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Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: case example nelfinavir.
Eur J Pharm Biopharm. 2011 Oct; 79(2):349-56.EJ

Abstract

The aim of this study was to evaluate the utility of biorelevant dissolution tests coupled with in silico simulation technology to forecast in vivo bioperformance of poorly water-soluble bases, using nelfinavir mesylate as a model compound. An in silico physiologically based pharmacokinetic (PBPK) model for poorly water-soluble, weakly basic drugs was used to generate plasma profiles of nelfinavir by coupling dissolution results and estimates of precipitation with standard gastrointestinal (GI) parameters and the disposition pharmacokinetics of nelfinavir. In vitro dissolution of nelfinavir mesylate film-coated tablets was measured in biorelevant and compendial media. Drug precipitation in the small intestine was estimated from crystal growth theory. GI parameters (gastric emptying rate and fluid volume) appropriate to the dosing conditions (fasting and fed states) were used in the PBPK model. The disposition parameters of nelfinavir were estimated by fitting compartmental models to the in vivo oral PK data. The in vivo performance in each prandial state was simulated with the PBPK model, and predicted values for AUC and C(max) were compared to observed values. Dissolution results in FaSSIF-V2 and FeSSIF-V2, simulating the fasting and fed small intestinal conditions, respectively, correctly predicted that there would be a positive food effect for nelfinavir mesylate, but overestimated the food effect observed in healthy human volunteers. In order to better predict the food effect, an in silico PBPK simulation model using STELLA® software was evolved. Results with the model indicated that invoking drug precipitation in the small intestine is necessary to describe the in vivo performance of nelfinavir mesylate in the fasted state, whereas a good prediction under fed state conditions is obtained without assuming any precipitation. In vitro-in silico-in vivo relationships (IVISIV-R) may thus be a helpful tool in understanding the critical parameters that affect the oral absorption of poorly soluble weak bases.

Authors+Show Affiliations

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

21527341

Citation

Shono, Yasushi, et al. "Precipitation in the Small Intestine May Play a More Important Role in the in Vivo Performance of Poorly Soluble Weak Bases in the Fasted State: Case Example Nelfinavir." European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, vol. 79, no. 2, 2011, pp. 349-56.
Shono Y, Jantratid E, Dressman JB. Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: case example nelfinavir. Eur J Pharm Biopharm. 2011;79(2):349-56.
Shono, Y., Jantratid, E., & Dressman, J. B. (2011). Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: case example nelfinavir. European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, 79(2), 349-56. https://doi.org/10.1016/j.ejpb.2011.04.005
Shono Y, Jantratid E, Dressman JB. Precipitation in the Small Intestine May Play a More Important Role in the in Vivo Performance of Poorly Soluble Weak Bases in the Fasted State: Case Example Nelfinavir. Eur J Pharm Biopharm. 2011;79(2):349-56. PubMed PMID: 21527341.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: case example nelfinavir. AU - Shono,Yasushi, AU - Jantratid,Ekarat, AU - Dressman,Jennifer B, Y1 - 2011/04/18/ PY - 2011/01/28/received PY - 2011/04/06/revised PY - 2011/04/11/accepted PY - 2011/4/30/entrez PY - 2011/4/30/pubmed PY - 2012/4/12/medline SP - 349 EP - 56 JF - European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V JO - Eur J Pharm Biopharm VL - 79 IS - 2 N2 - The aim of this study was to evaluate the utility of biorelevant dissolution tests coupled with in silico simulation technology to forecast in vivo bioperformance of poorly water-soluble bases, using nelfinavir mesylate as a model compound. An in silico physiologically based pharmacokinetic (PBPK) model for poorly water-soluble, weakly basic drugs was used to generate plasma profiles of nelfinavir by coupling dissolution results and estimates of precipitation with standard gastrointestinal (GI) parameters and the disposition pharmacokinetics of nelfinavir. In vitro dissolution of nelfinavir mesylate film-coated tablets was measured in biorelevant and compendial media. Drug precipitation in the small intestine was estimated from crystal growth theory. GI parameters (gastric emptying rate and fluid volume) appropriate to the dosing conditions (fasting and fed states) were used in the PBPK model. The disposition parameters of nelfinavir were estimated by fitting compartmental models to the in vivo oral PK data. The in vivo performance in each prandial state was simulated with the PBPK model, and predicted values for AUC and C(max) were compared to observed values. Dissolution results in FaSSIF-V2 and FeSSIF-V2, simulating the fasting and fed small intestinal conditions, respectively, correctly predicted that there would be a positive food effect for nelfinavir mesylate, but overestimated the food effect observed in healthy human volunteers. In order to better predict the food effect, an in silico PBPK simulation model using STELLA® software was evolved. Results with the model indicated that invoking drug precipitation in the small intestine is necessary to describe the in vivo performance of nelfinavir mesylate in the fasted state, whereas a good prediction under fed state conditions is obtained without assuming any precipitation. In vitro-in silico-in vivo relationships (IVISIV-R) may thus be a helpful tool in understanding the critical parameters that affect the oral absorption of poorly soluble weak bases. SN - 1873-3441 UR - https://www.unboundmedicine.com/medline/citation/21527341/Precipitation_in_the_small_intestine_may_play_a_more_important_role_in_the_in_vivo_performance_of_poorly_soluble_weak_bases_in_the_fasted_state:_case_example_nelfinavir_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0939-6411(11)00143-3 DB - PRIME DP - Unbound Medicine ER -