A Comprehensive Quantitative and Qualitative Evaluation of Extrapolation of Intravenous Pharmacokinetic Parameters From Rat, Dog, and Monkey to Humans. I. Clearance

Ward, Keith W.; Smith, Brian R.

doi:10.1124/dmd.32.6.603

Cited by 188 publications

(202 citation statements)

References 25 publications

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“…Several studies have demonstrated that monkeys are particularly useful in interspecies scaling for predicting human pharmacokinetics (Ward and Smith, 2004;Ward et al, 2005;Sakuda et al, 2006;Ogasawara et al, 2007). Recent studies have identified a number of P450 cDNAs from cynomolgus monkeys, including those of CYP3A8 and CYP3A5, which show high sequence identities (94 -95%) with the orthologous human CYP3A4 and CYP3A5, respectively (Uno et al, 2007(Uno et al, , 2010Iwasaki and Uno, 2009).…”

Section: Introductionmentioning

confidence: 99%

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Ohtsuka¹,

Yoshikawa²,

Kozakai³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Induction of the cytochrome P450 (P450) enzyme is a major concern in the drug discovery processes. To predict the clinical significance of enzyme induction, it is helpful to investigate pharmacokinetic alterations of a coadministered drug in a suitable animal model. In this study, we focus on the induction of CYP3A, which is involved in the metabolism of approximately 50% of marketed drugs and is inducible in both the liver and intestine. As a marker substrate for CYP3A activity, alprazolam (APZ) was selected and characterized using recombinant CYP3A enzymes expressed in Escherichia coli. Both human CYP3A4 and its cynomolgus P450 ortholog predominantly catalyzed APZ 4-hydroxylation with sigmoidal kinetics. When administered intravenously and orally to cynomolgus monkeys, APZ had moderate clearance; its first-pass extraction ratio after oral dosing was estimated to be 0.09 in the liver and 0.45 in the intestine. Pretreatment with multiple doses of rifampicin (20 mg/kg p.o. for 5 days), a known CYP3A inducer, significantly decreased plasma concentrations of APZ after intravenous and oral administrations (0.5 mg/kg), and first-pass extraction ratios were increased to 0.39 in the liver and 0.63 in the intestine. The results were comparable to those obtained in clinical drug-drug interaction (DDI) reports related to CYP3A induction, although the rate of recovery of CYP3A activity seemed to be slower than rates estimated in clinical studies. In conclusion, pharmacokinetic studies using APZ as a probe in monkeys may provide useful information regarding the prediction of clinical DDIs due to CYP3A induction.

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Section: Introductionmentioning

confidence: 99%

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Ohtsuka¹,

Yoshikawa²,

Kozakai³

et al. 2010

Drug Metab Dispos

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“…This can be explained by considerable species differences in gut-wall and hepatic clearances in addition to differences in f a (especially between dogs and humans) (Bogaards et al 2000;Clarke and Jeffrey 2001;Ward and Smith 2004;Cao et al 2006). This suggests that in order to predict F well, each of the processes determining F (f a and gut wall and hepatic extraction) need to be predicted separately.…”

Section: Prediction Of Fraction Absorbed In Humans From Fraction Absomentioning

confidence: 99%

Prediction of human pharmacokinetics —gastrointestinal absorption

Fagerholm

2007

Journal of Pharmacy and Pharmacology

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Permeability (P e ) and solubility/dissolution are two major determinants of gastrointestinal (GI) drug absorption. Good prediction of these is crucial for predicting doses, exposures and potential interactions, and for selecting appropriate candidate drugs. The main objective was to evaluate screening methods for prediction of GI P e , solubility/dissolution and fraction absorbed (f a ) in humans. The most accurate P e models for prediction of f a of passively transported and highly soluble compounds appear to be the 2/4/A1 rat small intestinal cell model (in-vitro and in-silico), a newly developed artificial-membrane method, and a semi-empirical approach based on in-vitro membrane affinity to immobilized lipid bilayers, effective molecular weight and physiological GI variables. The predictability of in-vitro Caco-2, in-situ perfusion and other artificial membrane methods seems comparably low. The P e and f a in humans for compounds that undergo mainly active transport were predicted poorly by all models investigated. However, the rat in-situ perfusion model appears useful for prediction of active uptake potential (complete active uptake is generally well predicted), and Caco-2 cells are useful for studying bidirectional active transport, respectively. Human intestinal in-vitro P e , which correlates well with f a for passively transported compounds, could possibly also have potential to improve/enable predictions of f a for actively transported substances. Molecular descriptor data could give an indication of the passive absorption potential. The 'maximum absorbable dose' and 'dose number' approaches, and solubility/dissolution data obtained in aqueous media, appear to underestimate in-vivo dissolution to a considerable extent. Predictions of in-vivo dissolution should preferably be done from in-vitro dissolution data obtained using either real or validated simulated GI fluids.

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“…The overprediction of the AUC value was largely due to the overprediction of t 1/2 (1.8-fold). The predicted AUC value with 4-fold error does not seem to fall in an acceptable range of the current industry criteria, i.e., 2-fold (Ward and Smith, 2004;Jones et al, 2006;Beaumont and Smith, 2009). In contrast, the fold errors for the AUC, C max , and t 1/2 based on ALS-free were 1.8, 1.8, and 1.6, respectively.…”

Section: In Vivo Blood Clearance and In Vitro Hepatic Clearance Of Pfmentioning

confidence: 99%

Prediction of Oral Pharmacokinetics of cMet Kinase Inhibitors in Humans: Physiologically Based Pharmacokinetic Model Versus Traditional One-Compartment Model

Yamazaki¹,

Skaptason²,

Romero³

et al. 2010

Drug Metab Dispos

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ABSTRACT:The objective of this study was to assess the physiologically based error) and PF04217903 (1.3-fold error) compared with the onecompartment PK model (1.8-and 1.9-fold errors, respectively). Of more importance, the simulated plasma concentration-time profiles of PF02341066 and PF04217903 by PBPK modeling seemed to be consistent with the observed profiles showing multiexponential declines, resulting in more accurate prediction of the apparent half-lives (t 1/2 ): the observed and predicted t 1/2 values were, respectively, 10 and 12 h for PF02341066 and 6.6 and 6.3 h for PF04217903. The predicted t 1/2 values by the one-compartment PK model were 17 h for PF02341066 and 1.9 h for PF04217903. Therefore, PBPK modeling has the potential to be more useful and reliable for the PK prediction of PF02341066 and PF04217903 in humans than the traditional one-compartment PK model. In summary, the present study has shown examples to indicate that the PBPK model can be used to predict PK profiles in humans.

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A Comprehensive Quantitative and Qualitative Evaluation of Extrapolation of Intravenous Pharmacokinetic Parameters From Rat, Dog, and Monkey to Humans. I. Clearance

Cited by 188 publications

References 25 publications

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Alprazolam as an In Vivo Probe for Studying Induction of CYP3A in Cynomolgus Monkeys

Prediction of human pharmacokinetics —gastrointestinal absorption

Prediction of Oral Pharmacokinetics of cMet Kinase Inhibitors in Humans: Physiologically Based Pharmacokinetic Model Versus Traditional One-Compartment Model

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