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.

12 Apr 2011·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

Simple HPLC Determination of the Concentrations of Epiroprim in the Serum and Brains of Mice

Q3 · MEDICINE

Article

Author: Chang, Hernan R ; Khoo, Yok Moi ; Lee, How Sung

AbstractEpiroprim, an analogue of trimethoprim, has been shown to potentiate the efficacy of dapsone in experimental parasitic infections. A simple and accurate HPLC method has been developed to estimate epiroprim in serum and brainBlood and brains from mice were sampled 0, 30, 75, 120 and 240 min after 50 or 100 mg kg−1 oral gavage. The drug and added internal standard metoprine in serum and brain supernatant were isolated by solid-phase extraction (Supelclean LC-SCX). The HPLC system consisted of a 150 × 4.6 mm Hypersil 5 μm ODS column. The mobile phases contained various proportions of acetonitrile, methanol and phosphate buffer (0.1 M). Peaks were detected by UV absorbance at 210 run. Serum concentrations (mean ± s.e.m.) of epiroprim were highest at 30 min for both 50 and 100 mg kg−1 doses, 173 ± 20 and 207 ± 25 ng mL−1, respectively, falling to 8 ± 5 and 18 ±6 ng mL−1, respectively, at 240 min. Epiroprim concentrations in the brain correlated well with those in the serum, with levels of 223 ±69 and 265 ±21 ng g−1 falling to 10 ± 10 and 31 ± 11 ng g−1, respectively.Epiroprim is rapidly absorbed and distributed to the brain.

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.

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

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