Standard Error of Empirical Bayes Estimate in NONMEM® VI.

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

Randomized Comparison of Four-Times-Daily versus Once-Daily Intravenous Busulfan in Conditioning Therapy for Hematopoietic Cell Transplantation

AbstractSixty patients were randomized to receive intravenous busulfan (iBU) either as 0.8 mg/kg, over 2 hours 4 times a day (BU4 arm) or 3.2 mg/kg, over 3 hours once a day (BU1 arm) in conditioning therapy for hematopoietic cell transplantation. The complete pharmacokinetic parameters for the first busulfan dose were obtained from all patients and were comparable between the 2 arms: for the BU4 and BU1 groups, elimination half-life (mean ± SD) was 2.75 ± 0.22 versus 2.83 ± 0.21 hours, estimated daily AUC was 6058.0 ± 1091.9 versus 6475.5 ± 1099.4 μM·min per day, and clearance was 2.05 ± 0.36 versus 1.91 ± 0.31 mL/min/kg, respectively. Times to engraftment after transplantation were similar between the 2 arms. No significant differences were evident in the occurrence of acute graft-versus-host disease (aGVHD) and hepatic veno-occlusion disease (VOD). Moreover, other toxicities observed within 100 days after transplantation were not significantly different between the 2 arms. The cumulative incidence of nonrelapse mortality was 20.8% in BU4 arm and 13.3% in BU1 arm. In conclusion, our randomized study demonstrates that the pharmacokinetic profiles and posttransplant complications are similar for once-daily iBU and traditional 4-times-daily iBU

Occurrence Prediction of the Citrus Flatid Planthopper (Metcalfa pruinosa (Say, 1830)) in South Korea Using a Random Forest Model

Invasive species cause a severe impact on existing ecosystems. The citrus flatid planthopper (CFP; Metcalfa pruinosa (Say, 1830)) is an invasive species in many countries. Predicting potential occurrence areas of the species related to environmental conditions is important for effective forest ecosystem management. In this study, we evaluated the occurrence patterns of the CFP and predicted its potential occurrence areas in South Korea using a random forest model for a hazard rating of forests considering meteorological and landscape variables. We obtained the occurrence data of the CFP in South Korea from literature and government documents and extracted seven environmental variables (altitude, slope, distance to road (geographical), annual mean temperature, minimum temperature in January, maximum temperature in July, and annual precipitation (meteorological)) and the proportion of land cover types across seven categories (urban, agriculture, forest, grassland, wetland, barren, and water) at each occurrence site from digital maps using a Geographic Information System. The CFP occurrence areas were mostly located at low altitudes, near roads and urbanized areas. Our prediction model also supported these results. The CFP has a high potential to be distributed over the whole of South Korea, excluding high mountainous areas. Finally, factors related to human activities, such as roads and urbanization, strongly influence the occurrence and dispersal of the CFP. Therefore, we propose that these factors should be considered carefully in monitoring and surveillance programs for the CFP and other invasive species

Standard Error of Empirical Bayes Estimate in NONMEM® VI

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

Pharmacokinetics of Hydroxychloroquine and Its Clinical Implications in Chemoprophylaxis against Malaria Caused by Plasmodium vivax

Hydroxychloroquine (HCQ) is an antimalarial drug used as chemoprophylaxis against malaria caused by Plasmodium vivax in the Republic of Korea Army (ROKA). In this study, we evaluated the pharmacokinetics (PK) of HCQ and its metabolites and the relationship between the PK of HCQ and the effect of treatment of HCQ on vivax malaria in South Koreans. Three PK studies of HCQ were conducted with 91 healthy subjects and patients with vivax malaria. Plasma concentrations were analyzed by noncompartmental and mixed-effect modeling approaches. A two-compartment model with first-order absorption best described the data. The clearance and the central and peripheral volumes of distribution were 15.5 liters/h, 733 liters, and 1,630 liters, respectively. We measured the plasma concentrations of HCQ in patients with prophylactic failure of HCQ and compared them with the prediction intervals of the simulated concentrations for HCQ from the final PK model built in this study. In 71% of the patients with prophylactic failure, the plasma concentrations of HCQ were below the lower bounds of the 95% prediction interval, while only 8% of them showed higher levels than the upper bounds of the 95% prediction interval. We report that a significant cause of prophylactic failure among the individuals in ROKA was ascribed to plasma concentrations of HCQ lower than those predicted by the PK model. However, prophylactic failure despite sufficient plasma concentrations of HCQ was confirmed in several individuals, warranting continued surveillance to monitor changes in the HCQ susceptibility of Plasmodium vivax in the Republic of Korea.*R PROJ, 2008, R PROJ STAT COMP*WFN, 2008, WFN BOOTSTRYeom JS, 2007, AM J TROP MED HYG, V76, P865Chen ML, 2006, CLIN PHARMACOKINET, V45, P957Yeom JS, 2005, J KOREAN MED SCI, V20, P707Yeom JS, 2005, AM J TROP MED HYG, V73, P604Baird JK, 2004, ANTIMICROB AGENTS CH, V48, P4075, DOI 10.1128/AAC.48.11.4075-4083.2004TATAMI S, 2004, DRUG METAB PHARMACOK, V19, P15Carmichael SJ, 2003, THER DRUG MONIT, V25, P671Park JW, 2003, AM J TROP MED HYG, V69, P159Sachs J, 2002, NATURE, V415, P680, DOI 10.1038/415680aEasterbrook M, 1999, INT OPHTHALMOL CLIN, V39, P49, DOI 10.1097/00004397-199903920-00005Krishna S, 1996, CLIN PHARMACOKINET, V30, P263Galinski MR, 1996, PARASITOL TODAY, V12, P20DUCHARME J, 1995, BRIT J CLIN PHARMACO, V40, P127BLAUER G, 1995, BIOCHEM MOL BIOL INT, V35, P231TETT SE, 1993, J RHEUMATOL, V20, P1874MCLACHLAN AJ, 1993, BRIT J CLIN PHARMACO, V36, P78TERKUILE F, 1993, EXP PARASITOL, V76, P85MURPHY GS, 1993, LANCET, V341, P96SLATER AFG, 1992, NATURE, V355, P167RIECKMANN KH, 1989, LANCET, V2, P1183TITUS EO, 1989, THER DRUG MONIT, V11, P369PAIK YH, 1988, JPN J EXP MED, V58, P55EDWARDS G, 1988, BRIT J CLIN PHARMACO, V25, P477TETT SE, 1987, EUR J CLIN PHARMACOL, V31, P729GUSTAFSSON LL, 1983, CLIN PHARMACOL THER, V34, P383*WHO, 1981, WKLY EPIDEMIOL REC, V56, P145HABERKORN A, 1979, TROPENMED PARASITOL, V30, P308MCCHESNEY EW, 1966, J PHARMACOL EXP THER, V151, P482HANKEY DD, 1953, AM J TROP MED HYG, V2, P958

Angiotensin II type 1 receptor 1166A/C polymorphism in association with blood pressure response to exogenous angiotensin II

BACKGROUND: The angiotensin II type 1 receptor (AT1R) 1166A/C polymorphism is reported to be implicated in cardiovascular diseases. The association between the 1166A/C polymorphism and diastolic blood pressure (DBP) changes in response to exogenous angiotensin II and valsartan was evaluated by pharmacokinetic and pharmacodynamic modeling. METHODS: Thirteen normotensive, healthy adults (six with the 1166A/A polymorphism and seven with 1166A/C) were enrolled in this clinical study. Angiotensin II was infused continuously over a 2-min period at four different rates (from 5 ng/kg/min and increased by 5 ng/kg/min) at 0 (before valsartan dosing), 2, 4, 8, 12, and 24 h after a single oral dose of valsartan (40 mg). BP was measured serially before and at the end of each rate of angiotensin II infusion. Plasma concentration-time profiles of valsartan were established over a 24-h period. We analyzed data using NONMEM and studied the relationship between the AT1R 1166A/C genotypes and BP responses. RESULTS: Plasma valsartan concentrations and DBP data best fitted into a two-compartment linear model and E(max) model (E(max) with baseline for angiotensin II and inhibitory E(max) for valsartan), respectively. The ED50 for angiotensin II in the subjects with 1166A/C [95% confidence interval (CI): 4.30 approximately 14.02 ng/kg/min] was significantly lower than in those with 1166A/A (95% CI: 14.23 approximately 28.77 ng/kg/min), while the E(max) for angiotensin II and EC50 for valsartan was similar in both genotype groups. CONCLUSIONS: These results suggest that exogenous human angiotensin II increases the BP more potently in subjects with 1166A/C than in those with 1166A/A