Application of Hybrid Approach Based on Empirical and Physiological Concept for Predicting Pharmacokinetics in Humans—Usefulness of Exponent on Prospective Evaluation of Predictability

Q2 · MEDICINE

Article

Author: Hiroyuki Sayama ; Hiroshi Komura ; Motohiro Kogayu

We developed a hybrid method for predicting plasma concentration-time curves in humans by integrating species differences in in vitro intrinsic clearance (CL(int)) into the Dedrick approach based on the allometry concept. With prediction of clearance (CL) by allometric scaling, taking in vitro CL(int) into consideration improved the accuracy and reduced the average fold error from 2.72 to 1.99. With the hybrid approach of applying the same concept to the Dedrick approach, the predictability of plasma concentration profiles was compared with the results of the conventional Dedrick approach and the physiologically based pharmacokinetic model using 15 compounds with widely ranging physicochemical and pharmacokinetic profiles. The hybrid approach showed the highest predictability among the examined methods. For CL and the apparent volume of distribution at the steady state (V(ss)), the relationship between the exponent of allometric equation and fold error was also evaluated with the hybrid approach. The relationship appeared to be a horseshoe curve. Six compounds with exponents ranging from 0.7 to 1.1 for both CL and V(ss) [antipyrine, caffeine, epiroprim, propafenone, theophylline, and verapamil] displayed higher predictability. Three compounds with an exponent ranging from 0.7 to 1.1 for CL showed better predictability for CL, and the other four compounds appeared to display similar relationship between the exponent and predictability for V(ss). These findings indicated that the exponent becomes a preliminary index to speculate on predictability. Combination of the hybrid approach and exponent allows us to prospectively draw human plasma concentration-time curves, with the implication of possible prediction accuracy prior to clinical studies.

01 Nov 2002·Bulletin de la Societe de pathologie exotique (1990)

[Preliminary study on isoniazid-epiroprim combination in a tuberculosis murine model].

Article

Author: Dosso, M ; Pescher, P ; Edy ; Romain, F ; Marchal, G ; N'guessan, K ; Chavarot, P

The purpose of this study regarding isoniazid-epiroprim's association applied to antituberculosis chemotherapy, carried through murine model, initiated into Institut Pasteur of Côte d'Ivoire and worked out at Institut Pasteur of Paris was to evaluate the epiroprim's effect alone and associated with isoniazid on Mycobacterium tuberculosis. Sixteen mouses (lineage C57Bl/6) were inoculated by venous way with 10(5) viable bacillus (strain H37Rv) suspended in 500 microliters sterile physiological aqueous solution and were shared out into 4 sets. Fifteen days later the sets have been submitted or not to a daily treatment by gavage during three weeks (epiroprim, isoniazid, isoniazid plus epiroprim). The mouses were euthanasied, spleen and lung were removed from each animal. The titres of determined bacillus into those organs prove that isoniazid and epiroprim associated seem more efficacious than the isoniazid monotherapy for mouses pulmonary tuberculosis. Bacillus obtained are sensitive to isoniazid.

01 Jan 2002·International Journal of Antimicrobial AgentsQ2 · MEDICINE

In vivo activity of epiroprim, a dihydrofolate reductase inhibitor, singly and in combination with dapsone, against Mycobacterium leprae

Q2 · MEDICINE

Article

Author: Dhople, Arvind M

The antimicrobial effects of a new dihydrofolate reductase inhibitor, epiroprim, either singly or in combination with dapsone against Mycobacterium leprae, were evaluated in vivo using a mouse footpad model. When fed to mice at concentration of 0.05% in diet, epiroprim completely inhibited the growth of both dapsone-sensitive and dapsone-resistant strains of M. leprae in the footpads of mice and the effects were bactericidal. To achieve similar effects, the concentration of dapsone in the diet had to be 0.0005 and 0.01%, respectively. When used in combination, the concentrations of the drugs in the diet could be lowered by 50-80% and still achieve bactericidal effects. The data support the earlier results on in vitro studies and suggest the use of epiroprim in the multidrug regimen in the treatment of leprosy.

100 Deals associated with Epiroprim

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Indication	Highest Phase	Country/Location	Organization	Date
Pneumonia	Phase 2	-	F. Hoffmann-La Roche Ltd.	-
Pneumonia, Pneumocystis	Phase 2	CH	Roche Holding AG	-
Toxoplasmosis	Phase 2	CH	Roche Holding AG	-
Bacterial Infections	Preclinical	US	James J. Peters Bronx Veterans Affairs Medical Center	01 Jul 1993

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