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Sökning: onr:"swepub:oai:DiVA.org:uu-154115" > Towards a Better Pr...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00005069naa a2200481 4500
001oai:DiVA.org:uu-154115
003SwePub
008110526s2011 | |||||||||||000 ||eng|
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1541152 URI
0247 a https://doi.org/10.2165/11539250-000000000-000002 DOI
040 a (SwePub)uu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Sinha, Vikash K.4 aut
2451 0a Towards a Better Prediction of Peak Concentration, Volume of Distribution and Half-Life after Oral Drug Administration in Man, Using Allometry
264 1b Springer Science and Business Media LLC,c 2011
338 a print2 rdacarrier
520 a Background: it is imperative that new drugs demonstrate adequate pharmacokinetic properties, allowing an optimal safety margin and convenient dosing regimens in clinical practice, which then lead to better patient compliance. Such pharmacokinetic properties include suitable peak (maximum) plasma drug concentration (C-max), area under the plasma concentration-time curve (AUC) and a suitable half-life (t(1/4)). The C-max and t(1/2) following oral drug administration are functions of the oral clearance (CL/F) and apparent volume of distribution during the terminal phase by the oral route (V-z/F), each of which may be predicted and combined to estimate C-max and t(1/4). Allometric scaling is a widely used methodology in the pharmaceutical industry to predict human pharmacokinetic parameters such as clearance and volume of distribution. In our previous published work, we have evaluated the use of allometry for prediction of CL/F and AUC. In this paper we describe the evaluation of different allometric scaling approaches for the prediction of C-max, V-z/F and t(1/2) after oral drug administration in man. Methods: Twenty-nine compounds developed at Janssen Research and Development (a division of Janssen Pharmaceutica NV), covering a wide range of physicochemical and pharmacokinetic properties, were selected. The C,, following oral dosing of a compound was predicted using (i) simple allometry alone; (ii) simple allometry along with correction factors such as plasma protein binding (PPB), maximum life-span potential or brain weight (reverse rule of exponents, unbound C-max approach); and (iii) an indirect approach using allometrically predicted CL/F and V-z/F and absorption rate constant (k(a)). The k(a) was estimated from (i) in vivo pharmacokinetic experiments in preclinical species; and (ii) predicted effective permeability in man Weir), using a Caco-2 permeability assay. The V-z/F was predicted using allometric scaling with or without PPB correction. The t(1/2) was estimated from the allometrically predicted parameters CL/F and V-z/F. Predictions were deemed adequate when errors were within a 2-fold range. Results: C-max and t(1/2), could be predicted within a 2-fold error range for 59% and 66% of the tested compounds, respectively, using allometrically predicted CL/F and V-z/F. The best predictions for Cif, were obtained when K-a values were calculated from the Caco-2 permeability assay. The V-z/F was predicted within a 2-fold error range for 72% of compounds when PPB correction was applied as the correction factor for scaling. Conclusions: We conclude that (i) C-max and t(1/2), are best predicted by indirect scaling approaches (using allometrically predicted CL/F and V-z/F and accounting for ka derived from permeability assay); and (ii) the PPB is an important correction factor for the prediction of V-z/F by using allometric scaling. Furthermore, additional work is warranted to understand the mechanisms governing the processes underlying determination of C-max so that the empirical approaches can be fine-tuned further.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng
653 a Dose-prediction
653 a Metabolism
653 a Pharmacokinetic-modelling
653 a Pharmacokinetics
653 a PHARMACY
653 a FARMACI
7001 a Vaarties, Karin4 aut
7001 a De Buck, Stefan S.4 aut
7001 a Fenu, Luca A.u Uppsala universitet,Institutionen för farmaci4 aut
7001 a Nijsen, Marjoleen4 aut
7001 a Gilissen, Ron A. H. J.4 aut
7001 a Sanderson, Wendy4 aut
7001 a Van Uytsel, Kelly4 aut
7001 a Hoeben, Eva4 aut
7001 a Van Peer, Achiel4 aut
7001 a Mackie, Claire E.4 aut
7001 a Smit, Johan W.4 aut
7102 a Uppsala universitetb Institutionen för farmaci4 org
7730 t Clinical Pharmacokineticsd : Springer Science and Business Media LLCg 50:5, s. 307-318q 50:5<307-318x 0312-5963x 1179-1926
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-154115
8564 8u https://doi.org/10.2165/11539250-000000000-00000

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