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Absorption Analysis and Bioavailability
Published in John G. Wagner, Pharmacokinetics for the Pharmaceutical Scientist, 2018
Let D = the dose of drug, Ar = the amount of drug remaining at the absorption site, AT = amount of drug absorbed to time T, A1 = VcC = amount of drug in the central compartment at time t, A2 = amount of drug in the peripheral compartment at time t, and Ae = amount of drug which has been eliminated by metabolism and excretion in time T. Then mass balance gives:
Incorporating Biological Information into The Assessment of Cancer Risk to Humans Under Various Exposure Conditions and Issues Related to High Background Tumor Incidence Rates
Published in Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach, Health Risk Assessment, 2017
For the liver, it is assumed that PERC ingested by gavage or by drinking water both follow an exponential elimination process, and all PERC metabolism occurs in the liver, with a rate of metabolism characterized by the Michaelis-Menten type equation. The mass balance results from the net difference between ingestion, metabolism, and systemic distribution:
The Rat
Published in Francis L. S. Tse, James M. Jaffe, Preclinical Drug Disposition, 2017
Francis L. S. Tse, James M. Jaffe
Excretion samples commonly collected from the rat include urine, feces, bile, and expirated air. By using properly designed cages and techniques, the samples can be completely collected so that the recovery of the administered dose (mass balance) is readily determined. These samples also serve to elucidate the biotransformation characteristics of the compound.
One small step in time, one giant leap for DMPK kind – a CRO perspective of the evolving core discipline of drug development
Published in Xenobiotica, 2022
John S. Kendrick, Colin Webber
Driven by the Animals (Scientific Procedures) Act species hierarchy in the UK, but compounded by first COVID impacting non-human primate availability and supply globally, and then by a reduction in the availability of Beagle dogs, DMPK scientists have needed to embrace the minipig as an alternative model. Specifically, different blood sampling techniques have had to be employed to enable robust pharmacokinetic study data to be generated, and metabolism caging has needed to be adapted to allow efficient urine and faeces collection to occur when determining mass balance endpoints. However, the largest change has occurred in the in vitro setting, where once a cross-species metabolism study was conducted in hepatocytes or microsomes from humans, rats, mice, dogs and primates to compare metabolite profiles, but now minipig test systems are included more often than not within development programs to provide data to confirm or discount the use of minipig.
The in vivo disposition of subcutaneous injected 14C-razuprotafib (14C-AKB-9778), a sulphamic acid phosphatase inhibitor, in nonclinical species and human
Published in Xenobiotica, 2021
Brandi Lynn Soldo, Patrick Camilleri, Akshay Buch, John Janusz
The human mass balance clinical trial was designed as an open-label, single-dose study and conducted in compliance with the International Conference on Harmonisation Guidelines and Good Clinical Practice (GCP). Healthy male volunteers (n = 6) were enrolled and all subjects completed eligibility screening and scheduled study procedures, and provided written informed consent. The subjects had an average (SD) age of 40.8 (8.04) years [range of 27–50 years], body weight of 87.3 (10.2) kg [range of 72.5–98.9 kg], and body mass index of 28.3 (4.22) kg/m2 [21.2–32.8 kg/m2]. Eligible subjects were admitted to the clinical research unit on Day −1, at least 24 h before dosing. Subjects remained confined to the clinical unit for approximately five days (through 96 h after Day 1 dosing) or until total radioactivity recovery criteria were met, which were: (1) >90% of the administered dose of radioactivity was recovered in excreta; or (2) <1% of the radioactivity dose was recovered in two consecutive 24-h urine and faecal collections.
Bridging the gap: academia, industry and FDA convergence for nanomaterials
Published in Drug Development and Industrial Pharmacy, 2020
Saurabh Shah, Shweta Nene, Nagarjun Rangaraj, Rajeev Singh Raghuvanshi, Shashi Bala Singh, Saurabh Srivastava
Apart from this general guidance covering all the nanomaterials, FDA has launched Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation guidance for industry specifically for liposomal drug products [14]. The physicochemical properties required by the applicants filing explicitly for liposomes include morphology, lamellarity, surface characteristics, charge, viscosity, entrapment efficiency, drug loading, phase transition temperature, in vitro release, drug leakage rate during its shelf life, integrity changes in presence of pH, salt, temperature, etc. In addition, for manufacturing and process control, critical quality attributes must be recognized and submitted via a process flow chart with a brief description on drug loading and free drug removal from the prepared liposomal batches. The purity, stability and degradation of lipid components is rather important for the FDA since it is the main carrier for the drug. Impurity profiling of the phospholipids includes the estimation of trans-fatty acids, free-fatty acids, peroxides lysophospholipids, solvents and catalysts utilized in the synthesis or purification procedures. Further, mass balance studies need to be conducted using radiolabelling studies and dose proportionality relationship studies and a comparison needs to be made with a non-liposomal drug moiety. FDA also encourages establishing an in vitro in vivo correlation (IVIVC) which may not follow impeccably level A but it may be possible to achieve a level B or C correlation.