Nonlinear Pharmacokinetics of Oral Quinidine and Verapamil in Healthy Subjects: A Clinical Microdosing Study

Maeda, Kazuya; Takano, Junichi; Ikeda, Yasuhiko; Fujita, Tomoe; Oyama, Yohtaro; Nozawa, Kohei; Kumagai, Yoshito; Sugiyama, Yuichi

doi:10.1038/clpt.2011.108

Cited by 46 publications

(43 citation statements)

References 22 publications

(26 reference statements)

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“…That verapamil elimination is dose dependent, with AUC VER ' increasing (Pang and Kwan, 1983); preformed norverapamil data are from Table 3. decreasing at higher dosing levels, confirmed nonlinearity in verapamil disposition, an observation that is in agreement with that inferred for the clinical pharmacokinetics of verapamil (Freedman et al, 1981;Shand et al, 1981;Anderson et al, 1982;Tartaglione et al, 1983;Toffoli et al, 1997;Maeda et al, 2011).…”

Section: Discussionsupporting

confidence: 70%

PBPK Modeling to Unravel Nonlinear Pharmacokinetics of Verapamil to Estimate the Fractional Clearance for Verapamil N-Demethylation in the Recirculating Rat Liver Preparation

Yang

Tang

et al. 2015

Drug Metab Dispos

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We applied physiologically based pharmacokinetic (PBPK) modeling to study the dose-dependent metabolism and excretion of verapamil and its preformed metabolite, norverapamil, to unravel the kinetics of norverapamil formation via N-demethylation. Various initial verapamil (1, 50, and 100 mM) and preformed norverapamil (1.5 and 5 mM) concentrations, perfused at 12 ml/min, were investigated in the perfused rat liver preparation. Perfusate and bile were collected over 90 minutes, and livers were harvested at the end of perfusion for high-performance liquid chromatography analysis. After correction for the adsorption of 10%-25% dose verapamil and norverapamil onto Tygon tubing and binding to albumin and red blood cell, fitting of verapamil and formed and preformed norverapamil data with ADAPT5 revealed nonlinearity for protein binding, N-demethylation ) decreased with the dose (8.16-10.2 ml/min), with values remaining high relative to perfusate blood flow rate among the doses. The hepatic clearance of preformed norverapamil (11 ml/min) remained unchanged for the concentrations studied and approximated perfusate blood flow rate, suggesting a high norverapamil extraction ratio. The fractional formation of norverapamil and biliary excretion of verapamil based on fitted constants were 31.1% and 0.64% of CL VER L , respectively. Enantiomeric disposition and autoinhibition of verapamil failed to perturb these estimaties according to PBPK modeling, due to the low values of the Michaelis-Menten constant, K m , and inhibition parameter, k I .

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Section: Discussionsupporting

confidence: 70%

PBPK Modeling to Unravel Nonlinear Pharmacokinetics of Verapamil to Estimate the Fractional Clearance for Verapamil N-Demethylation in the Recirculating Rat Liver Preparation

Yang

Tang

et al. 2015

Drug Metab Dispos

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“…For quinidine, but not verapamil, the high-dose enterocyte concentration also exceeded the K m for CYP3A metabolism. These conclusions are consistent with clinical findings (Table 3) [36].…”

Section: Evaluation Of the Decision Tree With Selected Casessupporting

confidence: 93%

“…A recent review indicated that 27 of 35 (77 %) published cases comparing microdose and therapeutic dose pharmacokinetics displayed dose proportionality [12]. Importantly, these published cases include compounds that were specifically selected to address concerns about saturable processes that were raised a priori [2,[33][34][35][36]. It was suggested that such cases may be foreseeable by integrating the available preclinical data, but this had not yet been formally evaluated.…”

Section: Discussionmentioning

confidence: 94%

“…From the published cases comparing microdose and therapeutic dose pharmacokinetics [2,[33][34][35][36], we addressed ten cases for which concerns were expressed a priori about processes that might saturate at higher doses ( Table 1). The K m values for the processes of concern, established with in vitro tests, were collected from scientific literature ( Table 1).…”

Section: Evaluation Of the Decision Tree With Selected Casesmentioning

confidence: 99%

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To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics

Bosgra¹,

Vlaming²,

Vaes³

2015

Clin Pharmacokinet

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Microdosing studies allow clinical investigation of pharmacokinetics earlier in drug development, before all high-dose safety concerns have been sorted out. Furthermore, microdosing allows inclusion of target groups that are inadmissible in high-dose phase I trials. A potential concern when considering a microdosing study is that a particular drug candidate may display non-linear pharmacokinetics. Saturation of, for example, membrane transport or metabolism at exposure levels between the microdose and therapeutic dose may limit the predictivity of high-dose pharmacokinetics from microdose observations. Guidance on the likelihood of appreciable non-linear pharmacokinetics based on preclinical information can be helpful in staging the clinical phase and the place of microdosing in it. We present a decision tree that evaluates concerns about non-linearities raised in the preclinical phase and their potential impact on the proportionality between microdose and intended therapeutic dose as predicted from preclinical information. The expected maximum concentrations at relevant sites are estimated by non-compartmental methods. These are compared with dissolution, Michaelis constants for active or enzymatic processes, and binding protein concentrations to assess the potential saturation of the processes below therapeutic doses. The decision tree was applied to ten published cases comparing microdose and therapeutic dose pharmacokinetics, for which concerns about non-linear pharmacokinetics were raised a priori. The decision tree was able to discriminate cases showing substantial non-linearities from cases displaying dose-proportional pharmacokinetics. The recommendations described in this paper may be useful in deciding whether a microdosing study is a sensible option to gain early insight in clinical pharmacokinetics of drug candidates.

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“…Lower availability was predicted with a microdose than with 40 mg, which corresponds to the clinical observation (Maeda et al, 2011). The simulated maximum concentration in the enterocytes was approximately 6.7 mM, which was smaller than the K m value of CYP3A4 (49.0 mM) and higher than the K m value for P-gp (0.622 mM).…”

Section: Discussionmentioning

confidence: 99%

A New Physiologically Based Pharmacokinetic Model for the Prediction of Gastrointestinal Drug Absorption: Translocation Model

2015

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This study aimed to construct a new local pharmacokinetic model of gastrointestinal absorption, the translocation model (TLM), using an anatomically relevant, minimally segmented structure to explain linear and nonlinear intestinal absorption, metabolism, and transport. The TLM was based on the concept of a single absorption site that flexibly moves, expands, and shrinks along with the length of the gastrointestinal tract after the intake of an oral dose. The structure of the small intestine is continuous, and various time-and location-dependent issues are freely incorporated in the analysis. Since the model has only one absorption site, understanding and modification of factors affecting absorption are simple. The absorption site is composed of four compartments: solid drug in the lumen, solution drug in the lumen, concentration in the enterocytes, and concentration in the lamina propria. The lamina propria includes the blood capillaries. Blood flow in the absorption site of the lamina propria appropriately accounts for the absorption. In the TLM, the permeability of the apical membrane and that of the basolateral membrane are distinct. By considering plicate, villi, and microvilli expansions of the surface area, the apparent permeability measured in Caco-2 experiments was converted to the effective permeability in vivo. The intestinal availability, bioavailability, and dose product of intestinal availability and absorption rate relationship of the model drugs were well explained using the TLM. The TLM would be a useful tool for the consideration of local pharmacokinetics in the gastrointestinal tract in various situations.

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Nonlinear Pharmacokinetics of Oral Quinidine and Verapamil in Healthy Subjects: A Clinical Microdosing Study

Cited by 46 publications

References 22 publications

PBPK Modeling to Unravel Nonlinear Pharmacokinetics of Verapamil to Estimate the Fractional Clearance for Verapamil N-Demethylation in the Recirculating Rat Liver Preparation

PBPK Modeling to Unravel Nonlinear Pharmacokinetics of Verapamil to Estimate the Fractional Clearance for Verapamil N-Demethylation in the Recirculating Rat Liver Preparation

To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics

A New Physiologically Based Pharmacokinetic Model for the Prediction of Gastrointestinal Drug Absorption: Translocation Model

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