Evaluation of a novel method to estimate absolute bioavailability of drugs from oral data

Abstract

The goal of this investigation was to evaluate the performance of a novel method allowing estimation of absolute bioavailability from oral data only. In contrast to the traditional method, which compares areas under the drug concentration time curves after oral and intravenous administration in subjects with normal renal function, the novel method uses total and renal clearance values following oral administration from subjects with varying renal functions to estimate bioavailability. The novel method can also provide estimates for nonrenal clearance.Published data on total clearance and renal clearance of drugs obtained from subjects with variable renal functions were collected, the novel method applied, estimates of bioavailability and nonrenal clearance obtained and compared with reported estimates by the traditional methods. In addition computations were performed to assess various factors that could possibly affect the reliability of the novel method. The results indicated that the novel method provides accurate estimates for bioavailability of drugs meeting the prerequisites: linear kinetics, predominant renal excretion in normals, absence of metabolic polymorphism and independence of bioavailability and nonrenal clearance from renal function. The average (standard deviation) of the prediction error and bias of the bioavailability estimates by the novel method was 7.8 (6.0) and -1.4 (9.8)%, respectively. The estimates for nonrenal clearance by the novel method were less accurate. The computations confirmed that the estimates by the novel method are sensitive to renal-function dependent changes in nonrenal clearance and bioavailability and also depend on the extent of renal excretion of a drug. In conclusion, the novel method's main use is to diagnose absence or presence of changes in bioavailability and non-renal clearance of drugs in populations with varying renal function.

A Nonlinear Mixed Effects Pharmacokinetic Model for Dapagliflozin and Dapagliflozin 3‐O‐glucuronide in Renal or Hepatic Impairment

“…Absolute oral bioavailability and nonrenal clearance can be determined from modeling oral data when plasma and urine data are available in subjects with varying renal function 16 , 17 , 18 . Estimating the absolute oral bioavailability, and thereby the absolute value of clearance, reduced the risk of biased estimates of apparent nonrenal clearance when only oral data were available 19 .…”

“…Absolute oral bioavailability and nonrenal clearance can be determined from modeling oral data when plasma and urine data are available in subjects with varying renal function. [16][17][18] Estimating the absolute oral bioavailability, and thereby the absolute value of clearance, reduced the risk of biased estimates of apparent nonrenal clearance when only oral data were available. 19 The model-estimated absolute bioavailability of dapagliflozin was 82% (base model), 84% (covariate model), and 86% (final model), which are in good agreement with the absolute oral bioavailability (geometric mean (90% CI): 78% (73-83%)) determined in healthy subjects following the concomitant administration of single intravenous 14 C-labeled microdose at time of maximum concentration (T max ) of the extravascular (unlabeled) therapeutic dose.…”

Bioavailability and its assessment

“…5). The conditions for this approach are twofold: the drug must be cleared mainly by the renal route (or any other measurable route), and patients under investigation should display a large inter‐individual variability in their renal clearance (see Hinderling, 2003 for application of the method).…”

Mechanistic modelling of tesaglitazar pharmacokinetic data in subjects with various degrees of renal function – evidence of interconversion

“…This enabled separation of the elimination and interconversion processes, as the ratio between tesaglitazar and the acyl glucuronide in plasma varies with varying renal functions. Hinderling has shown that the absolute bioavailability can be determined from oral data only, when assessing plasma and urine PK in subjects with different renal functions, which is in principle a similar approach to that suggested in the present analysis [17]. Further, simulation and re‐estimation of the interconversion model given the study design and final parameter estimates showed that the model is both structurally and numerically identifiable.…”