Population Pharmacokinetics Of Digoxin In Chinese Elderlies And Its Application In Clinical Practice

Digoxin, a drug of narrow therapeutic window, is affected by many factors (such as weight, renal function, concomitant medication and so on). Population pharmacokinetics (PPK), a combination of the classical pharmacokinetic model and the statistical model, is offen used to study the influence of various factors on drug serum concentration and to design individual medication in clinical practice. This paper had the following three aspects: 1) utilization analysis of digoxin in older patients; 2) PPK study of digoxin in older patients; 3) practical application of digoxin PPK model in individual medication regimen. Section I Utilization Analysis of Digoxin in 300 Older PatientsOBJECTIVE: To analyze the utilization of digoxin in older patients in general hospital of air force, PLA in recently decade to provide reference proof for deeply developing PPK study of digoxin.METHODS: The medical records of 300 older patients taking digoxin orally in general hospital of air force, PLA from 1999 to 2008 were statistically analyzed using proportion or ratio.RESULTS: In the cardiovascular diseases treated with digoxin, the diseases dominating the first 4 places were coronary heart disease, hypertensive disease, atrial fibrillation and rheumatic heart disease. In the administration regimen, digoxin brady-adminatration and sequential administration of cedilanid D and digoxin were used for 242 patients and 58 patients, whose proportion accounted for 80.7% and 19.3%, respectively. Drugs dominating the first 4 places in combination were potassium-removing diuretics, antibiotics, spironolactone and calcium channel blocker. In 300 patients, the patient number of digoxin serum concentrations in the range of therapeutic window 0.5 ~1.5μg·L-1, lower than 0.5μg·L-1 and higher than 1.5μg·L-1 was 163, 63 and 74, whose percentages were 54.3%, 21% and 24.6%, respectively. 31 of 74 patients appeared toxic reaction, whose percentage was 10.3%. The proportion of patients over 80a and with renal hypofunction was gradually elevated in the above various concentration ranges.CONCLUSIONS: Digoxin in combination with other drugs used for the older patients ( especially > 80 a ) ill with complicated conditions and renal hypofunction needs to be personalized medication by the method of monitoring serum concentration and so on. Section II Population Pharmacokinetics Study of Digoxin in Older Chinese PatientsOBJECTIVE: To set up a population pharmacokinetic model of digoxin in Chinese older patients to provide PPK parameters for individual medication in clinical practice.METHODS: 173 serum concentrations of digoxin and clinical related data including gender, age, weight (WT), serum creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), and coadministration were retrospectively collected from 119 old patients taking digoxin orally for over 7 d. The NONMEM software was used to get PPK parameter values, to set up a final model, and to assess the models in clinical practice.RESULTS: Spironolactone (SPI), WT, and Cr markedly affected the clearance rate of digoxin. The final model formula is: CL / F = 5.9×[1-0.412×SPI]×[1+0.0101×(WT-62.9 )]×[1-0.0012×( Cr-126.8 )] (L / h); Ka= 1.63 ( h-1 ); Vd / F = 550 ( L ). The population estimates for CL / F and Vd / F were 5.9 L / h and 550 L respectively. The interindividual variability ( CV ) was 49.0% for CL / F and 94.3% for Vd / F respectively. The residual variability ( SD ) between observed and predicted concentrations was 0.365μg / L. The difference between objective function value and the primitive function value was all less than 3.84 ( P > 0.05 ) by intra-validation. Clinical applications indicated that the percent of difference between the predicted concentrations estimated by the PPK final model and the observed was among -4.3%～25%. Correlation analysis displayed that there was linear correlation between observations and predicted values ( y =1.35x + 0.39, r = 0.9639, P < 0.0001).CONCLUSIONS: The PPK final model of digoxin in Chinese older patients can be established using the NONMEM software, which can be applied in clinical practice. SectionⅢPractical Application of Digoxin PPK Model in Individual Medication RegimenOBJECTIVE: To explain practical application of digoxin PPK model in individual medication regimen using case analysis.METHODS: The medical records of 7 older patients taking digoxin orally were collected from general hospital of air force, PLA. Firstly, we used the results of the second section to calculate the individual pharmacokinetic parameters of each patient. Secondly, steady-state plasma concentration formula was used to design the digoxin dosage regimen. Thirdly, we used NONMEM program to predict digoxin plasma concentration, then calculated the percent of difference between the predicted concentrations and the observed. If the percent of the difference is less than 20%, the predicted results are showed to be good.RESULTS: Predicted results of digoxin serum concentration in the former four patients were good for the percent of difference between the predicted concentrations estimated by the PPK final model and the observed was among -16.9%～-7.7%. But the latter three patients didn't meet the inclusion criteria and the percent of differences between the predicted values and the observed was more than 20%, so predicted results were not good.CONCLUSIONS: The PPK model can be applied in clinical practice to predict digoxin plasma concentration and to design individual dosage regimen at the start of treatment if patients meet sub-population characteristic of the second section.