건강한 성인에서 아토르바스타틴 경구흡수과정의 집단약동학 분석 = Population Pharmacokinetic Analysis of the oral Absorption Process of Aforuastatin in Healthy Volunteers

다국어 초록 (Multilingual Abstract)

Backgrounds: Atorvastatin which has a highly variable pharmacokinetic profileoften shows double peaks. However, in most cases it has been regarded as a noise or assay error. In this study we compared 4 different absorption models (zero order, 1st order, combined and parallel absorption model) to determine which model best describes the absorption process. Methods: Plasma atorvastatin data of 57 healthy subjects from two bioequivalence studies were used. Concentrations were measured up to 48
hours after drug administration. Mixed effect analysis to compare the 4 absorption models was performed using NONMEM version 6.0. Results: The absorption process was best described bycombined absorption model. CL/F and Vd/F were 400L/hand 779L, respectively, and KA and D were 0.09 hr-1 and 0.53 hr-1, respectively.
Conclusion: Although the combined absorption model did not fully describe the double peaks, this study demonstrated that absorption models other than simple first or zero order absorption are necessary to describe the double peaks phenomenon.

다국어 초록 (Multilingual Abstract)

Backgrounds: Atorvastatin which has a highly variable pharmacokinetic profileoften shows double peaks. However, in most cases it has been regarded as a noise or assay error. In this study we compared 4 different absorption models (zero order, 1st order, combined and parallel absorption model) to determine which model best describes the absorption process. Methods: Plasma atorvastatin data of 57 healthy subjects from two bioequivalence studies were used. Concentrations were measured up to 48
hours after drug administration. Mixed effect analysis to compare the 4 absorption models was performed using NONMEM version 6.0. Results: The absorption process was best described bycombined absorption model. CL/F and Vd/F were 400L/hand 779L, respectively, and KA and D were 0.09 hr-1 and 0.53 hr-1, respectively.
Conclusion: Although the combined absorption model did not fully describe the double peaks, this study demonstrated that absorption models other than simple first or zero order absorption are necessary to describe the double peaks phenomenon.

참고문헌 (Reference)

1 유경상, "이중 최고농도를 보이는 서방형 제제의 약동학/약력학적 분석: Spline 함수에 의한 비모수적 약동학 분석법의 적용" 6 (6): 16-, 1998

2 Suttle AB, "Use of a Pharmacokinetic Model Incorporating Discontinuous Gastrointestinal Absorption to Examine the Occurrence of Double Peaks in Oral Concentration-Time Profiles" 9 (9): 350-356, 1992

3 Oberle RL, "The influence of gastric emptying and intestinal transit rates on the plasma level curve of cimetidine: An explanation for the double peak phenomenon" 15 : 529-544, 1987

4 Jemal M, "Quantitation of the acid and lactone forms of atorvastatin and its biotransformation products in human serum by high? performance liquid chromatography with electrospray tandem mass spectrometry" 13 (13): 1003-1015, 1999

5 Ette EI, "Pharmacometrics : the science of quantitative pharmacology" Hoboken, N.J.: John Wiley & Sons 2007

6 Murata K, "Pharmacokinetic analysis of concentration data of drugs with irregular absorption profiles using multi-fraction absorption models" 76 (76): 109-113, 1987

7 Siedlik PH, "Erythromycin coadministration increasesplasma atorvastatin concentrations" 39 (39): 501-504, 1999

8 Lipka E, "Celiprolol double-peak occurrence and gastric motility: Nonlinear mixed effects modeling of bioavailability data obtained in dogs" 23 (23): 267-286, 1995

9 Koytchev R, "Bioequivalence study of atorvastatin tablets" 54 (54): 573-577, 2004

10 Dressman JB, "Absorption of flurbiprofen in the fed and fasted states" 9 (9): 901-907, 1992

11 Yin OQ, "A Modified Two-Portion Absorption Model to Describe Double-Peak Absorption Profiles of Ranitidine" 42 (42): 179-, 2003