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Clinical Pharmacology in Drug... May 2022This study aimed to evaluate the bioequivalence between a generic roxatidine acetate hydrochloride (RAH) sustained-release capsule and brand-named formulation (ALTAT)... (Randomized Controlled Trial)
Randomized Controlled Trial
This study aimed to evaluate the bioequivalence between a generic roxatidine acetate hydrochloride (RAH) sustained-release capsule and brand-named formulation (ALTAT) under fasting and fed conditions. An open-label, single-center, randomized 2-period crossover study with a 5-day washout period was conducted. A single oral dose of 75-mg generic RAH sustained-release capsule (test drug) or a commercial capsule (reference drug) was given to healthy volunteers under fasting (n = 36) and fed conditions (n = 36). Blood samples were collected at baseline and during the 24 hours after dosing. The concentrations of roxatidine acetate (ROX) and bioactive metabolite roxatidine in plasma were detected using a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were analyzed with noncompartmental methods. As prodrug, RAH was dehydrochloric acid to ROX in body and further rapidly converted to roxatidine. Such a rapid metabolism resulted in ROX that was hardly detected in plasma. Active metabolism roxatidine was therefore used to evaluate the pharmacokinetic process. The major pharmacokinetic parameters of roxatidine including peak plasma concentration, area under the plasma concentration-time curve from time 0 to time t, and area under the plasma concentration-time curve from time 0 to infinity were similar between the 2 preparations under fasting and fed conditions. The generic RAH sustained-release capsule is bioequivalent to the reference drug under fasting and fed conditions in healthy Chinese subjects.
Topics: Area Under Curve; Capsules; China; Cross-Over Studies; Delayed-Action Preparations; Drugs, Generic; Healthy Volunteers; Humans; Piperidines; Tablets; Therapeutic Equivalency
PubMed: 34978388
DOI: 10.1002/cpdd.1053 -
Wiener Klinische Wochenschrift Aug 2001The history of medicine provides ample evidence of the physicians' struggle with the subject of appropriate drug dosing. Recent studies indicate that drug-related... (Review)
Review
The history of medicine provides ample evidence of the physicians' struggle with the subject of appropriate drug dosing. Recent studies indicate that drug-related mortality due to inadequate dosing principles still is a leading cause of death, only surpassed by cardiovascular diseases, cancer and stroke. In an effort to rationalize drug therapy, pharmacokinetic (PK) principles were introduced in medical practice in the early 1970s, mainly in the field of therapeutic drug monitoring (TDM). This measure was shown to reduce mortality. Several limitations in traditional PK, however, have led to the belief among many physicians that clinical PK is an unnecessary assignment of limited clinical relevance. Despite the perceived limitations of traditional PK research, remarkable developments have taken place in recent years and have made clinical PK a "physiological-mechanism based endeavor" with important implications for clinical medicine. Notably, the introduction of (1) PK-PD (pharmacokinetic-pharmacodynamic) modeling (2) target site PK (3) population PK and (4) pharmacogenomics has permitted better integration of PK principles into clinical drug therapy. The aim of the present article is to provide an overview of these developments and to discuss their impact on our understanding of clinical drug therapy.
Topics: Biological Availability; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Metabolic Clearance Rate; Pharmacokinetics; Tissue Distribution
PubMed: 11571833
DOI: No ID Found -
Clinical Pharmacokinetics Dec 2000Reboxetine is a novel selective norepinephrine inhibitor that has been evaluated in the treatment of patients with depression. Reboxetine is a racemic mixture, and the... (Review)
Review
Reboxetine is a novel selective norepinephrine inhibitor that has been evaluated in the treatment of patients with depression. Reboxetine is a racemic mixture, and the (S,S)-(+)-enantiomer appears to be the more potent inhibitor. However, the ratio of the areas under the concentration-time curves of the (S,S)-(+)- and (R,R)-(-)-enantiomers in vivo is approximately 0.5. There is no evidence for chiral inversion. Differences in the clearances of the 2 enantiomers may be explained by differences in protein binding. The pharmacokinetics of reboxetine are linear following both single and multiple oral doses up to a dosage of 12 mg/day. The plasma concentration-time profile following oral administration is best described by a 1-compartment model, and the mean half-life (approximately 12 hours) is consistent with the recommendation to administer the drug twice daily. Reboxetine is well absorbed after oral administration. The absolute bioavailability is 94.5%, and maximal concentrations are generally achieved within 2 to 4 hours. Food affects the rate, but not the extent, of absorption. The distribution of reboxetine appears to be limited to a fraction of the total body water due to its extensive (>97%) binding to plasma proteins. The primary route of reboxetine elimination appears to be through hepatic metabolism. Less than 10% of the dose is cleared renally. A number of metabolites formed through hepatic oxidation have been identified, but reboxetine is the major circulating species in plasma. In vitro studies show that reboxetine is predominantly metabolised by cytochrome P450 (CYP) 3A4; CYP2D6 is not involved. Reboxetine plasma concentrations are increased in elderly individuals and in those with hepatic or renal dysfunction, probably because of reduced metabolic clearance. In these populations, reboxetine should be used with caution, and a dosage reduction is indicated. Ketoconazole decreases the clearance of reboxetine, so that the dosage of reboxetine may need to be reduced when potent inhibitors of CYP3A4 are coadministered. Quinidine does not affect the in vivo clearance of reboxetine, confirming the lack of involvement of CYP2D6. There is no pharmacokinetic interaction between reboxetine and lorazepam or fluoxetine. Reboxetine at therapeutic concentrations has no effect on the in vitro activity of CYP1A2, 2C9, 2D6, 2E1 or 3A4. The lack of effect of reboxetine on CYP2D6 and CYP3A4 was confirmed by the lack of effect on the metabolism of dextromethorphan and alprazolam in healthy volunteers. Thus, reboxetine is not likely to affect the clearance of other drugs metabolised by CYP isozymes.
Topics: Administration, Oral; Aged; Aging; Antidepressive Agents; Area Under Curve; Biological Availability; Female; Half-Life; Humans; Intestinal Absorption; Male; Metabolic Clearance Rate; Middle Aged; Morpholines; Protein Binding; Reboxetine; Stereoisomerism; Tissue Distribution
PubMed: 11192474
DOI: 10.2165/00003088-200039060-00003 -
Cancer Letters Apr 1993There has been considerable progress in recent years in developing physiological models for the pharmacokinetics of toxic chemicals and in the application of these... (Review)
Review
There has been considerable progress in recent years in developing physiological models for the pharmacokinetics of toxic chemicals and in the application of these models in cancer risk assessment. Physiological pharmacokinetic models consist of a number of individual compartments, based on the anatomy and physiology of the mammalian organism of interest, and include specific parameters for metabolism, tissue binding, and tissue reactivity. Because of the correspondence between these compartments and specific tissues or groups of tissues, these models are particularly useful for predicting the doses of biologically active forms of toxic chemicals at target tissues under a wide variety of exposure conditions and in different animal species, including humans. Due to their explicit characterization of the biological processes governing pharmacokinetic behaviour, these models permit more accurate predictions of the dose of active metabolites reaching target tissues in exposed humans and hence of potential cancer risk. In addition, physiological models also permit a more direct evaluation of the impact of parameter uncertainty and inter-individual variability in cancer risk assessment. In this article, we review recent developments in physiologic pharmacokinetic modeling for selected chemicals and the application of these models in carcinogenic risk assessment. We examine the use of these models in integrating diverse information on pharmacokinetics and pharmacodynamics and discuss challenges in extending these pharmacokinetic models to reflect more accurately the biological events involved in the induction of cancer by different chemicals.
Topics: Carcinogens; Models, Biological; Neoplasms; Pharmacokinetics; Tissue Distribution
PubMed: 8481888
DOI: 10.1016/0304-3835(93)90025-5 -
Journal of Pharmaceutical Sciences Nov 2009Oxaliplatin is used primarily in the treatment of metastatic colorectal cancer. In this minireview, we discuss potentially important biotransformation pathways in light... (Review)
Review
Oxaliplatin is used primarily in the treatment of metastatic colorectal cancer. In this minireview, we discuss potentially important biotransformation pathways in light of its short elimination half-life in vivo. We also highlight new information achieved using a selective analytical technique to measure intact oxaliplatin in pharmacokinetic studies (comprising intravenous, intraperitoneal, and intrahepatic administration) and compare to results obtained by measurements of total platinum. The use of selective analytical techniques is strongly recommended giving kinetic parameters of the parent compound and not only to a complex mixture of platinum containing endogenous compounds.
Topics: Antineoplastic Agents; Area Under Curve; Biotransformation; Colorectal Neoplasms; Half-Life; Humans; Metabolic Clearance Rate; Molecular Structure; Organoplatinum Compounds; Oxaliplatin
PubMed: 19340883
DOI: 10.1002/jps.21732 -
Immunotherapy Feb 2023Comparing pharmacokinetics and safety of CT-P17 and EU-approved reference adalimumab (EU-adalimumab) in Japan. Double-blind, parallel-group phase I trial at three... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparing pharmacokinetics and safety of CT-P17 and EU-approved reference adalimumab (EU-adalimumab) in Japan. Double-blind, parallel-group phase I trial at three hospitals. Healthy Japanese adults were randomized (1:1) to CT-P17 or EU-adalimumab (single 40-mg subcutaneous dose). The primary end point was pharmacokinetic equivalence for area under the concentration-time curve from time zero to infinity and maximum serum concentration. Of the 205 randomized subjects (102 CT-P17, 103 EU-adalimumab), 204 received study drug. CT-P17 and EU-adalimumab were pharmacokinetically equivalent: 90% CIs for geometric least-squares mean ratios were within predefined 80-125% equivalence margins. Secondary pharmacokinetic end points, safety and immunogenicity were similar between the groups. CT-P17 had pharmacokinetics, safety and immunogenicity comparable to EU-adalimumab in healthy Japanese adults.
Topics: Adult; Humans; Adalimumab; Area Under Curve; Biosimilar Pharmaceuticals; Double-Blind Method; East Asian People; Healthy Volunteers; Therapeutic Equivalency; Antibodies, Monoclonal, Humanized
PubMed: 36748363
DOI: 10.2217/imt-2022-0181 -
Pharmaceutical Research Sep 2009Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux... (Review)
Review
Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme.
Topics: Administration, Oral; Animals; Biological Availability; Biotransformation; Carrier Proteins; Half-Life; Humans; Pharmacokinetics
PubMed: 19568696
DOI: 10.1007/s11095-009-9924-0 -
The AAPS Journal May 2015The presentations at the Orlando Inhalation Conference on pharmacokinetic (PK) studies indicated that PK is the most sensitive methodology for detecting formulation...
The presentations at the Orlando Inhalation Conference on pharmacokinetic (PK) studies indicated that PK is the most sensitive methodology for detecting formulation differences of oral inhaled drug products (OIDPs) that have negligible gastrointestinal bioavailability or for which oral absorption can be prevented (e.g., ingestion of charcoal). PK studies, therefore, may represent the most appropriate methodology for assessing local and systemic bioequivalence (BE). It was believed by many (but not all participants) that potential differences between formulations are more likely to be detected in healthy adult volunteers, as variability is reduced while deposition to peripheral areas is not restricted. A study design allowing assessment and statistical consideration of intra-subject and inter-batch variability within the evaluation of BE studies was suggested, while optimal inhalation technique during PK studies should be enforced to decrease variability. Depending on the drug and in vitro method, in vitro tests may not detect differences in PK parameters. Harmonization of BE testing requirements among different countries should be encouraged to improve global availability of low cost OIDPs and decrease industry burden.
Topics: Administration, Inhalation; Adult; Biological Availability; Humans; Pharmaceutical Preparations; Pharmacokinetics; Research Design; Therapeutic Equivalency
PubMed: 25762449
DOI: 10.1208/s12248-015-9736-6 -
International Review of Neurobiology 2007Although there have been relatively few studies of the pharmacokinetics of antiepileptic drugs (AEDs) in old age, available evidence indicates that the clearance of most... (Review)
Review
Although there have been relatively few studies of the pharmacokinetics of antiepileptic drugs (AEDs) in old age, available evidence indicates that the clearance of most old and new generation AEDs is reduced on average by about 20-40% in elderly patients compared with nonelderly adults. Depending on the pharmacokinetic characteristics of the drug, the reduction in clearance can be ascribed to a physiological reduction in rate of drug metabolism, to a decrease in renal excretion rate, or to both. Studies have consistently demonstrated that interindividual pharmacokinetic variability in old age is particularly prominent, due not only to the influence of aging-related physiological changes, but also to the impact of comorbidities and drug-drug interactions. For extensively metabolized drugs, there are no reliable tools to predict with a high degree of accuracy the pharmacokinetic behavior of an AED in an individual patient. With renally eliminated drugs, determination of creatinine clearance may provide a useful clue in predicting individual changes in drug clearance and the consequent need for dosage adjustment. In the therapeutic setting, measurement of serum AED concentrations can be valuable in individualizing dosage in an elderly person, even though it should be remembered that in the case of drugs that are highly bound to plasma proteins the total serum concentration may underestimate the level of unbound, pharmacologically active drug. Because aging is also associated with important pharmacodynamic changes that may alter the relationship between serum drug concentration and pharmacological effects, pharmacokinetic measurements alone are not a substitute for the need to monitor clinical response carefully and to adjust dosage accordingly.
Topics: Absorption; Aging; Anticonvulsants; Biotransformation; Humans; Kidney; Tissue Distribution
PubMed: 17433924
DOI: 10.1016/S0074-7742(06)81011-1 -
Expert Review of Clinical Immunology May 2022Tocilizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody against the interleukin-6 receptor (IL-6 R). MSB11456 is a proposed tocilizumab biosimilar. (Randomized Controlled Trial)
Randomized Controlled Trial
Pharmacokinetics and pharmacodynamics of a proposed tocilizumab biosimilar MSB11456 versus both the US-licensed and EU-approved products: a randomized, double-blind trial.
BACKGROUND
Tocilizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody against the interleukin-6 receptor (IL-6 R). MSB11456 is a proposed tocilizumab biosimilar.
OBJECTIVES
To assess the pharmacokinetic and pharmacodynamic similarity of MSB11456 to both US-licensed and EU-approved tocilizumab.
METHODS
Healthy adult volunteers (N = 685) received a single 162 mg subcutaneous injection of MSB11456, US-licensed tocilizumab, or EU-approved tocilizumab in this randomized, double-blind, parallel-group study. Blood samples were taken pre-dose and for up to 48 days post-dose. Primary endpoint pharmacokinetic parameters were analyzed using analysis of covariance. Secondary pharmacodynamic measures included serum-soluble IL-6 R and serum C-reactive protein. Safety data were analyzed descriptively.
RESULTS
Pharmacokinetic equivalence (with all corresponding 90% confidence intervals for the geometric least squares mean ratios within the predefined 80.00% to 125.00% equivalence margin) was demonstrated between MSB11456 and both US-licensed and EU-approved tocilizumab, as well as between the reference products. Pharmacodynamic analyses demonstrated similarity of MSB11456 and both US-licensed and EU-approved tocilizumab, as well as between the reference products. Safety, tolerability, and immunogenicity were comparable between treatments.
CONCLUSION
Pharmacokinetic and pharmacodynamic similarity of MSB11456, US-licensed tocilizumab, and EU-approved tocilizumab were demonstrated, and the three products had comparable immunogenicity and safety, supporting MSB11456 as a biosimilar to tocilizumab.
Topics: Adult; Antibodies, Monoclonal, Humanized; Area Under Curve; Biosimilar Pharmaceuticals; Double-Blind Method; Healthy Volunteers; Humans; Interleukin-6; Therapeutic Equivalency
PubMed: 35354411
DOI: 10.1080/1744666X.2022.2060204