Prediction of human pharmacokinetics—biliary and intestinal clearance and enterohepatic circulation

Abstract

The main objective was to evaluate and propose methods for predicting biliary clearance (CL bile ) and enterohepatic circulation (EHC) of intact drugs in man. Another aim was to evaluate to role of intestinal drug secretion and propose a method for prediction of intestinal secretion CL (CL i ). Animal data poorly predict the CL and CL bile of biliary excreted drugs, and the suggested molecular weight threshold for bile excretion as the dominant elimination route does not seem to hold. Active transport, low metabolic intrinsic CL (CL int ) and, as an approximation, permeability (P e ) less than that of metoprolol is required for substantial CL bile to occur. The typical EHC plasma concentration vs time profile (multiple peaks) is demonstrated for many low metabolic CL int -compounds with efflux and moderate to high intestinal P e and fraction absorbed. Physiologically-based in-vitro to in-vivo (PB-IVIV) methodology with in-vitro intrinsic CL bile -data obtained with sandwich-cultured human hepatocytes has generated 2-and 5-fold underpredictions for two compounds with intermediate to high CL bile . This is despite not considering the unbound fraction. Possible explanations include low transporter activity and diffusion limitations in the in-vitro experiments. Intestinal reabsorption and EHC were also neglected in these predictions and in-vivo CL bile estimations. The sandwich model and these reference data are still very useful. Consideration of an empirical scaling factor and a newly developed approach that accounts for intestinal reabsorption and EHC could potentially lead to improved PB-IVIV predictions of CL bile . Apparently, no attempts have been made to predict CL i . Elimination via the intestinal route does not appear to be of great importance for the few compounds with available data, but could be equally as important as bile excretion. Net secretion in-vitro P e and newly estimated in-vivo intrinsic CL i data for digoxin and rosuvastatin could be useful for approximation of CL i of other compounds.

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…Moreover, intestinal secretion is not regarded as a major route of drug elimination. [178,179] Thus, the inhibition of the enterocytic influx via OSTa/b is probably not of concern with regards to DDIs. However, OSTa/b is also an intestinal basolateral absorptive transporter (along [165,168] 4.0/4.6 a Simvastatin [164] 85 a Tipranavir [165] 0.9 a OATP3A1_v1 (OATP-D)…”

Physicochemical Property Space of Hepatobiliary Transport and Computational Models for Predicting Rat Biliary Excretion

“…Biliary excretion (BE) is a major elimination pathway for many drugs and/or their metabolites and has a significant impact on exposure and pharmacological and toxicological effects of drugs (Gregus and Klaassen, 1987;Fagerholm, 2008). Estimating its contribution to the total systemic clearance is thus extremely valuable for predicting clinical pharmacokinetics and understanding the possible mechanisms of hepatobiliary toxicity and potential drug-drug interactions (DDIs) (Lavé et al, 2009).…”

Applications of Human Pharmacokinetic Prediction in First-in-Human Dose Estimation

“…Consistently, Wang and Prueksaritanont (35) reported that human CL of therapeutic proteins can be predicted reasonably well by simple allometric scaling with a fixed exponent of 0.8. On the other hand, as with tubular and intestinal secretion, reabsorption, and metabolism, the accurate prediction of renal (CL R ) and bile clearance (CL bile ) using SA is difficult (19,20). A coefficient of determination (r 2 ), which is obtained from a linear regression of log-transformed animal body weights and the corresponding CL, has been reported in most allometric scaling studies.…”

“…More effort is required to establish the in vitro/in vivo relationship for active secretion and to scale in vitro kidney microsomal data to in vivo metabolic clearance. Similarly, challenges posed by active transport, enterohepatic circulation, and metabolism have resulted in very few attempts to use physiologically based approaches to predict biliary and intestinal clearance, and the predictability is poor (19). One step to improve the prediction of biliary and intestinal clearance is to identify the interspecies differences in expression and activity of hepatic/bile and intestinal transporters and metabolizing enzymes.…”

“…Each approach has its advantages and disadvantages. Although several excellent review articles have discussed and compared some predictive approaches (3,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), to our knowledge, a comprehensive and practical summary of all the prediction approaches is still not available. Therefore, this review introduces commonly used methods for FIH dose estimation and summarizes 17 approaches to predict human CL, 6 methods to predict bioavailability, and 3 tools to generate PK profiles.…”