Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis
Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to descri...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Ferber, Georg [verfasserIn] Darpo, Borje [verfasserIn] Garnett, Christine [verfasserIn] Huang, Dalong [verfasserIn] Marathe, Dhananjay D. [verfasserIn] Sun, Yaning [verfasserIn] Liu, Jiang [verfasserIn] |
|---|
| Format: |
E-Artikel |
|---|---|
| Sprache: |
Englisch |
| Erschienen: |
2020 |
|---|
| Schlagwörter: |
|---|
| Übergeordnetes Werk: |
Enthalten in: Journal of Pharmacokinetics and Biopharmaceutics - Kluwer Academic Publishers-Plenum Publishers, 1973, 48(2020), 2 vom: 28. Okt., Seite 187-202 |
|---|---|
| Übergeordnetes Werk: |
volume:48 ; year:2020 ; number:2 ; day:28 ; month:10 ; pages:187-202 |
| Links: |
|---|
| DOI / URN: |
10.1007/s10928-020-09725-w |
|---|
| Katalog-ID: |
SPR043824773 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | SPR043824773 | ||
| 003 | DE-627 | ||
| 005 | 20230519181718.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 210422s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s10928-020-09725-w |2 doi | |
| 035 | |a (DE-627)SPR043824773 | ||
| 035 | |a (DE-599)SPRs10928-020-09725-w-e | ||
| 035 | |a (SPR)s10928-020-09725-w-e | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Ferber, Georg |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects. | ||
| 650 | 4 | |a QTc |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Exposure–response |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a PK/PD model |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a TQT study |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a PK/PD hysteresis |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a enGRI |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Darpo, Borje |e verfasserin |4 aut | |
| 700 | 1 | |a Garnett, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Dalong |e verfasserin |4 aut | |
| 700 | 1 | |a Marathe, Dhananjay D. |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Yaning |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Jiang |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of Pharmacokinetics and Biopharmaceutics |d Kluwer Academic Publishers-Plenum Publishers, 1973 |g 48(2020), 2 vom: 28. Okt., Seite 187-202 |w (DE-627)SPR014694166 |7 nnns |
| 773 | 1 | 8 | |g volume:48 |g year:2020 |g number:2 |g day:28 |g month:10 |g pages:187-202 |
| 856 | 4 | 0 | |u https://dx.doi.org/10.1007/s10928-020-09725-w |z lizenzpflichtig |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a SYSFLAG_A | ||
| 912 | |a GBV_SPRINGER | ||
| 912 | |a SSG-OLC-PHA | ||
| 912 | |a GBV_ILN_40 | ||
| 951 | |a AR | ||
| 952 | |d 48 |j 2020 |e 2 |b 28 |c 10 |h 187-202 | ||
| author_variant |
g f gf b d bd c g cg d h dh d d m dd ddm y s ys j l jl |
|---|---|
| matchkey_str |
ferbergeorgdarpoborjegarnettchristinehua:2020----:eetoadmatfytrsshnvlaigdustefcuigo |
| hierarchy_sort_str |
2020 |
| publishDate |
2020 |
| allfields |
10.1007/s10928-020-09725-w doi (DE-627)SPR043824773 (DE-599)SPRs10928-020-09725-w-e (SPR)s10928-020-09725-w-e DE-627 ger DE-627 rakwb eng Ferber, Georg verfasserin aut Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects. QTc (dpeaa)DE-He213 Exposure–response (dpeaa)DE-He213 PK/PD model (dpeaa)DE-He213 TQT study (dpeaa)DE-He213 PK/PD hysteresis (dpeaa)DE-He213 enGRI (dpeaa)DE-He213 Darpo, Borje verfasserin aut Garnett, Christine verfasserin aut Huang, Dalong verfasserin aut Marathe, Dhananjay D. verfasserin aut Sun, Yaning verfasserin aut Liu, Jiang verfasserin aut Enthalten in Journal of Pharmacokinetics and Biopharmaceutics Kluwer Academic Publishers-Plenum Publishers, 1973 48(2020), 2 vom: 28. Okt., Seite 187-202 (DE-627)SPR014694166 nnns volume:48 year:2020 number:2 day:28 month:10 pages:187-202 https://dx.doi.org/10.1007/s10928-020-09725-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_40 AR 48 2020 2 28 10 187-202 |
| spelling |
10.1007/s10928-020-09725-w doi (DE-627)SPR043824773 (DE-599)SPRs10928-020-09725-w-e (SPR)s10928-020-09725-w-e DE-627 ger DE-627 rakwb eng Ferber, Georg verfasserin aut Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects. QTc (dpeaa)DE-He213 Exposure–response (dpeaa)DE-He213 PK/PD model (dpeaa)DE-He213 TQT study (dpeaa)DE-He213 PK/PD hysteresis (dpeaa)DE-He213 enGRI (dpeaa)DE-He213 Darpo, Borje verfasserin aut Garnett, Christine verfasserin aut Huang, Dalong verfasserin aut Marathe, Dhananjay D. verfasserin aut Sun, Yaning verfasserin aut Liu, Jiang verfasserin aut Enthalten in Journal of Pharmacokinetics and Biopharmaceutics Kluwer Academic Publishers-Plenum Publishers, 1973 48(2020), 2 vom: 28. Okt., Seite 187-202 (DE-627)SPR014694166 nnns volume:48 year:2020 number:2 day:28 month:10 pages:187-202 https://dx.doi.org/10.1007/s10928-020-09725-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_40 AR 48 2020 2 28 10 187-202 |
| allfields_unstemmed |
10.1007/s10928-020-09725-w doi (DE-627)SPR043824773 (DE-599)SPRs10928-020-09725-w-e (SPR)s10928-020-09725-w-e DE-627 ger DE-627 rakwb eng Ferber, Georg verfasserin aut Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects. QTc (dpeaa)DE-He213 Exposure–response (dpeaa)DE-He213 PK/PD model (dpeaa)DE-He213 TQT study (dpeaa)DE-He213 PK/PD hysteresis (dpeaa)DE-He213 enGRI (dpeaa)DE-He213 Darpo, Borje verfasserin aut Garnett, Christine verfasserin aut Huang, Dalong verfasserin aut Marathe, Dhananjay D. verfasserin aut Sun, Yaning verfasserin aut Liu, Jiang verfasserin aut Enthalten in Journal of Pharmacokinetics and Biopharmaceutics Kluwer Academic Publishers-Plenum Publishers, 1973 48(2020), 2 vom: 28. Okt., Seite 187-202 (DE-627)SPR014694166 nnns volume:48 year:2020 number:2 day:28 month:10 pages:187-202 https://dx.doi.org/10.1007/s10928-020-09725-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_40 AR 48 2020 2 28 10 187-202 |
| allfieldsGer |
10.1007/s10928-020-09725-w doi (DE-627)SPR043824773 (DE-599)SPRs10928-020-09725-w-e (SPR)s10928-020-09725-w-e DE-627 ger DE-627 rakwb eng Ferber, Georg verfasserin aut Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects. QTc (dpeaa)DE-He213 Exposure–response (dpeaa)DE-He213 PK/PD model (dpeaa)DE-He213 TQT study (dpeaa)DE-He213 PK/PD hysteresis (dpeaa)DE-He213 enGRI (dpeaa)DE-He213 Darpo, Borje verfasserin aut Garnett, Christine verfasserin aut Huang, Dalong verfasserin aut Marathe, Dhananjay D. verfasserin aut Sun, Yaning verfasserin aut Liu, Jiang verfasserin aut Enthalten in Journal of Pharmacokinetics and Biopharmaceutics Kluwer Academic Publishers-Plenum Publishers, 1973 48(2020), 2 vom: 28. Okt., Seite 187-202 (DE-627)SPR014694166 nnns volume:48 year:2020 number:2 day:28 month:10 pages:187-202 https://dx.doi.org/10.1007/s10928-020-09725-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_40 AR 48 2020 2 28 10 187-202 |
| allfieldsSound |
10.1007/s10928-020-09725-w doi (DE-627)SPR043824773 (DE-599)SPRs10928-020-09725-w-e (SPR)s10928-020-09725-w-e DE-627 ger DE-627 rakwb eng Ferber, Georg verfasserin aut Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects. QTc (dpeaa)DE-He213 Exposure–response (dpeaa)DE-He213 PK/PD model (dpeaa)DE-He213 TQT study (dpeaa)DE-He213 PK/PD hysteresis (dpeaa)DE-He213 enGRI (dpeaa)DE-He213 Darpo, Borje verfasserin aut Garnett, Christine verfasserin aut Huang, Dalong verfasserin aut Marathe, Dhananjay D. verfasserin aut Sun, Yaning verfasserin aut Liu, Jiang verfasserin aut Enthalten in Journal of Pharmacokinetics and Biopharmaceutics Kluwer Academic Publishers-Plenum Publishers, 1973 48(2020), 2 vom: 28. Okt., Seite 187-202 (DE-627)SPR014694166 nnns volume:48 year:2020 number:2 day:28 month:10 pages:187-202 https://dx.doi.org/10.1007/s10928-020-09725-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_40 AR 48 2020 2 28 10 187-202 |
| language |
English |
| source |
Enthalten in Journal of Pharmacokinetics and Biopharmaceutics 48(2020), 2 vom: 28. Okt., Seite 187-202 volume:48 year:2020 number:2 day:28 month:10 pages:187-202 |
| sourceStr |
Enthalten in Journal of Pharmacokinetics and Biopharmaceutics 48(2020), 2 vom: 28. Okt., Seite 187-202 volume:48 year:2020 number:2 day:28 month:10 pages:187-202 |
| format_phy_str_mv |
Article |
| institution |
findex.gbv.de |
| topic_facet |
QTc Exposure–response PK/PD model TQT study PK/PD hysteresis enGRI |
| isfreeaccess_bool |
false |
| container_title |
Journal of Pharmacokinetics and Biopharmaceutics |
| authorswithroles_txt_mv |
Ferber, Georg @@aut@@ Darpo, Borje @@aut@@ Garnett, Christine @@aut@@ Huang, Dalong @@aut@@ Marathe, Dhananjay D. @@aut@@ Sun, Yaning @@aut@@ Liu, Jiang @@aut@@ |
| publishDateDaySort_date |
2020-10-28T00:00:00Z |
| hierarchy_top_id |
SPR014694166 |
| id |
SPR043824773 |
| language_de |
englisch |
| fullrecord |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR043824773</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519181718.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">210422s2020 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s10928-020-09725-w</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR043824773</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)SPRs10928-020-09725-w-e</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s10928-020-09725-w-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Ferber, Georg</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">QTc</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Exposure–response</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">PK/PD model</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">TQT study</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">PK/PD hysteresis</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">enGRI</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Darpo, Borje</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Garnett, Christine</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Huang, Dalong</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Marathe, Dhananjay D.</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Sun, Yaning</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Liu, Jiang</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Journal of Pharmacokinetics and Biopharmaceutics</subfield><subfield code="d">Kluwer Academic Publishers-Plenum Publishers, 1973</subfield><subfield code="g">48(2020), 2 vom: 28. Okt., Seite 187-202</subfield><subfield code="w">(DE-627)SPR014694166</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:48</subfield><subfield code="g">year:2020</subfield><subfield code="g">number:2</subfield><subfield code="g">day:28</subfield><subfield code="g">month:10</subfield><subfield code="g">pages:187-202</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://dx.doi.org/10.1007/s10928-020-09725-w</subfield><subfield code="z">lizenzpflichtig</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_SPRINGER</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">48</subfield><subfield code="j">2020</subfield><subfield code="e">2</subfield><subfield code="b">28</subfield><subfield code="c">10</subfield><subfield code="h">187-202</subfield></datafield></record></collection>
|
| author |
Ferber, Georg |
| spellingShingle |
Ferber, Georg misc QTc misc Exposure–response misc PK/PD model misc TQT study misc PK/PD hysteresis misc enGRI Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis |
| authorStr |
Ferber, Georg |
| ppnlink_with_tag_str_mv |
@@773@@(DE-627)SPR014694166 |
| format |
electronic Article |
| delete_txt_mv |
keep |
| author_role |
aut aut aut aut aut aut aut |
| collection |
springer |
| remote_str |
true |
| illustrated |
Not Illustrated |
| topic_title |
Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis QTc (dpeaa)DE-He213 Exposure–response (dpeaa)DE-He213 PK/PD model (dpeaa)DE-He213 TQT study (dpeaa)DE-He213 PK/PD hysteresis (dpeaa)DE-He213 enGRI (dpeaa)DE-He213 |
| topic |
misc QTc misc Exposure–response misc PK/PD model misc TQT study misc PK/PD hysteresis misc enGRI |
| topic_unstemmed |
misc QTc misc Exposure–response misc PK/PD model misc TQT study misc PK/PD hysteresis misc enGRI |
| topic_browse |
misc QTc misc Exposure–response misc PK/PD model misc TQT study misc PK/PD hysteresis misc enGRI |
| format_facet |
Elektronische Aufsätze Aufsätze Elektronische Ressource |
| format_main_str_mv |
Text Zeitschrift/Artikel |
| carriertype_str_mv |
cr |
| hierarchy_parent_title |
Journal of Pharmacokinetics and Biopharmaceutics |
| hierarchy_parent_id |
SPR014694166 |
| hierarchy_top_title |
Journal of Pharmacokinetics and Biopharmaceutics |
| isfreeaccess_txt |
false |
| familylinks_str_mv |
(DE-627)SPR014694166 |
| title |
Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis |
| ctrlnum |
(DE-627)SPR043824773 (DE-599)SPRs10928-020-09725-w-e (SPR)s10928-020-09725-w-e |
| title_full |
Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis |
| author_sort |
Ferber, Georg |
| journal |
Journal of Pharmacokinetics and Biopharmaceutics |
| journalStr |
Journal of Pharmacokinetics and Biopharmaceutics |
| lang_code |
eng |
| isOA_bool |
false |
| recordtype |
marc |
| publishDateSort |
2020 |
| contenttype_str_mv |
txt |
| container_start_page |
187 |
| author_browse |
Ferber, Georg Darpo, Borje Garnett, Christine Huang, Dalong Marathe, Dhananjay D. Sun, Yaning Liu, Jiang |
| container_volume |
48 |
| format_se |
Elektronische Aufsätze |
| author-letter |
Ferber, Georg |
| doi_str_mv |
10.1007/s10928-020-09725-w |
| author2-role |
verfasserin |
| title_sort |
detection and impact of hysteresis when evaluating a drug’s qtc effect using concentration-qtc analysis |
| title_auth |
Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis |
| abstract |
Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects. |
| abstractGer |
Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects. |
| abstract_unstemmed |
Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects. |
| collection_details |
GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_40 |
| container_issue |
2 |
| title_short |
Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis |
| url |
https://dx.doi.org/10.1007/s10928-020-09725-w |
| remote_bool |
true |
| author2 |
Darpo, Borje Garnett, Christine Huang, Dalong Marathe, Dhananjay D. Sun, Yaning Liu, Jiang |
| author2Str |
Darpo, Borje Garnett, Christine Huang, Dalong Marathe, Dhananjay D. Sun, Yaning Liu, Jiang |
| ppnlink |
SPR014694166 |
| mediatype_str_mv |
c |
| isOA_txt |
false |
| hochschulschrift_bool |
false |
| doi_str |
10.1007/s10928-020-09725-w |
| up_date |
2024-07-03T21:09:11.803Z |
| _version_ |
1803593661079879680 |
| fullrecord_marcxml |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR043824773</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519181718.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">210422s2020 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1007/s10928-020-09725-w</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR043824773</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)SPRs10928-020-09725-w-e</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s10928-020-09725-w-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Ferber, Georg</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term “hysteresis” has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25–4 h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">QTc</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Exposure–response</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">PK/PD model</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">TQT study</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">PK/PD hysteresis</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">enGRI</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Darpo, Borje</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Garnett, Christine</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Huang, Dalong</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Marathe, Dhananjay D.</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Sun, Yaning</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Liu, Jiang</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Journal of Pharmacokinetics and Biopharmaceutics</subfield><subfield code="d">Kluwer Academic Publishers-Plenum Publishers, 1973</subfield><subfield code="g">48(2020), 2 vom: 28. Okt., Seite 187-202</subfield><subfield code="w">(DE-627)SPR014694166</subfield><subfield code="7">nnns</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:48</subfield><subfield code="g">year:2020</subfield><subfield code="g">number:2</subfield><subfield code="g">day:28</subfield><subfield code="g">month:10</subfield><subfield code="g">pages:187-202</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://dx.doi.org/10.1007/s10928-020-09725-w</subfield><subfield code="z">lizenzpflichtig</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_A</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_SPRINGER</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ILN_40</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">48</subfield><subfield code="j">2020</subfield><subfield code="e">2</subfield><subfield code="b">28</subfield><subfield code="c">10</subfield><subfield code="h">187-202</subfield></datafield></record></collection>
|
| score |
7.399832 |