Characterization of Gastrointestinal Drug Absorption in Cynomolgus Monkeys

Takahashi, Masayuki; Washio, Takuo; Suzuki, Norio; Igeta, Katsuhiro; Fujii, Yoshimine; Hayashi, Masahiro; Shirasaka, Yoshiyuki; Yamashita, Shinji

doi:10.1021/mp700095p

Cited by 34 publications

(29 citation statements)

References 36 publications

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“…6) showed an outstanding discrepancy between the predicted and observed AUC oral for neratinib when the value of f a ×F G determined in the monkey was used for the prediction. These results were consistent with previous reports that the intestinal availability in vivo in monkeys is much lower than that in rats (Takahashi et al, 2008) and humans (Akabane et al, 2010;Nishimuta et al, 2010) when the substrate undergoes extensive metabolism in NADPH-fortified intestinal microsomes from monkeys (Akabane et al, 2010). These reports suggested that the monkey is not an appropriate species for the prediction of f a ×F G in humans (Takahashi et al, 2008;Akabane et al, 2010;Nishimuta et al, 2011).…”

Section: Downloaded Fromsupporting

confidence: 92%

The Role of Extrahepatic Metabolism in the Pharmacokinetics of the Targeted Covalent Inhibitors Afatinib, Ibrutinib, and Neratinib

Shibata

Chiba

2014

Drug Metab Dispos

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Despite the fact that much progress has been made recently in the development of targeted covalent inhibitors (TCIs), their pharmacokinetics (PK) have not been well characterized in the light of extrahepatic clearance (CL extH ) by glutathione (GSH)/glutathione S-transferase (GST)-dependent conjugation attributable to the unique electrophilic structure (e.g., acrylamide moiety) of TCI compounds. In the present study, CL extH values were examined in rat, dog, and monkey to predict the contribution of CL extH to the PK of the TCIs afatinib, ibrutinib, and neratinib in humans. Afatinib and neratinib both underwent extensive conjugation with GSH in buffer and cytosol fractions of liver and kidney, whereas ibrutinib showed much lower reactivity/susceptibility to GSH/GST-dependent conjugation. The CL extH in each species was calculated from the difference between observed total body clearance and predicted hepatic clearance (CL H ) in cryopreserved hepatocytes suspended in 100% serum of the corresponding species. The power-based simple allometry relating the CL extH for the unbound compound to animal body weight was applicable across species for afatinib and neratinib (R 2 ‡ 0.9) but not for ibrutinib (R 2 = 0.04). The predicted AUC after oral administration of afatinib and neratinib agreed reasonably closely with reported values in phase I dose-escalation studies. Comparisons of CL extH and CL H predicted that CL extH largely determined the PK of afatinib (>90% as a proportion of total body clearance) and neratinib (∼34%) in humans. The present method can serve as one of the tools for the optimization of PK in humans at the discovery stage for the development of TCI candidates.

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Section: Downloaded Fromsupporting

confidence: 92%

The Role of Extrahepatic Metabolism in the Pharmacokinetics of the Targeted Covalent Inhibitors Afatinib, Ibrutinib, and Neratinib

Shibata

Chiba

2014

Drug Metab Dispos

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“…More recently, several reports have stated that the intestinal transit process, namely Fa or Fg, is a major contributor to the low F in cynomolgus monkeys (Sakuda et al, 2006;Takahashi et al, 2008). However, unlike Fh, which can be easily calculated via conventional pharmacokinetic analysis, Fa and Fg are difficult to evaluate separately, particularly in the intestine.…”

Section: Introductionmentioning

confidence: 99%

A Comparison of Pharmacokinetics between Humans and Monkeys

Akabane¹,

Tabata²,

Kadono³

et al. 2009

Drug Metab Dispos

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ABSTRACT:To verify the availability of pharmacokinetic parameters in cynomolgus monkeys, hepatic availability (Fh) and the fraction absorbed multiplied by intestinal availability (FaFg) were evaluated to determine their contributions to absolute bioavailability (F) after intravenous and oral administrations. These results were compared with those for humans using 13 commercial drugs for which human pharmacokinetic parameters have been reported. In addition, in vitro studies of these drugs, including membrane permeability, intrinsic clearance, and p-glycoprotein affinity, were performed to classify the drugs on the basis of their pharmacokinetic properties. In the present study, monkeys had a markedly lower F than humans for 8 of 13 drugs. Although there were no obvious differences in Fh between humans and monkeys, a remarkable species difference in FaFg was observed. Subsequently, we compared the FaFg values for monkeys with the in vitro pharmacokinetic properties of each drug. No obvious FaFg differences were observed between humans and monkeys for drugs that undergo almost no in vivo metabolism. In contrast, low FaFg were observed in monkeys for drugs that undergo relatively high metabolism in monkeys. These results suggest that first-pass intestinal metabolism is greater in cynomolgus monkeys than in humans, and that bioavailability in cynomolgus monkeys after oral administration is unsuitable for predicting pharmacokinetics in humans. In addition, a rough correlation was also observed between in vitro metabolic stability and Fg in humans, possibly indicating the potential for Fg prediction in humans using only in vitro parameters after slight modification of the evaluation system for in vitro intestinal metabolism.Because the development of new drugs is a cost-and labor-intensive task, the selection of candidates with good pharmacokinetic profiles is becoming increasingly common. This practice minimizes the number of drug candidates dropped due to pharmacokinetic problems during the clinical phase (Wishart, 2007).When predicting human pharmacokinetics, the fraction absorbed (Fa), intestinal availability (Fg), and hepatic availability (Fh) are the main factors to consider. Fh prediction has become considerably accurate since several mathematical prediction models have been established, including the physiological model, well stirred model, parallel tube model, and dispersion model (Iwatsubo et al., 1996;Naritomi et al., 2001;De Buck et al., 2007). For FaFg, however, no quantitative prediction method has ever been established, although several qualitative prediction methods using human intestinal microsomes have been reported (Chiba et al., 1997;Shen et al., 1997;Fagerholm, 2007;Fisher and Labissiere, 2007;Yang et al., 2007). For these reasons, we have mainly used animal pharmacokinetic parameters to predict human FaFg in the drug discovery stage.It has been regarded as natural that monkey metabolism is the most similar to that of humans, and cynomolgus monkeys have been widely used in pharmacokinetic or drug-...

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“…3,4) In order to assess the permeability of drugs to the intestinal membrane, various in vitro, in situ and in vivo methods have been utilized. 8,9) Recently, in vitro cell culture models with Caco-2 [10][11][12][13] or Madin-Darby canine kidney (MDCK) 14,15) cells have been widely used to measure the membrane permeability of drugs.…”

Section: Discussionmentioning

confidence: 99%

“…The blood-to-plasma concentration ratio (R b ) values of the tested drugs were determined in the previous study. 3,4) However, since it was difficult to determine V portal , it was calculated from the (C in ϪC out ) and C abs of antipyrine, having assumed the Fg of antipyrine to be 1, as shown in Eq. 6.…”

Section: Lc/ms/ms Analysismentioning

confidence: 99%

“…From the kinetic analysis of the plasma concentrations of drugs after intravenous and oral administration, it was indicated that the low oral BAs in cynomolgus monkeys are mostly attributed to the low value of Fa*Fg. 3,4) However, only from the in vivo PK analysis, it is theoretically impossible to evaluate Fa and Fg separately, resulting the confusion in the contribution of intestinal absorption on the oral BA of various drugs.…”

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confidence: 99%

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Investigation of the Intestinal Permeability and First-Pass Metabolism of Drugs in Cynomolgus Monkeys Using Single-Pass Intestinal Perfusion

Takahashi

Washio

Suzuki

et al. 2010

Biological & Pharmaceutical Bulletin

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where Fa is the fraction of dose absorbed from the gastrointestinal (GI) tract, Fg is the intestinal availability, that correspondent to the fraction of dose not metabolized in the intestinal wall during the absorption process and Fh is the fraction of dose not metabolized in the liver before reaching the systemic circulation. Therefore, the values of (1ϪFg) and (1ϪFh) mean the first-pass metabolism of orally administered drugs in GI tract and the liver, respectively. In order to select the appropriate candidates for oral drug product, quantitative assessments on each process are highly required.Recently, not only the small animals such as mice and rats, but also cynomolgus monkeys are often used as an animal model for PK studies in the drug discovery stage. However, lower oral BAs of test compounds were often observed in cynomolgus monkeys compared with those in other animals.1,2) Also in our previous study, various marketed drugs showed low oral BAs in cynomolgus monkeys than those in humans. From the kinetic analysis of the plasma concentrations of drugs after intravenous and oral administration, it was indicated that the low oral BAs in cynomolgus monkeys are mostly attributed to the low value of Fa*Fg.3,4) However, only from the in vivo PK analysis, it is theoretically impossible to evaluate Fa and Fg separately, resulting the confusion in the contribution of intestinal absorption on the oral BA of various drugs.Tamura et al. investigated the mechanisms of intestinal absorption of tacrolims by using the simultaneous perfusion method of intestinal lumen and mesenteric veins in rats. 5)They have calculated the fraction of metabolized in the intestinal cells from the difference between eliminated amount of the drug from the intestinal lumen and absorbed amount into the blood perfusate. Also, Mihara et al. evaluated quantitatively the first-pass metabolism of eperison in rats by using the similar perfusion method. 6) Although the simultaneous perfusion method is useful to assess the intestinal metabolism of drugs, this method requires complicated operations of the mesenteric vein and is difficult to perform in cynomolgus monkeys. Moreover, perfusion of the mesenteric vein might affect the absorption and metabolism of drugs in the intestine.The present study is performed 1) to establish the experimental method to evaluate the drug permeability and the metabolism in the intestine of cynomolgus monkeys and then 2) to clarify the causes of low BA of drugs in cynomolgus monkeys. For these purposes, an in situ single-pass intestinal perfusion method was performed with blood sampling from both portal and peripheral veins, instead of the perfusion of the mesenteric vein. The intestinal permeability of drugs (P eff ) is calculated from the decrease in drug concentration in the perfusate after single pass perfusion through the intestinal tract. The intestinal metabolism during the absorption process (1ϪFg) is calculated from the difference between drug amounts that disappeared from the perfusate and absorbed into the por...

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Characterization of Gastrointestinal Drug Absorption in Cynomolgus Monkeys

Cited by 34 publications

References 36 publications

The Role of Extrahepatic Metabolism in the Pharmacokinetics of the Targeted Covalent Inhibitors Afatinib, Ibrutinib, and Neratinib

The Role of Extrahepatic Metabolism in the Pharmacokinetics of the Targeted Covalent Inhibitors Afatinib, Ibrutinib, and Neratinib

A Comparison of Pharmacokinetics between Humans and Monkeys

Investigation of the Intestinal Permeability and First-Pass Metabolism of Drugs in Cynomolgus Monkeys Using Single-Pass Intestinal Perfusion

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