AAPS PharmSci最新文献

{"title":"Comparison of stepwise covariate model building strategies in population pharmacokinetic-pharmacodynamic analysis.","authors":"Ulrika Wählby,&nbsp;E Niclas Jonsson,&nbsp;Mats O Karlsson","doi":"10.1208/ps040427","DOIUrl":"https://doi.org/10.1208/ps040427","url":null,"abstract":"<p><p>The aim of this study was to compare 2 stepwise covariate model-building strategies, frequently used in the analysis of pharmacokinetic-pharmacodynamic (PK-PD) data using nonlinear mixed-effects models, with respect to included covariates and predictive performance. In addition, the effects of stepwise regression on the estimated covariate coefficients were assessed. Using simulated and real PK data, covariate models were built applying (1) stepwise generalized additive models (GAM) for identifying potential covariates, followed by backward elimination in the computer program NONMEM, and (2) stepwise forward inclusion and backward elimination in NONMEM. Different versions of these procedures were tried (eg, treating different study occasions as separate individuals in the GAM, or fixing a part of the parameters when the NONMEM procedure was used). The final covariate models were compared, including their ability to predict a separate data set or their performance in cross-validation. The bias in the estimated coefficients (selection bias) was assessed. The model-building procedures performed similarly in the data sets explored. No major differences in the resulting covariate models were seen, and the predictive performances overlapped. Therefore, the choice of model-building procedure in these examples could be based on other aspects such as analyst- and computer-time efficiency. There was a tendency to selection bias in the estimates, although this was small relative to the overall variability in the estimates. The predictive performances of the stepwise models were also reasonably good. Thus, selection bias seems to be a minor problem in this typical PK covariate analysis.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E27"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040427","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22298255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interspecies considerations in the evaluation of human food safety for veterinary drugs.","authors":"Arthur L Craigmill,&nbsp;Kristy A Cortright","doi":"10.1208/ps040434","DOIUrl":"https://doi.org/10.1208/ps040434","url":null,"abstract":"<p><p>Residues are composed of the parent drug and metabolites, and therefore interspecies comparisons must involve a consideration of comparative xenobiotic metabolism. The focus of this article will be the residue studies that are required to establish human food safety, and the interspecies pharmacokinetic differences and similarities that impact drug residues in animal- derived foods. To illustrate the factors that can complicate and assist these comparisons, 2 drugs will be examined in detail: ivermectin and fenbendazole. In addition, the activities of 2 US programs, the Food Animal Residue Avoidance Databank (FARAD) and the NRSP-7 (National Research Support Project Number 7) Minor Use Animal Drug Program will be presented, along with strategies that may be employed in the study of species differences.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E34"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040434","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22296914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of antimicrobial resistance on regulatory policies in veterinary medicine: status report.","authors":"Linda Tollefson,&nbsp;William T Flynn","doi":"10.1208/ps040437","DOIUrl":"https://doi.org/10.1208/ps040437","url":null,"abstract":"<p><p>Increasing resistance to antimicrobial agents is of growing concern to public health officials worldwide. The concern includes infections acquired in hospitals, community infections acquired in outpatient care settings, and resistant foodborne disease associated with drug use in food-producing animals. In the United States, a significant source of antimicrobial-resistant foodborne infections in humans is the acquisition of resistant bacteria originating from animals. The US Food and Drug Administration's (FDA's) goal in resolving the public health impact arising from the use of antimicrobial drugs in food-producing animals is to ensure that significant human antimicrobial therapies are not compromised or lost while providing for the safe use of antimicrobials in food animals. The FDA's approach to the problem is multipronged and innovative. The strategy includes revision of the pre-approval safety assessment for new animal drug applications, use of risk assessment to determine the human health effect resulting from the use of antimicrobials in food animals, robust monitoring for changes in susceptibilities among foodborne pathogens to drugs that are important both in human and veterinary medicine, research, and risk management.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E37"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040437","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22296917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chitosan and sodium alginate-based bioadhesive vaginal tablets.","authors":"Amal El-Kamel,&nbsp;Magda Sokar,&nbsp;Viviane Naggar,&nbsp;Safaa Al Gamal","doi":"10.1208/ps040444","DOIUrl":"https://doi.org/10.1208/ps040444","url":null,"abstract":"<p><p>Metronidazole was formulated in mucoadhesive vaginal tablets by directly compressing the natural cationic polymer chitosan, loosely cross-linked with glutaraldehyde, together with sodium alginate with or without microcrystalline cellulose (MCC). Sodium carboxymethylcellulose (CMC) was added to some of the formulations. The drug content in tablets was 20%. Drug dissolution rate studies from tablets were carried out in buffer pH 4.8 and distilled water. Swelling indices and adhesion forces were also measured for all formulations. The formula (FIII) containing 6% chitosan, 24% sodium alginate, 30% sodium CMC, and 20% MCC showed adequate release properties in both media and gave lower values of swelling index compared with the other examined formulations. FIII also proved to have good adhesion properties with minimum applied weights. Moreover, its release properties (% dissolution efficiency, DE) in buffer pH 4.8, as well as release mechanism (n values), were negligibly affected by aging. Thus, this formula may be considered a good candidate for vaginal mucoadhesive dosage forms.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E44"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040444","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22298111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The prediction of plasma and brain levels of 2,3,5,6-tetramethylpyrazine following transdermal application.","authors":"Xiaohong Qi,&nbsp;Chrisita Ackermann,&nbsp;Duxin Sun,&nbsp;Rong Liu,&nbsp;Minli Sheng,&nbsp;Huimin Hou","doi":"10.1208/ps040446","DOIUrl":"https://doi.org/10.1208/ps040446","url":null,"abstract":"<p><p>The purpose of this study was to construct a pharmacokinetic (PK) model and to determine PK parameters of 2,3,5,6-tetramethylpyrazine (TMP) after application of TMP transdermal delivery system. Data were obtained in Sprague-Dawley (SD) rats following a single dose of TMP transdermal delivery system. Blood samples were obtained at 0, 0.25, 0.5, 1, 2, 4, 6, 16, and 24 hours after the transdermal application. In the brain level study, 18 SD rats were divided into 6 groups. Three SD rats before and after transdermal application were culled and sacrificed at each of the following time intervals: 2, 4, 6, 16, and 24 hours after the TMP-TTS application. TMP concentrations in plasma and brain tissues were determined using high performance liquid chromatography and data were fitted using a zero-order absorption and a first-order-elimination 3-compartment PK model. Fitted parameters included 2 volumes of distribution (V1, V2) and 2 elimination rate constants (k10, k20). The elimination half-life for TMP in plasma and brain was 26.5 and 31.2 minutes, respectively. The proposed PK model fit observed concentrations of TMP very well. This model is useful for predicting drug concentrations in plasma and brain and for assisting in the development of transdermal systems.</p>","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"4 4","pages":"E46"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1208/ps040446","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22298113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delivery of antibiotics to the eye using a positively charged polysaccharide as vehicle","authors":"O. Felt, R. Gurny, V. Baeyens","doi":"10.1208/ps030434","DOIUrl":"https://doi.org/10.1208/ps030434","url":null,"abstract":"The positively charged polysaccharide chitosan is able to increase precorneal residence time of ophthalmic formulations containing active compounds when compared with simple aqueous solutions. The purpose of the study was to evaluate tear concentration of tobramycin and ofloxacin after topical application of chitosan-based formulations containing 0.3% wt/vol of antibiotic and to compare them with 2 commercial solutions: Tobrex® and Floxal®, respectively. The influence of the molecular weight, deacetylation degree, and concentration of 4 different samples of chitosan on pharmacokinetic parameters (area under the curve values [AUCeff] and time of efficacy [teff]) of tobramycin and ofloxacin in tears was investigated over time. It was demonstrated that the 2 chitosan products of high molecular weight (1350 and 1930 kd) and low deacetylation degree (50%) significantly increased antibiotic availability when compared to the controls, with AUCeff showing a 2-to 3-fold improvement. The time of efficacy of ofloxacin was significantly increased from about 25 minutes to 46 minutes by the chitosan of higher Mw (1930 kd) at a concentration of 0.5% wt/vol, whereas a similar performance was achieved by a chitosan of low Mw (580 kd) at a concentration of 1.5% wt/vol in the case of tobramycin.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"57 1","pages":"87-93"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86738100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single nucleotide polymorphisms of the human M1 muscarinic acetylcholine receptor gene","authors":"Julie L. Lucas, W. Sadee, J. Deyoung","doi":"10.1208/ps030431","DOIUrl":"https://doi.org/10.1208/ps030431","url":null,"abstract":"The gene encoding the human muscarinic receptor, type 1 (CHRM1), was genotyped from 245 samples of the Coriell Collection (Coriell Institute for Medical Research, Camden, NJ). Fifteen single nucleotide polymorphisms (SNPs) were discovered, 9 of which are located in the coding region of the receptor. Of these, 8 represent synonymous SNPs, indicating that CHRM1 is highly conserved in humans. Only a single allele was found to contain a nonsynonymous SNP, which encodes an amino acid change of Cys to Arg at position 417. This may have functional consequences because a C417S point mutation in rat M1 was previously shown to affect receptor binding and coupling. Furthermore, 0 of 4 SNPs within CHRM1 previously deduced from sequencing of the human genome were found in this study despite a prediction that a majority of such inferred SNPs are accurate. The consensus sequence of CHRM1 obtained in our study differs from the deposited reference sequence (AC NM_000738) in 2 adjacent nucleotides, leading to a V173M change, suggesting a sequencing error in the reference sequence. The extraordinary sequence conservation of the CHRM1 gene-coding region was unexpected as M1-knockout mice show only minimal functional impairments.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"38 1","pages":"57-61"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81174834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selected physical and chemical properties of commercial Hypericum perforatum extracts relevant for formulated product quality and performance","authors":"Susan H. Kopleman, L. Augsburger, A. Nguyenpho, W. Zito, F. Muller","doi":"10.1208/ps030426","DOIUrl":"https://doi.org/10.1208/ps030426","url":null,"abstract":"Objective. The complex composition-activity relationship of botanicals such as St John's Wort (SJW) presents a major challenge to product development, manufacture, and establishment of appropriate quality and performance standards for the formulated products. As part of a larger study aimed at addressing that challenge, the goals of the present study are to (1) determine and compare the phytochemical profiles of 3 commercial SJW extracts; (2) assess the possible impact of humidity, temperature, and light on their stability; and (3) evaluate several physical properties important to the development of solid dosage forms for these extracts. Methods. An adapted analytical method was developed and validated to determine phytochemical profiles and assess their stability. The extract physical properties measured were particle size (Malvern Mastersizer), flow (Carr's compressibility index; minimum orifice diameter), hygroscopicity (method of Callahan et al), and low-pressure compression physics (method of Heda et al). Results. The phytochemical properties differed greatly among the extracts and were extremely sensitive to changes in storage conditions, with marked instability under conditions of elevated humidity. All extracts exhibited moderate to free-flow properties and were very hygroscopic. Compression properties varied among the extracts and differed from a common use excipient, microcrystalline cellulose. Conclusions. Three commercial sources of SJW extracts exhibited different physical and chemical properties. Standardization to 1 or 2 marker compounds does not ensure chemical equivalence nor necessarily equivalent pharmacological activity. Flow and compression properties appear suitable for automatic capsule-filling machines, but hydroscopicity and the moisture sensitivity of the phytochemical profile are concerns.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"20 1","pages":"1-18"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79885633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UGT1A1 polymorphism predicts irinotecan toxicity: Evolving proof","authors":"S. Mani","doi":"10.1208/ps0303_commentary2","DOIUrl":"https://doi.org/10.1208/ps0303_commentary2","url":null,"abstract":"The antineoplastic agent, irinotecan (CPT-11) is metabolized by enzymes known to exhibit polymorphic activity. Its active metabolite SN38 is glucuronidated to an inactive product by UDP-glucuronosyltransferase, UGT1A1, the isoform catalyzing bilirubin glucuronidation. Thus, glucuronidation may be an important determinant of net SN-38 concentration in bile (termed SN-38 biliary index). Additional factors that determine SN-38 concentrations relative to its glucuronidated product include the activity of gut beta-glucuronidase, which affects recirculation of SN-38 and direct gut exposure to SN-38. Recent results suggest that inter-patient variability in SN38/SN-38 glucuronide kinetics and possibly irinotecan toxicity results from genetic variations in UGT1A1 expression. For example, genetic defects in UGT1A1 determine Crigler-Najjar and Gilbert's syndromes characterized by unconjugated hyperbilirubinemia. Gilbert's syndrome often remains undiagnosed and occurs in up to 19% of individuals homozygous for the UGT1A1 (TA) allele (TA insertion in the TATAA promoter). Furthermore, since irinotecan toxicity is inversely related to SN-38 glucuronidation rate, individuals with low UGT1A1 expression may experience severe toxicity. In recent studies, decreased SN-38 glucuronidating activity has been observed in livers obtained from individuals carrying the (TA) allele. Ando et al attempted to determine whether UGT1A1 genotype is predictive of irinotecan toxicity, in a retrospective and case-controlled study (note: there was a 3.5:1 control to case ratio). Because of small data sets analyzed and failure to control for variations in treatment patterns and other determinants of toxicity unrelated to UGT1A1, their conclusions are somewhat limited. Despite these limitations, it is clear that certain promoter polymorphisms were associated with severe toxicity. In their analysis of Japanese patients, multivariate analysis suggested that genotypes either heterozygous or homozygous for UGT1A1*28 would be a significant risk factor for severe irinotecan toxicity (P < 0.001; odds ratio, 7.23; 95% confidence interval, 2.52-22.3). Individuals heterozygous for UGT1A1*27 also encountered severe toxicity. One must caution however that the same genotype in another racial group may be less predictive of toxicity as other variant alleles may be more frequently expressed. Nevertheless, variable promoter TA repeats have been demonstrated to alter promoter function and transcriptional activity; this could therefore replace direct phenotyping (glucuronidation activity). However, a detailed human genotype-phenotype analysis with respect to UGT1A1 expression and function is still needed. These studies could lead to strategies for optimizing therapy with antineoplastic agents that inherently have a low therapeutic index. In the future, UGT1A1 genotyping may serve to spare patients from excessive toxicity resulting from therapy with irinotecan.","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"140 1","pages":"3-3"},"PeriodicalIF":0.0,"publicationDate":"2001-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86776535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The MDR1 C3435T polymorphism: Effects on P-glycoprotein expression/function and clinical significance","authors":"M. Dresser","doi":"10.1208/ps0303_commentary3","DOIUrl":"https://doi.org/10.1208/ps0303_commentary3","url":null,"abstract":"C3435T, have been investigated. 1-3 Originally identified in a German Caucasian population by Hoffmeyer et al., C3435T was found to correlate with P-gp expression in the duodenum as determined by Western blots and quantitative immunohistology (P=0.056). 1 Individuals with the CC genotype (n=6) had higher levels of P-gp expression, approximately 2-fold, compared with individuals with the TT genotype (n=5); heterozygotes had intermediate expression levels (n=10). The mechanism by which the T allele results in lower duodenal P-gp expression is unknown, because C3435T is a silent mutation and does not result in changes in the P-gp sequence. However, Hoffmeyer et al. hypothesize that C3435T may be linked to other variants in the MDR1 gene. 1 The MDR1 gene product P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter family. P-gp utilizes the energy derived from ATP hydrolysis to pump a wide range of compounds, including numerous clinically used drugs, out of cells; this activity has important pharmacokinetic and pharmacodynamic consequences. For example, P-gp is expressed within the apical membranes of intestinal, renal, and hepatic epithelial cells, where it affects the absorption and elimination of its substrates. P-gp is also located within the apical membranes of capillary endothelial cells of the brain, where it can limit the penetration of drugs to the CNS. In addition to the roles of P-gp in absorption, distribution, and elimination, the overexpression of P-gp is implicated in the development of the multi-drug resistance (MDR) phenotype of some tumor cells. Consequently, P-gp inhibitors are now being developed as MDR reversal agents. Hoffmeyer et al. only examined the effects of the MDR1 C3435T polymorphism on P-gp expression in the duodenum. However, because the MDR1 gene is expressed in many normal tissues and cell types, it is important to establish whether the mutation alters P-gp expression exclusively in the duodenum, thereby affecting only drug absorption, or whether expression is altered in other tissues as well, leading to changes in distribution, elimination, or both of these processes. Using a rhodamine efflux assay as a measure of P-gp activity, Hitzl et al. examined P-gp activity in CD56+ natural killer cells from healthy subjects with the different genotypes at the 3435 locus. 2 Rhodamine is a P-gp substrate, thus CD56+ cells with higher P-gp activity would be predicted to have lower intracellular rhodamine fluorescence. Hitzl et al. found that CD56+ cells from individuals with the CC genotype (n=10) had lower rhodamine fluorescence (51.1 ± 11.4%) compared with CD56+ cells from individuals with the TT genotype (n=11) (67.5 ± 9.5%), indicating that cells from CC carriers have higher P-gp activity compared with cells isolated from TT carriers. 2 Although this difference was statistically significant, the consequences of a functional difference of this magnitude are debatable. In addition to these functional studi","PeriodicalId":6918,"journal":{"name":"AAPS PharmSci","volume":"9 1","pages":"4-6"},"PeriodicalIF":0.0,"publicationDate":"2001-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76338846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}