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… Show more
“…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 .…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Section: Absorption and Oral Bioavailabilitymentioning
Dapagliflozin is a sodium–glucose co-transporter 2 inhibitor in development for the treatment of type 2 diabetes mellitus. A semi-mechanistic population pharmacokinetic (PK) model was developed for dapagliflozin and its inactive metabolite dapagliflozin 3-O-glucuronide (D3OG) with emphasis on renal and hepatic contribution to dapagliflozin metabolism. Renal and hepatic impairment decreased the clearance of dapagliflozin to D3OG and the clearance of D3OG. The fraction of D3OG formed via the renal route decreased from 40–55% in subjects with normal renal function (creatinine clearance (CLcr) > 80 ml/min) to 10% in subjects with severe renal insufficiency (CLcr = 13 ml/min). The model-based simulations suggested that the increase of systemic exposure (AUCss) of dapagliflozin and D3OG was less than twofold in subjects with mild or moderate renal impairment. This population modeling analysis presents a useful approach to evaluate the impact of renal and hepatic function on the PK of dapagliflozin.
“…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 .…”
Section: Discussionmentioning
confidence: 99%
“…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.…”
Section: Absorption and Oral Bioavailabilitymentioning
Dapagliflozin is a sodium–glucose co-transporter 2 inhibitor in development for the treatment of type 2 diabetes mellitus. A semi-mechanistic population pharmacokinetic (PK) model was developed for dapagliflozin and its inactive metabolite dapagliflozin 3-O-glucuronide (D3OG) with emphasis on renal and hepatic contribution to dapagliflozin metabolism. Renal and hepatic impairment decreased the clearance of dapagliflozin to D3OG and the clearance of D3OG. The fraction of D3OG formed via the renal route decreased from 40–55% in subjects with normal renal function (creatinine clearance (CLcr) > 80 ml/min) to 10% in subjects with severe renal insufficiency (CLcr = 13 ml/min). The model-based simulations suggested that the increase of systemic exposure (AUCss) of dapagliflozin and D3OG was less than twofold in subjects with mild or moderate renal impairment. This population modeling analysis presents a useful approach to evaluate the impact of renal and hepatic function on the PK of dapagliflozin.
“…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).…”
Section: Measurement Of An Absolute Bioavailability When An IV Admimentioning
Bioavailability is a key pharmacokinetic parameter which expresses the proportion of a drug administered by any nonvascular route that gains access to the systemic circulation. Presented in this review are the different approaches to measurement of bioavailability (absolute and relative), including the case in which intravenous administration is impossible. The rate of drug absorption is also discussed with special emphasis on the possible difficulties encountered using C(max) and T(max) or curve fitting to evaluate the rate of drug absorption.
“…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.…”
A mechanistic population PK model for tesaglitazar and its metabolite was developed in subjects with varying degrees of renal insufficiency. The model and data give insight into the likely mechanism (interconversion) of the increased tesaglitazar exposure in renally impaired subjects, and separate elimination and interconversion processes without dosing of the metabolite.
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