Therapeutic Drug Monitoring Assessment - Assignment Example

Therapeutic drug monitoring assessment Introduction Individualized drug treatments are important in achieving optimum therapeutic benefits and minimizing adverse effects. This is done by maintaining the drug concentrations in blood or plasma within targeted therapeutic range. This is desirable particularly when there is a significant overlap between therapeutic and toxic drug concentration ranges such as fungal derived immunosuppressive drugs, Cyclosporin A also known as Prograf® and FK506 known as Tacrolimus ® commonly used after soft organ transplantation and in the treatment of autoimmune disease. The use of these compounds is associated with nephrotoxicity. Measuring blood concentration is helpful in indicating compliance. Moreover, acute rejection might occur when the whole blood circulating drug concentrations are too low. On the other hand, sidewhen the whole blood circulating drug concentration is high then the risk of adverse drug side effects also increases. In maintenance of appropriate drug interactions, drug interactions also play an important role. Administration of inhibitors or inducers of the cytochrome P-4503A-dependent monooxygenase system can either increase or decrease or decrease Cyclosporin A and FK506 circulating concentrations. Moreover, if a nephrotoxic compound such as aminoglycoside antibiotic is co-administered with either of the compounds, there is a potential for additive toxicity. It would be important to measure aminoglycoside blood concentration to distinguish between toxicity and infection. Pharmacokinetic properties have influence on the levels of drug circulating in the blood stream. There should be a balance between the rate of appearance into circulation and its removal, and any co administered agents that will affect the two parameters will have a profound effect on drug concentrations and therefore clinical management (Kang & Lee, 2009). 1. You are also presented above with duplicate measurements (from 6 days – Monday to Saturday) of analytical laboratory quality standards ‘A’ and ‘C’. Calculate the coefficient of variation for the measurement of these standards and comment on the within-batch variation. Coefficient of variation calculations for quality standards A Day Standard ‘A’ - Duplicates Duplicate mean Standard deviation Coefficient of variation Monday 2.377 2.342 2.3595 0.024748737 1.048898 Tuesday 2.268 2.298 2.283 0.021213203 0.929181 Wednesday 2.39 2.351 2.3705 0.027577164 1.163348 Thursday 2.189 2.36 2.375 0.12091526 5.091169 Friday 2.406 2.389 2.3975 0.012020815 0.50139 Saturday 2.117 2.186 2.1515 0.048790368 2.267737 Coefficient of variation calculations for quality standards C Day Standard ‘C’ - Duplicates Duplicate mean Standard deviation Coefficient of variation Monday 1.293 1.287 1.29 0.004243 0.3289 Tuesday 1.296 1.3 1.298 0.002828 0.2179 Wednesday 1.286 1.288 1.287 0.001414 0.1099 Thursday 1.29 1.296 1.293 0.004243 0.3281 Friday 1.292 1.294 1.293 0.001414 0.1094 Saturday 1.295 1.293 1.294 0.001414 0.1093 Coefficient of variation is used to estimate the within batch variation. The within batch variation is 0.2%. (Xu & Madden, 2013) 2. Prepare a suitable standard curve plotting log FK506 concentration against optical density. FK506 ELISA Standard curve FK506 Standard (ng/ml) log FK506 concentration Optical Density - Duplicate Duplicate mean Optical density Non-Specific Binding (NSB)   0.102 0.11 0.106 0 0 -∞ 2.626 2.582 2.604 2.498 0.3 -0.522878745 2.377 2.342 2.3595 2.2535 1 0 2 1.944 1.972 1.866 3 0.477121255 1.293 1.287 1.29 1.184 10 1 0.567 0.548 0.5575 0.4515 3. Explain why non-specific binding measured in an ELISA method? ELISA detects biological molecules through use of enzyme labelled antigens and antibodies. Small quantities of antigens such as protein, hormones and peptides can be detected in a sample through antigen binding to a specific antibody, which is detected subsequently by a secondary enzyme coupled antibody (Gan & Patel, 2013). Non-specific binding can be measured by ELISA method. Question 2 1. Using your standard curve produced above and by extrapolation, calculate the FK506 concentrations (g/L) for each of the 3 patients (A, B, C) for each day. Day Serum Creatinine (μmol/L) Optical Density (For determining FK506 conc.) Mean duplicate log FK506 concentration FK506 concentration (µg/l) 1 148 0.985 0.994 0.9895 2.025708 0.1060981961 2 156 0.598 0.61 0.604 1.831416 0.06782909147 3 139 0.499 0.511 0.505 1.78152 0.06046721969 4 160 0.358 0.372 0.365 1.71096 0.05139963086 5 149 0.525 0.543 0.534 1.796136 0.06253684972 6 159 0.286 0.292 0.289 1.672656 0.0470604418 7 178 0.278 0.264 0.271 1.663584 0.04608759014 8 174 0.378 0.372 0.375 1.716 0.05199959965 9 150 0.527 0.533 0.53 1.79412 0.06224722569 10 149 0.554 0.562 0.558 1.808232 0.06430311326 Day Serum Creatinine (μmol/L) Optical Density (For determining FK506 conc.) Mean duplicate log FK506 concentration FK506 concentration (µg/l) 1 190 0.486 0.49 0.488 1.772952 0.05928597957 2 186 0.459 0.465 0.462 1.759848 0.05752385727 3 180 0.496 0.49 0.493 1.775472 0.05963098731 4 185 0.488 0.488 0.488 1.772952 0.05928597957 5 190 0.53 0.51 0.52 1.78908 0.06152902029 6 196 0.51 0.502 0.506 1.782024 0.06053743281 7 212 0.498 0.502 0.5 1.779 0.06011737375 8 225 0.49 0.488 0.489 1.773456 0.05935482106 9 218 0.49 0.49 0.49 1.77396 0.05942374248 10 215 0.494 0.49 0.492 1.774968 0.05956182551 Day Serum Creatinine (μmol/L) Optical Density (For determining FK506 conc.) Mean duplicate log FK506 concentration FK506 concentration (µg/l) 1 178 0.51 0.52 0.515 1.78656 0.06117303108 2 167 0.5 0.505 0.5025 1.78026 0.06029204297 3 156 0.488 0.48 0.484 1.770936 0.05901141113 4 155 0.678 0.688 0.683 1.871232 0.07434161646 5 160 0.964 0.958 0.961 2.011344 0.1026464656 6 164 1.86 1.9 1.88 2.47452 0.2982084875 7 189 2.165 2.172 2.1685 2.619924 0.4167964392 8 225 2.46 2.468 2.464 2.768856 0.5872945897 9 280 2.545 2.538 2.5415 2.807916 0.6425634225 10 320 2.468 2.282 2.375 2.724 0.5296634439 2. Comment on the FK506 and serum creatinine concentrations for each patient and explain these in light of their presentations/histories. In patient A, the blood circulating concentration of FK506 concentration was stable as it did not trigger any eventful post transplant course or nephrotoxicity. Clinical management was effective due to suitable drug concentration in the patient’s system. The measured low concentration in the blood would also indicate poor compliance. Patient B had an episode of acute rejection. This indicates that the blood circulating concentration was too low and the levels of FK506 dropped as shown in the graph below. The patient was treated successfully with methylprenisolone and OKT3 therefore raising the FK506 concentration in the blood by inducing cytochrome P-4503A- dependent monooxygenase system. The patient was diagnosed with unary tract infection after showing symptoms of pyrexia and cloudy urine. She was treated with gentamicin which acted as an inhibitor therefore slightly reducing the levels of FK506 concentrations in the blood to stable amounts. Patient C had an uneventful post surgical course. However, treatment with rifampicin, increased toxicity that led to pyrexia, reduced urine output, and increased creatinine concentrations. The levels of FK506 further increased due to lymphocytic infiltration that was consistent with acute rejection thereby interfering with removal. This was initiated by the low blood circulating concentration. In conclusion, individualised drug treatments play an important role in development of safe and effective therapeutic medications. The dosage history, the patient’s response and the desired clinical targets are factors that need to be considered when interpreting drug concentration in blood. In order to achieve the optimum therapeutic benefits and minimise any adverse effects, a combined approach encompassing pharmacodynamics, pharmacokinetics and drug interactions should be considered. Bibliography Gan, S. D., & Patel, K. R. (2013). Enzyme Immunoassay and Enzyme Linked Immunosorbent Assay. Journal of Investigative Dermatology , 133, 85-93. Kang, J.-S., & Lee, M.-H. (2009). Overview of Therapeutic Drug Monitoring. The Korean Journal of Internal Medicine , 24 (1), 1-10. Xu, A. Q., & Madden, T. L. (2013). Analytical methods for therapeutic drug monitoring and toxicology. Hoboken: Wiley. Read More