Virtual bioequivalence for achlorhydric subjects: The use of PBPK modelling to assess the formulation-dependent effect of achlorhydria

Majority of bioequivalence studies are conducted in healthy volunteers. It has been argued that bioequivalence may not necessarily hold true in relevant patient populations due to a variety of reasons which affect one formulation more than the other for instance in achlorhydric patients where elevated gastric pH may lead to differential effects on formulations which are pH-sensitive with respect to release or dissolution. We therefore examined achlorhydria-related disparity in bioequivalence of levothyroxine and nifedipine formulations using virtual bioequivalence within a physiologically-based pharmacokinetic (PBPK) modelling framework. The in vitro dissolution profiles at neutral pH were incorporated into PBPK models to mimic the achlorhydria with in vitro–in vivo relationship established using bio-relevant pH media. The PBPK models successfully reproduced the outcome of the bioequivalence studies in healthy volunteers under the normal conditions as well as under proton pump inhibitor-induced achlorhydria. The geometric mean test/reference ratios for Cmax and AUC between levothyroxine tablet and capsule in patients receiving proton pump inhibitor were 1.21 (90%CI, 1.13–1.29) and 1.09 (90%CI, 1.02–1.17), respectively. Extension of the virtual bioequivalence study to Japanese elderly, who show high incidence of achlorhydria, indicated bio-inequivalence which Cmax and AUC ratios between nifedipine control-released reference and test formulations were 3.08 (90%CI, 2.81–3.38) and 1.57 (90%CI, 1.43–1.74), respectively. Virtual bioequivalence studies through the PBPK models can highlight the need for conduct of specific studies in elderly Japanese populations where there are discrepancies in pH-sensitivity of dissolution between the test and reference formulations

Assessing Potential Drug–Drug Interactions Between Dabigatran Etexilate and a P‐Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling

Plasma concentrations of dabigatran, an active principle of prodrug dabigatran etexilate (DABE), are increased by renal impairment (RI) or coadministration of a P‐glycoprotein inhibitor. Because the combined effects of drug–drug interactions and RI have not been evaluated by means of clinical studies, the decision of DABE dosing for RI patients receiving P‐glycoprotein inhibitors is empirical at its best. We conducted virtual drug–drug interactions studies between DABE and the P‐glycoprotein inhibitor verapamil in RI populations using physiologically based pharmacokinetic modeling. The developed physiologically based pharmacokinetic model for DABE and dabigatran was used to predict trough dabigatran concentrations in the presence and absence of verapamil in virtual RI populations. The population‐based physiologically based pharmacokinetic model provided the most appropriate dosing regimen of DABE for likely clinical scenarios, such as drug–drug interactions in this RI population based on available knowledge of the systems changes and in the absence of actual clinical studies

心筋ナトリウムチャネル関連遺伝子解析に基づく抗不整脈薬の個別投与設計法の構築

科学研究費助成事業 研究成果報告書：若手研究(B)2013-2015課題番号 : 2586010

抗不整脈薬の薬理遺伝学的情報に基づく効果的な治療薬物モニタリング

Antiarrhythmic drugs require therapeutic drug monitoring (TDM) to avoid adverse effects such as proarrhythmia. However, TDM is not necessarily used to adjust the dosage of antiarrhythmic drugs because there is a lack of information regarding the therapeutic range of the serum concentration and the selection of patients who require TDM. The aim of this review was to provide an overview of the pharmacogenetic information on the pharmacokinetics and drug response of flecainide, a class Ic antiarrhythmic drug with a sodium channel-blocking effect. A population pharmacokinetic analysis revealed that the CYP2D6 genotype was a determining factor of the age-related decline in flecainide clearance. Elderly patients show large interindividual variability of flecainide clearance because they have a more pronounced effect of the CYP2D6 genotype and require more frequent monitoring of serum flecainide concentrations. Carriers of an Asian-specific promoter haplotype B of the cardiac sodium channel gene (SCN5A) more frequently achieve clinically relevant flecainide efficacy even at lower concentrations. This suggests that the therapeutic range of serum flecainide concentrations is lower in SCN5A promoter haplotype B carriers than in the wild-type haplotype A homozygotes. The β1-adrenergic receptor Gly389 polymorphism decreases the antiarrhythmic efficacy of flecainide when co-administered with β-blockers. Carriers of Gly389 with co-administration of β-blockers may not achieve clinically relevant flecainide efficacy even when the serum flecainide concentrations are within the therapeutic range. These findings provide pharmacogenetic information for the effective utilization of TDM in antiarrhythmic drug therapy

アミオダロンの血清リポタンパク質への分布を考慮した副作用モニタリング法の構築

科学研究費助成事業 研究成果報告書：基盤研究(C)2019-2021課題番号 : 19K0718