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A strategy for preclinical formulation development using GastroPlus as pharmacokinetic simulation tool and a statistical screening design applied to a dog study.
Eur J Pharm Sci. 2006 Jan; 27(1):91-9.EJ

Abstract

The aim of this paper is to propose a pharmaceutical risk assessment strategy that goes beyond the usual characterisation of a clinical candidate molecule according to the biopharmaceutical classification system (BCS). This strategy was evaluated for a new CNS drug with poor solubility and good permeability. In a first step, GastroPlus was used to simulate the absorption process based on preformulation data. These input data involved a physicochemical drug characterisation including drug solubility measurements in simulated physiological media, as well as permeability determination. Further computer simulations were conducted to determine the sensitivity to changes of selected input values. Thus, oral bioavailability prediction was studied as a function of the particle size and drug solubility. The second part of the presented strategy for preclinical formulation development was to test specially designed formulations in a 2(3) screening factorial plan using the dog as the animal model. The factors were the dosage form, food effect and dose strength. One of the two experimental formulations was a capsule filled with the micronised drug, whereas the other formulation was a surfactant solution of the drug. Accordingly, a "worst case" formulation was compared with a "best case" drug solution over the clinically relevant dose range in fasted and fed dogs. The results of the computer simulation indicated that a fraction of the dose is dissolved in the stomach and precipitates partially in the small intestine. The simulation predicted almost full drug absorption during the GI transit time. Interestingly, the simulation implies that stomach drug solubility had little impact on overall fraction absorbed. The results also showed that changes of particle size and reference solubility within two orders of magnitude hardly affected the oral bioavailability. This in silico deduction was subsequently compared with the results of the dog studies. Indeed a surfactant drug solution showed no clear biopharmaceutical superiority over a solid capsule formulation on the average of both dose strengths in fasted and fed dogs. Despite the substantial variability of the in vivo data, the factorial screening design indicated marginal significant interaction between the dose level and feeding status. This can be viewed as a flag for the planning of further studies, since a potential effect of one factor may depend on the level of the other. In summary, the GastroPlus simulation together with the statistically designed dog study provided a thorough biopharmaceutical assessment of the new CNS drug. Based on these findings, it was decided to develop a standard granulate in capsules for phase I studies. More sophisticated formulation options were abandoned and so the clinical formulation development was conducted in a cost-efficient way.

Authors+Show Affiliations

F. Hoffmann-La Roche Ltd., Pharmaceutical and Analytical R&D, Bldg./Lab. 072/338, Grenzacherstrasse, CH-4070 Basel, Switzerland. martin.kuentz@roche.comNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

16219449

Citation

Kuentz, Martin, et al. "A Strategy for Preclinical Formulation Development Using GastroPlus as Pharmacokinetic Simulation Tool and a Statistical Screening Design Applied to a Dog Study." European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, vol. 27, no. 1, 2006, pp. 91-9.
Kuentz M, Nick S, Parrott N, et al. A strategy for preclinical formulation development using GastroPlus as pharmacokinetic simulation tool and a statistical screening design applied to a dog study. Eur J Pharm Sci. 2006;27(1):91-9.
Kuentz, M., Nick, S., Parrott, N., & Röthlisberger, D. (2006). A strategy for preclinical formulation development using GastroPlus as pharmacokinetic simulation tool and a statistical screening design applied to a dog study. European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences, 27(1), 91-9.
Kuentz M, et al. A Strategy for Preclinical Formulation Development Using GastroPlus as Pharmacokinetic Simulation Tool and a Statistical Screening Design Applied to a Dog Study. Eur J Pharm Sci. 2006;27(1):91-9. PubMed PMID: 16219449.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A strategy for preclinical formulation development using GastroPlus as pharmacokinetic simulation tool and a statistical screening design applied to a dog study. AU - Kuentz,Martin, AU - Nick,Sonja, AU - Parrott,Neil, AU - Röthlisberger,Dieter, Y1 - 2005/10/10/ PY - 2005/02/21/received PY - 2005/08/11/revised PY - 2005/08/20/accepted PY - 2005/10/13/pubmed PY - 2006/3/24/medline PY - 2005/10/13/entrez SP - 91 EP - 9 JF - European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences JO - Eur J Pharm Sci VL - 27 IS - 1 N2 - The aim of this paper is to propose a pharmaceutical risk assessment strategy that goes beyond the usual characterisation of a clinical candidate molecule according to the biopharmaceutical classification system (BCS). This strategy was evaluated for a new CNS drug with poor solubility and good permeability. In a first step, GastroPlus was used to simulate the absorption process based on preformulation data. These input data involved a physicochemical drug characterisation including drug solubility measurements in simulated physiological media, as well as permeability determination. Further computer simulations were conducted to determine the sensitivity to changes of selected input values. Thus, oral bioavailability prediction was studied as a function of the particle size and drug solubility. The second part of the presented strategy for preclinical formulation development was to test specially designed formulations in a 2(3) screening factorial plan using the dog as the animal model. The factors were the dosage form, food effect and dose strength. One of the two experimental formulations was a capsule filled with the micronised drug, whereas the other formulation was a surfactant solution of the drug. Accordingly, a "worst case" formulation was compared with a "best case" drug solution over the clinically relevant dose range in fasted and fed dogs. The results of the computer simulation indicated that a fraction of the dose is dissolved in the stomach and precipitates partially in the small intestine. The simulation predicted almost full drug absorption during the GI transit time. Interestingly, the simulation implies that stomach drug solubility had little impact on overall fraction absorbed. The results also showed that changes of particle size and reference solubility within two orders of magnitude hardly affected the oral bioavailability. This in silico deduction was subsequently compared with the results of the dog studies. Indeed a surfactant drug solution showed no clear biopharmaceutical superiority over a solid capsule formulation on the average of both dose strengths in fasted and fed dogs. Despite the substantial variability of the in vivo data, the factorial screening design indicated marginal significant interaction between the dose level and feeding status. This can be viewed as a flag for the planning of further studies, since a potential effect of one factor may depend on the level of the other. In summary, the GastroPlus simulation together with the statistically designed dog study provided a thorough biopharmaceutical assessment of the new CNS drug. Based on these findings, it was decided to develop a standard granulate in capsules for phase I studies. More sophisticated formulation options were abandoned and so the clinical formulation development was conducted in a cost-efficient way. SN - 0928-0987 UR - https://www.unboundmedicine.com/medline/citation/16219449/A_strategy_for_preclinical_formulation_development_using_GastroPlus_as_pharmacokinetic_simulation_tool_and_a_statistical_screening_design_applied_to_a_dog_study_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0928-0987(05)00257-5 DB - PRIME DP - Unbound Medicine ER -