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배균섭,임동석 대한임상약리학회 2016 Translational and Clinical Pharmacology Vol.24 No.4
The first-order conditional estimation (FOCE) method is more complex than the first-order (FO) approximation method because it estimates the empirical Bayes estimate (EBE) for each iteration. By contrast, it is a further approximation of the Laplacian (LAPL) method, which uses second-order expansion terms. FOCE without INTERACTION can only be used for an additive error model, while FOCE with INTERACTION (FOCEI) can be used for any error model. The formula for FOCE without INTERACTION can be derived directly from the extension of the FO method, while the FOCE with INTERACTION method is a slight simplification of the LAPL method. De¬tailed formulas and R scripts are presented here for the reproduction of objective function values by NONMEM.
약물대사효소 CYP2D6와 N-acetyltransferase 활성의 고령화에 따른 변화에 관한 연구
배균섭 대한임상약리학회 2002 Translational and Clinical Pharmacology Vol.10 No.2
Background : The effect of age on the activity of drug metabolizing enzymes has not been studied thoroughly. We examined the effect of age on the metabolic activity of CYP2D6 and N-acetyltransferase. Methods : Metoprolol and isoniazid were used as probe drugs of CYP2D6 and N-acetyltransferase, respectively. We measured metabolic ratios of metoprolol and isoniazid in 80 subjects of 21~85 years old. Metabolic ratio(MR) of metoprolol was defined as the ratio of metoprolol/α-hydroxymetoprolol in the urine collected for 8 hours after the administration. Isoniazid/acetylisoniazid was used for MR of isoniazid. Concentrations of parent drug and metabolite were assayed by HPLC simultaneously. General linear model in SAS 8.1Ⓡ was used for the statistical analysis after visual exploration. Metabolic ratios were log-transformed to be normalized for analysis. Results : Demographic characteristics were similar between groups of metabolic activities. MRs of both drugs were not significantly different between groups by age, sex and smoking. Mean MR of metoprolol for adult group(age<65) was 0.85(90% CI: 0.48~1.48) times that of elderly group(age≥65) and mean MR of isoniazid for adult group was 1.01(90% CI: 0.57~1.79) times that of elderly group. The proportions of poor metabolizer(adult: elderly=1.75%: 0 %) or slow acetylator(adult: elderly=17.54%: 17.39%) were not different between age groups. The effect of age on the metabolism was not significant even when it was adjusted with phenotype(p-value=0.58 and 0.54 for metoprolol and isoniazid, respectively). Conclusion : The effect of age on the metabolic activities of CYP2D6 and N-acetyltransferase was not significant. Therefore, dosage adjustment according to age may not be necessary for the drugs that are eliminated through these enzymes and a confirmatory study is need.
Bioequivalence data analysis for the case of separate hospitalization
배균섭,강승호 대한임상약리학회 2017 Translational and Clinical Pharmacology Vol.25 No.2
A bioequivalence study is usually conducted with the same-day drug administration. However, hospitalizationis occasionally separated for logistical, operational, or other reasons. Recently, there wasa case of separate hospitalization because of difficulties in subject recruitment. This article suggestsa better way of bioequivalence data analysis for the case of separate hospitalization. The key featuresare (1) considering the hospitalization date as a random effect than a fixed effect and 2) using “PROCMIXED” instead of “PROC GLM” to include incomplete subject data.
Standard Error of Empirical Bayes Estimate in NONMEMⓇ VI
배균섭 대한약리학회 2012 The Korean Journal of Physiology & Pharmacology Vol.16 No.2
The pharmacokinetics/pharmacodynamics analysis software NONMEMⓇ output provides model parameter estimates and associated standard errors. However, the standard error of empirical Bayes estimates of inter-subject variability is not available. A simple and direct method for estimating standard error of the empirical Bayes estimates of inter-subject variability using the NONMEMⓇ VI internal matrix POSTV is developed and applied to several pharmacokinetic models using intensively or sparsely sampled data for demonstration and to evaluate performance. The computed standard error is in general similar to the results from other post-processing methods and the degree of difference, if any, depends on the employed estimation options.
노육환,배균섭,조상헌,최상민,김종률,정진아,김운집,진석준,박현정,김정철,임형석,Noh, Yook-Hwan,Bae, Kyun-Seop,Cho, Sang-Heon,Choe, Sangmin,Ghim, Jong-Lyul,Jung, Jin Ah,Kim, Un-Jib,Jin, Seok-Joon,Park, Hyun-Jung,Kim, Jung-Chul,Lim, Hyeon Korean Society for Clinical Pharmacology and Thera 2012 臨床藥理學會誌 Vol.20 No.2
배경: 레트로졸은 유방암 치료에 사용되는 경구용 비스테로이드성 aromatase 억제제이다. 방법: 이 연구는 건강한 성인 남성을 대상으로 무작위 배정, 단회 투여, 공개설계로서 두 치료군, 두 순서, 두 시기의 교차 시험법으로 진행되었다. 각 순서군에 13명씩 무작위 배정되어, 한군은 1기에 페마라$^{(R)}$정(대조약)을, 2기에 유한 레트로졸정(시험약)을, 다른 한군은 반대 순서로 두 시기 사이에 약 5주의 휴약기를 가지고 각각 2.5 mg정 1정씩 투여 받았다. 약동학 분석을 위한 혈액 검체는 공복 상태에서 투약 후 312 시간까지 얻어졌다. 레트로졸의 혈장 내 농도는 liquid chromatography-tandem mass spectrometry를 이용하여 측정하였다. 안전성 평가는 활력징후, 문진 및 신체검사, 심전도, 진단검사실 검사와 이상반응 모니터링을 통하여 이루어졌다. 결과: 총 26명의 피험자가 연구를 완료하였고, 약동학 분석에 26명의 자료가 모두 사용되었다. $C_{max}$와 $AUC_{last}$ 파라미터에 대한 시험약과 대조약의 기하평균비는 각각 0.92 (90 % 신뢰구간: 0.85 - 0.99)와 1.01 (90 % 신뢰구간: 0.97 - 1.04)였다. 보고된 중대한 이상반응은 없었으며, 임상적으로 유의한 변화도 관찰되지 않았다. 결론: 건강한 자원자에서 페마라$^{(R)}$정과 유한 레트로졸정의 약동학 특성과 안전성은 유사하였다. Background: Letrozole is an oral non-steroidal inhibitor of the aromatase enzyme, which has proven to be a useful drug against breast cancer. Methods: This single-dose, randomized $2{\times}2$ crossover study was conducted in healthy male volunteers. Participants of each sequence group (each 13 volunteers for sequence group) received, in randomized sequence, a single oral 2.5-mg dose of generic letrozole (test) or branded letrozole (reference). Each treatment period was separated by a 5-week washout period. Blood samples were collected for up to 312 hours after drug administration, and drug concentrations were determined using validated LC/MS-MS. Pharmacokinetic properties were obtained using noncompartmental analysis. Drug tolerability was assessed throughout the study, using measurements of vital signs, physical examination, clinical chemistry testing, EKG, and interviews. Results: A total of 26 subjects completed the study. The geometric mean ratios (90% CI) of $C_{max}$ and $AUC_{last}$ were 0.92 (0.85 - 0.99) and 1.01 (0.97 - 1.04), respectively. No serious AEs were reported, and there were no clinically significant differences between test and reference groups. Conclusion: The findings from this study suggest bioequivalence between two formulations of letrozole in healthy male volunteers. The safety profile of two formulations had similar characteristics.