Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function

Lot A. Devriese, Petronella O. Witteveen, Marja Mergui-Roelvink, Deborah A. Smith, Lionel D. Lewis, David S. Mendelson, Yung Jue Bang, Hyuncheol Chung, Mohammed M. Dar, Alwin D.R. Huitema, Jos H. Beijnen, Emile E. Voest, Jan H.M. Schellens

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Abstract

Aims The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy. Methods A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CLcr)=50-79 ml min-1], moderate [CLcr=30-49 ml min-1], severe [CLcr <30 ml min-1]). Results Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m-2 day-1, given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m-2 day-1 for patients with moderate renal impairment (suggested dose 1.9 mg m-2 day-1 for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m-2 day-1 in this cohort. Conclusions Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.

Original languageEnglish
Pages (from-to)253-266
Number of pages14
JournalBritish Journal of Clinical Pharmacology
Volume80
Issue number2
DOIs
Publication statusPublished - 2015 Aug 1

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Topotecan
Pharmacokinetics
Kidney
Platinum
Neoplasms
Drug Therapy
Maximum Tolerated Dose
Lactones
Area Under Curve
Creatinine

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Devriese, L. A., Witteveen, P. O., Mergui-Roelvink, M., Smith, D. A., Lewis, L. D., Mendelson, D. S., ... Schellens, J. H. M. (2015). Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function. British Journal of Clinical Pharmacology, 80(2), 253-266. https://doi.org/10.1111/bcp.12606
Devriese, Lot A. ; Witteveen, Petronella O. ; Mergui-Roelvink, Marja ; Smith, Deborah A. ; Lewis, Lionel D. ; Mendelson, David S. ; Bang, Yung Jue ; Chung, Hyuncheol ; Dar, Mohammed M. ; Huitema, Alwin D.R. ; Beijnen, Jos H. ; Voest, Emile E. ; Schellens, Jan H.M. / Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function. In: British Journal of Clinical Pharmacology. 2015 ; Vol. 80, No. 2. pp. 253-266.
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abstract = "Aims The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy. Methods A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CLcr)=50-79 ml min-1], moderate [CLcr=30-49 ml min-1], severe [CLcr <30 ml min-1]). Results Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109{\%} and 174{\%}, respectively, topotecan lactone and 148{\%} and 298{\%}, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m-2 day-1, given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m-2 day-1 for patients with moderate renal impairment (suggested dose 1.9 mg m-2 day-1 for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m-2 day-1 in this cohort. Conclusions Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.",
author = "Devriese, {Lot A.} and Witteveen, {Petronella O.} and Marja Mergui-Roelvink and Smith, {Deborah A.} and Lewis, {Lionel D.} and Mendelson, {David S.} and Bang, {Yung Jue} and Hyuncheol Chung and Dar, {Mohammed M.} and Huitema, {Alwin D.R.} and Beijnen, {Jos H.} and Voest, {Emile E.} and Schellens, {Jan H.M.}",
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Devriese, LA, Witteveen, PO, Mergui-Roelvink, M, Smith, DA, Lewis, LD, Mendelson, DS, Bang, YJ, Chung, H, Dar, MM, Huitema, ADR, Beijnen, JH, Voest, EE & Schellens, JHM 2015, 'Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function', British Journal of Clinical Pharmacology, vol. 80, no. 2, pp. 253-266. https://doi.org/10.1111/bcp.12606

Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function. / Devriese, Lot A.; Witteveen, Petronella O.; Mergui-Roelvink, Marja; Smith, Deborah A.; Lewis, Lionel D.; Mendelson, David S.; Bang, Yung Jue; Chung, Hyuncheol; Dar, Mohammed M.; Huitema, Alwin D.R.; Beijnen, Jos H.; Voest, Emile E.; Schellens, Jan H.M.

In: British Journal of Clinical Pharmacology, Vol. 80, No. 2, 01.08.2015, p. 253-266.

Research output: Contribution to journalArticle

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T1 - Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function

AU - Devriese, Lot A.

AU - Witteveen, Petronella O.

AU - Mergui-Roelvink, Marja

AU - Smith, Deborah A.

AU - Lewis, Lionel D.

AU - Mendelson, David S.

AU - Bang, Yung Jue

AU - Chung, Hyuncheol

AU - Dar, Mohammed M.

AU - Huitema, Alwin D.R.

AU - Beijnen, Jos H.

AU - Voest, Emile E.

AU - Schellens, Jan H.M.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Aims The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy. Methods A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CLcr)=50-79 ml min-1], moderate [CLcr=30-49 ml min-1], severe [CLcr <30 ml min-1]). Results Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m-2 day-1, given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m-2 day-1 for patients with moderate renal impairment (suggested dose 1.9 mg m-2 day-1 for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m-2 day-1 in this cohort. Conclusions Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.

AB - Aims The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy. Methods A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CLcr)=50-79 ml min-1], moderate [CLcr=30-49 ml min-1], severe [CLcr <30 ml min-1]). Results Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m-2 day-1, given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m-2 day-1 for patients with moderate renal impairment (suggested dose 1.9 mg m-2 day-1 for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m-2 day-1 in this cohort. Conclusions Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.

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