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Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data

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Abstract

The aim of this study was to evaluate a strategy based on a physiologically based pharmacokinetic (PBPK) model for the prediction of PK profiles in human using in vitro data when elimination of compounds relies on active transport processes. The strategy was first applied to rat in vivo and in vitro data in order to refine the PBPK model. The model could then be applied to human in vitro uptake transport data using valsartan as a probe substrate. Plated rat and human hepatocytes, and cell lines overexpressing human OATP1B1 and OATP1B3 were used for in vitro uptake experiments. The uptake rate of valsartan was higher for rat hepatocytes (K m,u = 28.4 ± 3.7 μM, V max = 1318 ± 176 pmol/mg/min and P dif = 1.21 ± 0.42 μl/mg/min) compared to human hepatocytes (K m,u = 44.4 ± 14.6 μM, V max = 304 ± 85 pmol/mg/min and P dif = 0.724 ± 0.271 μl/mg/min). OATP1B1 and 1B3 parameters were correlated to human hepatocyte data using experimentally established relative activity factors (RAF). Resulting PBPK simulations using those in vitro data were compared for plasma (human and rat) and bile (rat) concentration–time profiles following i.v. bolus administration of valsartan. An uncertainty analysis indicated that the scaled in vitro uptake clearance had to be adjusted with an additional empirical scaling factor of 5 to match the plasma concentrations and biliary excretion profiles. Applying this model, plasma clearances (CLP) for rat and human were predicted within two-fold relative to predictions based on respective in vitro data. The corrected hepatic uptake transport kinetic parameters enabled the prediction of valsartan in vivo PK profiles and plasma clearances, using PBPK modeling. Moreover, the interspecies difference in elimination rate observed in vivo was correctly reflected in the transport parameters determined in vitro. More data are needed to support more general applications of the proposed approach including its use for metabolized compounds.

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Abbreviations

CLP (ml/min/kg):

Plasma clearance

CLHP (ml/min/kg):

Plasma hepatic clearance \( {\text{CL}}_{\text{HP}} = {\text{CL}}_{\text{P}} \times f_{\text{bile}} \)

CLRP (ml/min/kg):

Plasma renal clearance \( {\text{CL}}_{\text{RP}} = {\text{CL}}_{\text{P}} \times fe \)

EHR:

Enterohepatic recirculation

f bile :

Fraction of the dose excreted unchanged in bile

fe :

Fraction of the dose excreted unchanged in urine

fu p :

Fraction unbound in plasma

HPGL:

Hepatocytes per gram of liver

K m,u (μM):

Michaelis–Menten affinity constant unbound (I influx, E efflux)

MTPMH:

mg of total protein per million hepatocytes

mw (g/mol):

Molecular weight

OATP:

Organic anion transporting peptide

PBPK:

Physiologically based pharmacokinetic

P dif (μl/min/mg):

Passive diffusion at the basolateral membrane determined in vitro (through CHO cells membrane \( \_{\text{CHO}} \) or human hepatocytes membrane \( \_{\text{HH}} \))

RAF:

Relative activity factor

R bp :

Blood-plasma ratio

V max (pmol/min/mg):

Michaelis–Menten maximum velocity (I influx, E efflux)

C int (μM):

Compound concentration in intracellular space in vitro

C ex (μM):

Compound concentration in the medium in vitro

f b :

Fraction non-specifically bound in the in vitro system

V int (μl):

Intracellular volume of all cells in one well

V ex (μl):

Volume of the incubation medium in vitro

Cbi (μg/ml):

Blood concentration in (arterial) of tissue

Cbo (μg/ml):

Blood concentration out (venous) of tissue

C e (μg/ml):

Drug concentration in extracellular space (u = unbound) in vivo

C t (μg/ml):

Drug concentration in intracellular space (u = unbound) in vivo

fu inc :

Fraction unbound in the in vitro incubation

fu L :

Fraction unbound in liver

h :

Hematocrit

J max (mg/s):

Michaelis–Menten maximum velocity scaled to in vivo (I influx, E efflux)

Kp :

Partition coefficient

Kp e :

Partition coefficient in extracellular space (L: in liver = in Disse space)

M bile (μg):

Amount of drug cleared by biliary excretion

PSTC (ml/s):

Permeability-surface area product at the basolateral membrane

PSTCAp (ml/s):

Permeability-surface area product at the apical membrane

Q L (ml/min/kg):

Liver blood flow

V e (ml):

Extracellular volume fraction of tissue

V P (ml):

Plasma volume

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Authors and Affiliations

  1. Non-Clinical Development-Drug Safety, F. Hoffmann-La Roche Ltd., Basel, Switzerland

    Agnès Poirier, Anne-Christine Cascais, Christoph Funk & Thierry Lavé

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  1. Agnès Poirier
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  2. Anne-Christine Cascais
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  3. Christoph Funk
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Correspondence to Agnès Poirier.

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Poirier, A., Cascais, AC., Funk, C. et al. Prediction of pharmacokinetic profile of valsartan in human based on in vitro uptake transport data. J Pharmacokinet Pharmacodyn 36, 585–611 (2009). https://doi.org/10.1007/s10928-009-9139-3

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  • DOI: https://doi.org/10.1007/s10928-009-9139-3

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