M Rowland & RN Tozer Clinical Pharmacokinetics. 4th ed., Lippincott Williams & Wilkins ▫ AJ Atkinson et al. (eds). Principles of Clinical. Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of Drug Therapy 1st Edition. by Thomas N. Tozer PharmD PhD (Author). by Thomas N. Tozer PharmD PhD (Author), Malcolm Rowland (Author) . Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of.
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Introduction to Pharmacokinetics and Pharmacodynamics by T.N. Tozer, , available at Book Depository with free delivery. Introduction to Pharmacokinetics and Pharmacodynamics: The Quantitative Basis of Drug Dr. Tozer, together with Dr. Malcolm Rowland, authored Clinical. Pharmacokinetic concepts have been used Table|Download .pdf).
Drug discovery and development can be viewed as a model building exercise during in which the knowledge of new compounds is continuously updated and used to inform decision-making and drug development strategy Lalonde et al.
Establish effective partnerships of pharmacology and DMPK A core drug discovery team in the pharmaceutical industry e.
It is essential that a partnership between pharmacologists and pharmacokineticists starts as early as possible in the course of a discovery program, and that the collaboration continues through to the transition of the program to early stage development and beyond into the clinic. It is highly recommended that the team set up an infrastructure for data sharing. Historical data highlighting examples of both success and failure with disease models are valuable additions to this collection, and teams are encouraged to determine whether a mechanistic or disease animal model is suitable for the project.
An important consideration is whether robust and clinically validated biomarkers are available.
If not as in case of working with a novel target or rare disease , it may be necessary to evaluate the translatability of preclinical PD biomarker data to the clinical setting. In cases where those data are not available, it may be advantageous to invest adequate resources to generate a complete data package with a reference compound before starting to test a series of novel compounds in the model.
Although project teams may see this as a significant investment at a very early stage of the program, extensive early understanding of the relationship between PK and PD will likely decrease the resource investment in the long term. One risk of moving directly into assessment of novel compounds with limited insight on optimal study design is that considerable effort and resources might be spent on a model that is not fully understood, characterized, or optimized based upon the intrinsic pharmacokinetic and pharmacologic properties of the compounds of interest.
Care must be taken to analyze the data and draw first conclusions and establish a working hypothesis that can be tested by subsequent study design. Ultimately, the goal with studies using a reference or tool compound is to understand the driving force s for response, i.
This can be achieved in a process where contributing scientists meet repeatedly to discuss data and evaluate whether further optimization is possible or necessary.
At this stage the team members need to have effective mechanisms in place to exchange and share data. Relevant data e. The acute disease models are fairly simple in scope and of short duration e.
Thus, a pharmacodynamic PD assessment is recommended for a similarity assessment of the two biologic products. Furthermore, the concentration—response relationships of the two formulations were assessed and compared.
Subjects and methods Study design A randomized, double-blind, single-dose, two-sequence, crossover study was conducted in healthy Korean volunteers. Subjects were provided detailed information on the study, and they confirmed their voluntary participation in the study by signing the informed consent form.
Healthy male volunteers aged 19—50 years and weighing The number of subjects was determined based on the results of a previous clinical study on a single subcutaneous injection of epoetin alfa in healthy subjects.
Blood samples for the PK assessment were obtained at predose and 1, 2, 4, 6, 8, 10, 12, 14, 16, 24, 36,48, 72, 96, and h postdose. Bioanalytical methods Serum EPO concentrations were quantified by a validated enzyme-linked immunosorbent assay method.
The calibration curve was constructed with calibration standard samples using seven different concentrations excluding the blank sample. For the quality control, samples of low, medium and high concentration Calibration curves of the test and comparator drugs showed linearity within a concentration range of 5. The AUClast was calculated by the linear trapezoidal method up to Tmax and by the log trapezoidal method after Tmax. Safety and tolerability analysis Safety and tolerability profiles of the drug were assessed with subjects who received at least a single dose of the study drug.
Safety and tolerability assessments were based on the reports of adverse events AEs , results of vital sign assessment, electrocardiogram and clinical laboratory tests. Local reaction of the drug was evaluated 1, 24 and 48 h after the injection. To evaluate the immunogenicity of the study drug, anti-drug antibody ADA formation was assessed at the predose of each period and the post-study visit.
Statistical analysis SAS Version 9.
For the log-transformed Cmax and AUCinf, linear mixed-effect analysis of variance was performed with a fixed effect for the formulation, period and sequence and a random effect for the subject nested for the sequence. The PD similarity was confirmed by a P-value above 0. Results Demographics A total of 43 subjects were enrolled in this study. Except for one subject who dropped out before receiving the treatment, all the enrolled subjects completed the study. Demographic and other baseline characteristics were not significantly different between the two sequences.
PK results The time courses of the serum EPO concentration were similar after a single subcutaneous injection of both formulations. For both formulations, EPO had a slow systemic absorption with a median Tmax of 10—12 h and exhibited multiphasic behaviors in the elimination phase Figure 1. The other PK parameters were also comparable between the two formulations Table 1.
Figure 1 Mean serum concentration—time profile of serum erythropoietin following a single subcutaneous administration of the test black circle or the comparator gray circle epoetin alfa. Note: A Linear scale and B semi-log scale. PD results The mean RET counts gradually increased up to h after the drug administration and decreased until the last observation time h.
The time courses for the RET count change were similar between the test and comparator epoetin alfa. Figure 2 Mean change in hematologic parameter levels following a single subcutaneous administration of the test black circle or the comparator gray circle epoetin alfa. The RET count level did not directly correspond to the change in the serum EPO concentration, but showed a hysteretic relationship.
The plot of the serum EPO concentration versus the RET count joined in the time sequence had a counterclockwise hysteresis loop. The RET count was still in an increased state from the baseline until h after the dosing.
The relationship of the RET count and the serum EPO concentration was similar in both the test and comparator epoetin alfa. However, all PD marker values recovered to the baseline values at h after the dosing. Safety and tolerability After a single subcutaneous injection of 4, IU epoetin alfa into the healthy male subjects, 57 AEs were reported from 22 subjects. Among the 57 AEs, 11 cases from four subjects were considered to be treatment related eight cases in the test drug group and three cases in the comparator drug group , which were considered mild and resolved without any treatment.
The most commonly reported treatment-related AEs were headache and vomiting three cases for each AE , which are already known as common adverse drug reactions for the rHuEPO formulations. No clinically significant changes were observed regarding clinical laboratory results, electrocardiogram results, vital signs and physical examinations.
Local injection reactions were observed in four subjects erythema in one subject and bruise in three subjects ; however, all the reactions were mild in severity and resolved without any other treatment. The ADA reactivity was negative for all samples from both treatment groups. Discussion and conclusion In this study, the PK and PD properties of two epoetin alfa formulations were assessed and compared. A previous study has reported that there was no significant difference between male and female subjects in serum EPO concentrations and hematologic response RET, RBC and Hb following the administration of epoetin alfa.