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Expert Opinion on Drug Metabolism &... Dec 2019: After administration, a drug undergoes absorption, distribution, metabolism, and elimination (ADME) before exerting its effect on the body. The combination of these... (Review)
Review
: After administration, a drug undergoes absorption, distribution, metabolism, and elimination (ADME) before exerting its effect on the body. The combination of these process yields the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of a drug. Although accurate prediction of PK and PD profiles is essential for drug development, conventional in vitro models are limited by their lack of physiological relevance. Recently, microtechnology-based in vitro model systems, termed 'organ-on-a-chip,' have emerged as a potential solution.: Orally administered drugs are absorbed through the intestinal wall and transported to the liver before entering systemic circulation, which plays an important role in the PK and PD profiles. Recently developed, chip-based in vitro models can be useful models for simulating such processes and will be covered in this paper.: The potential of intestine-on-a-chip models combined with conventional PK-PD modeling has been demonstrated with promising preliminary results. However, there are several challenges to overcome. Development of the intestinal wall, integration of the gut microbiome, and the provision of an intestine-specific environment must be achieved to realize in vivo-like intestinal model and enhance the efficiency of drug development.
Topics: Administration, Oral; Animals; Drug Development; Humans; Intestinal Absorption; Lab-On-A-Chip Devices; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 31794278
DOI: 10.1080/17425255.2019.1700950 -
Basic & Clinical Pharmacology &... Jan 2022Oral anticancer drugs suffer from significant variability in pharmacokinetics and pharmacodynamics partially due to limited bioavailability. The limited bioavailability... (Review)
Review
Oral anticancer drugs suffer from significant variability in pharmacokinetics and pharmacodynamics partially due to limited bioavailability. The limited bioavailability of anticancer drugs is due to both pharmaceutical limitations and physiological barriers. Pharmacokinetic boosting is a strategy to enhance the oral bioavailability of a therapeutic drug by inhibiting physiological barriers through an intentional drug-drug interaction (DDI). This type of strategy has proven effective across several therapeutic indications including anticancer treatment. Pharmacokinetic boosting could improve anticancer drugs lacking or with otherwise unacceptable oral formulations through logistic, economic, pharmacodynamic and pharmacokinetic benefits. Despite these benefits, pharmacokinetic boosting strategies could result in unintended DDIs and are only likely to benefit a limited number of targets. Highlighting this concern, pharmacokinetic boosting has mixed results depending on the boosted drug. While pharmacokinetic boosting did not significantly improve certain drugs, it has resulted in the commercial approval of boosted oral formulations for other drugs. Pharmacokinetic boosting to improve oral anticancer therapy is an expanding area of research that is likely to improve treatment options for cancer patients.
Topics: Administration, Oral; Antineoplastic Agents; Biological Availability; Drug Interactions; Humans; Neoplasms
PubMed: 34117715
DOI: 10.1111/bcpt.13623 -
European Review For Medical and... Dec 2023Amiodarone (AMD), a drug of choice to treat cardiac arrhythmias, has a narrow therapeutic index (NTI). It inhibits CYP3A4, CYP2C9, and CYP2D6 enzymes. Quercetin (QUE), a...
OBJECTIVE
Amiodarone (AMD), a drug of choice to treat cardiac arrhythmias, has a narrow therapeutic index (NTI). It inhibits CYP3A4, CYP2C9, and CYP2D6 enzymes. Quercetin (QUE), a pharmacologically important bioflavonoid in vegetables and fruits, is important in treating cardiovascular comorbidities. QUE alters the bioavailability of drugs used concurrently by dual inhibition of P-glycoproteins (P-gp) and cytochrome (CYP) enzyme systems. The current study aimed to investigate the pre-treatment and co-administration effect of QUE on AMD pharmacokinetics in rats.
MATERIALS AND METHODS
Two separate animal trials (I and II) were planned to probe the effect of QUE on AMD pharmacokinetics by following previously cited studies. The pre-treatment group received oral doses of QUE for 14 days, and a single dose of AMD on the 15th day. Rats were administered single doses of QUE (20 mg/kg) and AMD (50 mg/kg) concurrently in a carboxymethylcellulose (CMC) in the co-administration study. Blood was collected at pre-determined time points. AMD was quantified by HPLC, and data was analyzed by PK solver software.
RESULTS
In the pre-treated group, peak plasma concentration (Cmax) and area under the curve (AUC0-∞) of AMD were increased by 45.52% and 13.70%, respectively, while time to achieve maximum concentration (tmax), half-life (t1/2) and clearance (CL) were declined by 35.72%, 16.75%, and 11.0% respectively compared to the control. In the co-administered group, compared to controls, Cmax and AUC0-∞ were elevated to 12.90% and 7.80%, respectively, while tmax, t1/2, and CL declined by 16.70%, 2.35%, and 13.40%. Further, AMD was increased in lung tissue of both treated groups, relative to the respective controls.
CONCLUSIONS
A notable pharmacokinetic drug interaction between QUE and AMD was observed in rats and warrants possible drug interaction study in humans, suggesting AMD dose adjustment specifically in patients with arrhythmia having a pre-treatment history and simultaneous administration of QUE-containing products.
Topics: Humans; Rats; Animals; Quercetin; Amiodarone; Tissue Distribution; Drug Interactions; Biological Availability; Area Under Curve
PubMed: 38095371
DOI: 10.26355/eurrev_202312_34561 -
International Journal of Clinical... Apr 2023The physiological and pathological conditions of individuals could influence the absorption and metabolism of drugs in vivo, so this study assessed the bioequivalence... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSES
The physiological and pathological conditions of individuals could influence the absorption and metabolism of drugs in vivo, so this study assessed the bioequivalence and pharmacokinetics of lenalidomide 25 mg capsules (test formulation) and Revlimid 25 mg capsules (reference formulation) in Chinese patients with multiple myeloma (MM).
MATERIALS AND METHODS
A multicenter, open-label, randomized, two-period, crossover trial was established to evaluate a single capsule of test and reference formulations under fasting conditions. Pharmacokinetic parameters were assessed, and adverse events (AEs) were monitored throughout.
RESULTS
Overall, 40 patients with MM completed the study. 17 AEs were reported, among which there was 1 serious event during the study. Geometric ratios for the maximum plasma concentration (C) (98.50%; 90% confidence interval (CI), 91.89 - 105.60%), area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration (AUC) (94.74%; CI, 92.07 - 97.50%), and AUC from time 0 to infinity (AUC) (95.55%; CI, 93.07 - 98.09%) all met bioequivalence criteria. Statistics of the data of 39 patients after oral administration of lenalidomide (both test and reference formulation) demonstrated that plasma exposure tends to increase with age.
CONCLUSION
The two formulations of lenalidomide 25 mg displayed similar pharmacokinetic profiles and were bioequivalent. Age was verified to change the pharmacokinetics of lenalidomide, as increasing age was correlated with higher total exposure.
Topics: Humans; Therapeutic Equivalency; Lenalidomide; Biological Availability; Multiple Myeloma; Capsules; Area Under Curve; Administration, Oral; Cross-Over Studies; Tablets
PubMed: 36683548
DOI: 10.5414/CP204224 -
Bioanalysis Jan 2023Analysis of "free" drug/target concentrations is important to set up appropriate pharmacokinetic-pharmacodynamic models, to evaluate active-drug exposure and target... (Review)
Review
Analysis of "free" drug/target concentrations is important to set up appropriate pharmacokinetic-pharmacodynamic models, to evaluate active-drug exposure and target engagement. Such "free-analyte" determination could be done by direct bioanalysis using an appropriate "free-analyte" assay. Development of "free" assays is often considered challenging from a technological and regulatory perspective. The application of a "total-total" approach, where the "free-analyte" concentration is determined mathematically, is considered a more convenient option. In this perspective, we examine and discuss the challenges of this "total-total" approach, from the affinity data, the importance of applying an appropriate "total" assay, the impact of additional binding partners and the variability of the total drug/target assays and their impact on the quality and variability of the final "free-analyte" dataset.
Topics: Pharmacokinetics; Pharmaceutical Preparations
PubMed: 36762451
DOI: 10.4155/bio-2022-0246 -
PloS One 2022Imidocarb (IMD) is commonly used for treatment of eperythrozoon, babesia, piroplasma and trypanosoma in animals, but there are few studies on its pharmacokinetics in...
Imidocarb (IMD) is commonly used for treatment of eperythrozoon, babesia, piroplasma and trypanosoma in animals, but there are few studies on its pharmacokinetics in cattle. The purpose of this study was to obtain pharmacokinetic parameters and assess the bioequivalence of subcutaneous injections of two IMD formulations in cattle. Forty-eight healthy cattle, 24 males and 24 females, were randomLy divided into two groups (test group and reference group) with 12 males and 12 females per group. The generic IMD was injected subcutaneously with a single dose of 3.0 mg/kg in the test group. Reference group animals were given one injection of the marketed IMD at the same dosage. The limit of detection (LOD) and limit of quantification (LOQ) for IMD in cattle plasma were 0.05 ng/mL and 0.1 ng/mL, respectively. The recoveries ranged from 88.50% to 92.42%, and the equation of this calibration curve was Y = 13672.1X+187.43. The pharmacokinetics parameters of the test group showed that the maximum concentration of 2257.5±273.62 ng/mL was obtained at 2.14±0.67 h, AUC0-t 14553.95±1946.85 ng·h/mL, AUC∞ 15077.88±1952.19 ng·h/mL, T1/2 31.77±25.75 h, CL/F 0.14±0.02 mL/h/g, and Vz/F 6.53±5.34 mL/g. There was no significant difference in AUC0-t, AUC∞ and Cmax between the test group and the reference group (P>0.05). The 90% confidence interval of AUC0-t, AUC0-∞ and Cmax in the test group was included in 80%-125% AUC0-t, AUC0-∞ and 70%-143% Cmax in the reference group, respectively. Based on these results, the two preparations were found to be bioequivalent.
Topics: Animals; Cattle; Female; Male; Area Under Curve; Cross-Over Studies; Imidocarb; Injections, Subcutaneous; Tablets; Therapeutic Equivalency
PubMed: 35749453
DOI: 10.1371/journal.pone.0270130 -
The Journal of Veterinary Medical... Oct 2023The aim of this study was to measure the concentrations of enrofloxacin (ERFX) and other fluoroquinolones; orbifloxacin (OBFX), marbofloxacin (MBFX), and ofloxacin...
The aim of this study was to measure the concentrations of enrofloxacin (ERFX) and other fluoroquinolones; orbifloxacin (OBFX), marbofloxacin (MBFX), and ofloxacin (OFLX) in the plasma and bile of rabbits after a single intravenous (IV) injection. Twenty male rabbits were divided into four groups and given each drug by IV injection into the ear vein at a dose of 5.0 mg/kg BW. The concentration of ERFX, ciprofloxacin (CPFX), OBFX, MBFX and OFLX in plasma and bile were determined by HPLC. CPFX, metabolite of ERFX, was also measured by HPLC in plasma and bile of rabbits receiving ERFX. Several pharmacokinetic parameters in plasma were calculated and biliary clearance (CL) was calculated from extent of biliary excretion and accumulation of AUC of each drug. After IV injection, elimination half-life (t) was 4.13, 3.68, 6.60, 5.14 hr; volume of distribution at a steady state (V) was 1.24, 0.503, 0.771, 1.02 L/kg; and total body clearance (CL) was 1.05, 0.418, 0.271, 0.453 L/kg/hr, respectively. The values for CL for ERFX, OBFX, MBFX, and OFLX were 0.0048, 0.0050, 0.0057, and 0.0094 L/kg/hr, respectively. These values represent 0.48%, 1.2%, 2.1%, and 2.3% of the total body clearance (CL) of each drug, respectively. The biliary clearance of CPFX was also measured and found to be 0.0199 L/kg/hr with ERFX administration. The results showed that ERFX, OBFX, MBFX, and OFLX were not excreted into the bile to a significant extent, making them safe drugs to use in rabbits.
Topics: Rabbits; Male; Animals; Injections, Intravenous; Hepatobiliary Elimination; Fluoroquinolones; Enrofloxacin; Area Under Curve; Half-Life
PubMed: 37635088
DOI: 10.1292/jvms.23-0246 -
Expert Opinion on Investigational Drugs Mar 2023Dasatinib (Sprycel®) is a tyrosine kinase inhibitor for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.
BACKGROUND
Dasatinib (Sprycel®) is a tyrosine kinase inhibitor for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.
RESEARCH DESIGN & METHODS
We designed a clinical study to demonstrate that the dasatinib tablet (YiNiShu®) (Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and Dasatinib (Bristol Myers Squibb) were bioequivalent under fasting and fed conditions. The whole study was structured into the fasting trial and the postprandial trial. Each period, subjects were given 50 mg dasatinib or its generic. The RSABE (reference scale average bioequivalence) and ABE (average bioequivalence) methods were employed to assess bioequivalence by pharmacokinetics (PK) parameters for a highly variable drug.
RESULTS
32 and 24 eligible volunteers were enrolled in the fasting and postprandial trials, respectively. In the fasting trial, the RSABE method was performed, and point estimates of C, AUC, and AUC met the bioequivalence criteria. In the postprandial trial, the ABE method was performed, and the 90% CI of the geometric mean ratio (GMR) for PK parameters met the requirements of bioequivalence standards.
CONCLUSION
The results proved that the PK parameters of the two drugs were similar and bioequivalent, indicating that both drugs had a good safety profile.
CLINICAL TRIAL REGISTRATION
This trial was registered in ClinicalTrials.gov (Number: NCT05640804) and Drug Clinical Trial Registration and Information Disclosure Platform (Number: CTR20181708).
Topics: Humans; Area Under Curve; Biological Availability; Dasatinib; Drugs, Generic; East Asian People; Fasting; Therapeutic Equivalency
PubMed: 36757390
DOI: 10.1080/13543784.2023.2179481 -
Clinical Pharmacology in Drug... Jun 2023Ibuprofen is a nonsteroidal anti-inflammatory agent. In this study, we compared the pharmacokinetic properties, bioequivalence, and safety of a newly developed generic... (Randomized Controlled Trial)
Randomized Controlled Trial
Ibuprofen is a nonsteroidal anti-inflammatory agent. In this study, we compared the pharmacokinetic properties, bioequivalence, and safety of a newly developed generic formulation (test) and a branded formulation (reference) of 0.2 g ibuprofen granules in healthy Chinese participants in fasting and fed arms. The randomized, single-dose, open-label, two-preparation, two-sequence, two-period crossover study had a washout period of 7 days between each period. It was conducted in 72 participants, 24 in the fasting arm and 48 in the fed arm. The concentration of ibuprofen in the plasma was determined using high-performance liquid chromatography-tandem mass spectroscopy. The primary pharmacokinetic parameters were calculated using a noncompartmental model. Safety assessments were performed throughout the study. The mean values of C , AUC , and AUC for the test and reference preparations of ibuprofen were 19 295 and 21 101 ng/mL, 70 795 and 70 558 ng * h/mL, and 72 023 and 71 647 ng * h/mL, respectively, in the fasting arm and 11 299 and 11 605 ng/mL, 70 983 and 69 157 ng * h/mL, and 73 279 and 71 267 ng * h/mL, respectively, in the fed arm. For all parameters, bioequivalence was within acceptable limits. No serious adverse reactions were reported in this study. This study demonstrated that the 2 formulations of ibuprofen granules were bioequivalent in healthy Chinese volunteers under fasting and fed conditions.
Topics: Humans; Therapeutic Equivalency; Ibuprofen; Cross-Over Studies; Area Under Curve; Biological Availability
PubMed: 36575962
DOI: 10.1002/cpdd.1211 -
Journal of Veterinary Internal Medicine Jul 2022Isavuconazole is a triazole antifungal drug that has shown good efficacy in human patients. Absorption and pharmacokinetics have not been evaluated in cats.
BACKGROUND
Isavuconazole is a triazole antifungal drug that has shown good efficacy in human patients. Absorption and pharmacokinetics have not been evaluated in cats.
OBJECTIVES
To determine the pharmacokinetics of isavuconazole in cats given a single IV or PO dose.
ANIMALS
Eight healthy, adult research cats.
METHODS
Four cats received 100 mg capsules of isavuconazole PO. Four cats received 5 mg/kg isavuconazole solution IV. Serum was collected at predetermined intervals for analysis using ultra-high performance liquid chromatography-tandem mass spectrometry. Data were analyzed using a 2-compartment uniform weighting pharmacokinetic analysis with lag time for PO administration and a 2 compartment, 1/y weighting for IV administration. Predicted 24 and 48-hour dosing intervals of 100 mg isavuconazole administered PO were modeled and in vitro plasma protein binding was assessed.
RESULTS
Both PO and IV drug administration resulted in high serum concentrations. Intravenous and PO formulations of isavuconazole appear to be able to be used interchangeably. Peak serum isavuconazole concentrations occurred 5 ± 3.8 hours after PO administration with an elimination rate half-life of 66.2 ± 55.3 hours. Intersubject variability was apparent in both the PO and IV groups. Two cats vomited 6 to 8 hours after PO administration. No adverse effects were observed in the IV group. Oral bioavailability was estimated to be approximately 88%. Serum protein binding was calculated to be approximately 99.0% ± 0.03%.
CONCLUSIONS AND CLINICAL IMPORTANCE
Isavuconazole might prove to be useful in cats with fungal disease given its favorable pharmacokinetics. Additional studies on safety, efficacy, and tolerability of long-term isavuconazole use are needed.
Topics: Administration, Intravenous; Administration, Oral; Animals; Area Under Curve; Biological Availability; Cats; Half-Life; Humans; Nitriles; Pyridines; Triazoles
PubMed: 35616184
DOI: 10.1111/jvim.16452