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Journal of Clinical Pharmacology Feb 2022Population pharmacokinetics consists of analyzing pharmacokinetic (PK) data collected in groups of individuals. Population PK is widely used to guide drug development... (Review)
Review
Population pharmacokinetics consists of analyzing pharmacokinetic (PK) data collected in groups of individuals. Population PK is widely used to guide drug development and to inform dose adjustment via therapeutic drug monitoring and model-informed precision dosing. There are 2 main types of population PK methods: parametric (P) and nonparametric (NP). The characteristics of P and NP population methods have been previously reviewed. The aim of this article is to answer some frequently asked questions that are often raised by scholars, clinicians, and researchers about P and NP population PK methods. The strengths and limitations of both approaches are explained, and the characteristics of the main software programs are presented. We also review the results of studies that compared the results of both approaches in the analysis of real data. This opinion article may be informative for potential users of population methods in PK and guide them in the selection and use of those tools. It also provides insights on future research in this area.
Topics: Age Factors; Algorithms; Area Under Curve; Humans; Metabolic Clearance Rate; Models, Biological; Models, Statistical; Pharmacokinetics; Sex Factors; Software Design
PubMed: 34713491
DOI: 10.1002/jcph.1993 -
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 -
Leukemia Dec 2023Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel...
Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both C and AUC of dasatinib were within standard 80.00-125.00% range, while the intra- and inter-subject variability for AUC after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug-drug interaction study, omeprazole 40 mg reduced the mean AUC of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.
Topics: Humans; Dasatinib; Biological Availability; Omeprazole; Cross-Over Studies; Area Under Curve; Administration, Oral
PubMed: 37789147
DOI: 10.1038/s41375-023-02045-1 -
Expert Review of Clinical Immunology Apr 2023Tocilizumab is a monoclonal immunoglobulin G interleukin-6 receptor antagonist. MSB11456 is a proposed tocilizumab biosimilar. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Tocilizumab is a monoclonal immunoglobulin G interleukin-6 receptor antagonist. MSB11456 is a proposed tocilizumab biosimilar.
OBJECTIVE
To determine the pharmacokinetic equivalence of a single subcutaneous injection of MSB11456, when delivered via autoinjector (AI) and prefilled syringe (PFS), in healthy adult subjects.
RESEARCH DESIGN AND METHODS
In this randomized, open-label, single fixed-dose, crossover study, 91 subjects received subcutaneous administration of tocilizumab 162 mg via AI and PFS presentations. The primary endpoint pharmacokinetic parameters were analyzed using analysis of variance. Safety data were summarized descriptively.
RESULTS
There were no differences in pharmacokinetic parameters between presentations, and safety parameters were comparable. The 90% confidence intervals for the geometric least squares mean ratios of all primary pharmacokinetic parameters were contained within the predefined 80.00% to 125.00% bioequivalence limits, indicating pharmacokinetic equivalence between the AI and PFS.
CONCLUSIONS
MSB11456 administration via AI was bioequivalent to administration via PFS. MSB11456 can be administered by AI or PFS, increasing the available range of self-injection devices.
TRIAL REGISTRATION
The trial is registered at EudraCT, number 2020-003419-86.
Topics: Adult; Humans; Syringes; Cross-Over Studies; Antibodies, Monoclonal, Humanized; Therapeutic Equivalency; Injections, Subcutaneous
PubMed: 36789991
DOI: 10.1080/1744666X.2023.2174970 -
BMC Veterinary Research Apr 2022Buserelin is a luteinizing hormone releasing hormone (LHRH) agonist used for the treatment of hormone-dependent diseases in males and females. However, the...
BACKGROUND
Buserelin is a luteinizing hormone releasing hormone (LHRH) agonist used for the treatment of hormone-dependent diseases in males and females. However, the pharmacokinetics of buserelin in pigs and cows are not fully understood. This study was designed to develop a sensitive method to determine the concentration of buserelin in blood plasma and to investigate the pharmacokinetic parameters after intramuscular (i.m.) administration in pigs and cows.
RESULTS
A sensitive and rapid stability method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed. The pharmacokinetic parameters of buserelin after i.m. administration were studied in five pigs and five cows at a single dose of 1 mg per pig and 3 mg per cow. The plasma kinetics were analyzed by WinNonlin 8.1.0 software using a non-compartmental model. The mean concentration area under the curve (AUC) was 25.02 ± 6.93 h × ng/mL for pigs and 5.63 ± 1.86 h × ng/mL for cows. The maximum plasma concentration (C) and time to reach the maximum concentration (t) were 10.99 ± 2.04 ng/mL and 0.57 ± 0.18 h for pigs and 2.68 ± 0.36 ng/mL and 1.05 ± 0.27 h for cows, respectively. The apparent volume of distribution (V) in pigs and cows was 80.49 ± 43.88 L and 839.88 ± 174.77 L, respectively. The elimination half-time (t), and clearance (CL) were 1.29 ± 0.40 h and 41.15 ± 11.18 L/h for pigs and 1.13 ± 0.3 h and 545.04 ± 166.40 L/h for cows, respectively. No adverse effects were observed in any of the animals.
CONCLUSION
This study extends previous studies describing the pharmacokinetics of buserelin following i.m. administration in pigs and cows. Further studies investigating other factors were needed to establish therapeutic protocol in pigs and cows and to extrapolate these parameters to others economic animals.
Topics: Animals; Area Under Curve; Biological Availability; Buserelin; Cattle; Chromatography, Liquid; Female; Male; Swine; Tandem Mass Spectrometry
PubMed: 35410205
DOI: 10.1186/s12917-022-03237-0 -
Journal of Veterinary Pharmacology and... Jul 2021This study was designed to investigate the safety and pharmacokinetic (PK) profile of tildipirosin in horses after intravenous (i.v.) and subcutaneous (s.c.) injection...
This study was designed to investigate the safety and pharmacokinetic (PK) profile of tildipirosin in horses after intravenous (i.v.) and subcutaneous (s.c.) injection of a single dose at 4 mg/kg of body weight (b.w.). A total of 12 healthy mixed breed horses were used in the study. Horses were monitored for systemic and local adverse effects, and whole blood samples were collected for hematology and plasma biochemistry analysis at time (0) and at 6, 24, and 72 h after drug administration. For PK analysis, blood samples were collected at pre-determined times before and after tildipirosin administration. Plasma concentrations of tildipirosin were determined using ultra-high-performance liquid chromatography-ultraviolet detection method (UHPLC-UV). All horses tolerated the i.v. injection of tildipirosin without showing any systemic adverse effects. However, a non-painful, soft swelling appeared at the s.c. injection site in 5 horses (41.7%). On average, tildipirosin reached a maximum plasma concentration (C ) of 1257 ng/ml (geometric mean) between 0.5 and 1.5 h after s.c. administration (T ). The geometric mean values for total body clearance (Cl), the apparent volume of distribution based on the terminal phase (V ), and the apparent volume of distribution at steady-state (V ) were 0.52 L/kg·h, 22 L/kg, and 10.0 L/kg, respectively. Data collected in this study suggests that tildipirosin can be used safely in horses with caution.
Topics: Administration, Oral; Animals; Area Under Curve; Biological Availability; Horses; Injections, Intravenous; Tylosin
PubMed: 33609061
DOI: 10.1111/jvp.12958 -
Clinical Pharmacology in Drug... Aug 2022Letermovir is a human cytomegalovirus terminase inhibitor for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant...
Letermovir is a human cytomegalovirus terminase inhibitor for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients. The pharmacokinetics, safety, and tolerability of letermovir were assessed in healthy Japanese subjects in 2 phase 1 trials: trial 1-single ascending oral doses (240, 480, and 720 mg) and intravenous (IV) doses (240, 480, and 960 mg), and trial 2-multiple oral doses (240 and 480 mg once daily for 7 days). Following administration of oral single and multiple doses, letermovir was absorbed with a median time to maximum plasma concentration of 2 to 4 hours, and concentrations declined in a biphasic manner with a terminal half-life of ≈10 to 13 hours. The post absorption plasma concentration-time profile of letermovir following oral administration was similar to the profile observed with IV dosing. There was minimal accumulation with multiple-dose administration. Letermovir exposure in healthy Japanese subjects was ≈1.5- to 2.5-fold higher than that observed in non-Japanese subjects. Based on the population pharmacokinetic analysis, weight differences primarily accounted for the higher exposures observed in Asians. Letermovir was generally well tolerated following oral and IV administration to healthy Japanese subjects.
Topics: Acetates; Area Under Curve; Humans; Metabolic Clearance Rate; Quinazolines
PubMed: 35238179
DOI: 10.1002/cpdd.1081 -
Clinical Pharmacology in Drug... Dec 2021The study was conducted to compare the pharmacokinetics and safety profiles of 2 brands of tenofovir alafenamide (TAF) fumarate tablets. This research was a...
The study was conducted to compare the pharmacokinetics and safety profiles of 2 brands of tenofovir alafenamide (TAF) fumarate tablets. This research was a 2-preparation, 2-sequence, 4-period crossover, completely replicated study in 68 healthy Chinese subjects under fasting and fed conditions. The mean values of the area under the concentration-time curve from time 0 to the last time point with blood sample collection (AUC ), area under the concentration-time curve from time 0 to infinity (AUC ), and maximum concentration (C ) for the test and reference products of TAF were 248.5 and 275.7 ng/mL, 148.1 and 157.8 ng • h/mL, and 148.4 and 158.1 ng • h/mL, respectively, under the fasting condition. On the other hand, the mean value of C , AUC , and AUC for the test and reference formulations of TAF were 244.6 and 246.7 ng/mL, 230.4 and 244.9 ng • h/mL, and 233.2 and 246.2 ng • h/mL, respectively, under the fed condition. The 90% confidence intervals for geometric mean ratios of AUC and AUC of TAF in fasting and fed states were within the bioequivalence acceptance limits when tested using the average-bioequivalence method. The point estimate value for geometric mean ratio of C in fasting and fed states (88.4% and 95.5%, respectively) were within the bioequivalence acceptance limits as per the reference-scaled average-bioequivalence method. The safety profiles of the 2 formulations were comparable. Pharmacokinetic analysis demonstrated that the test formulations of TAF exhibited bioequivalence to the reference and were well tolerated by healthy Chinese subjects (Study Registry Identification Number: CTR20190086; CTR20190087).
Topics: Alanine; Area Under Curve; Cross-Over Studies; Humans; Tablets; Tenofovir; Therapeutic Equivalency
PubMed: 34352149
DOI: 10.1002/cpdd.985 -
Dermatologic Clinics Jul 2022The evaluation of bioequivalence (BE) involves comparing the test product to its reference product in a study whose fundamental scientific principles allow inferring of... (Review)
Review
The evaluation of bioequivalence (BE) involves comparing the test product to its reference product in a study whose fundamental scientific principles allow inferring of the clinical performance of the products. Several test methods have been discussed and developed to evaluate topical bioavailability (BA) and BE. Pharmacokinetics-based approaches characterize the rate and extent to which an active ingredient becomes available at or near its site of action in the skin. Such methodologies are considered to be among the most accurate, sensitive, and reproducible approaches for determining the BA or BE of a product.
Topics: Administration, Cutaneous; Biological Availability; Humans; Skin; Therapeutic Equivalency
PubMed: 35750415
DOI: 10.1016/j.det.2022.02.007 -
Expert Opinion on Drug Discovery Dec 2021The pharmacological action of a drug is linked to its affinity for a specific molecular target as quantified by in vitro equilibrium measurements. However, it is clear...
The pharmacological action of a drug is linked to its affinity for a specific molecular target as quantified by in vitro equilibrium measurements. However, it is clear that for many highly effective drugs, interactions with their molecular targets do not conform to simple, equilibrium conditions in vivo and this results in a temporal discordance between pharmacokinetics and pharmacodynamics. The drug-target residence time model was developed to provide a theoretical framework with which to understand cases in which very slow dissociation of the drug-target complex in vivo results in durable PD effects even after systemic concentrations of drug have waned.In this article, the author provides a brief description of the drug-target residence time model and focuses on the refinements that have been made to the original model to incorporate the influences of compound rebinding in cells and pharmacokinetic properties of drug molecules.There is now overwhelming evidence for the utility of the drug-target residence time model as a framework for understanding in vivo drug action. The in vitro measured residence time (τ) must be used in concert with equilibrium measures of drug-target affinity (e.g. IC) and with in vivo measures of pharmacokinetic half-life, to afford the researcher a powerful approach to compound optimization for clinical effect. Despite the significant use and refinement of this model, continued studies are required to better understand the dynamic interplay between residence time, target pathobiology, drug distribution and drug pharmacokinetics.
Topics: Drug Delivery Systems; Half-Life; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 34210223
DOI: 10.1080/17460441.2021.1948997