Therapeutic Drug Monitoring - Assignment Example

Therapeutic Drug Monitoring Introduction It is important to individualise drug treatments in individuals whenever possible in order to achieve the optimum therapeutic benefits and minimize any adverse side effects. This is particularly desirable when there is a significant overlap between the therapeutic and toxic drug concentration ranges. One such category of therapeutic agents that demonstrate a significant overlap between the therapeutic and toxic ranges are the fungal-derived immunosuppressive drugs (e.g. Cyclosporin A known as Prograf and FK506 known as Tacrolimus), commonly used following soft organ transplantation and in the treatment of autoimmune disease. The clinical use of both these compounds is also associated with the adverse side effect of nephrotoxicity. When whole blood circulating concentrations are too low to suppress the immune response, then the acute rejection process may be initiated. Conversely, when whole blood circulating drug concentrations increase, the risk of adverse drug side effects also increases (e.g. nephrotoxicity). Drug interactions also play an important role in the maintenance of appropriate circulating drug concentrations. For example, for Cyclosporin A and FK506, circulating concentrations can either be increased or decreased by the co-administration of either inhibitors or inducers of the cytochrome P-4503A-dependent monooxygenase system. In addition, if a nephrotoxic compound (e.g. aminoglycoside antibiotics) is co-administered with either of these compounds there is the potential for additive toxicity. The level of any drug circulating in the blood stream is a balance between the rate of appearance into the circulation (absorption, gut metabolism etc.) and its removal (excretion, metabolism etc.) and any co-administered agents which affect either of these two sets of parameters will have a profound effect on drug concentrations and hence clinical management. Answers to the questions Question one a) Calculation of coefficient of variation Coefficient of variation is got by dividing the standard deviation by the mean. The standard deviations of the data given are Day Standard ‘A’ - Duplicates Standard ‘C’ - Duplicates Monday 2.377 2.342 1.293 1.287 Tuesday 2.268 2.298 1.296 1.300 Wednesday 2.390 2.351 1.286 1.288 Thursday 2.189 2.360 1.290 1.296 Friday 2.406 2.389 1.292 1.294 Saturday 2.117 2.186 1.295 1.293 Standard deviation 0.1197 0.0724 0.0036 0.0049 Mean 2.2912 2.321 1.292 1.293 CV 0.05223986178701162 0.03121201253989629 0.0028120591524125145 0.003788847243284136 The calculated coefficient of variations allows one to determine the within batch variation of the collected set of data. The greatest variation is between 0.05223986178701162 and 0.003788847243284136 having a difference of 0.048451014. There is no systematic batch variation in the data. Variation noticeable in this data is called the within batch precision due to the dispersion in the difference between the coefficients of variation b) Computed data table for plotting the log FK506 concentration against Optical density graph FK506 Standard (ng/ml) Optical Density - Duplicate Log FK506 conc Average of OD minus the NSB Non-Specific Binding (NSB) 0.102 0.110 0 2.626 2.582 -infinity 2.496 0.3 2.377 2.342 -0.5229 2.254 1.0 2.000 1.944 0 1.866 3.0 1.293 1.287 0.4771 1.184 10.0 0.567 0.548 1 0.4515 30 0.292 0.297 1.4771 0.1885 c) Enzyme-linked Immunosorbent Assay (ELISA) is a sensitive method that is used for the detection of antibody or antigens. One main advantage that accrues to the use of this method is that the antibodies or antigens being tested can be detected at low levels or rather a low concentration of up to 1ng/ml. In this experiment, quantification is the major concern, and the method is efficient when quantifying the antigens or antibodies. Question 2 a) Through extrapolation and use of the graph values of the FK506 concentration of the patients can be calculated. Y(x) = y1 + (x−x1) *(y2−y1) (x2−x1) Patient A Day Serum Creatinine (μmol/L) Optical Density (For determining FK506 conc.) Extrapolated values of Fk506 1 148 0.985 0.994 4.8587 2 156 0.598 0.610 8.5430 3 139 0.499 0.511 9.4887 4 160 0.358 0.372 16.5779 5 149 0.525 0.543 9.2116 6 159 0.286 0.292 22.3574 7 178 0.278 0.264 23.7262 8 174 0.378 0.372 15.8174 9 150 0.527 0.533 10.7310 10 149 0.554 0.562 8.9822 Patient B Day Serum Creatinine (μmol/L) Optical Density (For determining FK506 conc.) Extrapolated values of Fk506 1 190 0.486 0.490 9.6511 2 186 0.459 0.465 9.8996 3 180 0.496 0.490 9.6034 4 185 0.488 0.488 9.6511 5 190 0.530 0.510 9.3453 6 196 0.510 0.502 9.4791 7 212 0.498 0.502 9.5365 8 225 0.490 0.488 9.6416 9 218 0.490 0.490  9.6320 10 215 0.494 0.490 9.6129 Patient C Day Serum Creatinine (μmol/L) Optical Density (For determining FK506 conc.) Extrapolated values of Fk506 1 178 0.510 0.520 9.3931 2 167 0.500 0.505 9.5126 3 156 0.488 0.480 9.6894 4 155 0.678 0.688 7.7877 5 160 0.964 0.958 5.1310 6 164 1.860 1.900 0.9747 7 189 2.165 2.172 0.4542 8 225 2.460 2.468 0.0397 9 280 2.545 2.538 -0.0564 10 320 2.468 2.282 0.15 b) Graph showing variations of SCr level variations in respect to FK506 concentration Patient A Patient B Patient C The above graphs clearly indicate the relationship between FK506 concentration and Serum Creatinine. The first noticeable difference between the three patients is age. There is a difference of 10 years between the patients that are contributing factor to the variations in the Serum Creatinine and FK506. As one grows old, the skeletal muscles tissue responsible for the production of the serum grows weaker. A reduction in muscle mass also occurs as one grows old thus limited response to stimuli of the FK concentration. Furthermore, patient B had a case of acute rejection after transplant that led to administering of some drugs that increase toxicity in the body stimulating muscles in secreting the serum. A significant change is seen after the patient started using gentamicin from day 4. The change in the serum level was more pronounced compared to the changes in concentration of FK506 in the system. Patient C is much older, and SCr levels display an abnormal increment after two days. The patient shows pyrexia and reduced urine output. Functionality of the kidney is reduced due to age among other factors and also the reduced muscle mass. Filtration process at the kidney becomes impaired. References Baron, D. (12009). A short textbook of chemical pathology. London: Hodder and Stoughton. Coakley, J. (2015). 40 YEARS OF PAEDIATRIC CHEMICAL PATHOLOGY – A PERSONAL VIEW. Pathology, 47, p.S14. Dasgupta, A. (2012). Therapeutic drug monitoring. London: AcademicElsevier Science. Rowland, M. (2011). Plasma Protein Binding and Therapeutic Drug Monitoring. Therapeutic Drug Monitoring, 2(1), pp.29-38. Read More