Cancer Chemotherapy and Pharmacology

, Volume 36, Issue 6, pp 451–458 | Cite as

A phase I and pharmacology study of an oral platinum complex, JM216: dose-dependent pharmacokinetics with single-dose administration

  • Mark J. McKeage
  • Prakash Mistry
  • Janet Ward
  • Frances E. Boxall
  • Swee Loh
  • Ciaran O'Neill
  • Paul Ellis
  • Lloyd R. Kelland
  • Sarah E. Morgan
  • Barry Murrer
  • Pedro Santabarbara
  • Kenneth R. Harrap
  • Ian R. Judson
Original Article Phase l, Oral Administration, Platinum, Dose-Dependent Pharmacokinetics, JM216

Abstract

JM216 [bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV)] is an oral platinum complex with in vivo activity against murine and human tumor models and a lack of nephro- and neurotoxicity in rodents. During a phase I study of a single-dose schedule, JM216 was given in dry-filled hard gelatin capsules by mouth without hydration or diuresis. In all, 37 patients were given a total of 88 courses at doses ranging from 60 to 700 mg/m2. The study was stopped before the MTD was reached because of nonlinear pharmacokinetics. Myelosuppression was manifest by leucopenia or thrombocytopenia and showed marked variability at 420–700 mg/m2. Vomiting was mild and controllable by antiemetics in approximately 50% of courses. The onset of vomiting was delayed to 4 h after during ingestion. There was no nephro-, oto- or neurotoxicity. A partial response was recorded in a patient with recurrent ovarian cancer, and significant falls in plasma tumour markers (CA125) were seen in two further cases. Plasma pharmacokinetics were linear and showed moderate interpatient variability at dose levels of ≤120 mg/m2. At dose levels of ≥200 mg/m2, Cmax and AUC increased less than proportionally to dose. This was associated with greater interpatient pharmacokinetic variability and reduced urinary platinum recovery. A significant sigmoidal relationship existed between ultrafilterable plasma AUC and the percentage of reduction in platelet count (r2=0.78). Nonlinear absorption was a limitation to this single-dose schedule of oral NM216; however, little nonhaematological toxicity was seen at doses associated with myelosuppression and antitumour activity. Clinical studies of divided dose schedules using doses within the range of pharmacokinetic linearity (≤120 mg/m2) are now being investigated.

Key words

Phase I Oral administration Platinum Dose-dependent pharmacokinetics JM216 

Abbreviations

AUC

Area under the plasma concentration versus time curve

Cmax

peak plasma concentration

cxs

courses

FAAS

flameless atomic absorption spectrophotometry

Gd

CTC toxicity severity grade

JM216

bis-acetato-ammine-dichloro-cyclohexylamineplatinum(IV)

MRT

mean residence time

MTD

maximally tolerable dose

pts

patients

Tmax

time of peak plasma concentration

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Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Mark J. McKeage
    • 1
  • Prakash Mistry
    • 1
  • Janet Ward
    • 1
  • Frances E. Boxall
    • 1
  • Swee Loh
    • 1
  • Ciaran O'Neill
    • 1
  • Paul Ellis
    • 1
  • Lloyd R. Kelland
    • 1
  • Sarah E. Morgan
    • 1
  • Barry Murrer
    • 2
  • Pedro Santabarbara
    • 3
  • Kenneth R. Harrap
    • 1
  • Ian R. Judson
    • 1
  1. 1.Drug Development Section Institute of Cancer Research and Royal Marsden HospitalSuttonUK
  2. 2.Johnson Matthey Technology CentreReadingUK
  3. 3.Bristol-Myers Squibb Pharmaceutical Research InstituteSyracuseUSA
  4. 4.Oncology Research Centre, Institute of OncologyThe Prince of Wales HospitalSydneyAustralia

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