Tikhonov adaptively regularized gamma variate fitting to assess plasma clearance of inert renal markers

The Tk-GV model fits Gamma Variates (GV) to data by Tikhonov regularization (Tk) with shrinkage constant, λ, chosen to minimize the relative error in plasma clearance, CL (ml/min). Using 169Yb-DTPA and 99mTc-DTPA (n = 46, 8–9 samples, 5–240 min) bolus-dilution curves, results were obtained for fit methods: (1) Ordinary Least Squares (OLS) one and two exponential term (E1 and E2), (2) OLS-GV and (3) Tk-GV. Four tests examined the fit results for: (1) physicality of ranges of model parameters, (2) effects on parameter values when different data subsets are fit, (3) characterization of residuals, and (4) extrapolative error and agreement with published correction factors. Test 1 showed physical Tk-GV results, where OLS-GV fits sometimes-produced nonphysical CL. Test 2 showed the Tk-GV model produced good results with 4 or more samples drawn between 10 and 240 min. Test 3 showed that E1 and E2 failed goodness-of-fit testing whereas GV fits for t > 20 min were acceptably good. Test 4 showed CLTk-GV clearance values agreed with published CL corrections with the general result that CLE1 > CLE2 > CLTk-GV and finally that CLTk-GV were considerably more robust, precise and accurate than CLE2, and should replace the use of CLE2 for these renal markers.

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Estimated hyperparameters were V1 = 8.9 L, L21 = 0.026 min(-1), and L12 = 0.040 min(-1). Conventional methods led to fitting failures in 2 of the 79 subjects but there were no failures with the Bayesian method. The hyperparameters were used to calculate the glomerular filtration rate for each subject from a single plasma sample with a root-mean-square error of 7.3 mL/min, which was not significantly different from the widely used Christensen-Groth formula.



Fewer fitting failures were encountered than with conventional methods, offering an objective means of dealing with problem data. This conceptually simple model can be used directly to calculate clearance from a single plasma sample. It requires only the 3 parameters described above, whereas the Christensen-Groth method requires 6 parameters.

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abstract: The glomerular filtration rate was estimated by a single compartment analysis of the rate of fall of plasma concentration of 51-chromium edetic acid after a single intravenous injection. This slope clearance consistently overestimated the simultaneously determined standard urinary clearance, but could be used to predict the latter with an accuracy of ±9% (95% confidence limits). The coefficient of variation of replicate estimates of the slope clearance in the same individual was 3·9%; thus two estimates of glomerular filtration rate by this technique which differ by 11% have a 95% probability of reflecting a genuine difference. The method requires an intravenous injection and blood samples at 2 and 4 hours; urine samples are not required. It is simple, safe, and precise, and is applicable to children.

title: Optimum sample times for single-injection, multisample renal clearance methods.
abstract: The best choice of sample times for measuring renal function in adults by single-injection multisample plasma clearance methods was determined by Monte Carlo simulation, using a two-compartment model with parameters chosen to fit average values (from published clinical studies) for each of the three radiopharmaceuticals 99mTc-MAG3, 99mTc-DTPA and 131I-ortho-iodohippurate. Random errors were added and the simulated data were then fit to a two-exponential model using a weighted nonlinear curve fitting method. The calculated clearance values were compared with the original values to determine random and systematic errors for different selections of sample time for each radiopharmaceutical at various levels of renal function. The results show that for research-level accuracy with a GFR agent such as 99mTc-DTPA, plasma sampling must begin by 10 min after injection and continue at least 3 hr (in adults). With an ERPF agent such as 99mTc-MAG3 or 131I-OIH, sampling must begin by 5 min and continue for at least 90 min. Six logarithmically distributed samples are sufficient.

title: Anaphylaxis to intravenous sinistrin
abstract: 1. Hauben M, Reich L. Safety related drug-labeling changes: findings from two data mining algorithms. Drug Saf 2004;27:735-44. 2. Hauben M, Reich L. Drug-induced pancreatitis: lessons in data mining. Br J Clin Pharmacol 2004;58:560-2.  Matsui A, Matsuo H, Hitomi T, Sasaki S, Maeda M, Sawada Y. Prediction of catalepsies induced by amiodarone, aprindine and procaine: similarity in conformation of diethylaminoethyl side chain.  1998;287:725-32. 4. Matsuo H, Matsui A, Risa N, Takanaga H, Inoue N, Hattori F, et al. Propiverine-induced parkinsonism: a case report and a pharmacokinetic/pharmacodynamic study in mice. Pharm Res 2000;17:565-71. 5. Sawada Y, Nasu R, Matsuo H, Ohtani H. Relationship between structure and drug-induced parkinsonism (letter).  DOI 10.1345/aph.19253

title: Anaphylactic reaction to intravenous sinistrin (Inutest)
abstract: Inulin clearance is the 'gold standard' for the determination of glomerular filtration rate, This is the first report of anaphylaxis following intravenous administration of inulin.