part C, participants received an open-label single dose of 200 mg MHV370 under fasted or fed conditions. Safety, pharmacokinetic and pharmacodynamic parameters were evaluated.
RESULTS
MHV370 was well tolerated, and no safety signal was observed in the study. No dose-limiting adverse events occurred across the dose range evaluated. Plasma concentrations of MHV370 increased with dose (mean [SD] maximum plasma concentrations ranged from 0.97 [0.48] to 1670 [861.0] ng/mL for SAD of 3-1000 mg, 29.5 [7.98] to 759 [325.0] ng/mL for MAD of 25-400 mg b.i.d. on day 1). The intake of food did not have a relevant impact on the pharmacokinetics of MHV370. Pharmacodynamic data indicated time- and dose-dependent inhibition of TLR7-mediated CD69 expression on B cells (100% inhibition at 24 h post-dose starting from SAD 160 mg and MAD 50 mg b.i.d.) and TLR8-mediated TNF release after ex vivo stimulation (>90% inhibition at 24 h post-dose starting from SAD 320 mg and MAD 100 mg b.i.d.).
CONCLUSION
The safety, pharmacokinetic and pharmacodynamic data support the further development of MHV370 in systemic autoimmune diseases driven by the overactivation of TLR7 and TLR8.
Topics: Humans; Adult; Animals; Mice; Toll-Like Receptor 7; Toll-Like Receptor 8; Area Under Curve; Fasting; Administration, Oral; Double-Blind Method; Dose-Response Relationship, Drug; Healthy Volunteers
PubMed: 37532923
DOI: 10.1007/s13318-023-00847-3 -
Clinical Pharmacokinetics Dec 2023Small-interfering ribonucleic acids (siRNAs) with N-acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs that modulate...
Small-interfering ribonucleic acids (siRNAs) with N-acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs that modulate liver-expressed therapeutic targets. The pharmacokinetics of GalNAc-siRNAs are characterized by a rapid distribution from plasma to tissue (hours) and a long terminal plasma half-life, analyzed in the form of the antisense strand, driven by redistribution from tissue (weeks). Understanding how clinical pharmacokinetics relate to the dose and type of siRNA chemical stabilizing method used is critical, e.g., to design studies, to investigate safety windows, and to predict the pharmacokinetics of new preclinical assets. To this end, we collected and analyzed pharmacokinetic data from the literature regarding nine GalNAc-siRNAs. Based on this analysis, we showed that the clinical plasma pharmacokinetics of GalNAc-siRNAs are approximately dose proportional and similar between chemical stabilizing methods. This holds for both the area under the concentration-time curve (AUC) and the maximum plasma concentration (C). Corresponding rat and monkey pharmacokinetic data for a subset of the nine GalNAc-siRNAs show dose-proportional C, supra-dose-proportional AUC, and similar pharmacokinetics between chemical stabilizing methods. Together, the animal and human pharmacokinetic data indicate that plasma clearance divided by bioavailability follows allometric principles and scales between species with an exponent of 0.75. Finally, the clinical plasma concentration-time profiles can be empirically described by standard one-compartment kinetics with first-order absorption up to 24 h after subcutaneous dosing, and by three-compartment kinetics with first-order absorption in general. To describe the system more mechanistically, we report a corrected and unambiguously defined version of a previously published physiologically based pharmacokinetic model.
Topics: Humans; Rats; Animals; Acetylgalactosamine; Liver; RNA, Small Interfering; Biological Availability
PubMed: 37824025
DOI: 10.1007/s40262-023-01314-7 -
Clinical Pharmacokinetics Dec 2023Zibotentan, a selective endothelin A receptor antagonist, is in development for chronic liver and kidney disease. The pharmacokinetics (PK) of zibotentan were previously...
BACKGROUND AND OBJECTIVE
Zibotentan, a selective endothelin A receptor antagonist, is in development for chronic liver and kidney disease. The pharmacokinetics (PK) of zibotentan were previously investigated in patients with either renal impairment or hepatic impairment, but the impact of both pathologies on PK was not evaluated. This study evaluated the PK and tolerability of a single oral dose of zibotentan in participants with concurrent moderate renal impairment and moderate hepatic impairment versus control participants.
METHODS
Twelve participants with moderate renal and hepatic impairment and 11 healthy matched control participants with no clinically significant liver or kidney disease were enrolled in an open-label, parallel-group study design. After administration of a single oral dose of zibotentan 5 mg, blood and urine sampling was performed. Pharmacokinetic parameters were determined for each of the two cohorts and compared. Comparisons between the cohorts were based on the geometric least squares mean ratio for the primary endpoints, which were area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC) and from time zero to the time of the last measurable concentration (AUC), and maximum plasma drug concentration (C) on Day 1 through 120 h post-dose. Secondary endpoints included apparent total body clearance (CL/F) on Day 1 through 120 h post-dose. Safety endpoints were assessed up to discharge.
RESULTS
In total, 11 participants with concurrent moderate renal and hepatic impairment, and 11 controls, completed the study. Zibotentan was generally well tolerated, and no new clinically significant safety findings were observed. Total exposure (AUC and AUC) was approximately 2.10-fold higher in participants with concurrent moderate renal and hepatic impairment versus controls, while C and total nonrenal body clearance were similar among all groups. A regression-based post hoc analysis, comparing exposure and CL/F in patients with concurrent impairment to patients with either renal or hepatic impairment alone, showed that CL/F with concurrent impairment was approximately half of that in controls and was positively correlated with reduction of renal function. Inclusion of the data on concurrent moderate renal and hepatic impairment in the regression analysis led to a narrower confidence interval for the predicted mean CL/F in participants with moderate hepatic impairment.
CONCLUSION
The presented findings advance the understanding of the PK of zibotentan in both renal impairment and hepatic impairment, with and without overlapping pathologies, and will thus increase the confidence of dose selection in future studies, particularly in vulnerable patient populations with concurrent renal and hepatic impairment.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT05112419.
Topics: Humans; Area Under Curve; Kidney; Liver Diseases; Renal Insufficiency; Kidney Diseases
PubMed: 37801266
DOI: 10.1007/s40262-023-01306-7