Comparative Assessment of Empirical and Physiological Approaches on Predicting Human Clearances

Tamaki, Sekihiro; Kono, Hiroshi; Kogayu, Motohiro; Yamada, Shizuo

doi:10.1002/jps.22321

Cited by 7 publications

(5 citation statements)

References 38 publications

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“…In vitro and in vivo clearance correlations that factor in free fraction have been reported, and they express in vitro clearance as unbound Cl int . These correlations were developed for compounds with log P < 3 and MW <500, , but many of our potent CB1 antagonists are outside of these limits . To improve our correlation, we factored in free fraction by using unbound Cl instead of Cl and we filtered the data set to only consider compounds with protein binding ≤95% .…”

Section: Resultsmentioning

confidence: 99%

Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties

Ellsworth

Sher

et al. 2013

J. Med. Chem.

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Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.

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Section: Resultsmentioning

confidence: 99%

Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties

Ellsworth

Sher

et al. 2013

J. Med. Chem.

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“…The hepatic intrinsic clearance (CL’h,int) of KBP-7018 in various species was estimated from liver microsomal data using the following equation: 5

where 45 mg of microsomal protein per gram of liver tissue was applied to all species, and 87 g, 40 g, 30 g, 32 g, and 26 g of liver tissue per kilogram of body weight (BW) were used for mice, rats, dogs, monkeys, and humans, respectively. Then in vivo hepatic clearance of KBP-7018 was calculated by the well-stirred model 6 by

where Q is hepatic blood flow (90 mL/min/kg, 55 mL/min/kg, 31 mL/min/kg, 44 mL/min/kg, and 21 mL/min/kg in mice, rats, dogs, monkeys, and humans, respectively), fu b and fu inc were the unbound fraction of protein binding in blood and microsomes, respectively, and CL int is the scaled intrinsic clearance determined from Equation 1 . fu inc was calculated by substitution of clog P (3.81) to the following equation for liver microsomes:

…”

Section: Methodsmentioning

confidence: 99%

“…Prior to the investigational new drug filing, the PKs in preclinical species were used to predict human PKs for the first-in-human clinical study. In the present study, allometric scaling method, 12 , 13 liver blood flow method, 6 and estimation based on monkey data alone 14 were used for the prediction of human CL of KBP-7018. The allometric scaling employed in the present study is universal equation based on a log–log relationship with a given PK parameter × brain weight (BrW) and animal BW.…”

Section: Methodsmentioning

confidence: 99%

Characterization of preclinical in vitro and in vivo pharmacokinetics properties for KBP-7018, a new tyrosine kinase inhibitor candidate for treatment of idiopathic pulmonary fibrosis

Huang¹,

Li²,

Zhang³

et al. 2015

DDDT

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KBP-7018 is a novel selective tyrosine kinase inhibitor with potential for the treatment of idiopathic pulmonary fibrosis. The objective of this study was to characterize the preclinical pharmacokinetics of KBP-7018 in vitro and in vivo, and then to assess the likelihood of developing KBP-7018 as a clinical candidate. The systemic clearance (CL) of KBP-7018 was relatively low in rodents and monkeys with a value of less than 30% of hepatic blood flow, while it was high in dogs. The steady-state volume of distribution (Vss) ranged from 1.51 L/kg to 4.65 L/kg across the species tested. The maximum concentration (Cmax) of KBP-7018 occurred at 0.25–6 hours after oral dosing, and the bioavailability was moderate (21%–68%). The human CL (~20% of hepatic blood flow) and Vss (1.6–5.3 L/kg) were predicted by allometric scaling method and together with the other modeling methods indicated low metabolism and acceptable half-time (4.8–19.3 hours) in vivo. Overall, the preclinical data make it amenable to further oral solid dosage from design for the upcoming Phase I trials in human.

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“…Animal scale-up based on the allometry concept has been widely used to predict pharmacokinetic parameters in humans (Shiran et al, 2006;Tamaki et al, 2011), and there have been advantages and disadvantages in the predictions by this method. In general, development of PBPK model needs clarification of elimination mechanisms from the body; however, in the drug discovery phase, detailed investigation for the major elimination mechanism of an individual development candidate is practically difficult within the limited timeframe.…”

Section: Discussionmentioning

confidence: 99%

Application of Hybrid Approach Based on Empirical and Physiological Concept for Predicting Pharmacokinetics in Humans—Usefulness of Exponent on Prospective Evaluation of Predictability

2012

Self Cite

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We developed a hybrid method for predicting plasma concentration-time curves in humans by integrating species differences in in vitro intrinsic clearance (CL int ) into the Dedrick approach based on the allometry concept. With prediction of clearance (CL) by allometric scaling, taking in vitro CL int into consideration improved the accuracy and reduced the average fold error from 2.72 to 1.99. With the hybrid approach of applying the same concept to the Dedrick approach, the predictability of plasma concentration profiles was compared with the results of the conventional Dedrick approach and the physiologically based pharmacokinetic model using 15 compounds with widely ranging physicochemical and pharmacokinetic profiles. The hybrid approach showed the highest predictability among the examined methods. For CL and the apparent volume of distribution at the steady state (V ss ), the relationship between the exponent of allometric equation and fold error was also evaluated with the hybrid approach. The relationship appeared to be a horseshoe curve. Six compounds with exponents ranging from 0.7 to 1.1 for both CL and V ss [antipyrine, caffeine, epiroprim, propafenone, theophylline, and verapamil] displayed higher predictability. Three compounds with an exponent ranging from 0.7 to 1.1 for CL showed better predictability for CL, and the other four compounds appeared to display similar relationship between the exponent and predictability for V ss . These findings indicated that the exponent becomes a preliminary index to speculate on predictability. Combination of the hybrid approach and exponent allows us to prospectively draw human plasma concentration-time curves, with the implication of possible prediction accuracy prior to clinical studies.

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Comparative Assessment of Empirical and Physiological Approaches on Predicting Human Clearances

Cited by 7 publications

References 38 publications

Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties

Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties

Characterization of preclinical in vitro and in vivo pharmacokinetics properties for KBP-7018, a new tyrosine kinase inhibitor candidate for treatment of idiopathic pulmonary fibrosis

Application of Hybrid Approach Based on Empirical and Physiological Concept for Predicting Pharmacokinetics in Humans—Usefulness of Exponent on Prospective Evaluation of Predictability

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