Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors

C. J A Van Moorsel, J. R. Kroep, H. M. Pinedo, G. Veerman, D. A. Voorn, P. E. Postmus, J. B. Vermorken, C. J. Van Groeningen, W. J F Van Der Vijgh, G. J. Peters

Research output: Contribution to journalArticle

Abstract

Purpose: To determine possible schedule dependent pharmacokinetic and pharmacodynamic interactions between gemcitabine (2',2'- difluorodeoxycytidine, dFdC) and cisplatin (cis-diammine-dichloroplatinum, CDDP) in patients with advanced stage solid tumors in a phase I trial. Patients and methods: A total of 33 patients with advanced stage solid tumors were treated with gemcitabine (30-min infusion, 800 mg/m2) and cisplatin (one-hour infusion, 50 mg/m2). Sixteen patients had a four-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 1 and 8), followed by the reverse schedule and seventeen patients had a 24-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 2 and 9), followed by the reverse schedule. Gemcitabine and cisplatin pharmacokinetics were measured in plasma and white blood cells (WBC), isolated from blood samples taken at several time points after the start of treatment. Results: A four-hour time interval between both agents did not reveal major differences in plasma pharmacokinetics of gemcitabine, dFdU (deaminated gemcitabine) and platinum (Pt), and of gemcitabine-triphosphate (dFdCTP) accumulation and Pt-DNA adduct formation in WBC between the two different sequences of gemcitabine and cisplatin. In the patients treated with the 24-hour interval, cisplatin before gemcitabine did not significantly change peak gemcitabine levels and the AUC of plasma dFdU, but tended to increase dFdCTP AUC in WBC 1.5-fold (P <0.06). Gemcitabine before cisplatin decreased the plasma AUC of Pt 2.1- fold (P = 0.03). No significant differences in Pt-DNA adduct levels in WBC were found, although gemcitabine before cisplatin tended to increase the 24- hour retention of Pt-DNA adducts. Creatinine clearance on day 28 was related to the peak plasma levels of total Pt (linear regression coefficient (r) = 0.47, P = 0.02, n = 26). Furthermore, the increase in the Pt-GG to Pt-AG ratio 24 hours after cisplatin treatment was related to the overall response of patients (r = 0.89, P <0.01, n = 8). Conclusions: Of all schedules the treatment of patients with cisplatin 24 hours before gemcitabine led to the highest dFdCTP accumulation in WBC and total Pt levels in plasma. These characteristics formed the basis for further investigation of this schedule in a phase II clinical study.

Original languageEnglish (US)
Pages (from-to)441-448
Number of pages8
JournalAnnals of Oncology
Volume10
Issue number4
DOIs
StatePublished - 1999
Externally publishedYes

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gemcitabine
Cisplatin
Appointments and Schedules
Pharmacokinetics
Platinum
Neoplasms
Leukocytes
DNA Adducts
Area Under Curve

Keywords

  • Cisplatin
  • dFdCTP accumulation
  • Gemcitabine
  • Pharmacodynamics
  • Pharmacokinetics
  • Phase I study
  • Pt- DNA adducts

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Van Moorsel, C. J. A., Kroep, J. R., Pinedo, H. M., Veerman, G., Voorn, D. A., Postmus, P. E., ... Peters, G. J. (1999). Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors. Annals of Oncology, 10(4), 441-448. https://doi.org/10.1023/A:1008301522349

Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors. / Van Moorsel, C. J A; Kroep, J. R.; Pinedo, H. M.; Veerman, G.; Voorn, D. A.; Postmus, P. E.; Vermorken, J. B.; Van Groeningen, C. J.; Van Der Vijgh, W. J F; Peters, G. J.

In: Annals of Oncology, Vol. 10, No. 4, 1999, p. 441-448.

Research output: Contribution to journalArticle

Van Moorsel, CJA, Kroep, JR, Pinedo, HM, Veerman, G, Voorn, DA, Postmus, PE, Vermorken, JB, Van Groeningen, CJ, Van Der Vijgh, WJF & Peters, GJ 1999, 'Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors', Annals of Oncology, vol. 10, no. 4, pp. 441-448. https://doi.org/10.1023/A:1008301522349
Van Moorsel, C. J A ; Kroep, J. R. ; Pinedo, H. M. ; Veerman, G. ; Voorn, D. A. ; Postmus, P. E. ; Vermorken, J. B. ; Van Groeningen, C. J. ; Van Der Vijgh, W. J F ; Peters, G. J. / Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors. In: Annals of Oncology. 1999 ; Vol. 10, No. 4. pp. 441-448.
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TY - JOUR

T1 - Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors

AU - Van Moorsel, C. J A

AU - Kroep, J. R.

AU - Pinedo, H. M.

AU - Veerman, G.

AU - Voorn, D. A.

AU - Postmus, P. E.

AU - Vermorken, J. B.

AU - Van Groeningen, C. J.

AU - Van Der Vijgh, W. J F

AU - Peters, G. J.

PY - 1999

Y1 - 1999

N2 - Purpose: To determine possible schedule dependent pharmacokinetic and pharmacodynamic interactions between gemcitabine (2',2'- difluorodeoxycytidine, dFdC) and cisplatin (cis-diammine-dichloroplatinum, CDDP) in patients with advanced stage solid tumors in a phase I trial. Patients and methods: A total of 33 patients with advanced stage solid tumors were treated with gemcitabine (30-min infusion, 800 mg/m2) and cisplatin (one-hour infusion, 50 mg/m2). Sixteen patients had a four-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 1 and 8), followed by the reverse schedule and seventeen patients had a 24-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 2 and 9), followed by the reverse schedule. Gemcitabine and cisplatin pharmacokinetics were measured in plasma and white blood cells (WBC), isolated from blood samples taken at several time points after the start of treatment. Results: A four-hour time interval between both agents did not reveal major differences in plasma pharmacokinetics of gemcitabine, dFdU (deaminated gemcitabine) and platinum (Pt), and of gemcitabine-triphosphate (dFdCTP) accumulation and Pt-DNA adduct formation in WBC between the two different sequences of gemcitabine and cisplatin. In the patients treated with the 24-hour interval, cisplatin before gemcitabine did not significantly change peak gemcitabine levels and the AUC of plasma dFdU, but tended to increase dFdCTP AUC in WBC 1.5-fold (P <0.06). Gemcitabine before cisplatin decreased the plasma AUC of Pt 2.1- fold (P = 0.03). No significant differences in Pt-DNA adduct levels in WBC were found, although gemcitabine before cisplatin tended to increase the 24- hour retention of Pt-DNA adducts. Creatinine clearance on day 28 was related to the peak plasma levels of total Pt (linear regression coefficient (r) = 0.47, P = 0.02, n = 26). Furthermore, the increase in the Pt-GG to Pt-AG ratio 24 hours after cisplatin treatment was related to the overall response of patients (r = 0.89, P <0.01, n = 8). Conclusions: Of all schedules the treatment of patients with cisplatin 24 hours before gemcitabine led to the highest dFdCTP accumulation in WBC and total Pt levels in plasma. These characteristics formed the basis for further investigation of this schedule in a phase II clinical study.

AB - Purpose: To determine possible schedule dependent pharmacokinetic and pharmacodynamic interactions between gemcitabine (2',2'- difluorodeoxycytidine, dFdC) and cisplatin (cis-diammine-dichloroplatinum, CDDP) in patients with advanced stage solid tumors in a phase I trial. Patients and methods: A total of 33 patients with advanced stage solid tumors were treated with gemcitabine (30-min infusion, 800 mg/m2) and cisplatin (one-hour infusion, 50 mg/m2). Sixteen patients had a four-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 1 and 8), followed by the reverse schedule and seventeen patients had a 24-hour interval between gemcitabine (days 1, 8, 15) and cisplatin (days 2 and 9), followed by the reverse schedule. Gemcitabine and cisplatin pharmacokinetics were measured in plasma and white blood cells (WBC), isolated from blood samples taken at several time points after the start of treatment. Results: A four-hour time interval between both agents did not reveal major differences in plasma pharmacokinetics of gemcitabine, dFdU (deaminated gemcitabine) and platinum (Pt), and of gemcitabine-triphosphate (dFdCTP) accumulation and Pt-DNA adduct formation in WBC between the two different sequences of gemcitabine and cisplatin. In the patients treated with the 24-hour interval, cisplatin before gemcitabine did not significantly change peak gemcitabine levels and the AUC of plasma dFdU, but tended to increase dFdCTP AUC in WBC 1.5-fold (P <0.06). Gemcitabine before cisplatin decreased the plasma AUC of Pt 2.1- fold (P = 0.03). No significant differences in Pt-DNA adduct levels in WBC were found, although gemcitabine before cisplatin tended to increase the 24- hour retention of Pt-DNA adducts. Creatinine clearance on day 28 was related to the peak plasma levels of total Pt (linear regression coefficient (r) = 0.47, P = 0.02, n = 26). Furthermore, the increase in the Pt-GG to Pt-AG ratio 24 hours after cisplatin treatment was related to the overall response of patients (r = 0.89, P <0.01, n = 8). Conclusions: Of all schedules the treatment of patients with cisplatin 24 hours before gemcitabine led to the highest dFdCTP accumulation in WBC and total Pt levels in plasma. These characteristics formed the basis for further investigation of this schedule in a phase II clinical study.

KW - Cisplatin

KW - dFdCTP accumulation

KW - Gemcitabine

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Phase I study

KW - Pt- DNA adducts

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