Foreword Special Focus Issue: Special Populations
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Special bioanalysis for special populations? “It is important that the bioanalytical scientist is fully aware of the source of samples...” Keywords: elderly • food effect • hepatic clearance • micro sampling • pediatrics • renal clearance • selectivity • specificity • stability
’A rat is a rat’ is what some people within the bioanalytical community tend to say when confronted with a question whether calibration standards made in, for example, Wistar rat plasma can appropriately be used for Sprague–Dawley rat plasma samples. In day-to-day practice they are probably right as, within the accuracy and precision boundaries of ±15%, only a substantial influence of the matrix of another race would be considered important and such strong effects are usually not seen. On the other hand, anybody who has been long enough in this business has heard of, or encountered, cases in which a method suddenly behaved unforeseen when applied to a somewhat different matrix. Regulators have recognized this and described a number of situations in which a (partial) validation or some specific tests are considered relevant: change of anticoagulant and matrix effect of hyperlipidemic or hemolytic plasma or from the relevant diseased population [1–4] . Ingelse and co-authors summarize the results from the European Bioanalysis Forum on the definition of hemolytic and hyperlipidemic plasma samples, the validation of the respective bioanalytical methods for these matrices and their application to hemolytic and hyperlipidemic study samples [5] . ’All men are created equal’ is the wellknown phrase first used by Thomas Jefferson in the US Declaration of Independence. Unfortunately the biological reality is a bit different and humans participating in clinical trials are not all the same: they can be healthy, diseased, young, old, Caucasian,
10.4155/BIO.14.285 © 2014 Future Science Ltd
Asian, etc. The question a bioanalyst thus needs to address is: should samples from specific population be treated in a specific manner? Let us elaborate a bit on special populations and identify a number of aspects that are potentially relevant for the bioanalytical scientist. Elderly population With increasing age, the functioning of the kidney decreases and thus the systemic concentration of (renally cleared) drugs and metabolites increases. The same can be said about the functioning of the liver and hepatic clearance of the drug of interest may decrease with age. Both effects can thus lead to not only higher drug and metabolite plasma concentrations, but also to different drug to metabolite(s) ratios. Another aspect is that elderly have an increased percentage body fat relative to skeletal muscle compared with young adults. Depending on whether or not body fat acts as a depot for the drug and its metabolites, the volume of distribution changes and thus effects on plasma concentrations and drug-to-metabolite ratios may be observed. Increased drug concentrations and metabolite levels in elderly compared with young adults could potentially be that strong that a calibration range and QC levels need to be adapted and possibly also that even stability and specificity may need to be re-evaluated. The latter may anyway be wise to be monitored given the not uncommon multi-drug use among elderly. Although sampling is often not of concern for the bioanalyst,
Bioanalysis (2014) 6(23), 3069–3071
Peter van Amsterdam Author for correspondence: Department of Clinical Pharmacology & Bioanalytics, Abbott Healthcare Products, CJ van Houtenlaan 36, Weesp, The Netherlands Tel.: +31 294 477691 [email protected]
Margarete Brudny-Kloeppel Department of Bioanalytics & Nonclinical Pharmacokinetics, Bayer Pharma AG, Müllerstr. 170-178, 13342 Berlin, Germany
part of
ISSN 1757-6180
3069
Foreword van Amsterdam & Brudny-Kloeppel there are challenges like limited saliva volume and fragile skin and veins which may impact the quality and consistency of the samples entering the laboratory. As Lakshmy and co-workers nicely evaluated that dried blood spot (DBS) collected through finger pricking offers several advantages over the traditional collection method using venipuncture in elderly patients [6] . The DBS collection circumvents the need for a trained phlebotomist, is easy and less invasive for patients that require frequent monitoring. Their review presents a brief general overview of DBS, its advantages and disadvantages and potential use in disease diagnosis in elderly. Diseased population What immediately come to mind are the studies conducted on renal and hepatic impaired patients. The same type of considerations as described above for the elderly population with a decreased kidney or liver function are to be made. Another important aspect is that the composition in endogenous compounds in the sample matrix can be different in a certain diseased population compared with healthy humans. Extra attention to matrix effects, especially in ligand-binding assays, should thus be paid. Pediatric population The immune system is not fully developed yet in very young children and also the concentrations of a number of endogenous compounds are different in children than in adults. Matrix effects and specificity may thus deserve additional attention when samples from this population are to be run in methods developed and validated for the adult population. The sampling challenges, volume and collection procedure, with babies and very young children may result in the need to set up an adapted method to run these nonstandard samples. For example, blood collection via finger or heel pricking into capillary tubes may be an alternative sample collection method for pediatric patients with a caveat of very low sample volume. Kjellin et al. have reported an LC–MS/MS-based assay for the determination of piperaquine and its application to plasma samples collected into capillary tubes from young children enrolled in a clinical trial based in Uganda [7] . Pregnant women Mother’s and and child’s blood circulation are connected via the umbilical cord and the placenta. Prenatal exposure to alcohol, tobacco and drugs of abuse has been associated with deleterious short- and longterm effects in exposed children. Drugs in mother’s blood reach the fetus at an increased concentration
3070
Bioanalysis (2014) 6(23)
due to the smaller volume of distribution. The deleterious effects of some drugs result in fetal growth disruption, or may cause direct teratogenic effect in fetus organs. Concheiro-Guisan et al. have reviewed the literature from 2007 to 2014 on bioanalytical methods for determination of in utero drug exposure with a special focus on the analysis of meconium, placenta, umbilical cord and newborn hair, the possible correlations between the analytical findings and the clinical outcomes [8] . Ethnic groups Polymorphic drug transporters or metabolizing enzymes often show a different efficacy for the various haplotypes and the relative occurrence of haplotypes can differ from race to race. The effect on drug metabolites concentrations can be negligible, an increase or a decrease. Consequently, the same considerations should be made as described above for the elderly population. But also environmental aspects like diet cannot be ruled out a priori, for example, the pH urine is low for people on a mainly protein diet and high for vegetarians and veganists. Obviously this may have an impact on sample stabilization or acceptable storage periods for labile drugs and metabolites. Kale et al. could demonstrate a difference in matrix characteristics of samples from Canadian and Indian population in an LC–MS/MS assay for the determination of atorvastatin and its two metabolites [9] , while Lachance et al. showed that the impact on the quantitation of the analyte of interest of the alimentary customs, provenance of the study samples or type of study should be carefully investigated during bioanalytical method development and validation [10] . In conclusion, we can say that samples from special populations may, case by case, differ in drug and metabolite concentrations, levels of endogenous compounds, matrix effects and even may show a different stability. It is thus important that the bioanalytical scientist is fully aware of the source of the samples so that the potential impact of a special population on the assay can be evaluated and proper actions taken if deemed necessary. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
future science group
Special bioanalysis for special populations?
References 1
ANVISA. Resolution- RDC Nº 27, requirements for the validation of bioanalytical methods. http://bvsms.saude.gov.br
2
EMA. Guideline on the validation of bioanalytical methods www.ema.europa.eu
3
MHLW. Guideline on bioanalytical method validation in pharmaceutical development www.nihs.go.jp
4
MHLW. Guideline on bioanalytical method (ligand binding assay) validation in pharmaceutical development www.nihs.go.jp
5
Ingelse B, Barroso B, Gray N et al. European Bioanalysis Forum: recommendation on dealing with haemolysed and hyperlipidemic matrices. Bioanalysis 6(23), 3113–3120 (2014).
6
Lakshmy R, Tarik M, Abraham RA. Role of dried blood spots (DBS) in health and disease diagnosis in older adults. Bioanalysis 6(23), 3121–3131 (2014).
future science group
7
Kjellin LL, Dorsey G, Rosenthal PJ, Aweeka F, Huang L. Determination of the antimalarial drug piperaquine in small volume pediatric plasma samples by LC–MS/MS. Bioanalysis 6(23), 3081–3089 (2014).
8
Concheiro-Guisan A and Concheiro M. Bioanalysis during pregnancy: recent advances and novel sampling strategies. Bioanalysis 6(23), 3133–3153 (2014).
9
Kale P, Shukla M, Soni G, Patel R, Gupta S. Challenges encountered in the application of bioanalytical method on different populations and the effect of population on PK. Bioanalysis 6(23), 3091–3100 (2014).
10
Lachance S, Lévesque A. The importance to choose the appropriate matrix to validate a bioanalytical method according to the study needs. Bioanalysis 6(23), 3101–3111 (2014).
www.future-science.com
Foreword
3071
For reprint orders, please contact [email protected]
Special bioanalysis for special populations? “It is important that the bioanalytical scientist is fully aware of the source of samples...” Keywords: elderly • food effect • hepatic clearance • micro sampling • pediatrics • renal clearance • selectivity • specificity • stability
’A rat is a rat’ is what some people within the bioanalytical community tend to say when confronted with a question whether calibration standards made in, for example, Wistar rat plasma can appropriately be used for Sprague–Dawley rat plasma samples. In day-to-day practice they are probably right as, within the accuracy and precision boundaries of ±15%, only a substantial influence of the matrix of another race would be considered important and such strong effects are usually not seen. On the other hand, anybody who has been long enough in this business has heard of, or encountered, cases in which a method suddenly behaved unforeseen when applied to a somewhat different matrix. Regulators have recognized this and described a number of situations in which a (partial) validation or some specific tests are considered relevant: change of anticoagulant and matrix effect of hyperlipidemic or hemolytic plasma or from the relevant diseased population [1–4] . Ingelse and co-authors summarize the results from the European Bioanalysis Forum on the definition of hemolytic and hyperlipidemic plasma samples, the validation of the respective bioanalytical methods for these matrices and their application to hemolytic and hyperlipidemic study samples [5] . ’All men are created equal’ is the wellknown phrase first used by Thomas Jefferson in the US Declaration of Independence. Unfortunately the biological reality is a bit different and humans participating in clinical trials are not all the same: they can be healthy, diseased, young, old, Caucasian,
10.4155/BIO.14.285 © 2014 Future Science Ltd
Asian, etc. The question a bioanalyst thus needs to address is: should samples from specific population be treated in a specific manner? Let us elaborate a bit on special populations and identify a number of aspects that are potentially relevant for the bioanalytical scientist. Elderly population With increasing age, the functioning of the kidney decreases and thus the systemic concentration of (renally cleared) drugs and metabolites increases. The same can be said about the functioning of the liver and hepatic clearance of the drug of interest may decrease with age. Both effects can thus lead to not only higher drug and metabolite plasma concentrations, but also to different drug to metabolite(s) ratios. Another aspect is that elderly have an increased percentage body fat relative to skeletal muscle compared with young adults. Depending on whether or not body fat acts as a depot for the drug and its metabolites, the volume of distribution changes and thus effects on plasma concentrations and drug-to-metabolite ratios may be observed. Increased drug concentrations and metabolite levels in elderly compared with young adults could potentially be that strong that a calibration range and QC levels need to be adapted and possibly also that even stability and specificity may need to be re-evaluated. The latter may anyway be wise to be monitored given the not uncommon multi-drug use among elderly. Although sampling is often not of concern for the bioanalyst,
Bioanalysis (2014) 6(23), 3069–3071
Peter van Amsterdam Author for correspondence: Department of Clinical Pharmacology & Bioanalytics, Abbott Healthcare Products, CJ van Houtenlaan 36, Weesp, The Netherlands Tel.: +31 294 477691 [email protected]
Margarete Brudny-Kloeppel Department of Bioanalytics & Nonclinical Pharmacokinetics, Bayer Pharma AG, Müllerstr. 170-178, 13342 Berlin, Germany
part of
ISSN 1757-6180
3069
Foreword van Amsterdam & Brudny-Kloeppel there are challenges like limited saliva volume and fragile skin and veins which may impact the quality and consistency of the samples entering the laboratory. As Lakshmy and co-workers nicely evaluated that dried blood spot (DBS) collected through finger pricking offers several advantages over the traditional collection method using venipuncture in elderly patients [6] . The DBS collection circumvents the need for a trained phlebotomist, is easy and less invasive for patients that require frequent monitoring. Their review presents a brief general overview of DBS, its advantages and disadvantages and potential use in disease diagnosis in elderly. Diseased population What immediately come to mind are the studies conducted on renal and hepatic impaired patients. The same type of considerations as described above for the elderly population with a decreased kidney or liver function are to be made. Another important aspect is that the composition in endogenous compounds in the sample matrix can be different in a certain diseased population compared with healthy humans. Extra attention to matrix effects, especially in ligand-binding assays, should thus be paid. Pediatric population The immune system is not fully developed yet in very young children and also the concentrations of a number of endogenous compounds are different in children than in adults. Matrix effects and specificity may thus deserve additional attention when samples from this population are to be run in methods developed and validated for the adult population. The sampling challenges, volume and collection procedure, with babies and very young children may result in the need to set up an adapted method to run these nonstandard samples. For example, blood collection via finger or heel pricking into capillary tubes may be an alternative sample collection method for pediatric patients with a caveat of very low sample volume. Kjellin et al. have reported an LC–MS/MS-based assay for the determination of piperaquine and its application to plasma samples collected into capillary tubes from young children enrolled in a clinical trial based in Uganda [7] . Pregnant women Mother’s and and child’s blood circulation are connected via the umbilical cord and the placenta. Prenatal exposure to alcohol, tobacco and drugs of abuse has been associated with deleterious short- and longterm effects in exposed children. Drugs in mother’s blood reach the fetus at an increased concentration
3070
Bioanalysis (2014) 6(23)
due to the smaller volume of distribution. The deleterious effects of some drugs result in fetal growth disruption, or may cause direct teratogenic effect in fetus organs. Concheiro-Guisan et al. have reviewed the literature from 2007 to 2014 on bioanalytical methods for determination of in utero drug exposure with a special focus on the analysis of meconium, placenta, umbilical cord and newborn hair, the possible correlations between the analytical findings and the clinical outcomes [8] . Ethnic groups Polymorphic drug transporters or metabolizing enzymes often show a different efficacy for the various haplotypes and the relative occurrence of haplotypes can differ from race to race. The effect on drug metabolites concentrations can be negligible, an increase or a decrease. Consequently, the same considerations should be made as described above for the elderly population. But also environmental aspects like diet cannot be ruled out a priori, for example, the pH urine is low for people on a mainly protein diet and high for vegetarians and veganists. Obviously this may have an impact on sample stabilization or acceptable storage periods for labile drugs and metabolites. Kale et al. could demonstrate a difference in matrix characteristics of samples from Canadian and Indian population in an LC–MS/MS assay for the determination of atorvastatin and its two metabolites [9] , while Lachance et al. showed that the impact on the quantitation of the analyte of interest of the alimentary customs, provenance of the study samples or type of study should be carefully investigated during bioanalytical method development and validation [10] . In conclusion, we can say that samples from special populations may, case by case, differ in drug and metabolite concentrations, levels of endogenous compounds, matrix effects and even may show a different stability. It is thus important that the bioanalytical scientist is fully aware of the source of the samples so that the potential impact of a special population on the assay can be evaluated and proper actions taken if deemed necessary. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
future science group
Special bioanalysis for special populations?
References 1
ANVISA. Resolution- RDC Nº 27, requirements for the validation of bioanalytical methods. http://bvsms.saude.gov.br
2
EMA. Guideline on the validation of bioanalytical methods www.ema.europa.eu
3
MHLW. Guideline on bioanalytical method validation in pharmaceutical development www.nihs.go.jp
4
MHLW. Guideline on bioanalytical method (ligand binding assay) validation in pharmaceutical development www.nihs.go.jp
5
Ingelse B, Barroso B, Gray N et al. European Bioanalysis Forum: recommendation on dealing with haemolysed and hyperlipidemic matrices. Bioanalysis 6(23), 3113–3120 (2014).
6
Lakshmy R, Tarik M, Abraham RA. Role of dried blood spots (DBS) in health and disease diagnosis in older adults. Bioanalysis 6(23), 3121–3131 (2014).
future science group
7
Kjellin LL, Dorsey G, Rosenthal PJ, Aweeka F, Huang L. Determination of the antimalarial drug piperaquine in small volume pediatric plasma samples by LC–MS/MS. Bioanalysis 6(23), 3081–3089 (2014).
8
Concheiro-Guisan A and Concheiro M. Bioanalysis during pregnancy: recent advances and novel sampling strategies. Bioanalysis 6(23), 3133–3153 (2014).
9
Kale P, Shukla M, Soni G, Patel R, Gupta S. Challenges encountered in the application of bioanalytical method on different populations and the effect of population on PK. Bioanalysis 6(23), 3091–3100 (2014).
10
Lachance S, Lévesque A. The importance to choose the appropriate matrix to validate a bioanalytical method according to the study needs. Bioanalysis 6(23), 3101–3111 (2014).
www.future-science.com
Foreword
3071
