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Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption.
J Pharm Pharmacol. 2009 Jul; 61(7):891-9.JP

Abstract

OBJECTIVES

Inter-individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated.

METHODS

Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature. Various scenarios incorporating different extents of inter-individual physiological variability were simulated and the simulation results were compared with experimental human study data obtained after oral cimetidine administration of four different tablets with varying release kinetics.

KEY FINDINGS

The inter-individual variability in effective surface area was the largest contributor to absorption variability. Based on in-vitro dissolution profiles, the mean plasma cimetidine concentration-time profiles as well as the inter-individual variability could be well described for three cimetidine formulations. In the case of the formulation with the slowest dissolution kinetic, model predictions on the basis of the in-vitro dissolution profile underestimated the plasma exposure.

CONCLUSIONS

The model facilitates predictions of the inter-individual pharmacokinetic variability after oral drug administration for immediate and extended-release formulations of cimetidine, given reasonable in-vitro dissolution kinetics.

Authors+Show Affiliations

Bayer Technology Services GmbH, Leverkusen, Germany. stefan.willmann@bayertechnology.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19589231

Citation

Willmann, Stefan, et al. "Whole-body Physiologically Based Pharmacokinetic Population Modelling of Oral Drug Administration: Inter-individual Variability of Cimetidine Absorption." The Journal of Pharmacy and Pharmacology, vol. 61, no. 7, 2009, pp. 891-9.
Willmann S, Edginton AN, Kleine-Besten M, et al. Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption. J Pharm Pharmacol. 2009;61(7):891-9.
Willmann, S., Edginton, A. N., Kleine-Besten, M., Jantratid, E., Thelen, K., & Dressman, J. B. (2009). Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption. The Journal of Pharmacy and Pharmacology, 61(7), 891-9. https://doi.org/10.1211/jpp/61.07.0008
Willmann S, et al. Whole-body Physiologically Based Pharmacokinetic Population Modelling of Oral Drug Administration: Inter-individual Variability of Cimetidine Absorption. J Pharm Pharmacol. 2009;61(7):891-9. PubMed PMID: 19589231.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Whole-body physiologically based pharmacokinetic population modelling of oral drug administration: inter-individual variability of cimetidine absorption. AU - Willmann,Stefan, AU - Edginton,Andrea N, AU - Kleine-Besten,Marcus, AU - Jantratid,Ekarat, AU - Thelen,Kirstin, AU - Dressman,Jennifer B, PY - 2009/7/11/entrez PY - 2009/7/11/pubmed PY - 2009/8/27/medline SP - 891 EP - 9 JF - The Journal of pharmacy and pharmacology JO - J Pharm Pharmacol VL - 61 IS - 7 N2 - OBJECTIVES: Inter-individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated. METHODS: Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature. Various scenarios incorporating different extents of inter-individual physiological variability were simulated and the simulation results were compared with experimental human study data obtained after oral cimetidine administration of four different tablets with varying release kinetics. KEY FINDINGS: The inter-individual variability in effective surface area was the largest contributor to absorption variability. Based on in-vitro dissolution profiles, the mean plasma cimetidine concentration-time profiles as well as the inter-individual variability could be well described for three cimetidine formulations. In the case of the formulation with the slowest dissolution kinetic, model predictions on the basis of the in-vitro dissolution profile underestimated the plasma exposure. CONCLUSIONS: The model facilitates predictions of the inter-individual pharmacokinetic variability after oral drug administration for immediate and extended-release formulations of cimetidine, given reasonable in-vitro dissolution kinetics. SN - 0022-3573 UR - https://www.unboundmedicine.com/medline/citation/19589231/Whole_body_physiologically_based_pharmacokinetic_population_modelling_of_oral_drug_administration:_inter_individual_variability_of_cimetidine_absorption_ L2 - https://doi.org/10.1211/jpp/61.07.0008 DB - PRIME DP - Unbound Medicine ER -