Intestinal P‐glycoprotein (P‐gp) Contribution to Talinolol Pharmacokinetics in Human

Abstract

ObjectiveUnderstanding the mechanisms of intestinal secretion and recirculation is important to the realm of drug metabolism and pharmacokinetics (DMPK). P‐glycoprotein (P‐gp), one of the major efflux transporters in the intestine, has broad substrate specificity and could contribute to the intestinal secretion/recirculation of drugs. The pharmacokinetic (PK) model incorporating intestinal P‐gp contribution will be able to accurately capture the interactions for the compounds of P‐gp substrate, allowing the model to aid in determining first in‐human (FIH) dose predictions as well as related potential drug‐drug interactions (DDIs). Talinolol, a beta‐adrenergic receptor antagonist utilized for cardioprotective and antihypertensive treatments, is a good substrate of P‐gp, and a double peak of plasma concentration has been observed. We hypothesize that intestinal secretion/recirculation by P‐gp could contribute to this unique plasma concentration‐time profile of talinolol. The aim of this study was to assess whether the double peak of plasma concentration of orally administered talinolol can be captured using physiological‐based pharmacokinetic (PBPK) modeling.MethodsThe plasma concentration‐time profiles of talinolol were obtained by digitizing literature data. The P‐gp‐mediated transport kinetics of talinolol were also obtained from Caco‐2 assays present in literature. Using the plasma concentration of talinolol data after intravenous (IV) administration, the intestinal secretion clearance (CLGI) was estimated using SimCYP (v19). After estimating CLGI, the regional absorption of talinolol affected by intestinal P‐gp was assessed using plasma talinolol concentration data after oral administration and the advanced dissolution, absorption, and metabolism (ADAM) model was subsequently generated utilizing SimCYP.ResultsCLGI of talinolol was estimated through using plasma concentration data of the drug after IV infusion reported by Schwarz et al., and CLGI was estimated to be 12.6 L/hr. This CLGI value was validated by capturing another plasma concentration‐time profile of talinolol after IV infusion reported by Westphal et al. The dual‐peak of the plasma talinolol concentration after oral administration was captured using ADAM model, but this model will be further refined to better capture this dual‐peak after oral administration of talinolol in human with consideration of regional differences of absorption and/or recirculation (i.e., more P‐gp in ileum compared to duodenum and jejunum).ConclusionA model was successfully generated to accurately capture the PK profiles of talinolol after IV administration. Further refinement of the model will be required for oral administration. The outcomes from the investigation essentially broaden our overall understanding of the processes underlying intestinal secretion and recirculation.